AND LYMPHOPROLIFERATIVE DISORDERS

FIELD OF THE INVENTION

The present invention relates to methods for treating IL-6 associated histiocytic and lymphoproliferative disorders including idiopathic multicentric Castleman disease with an anti-IL- 6 antibody; and compositions for use in such methods.

BACKGROUND TO THE INVENTION

Lymphoproliferative disorders (LPD) comprise a heterogeneous group of diseases characterized by uncontrolled production of lymphocytes that cause monoclonal lymphocytosis, lymphadenopathy and bone marrow infiltration, as described in Justiz Vaillant AA, Stang CM. Lymphoproliferative Disorders. [Updated 2020 Aug 30]. In : StatPearls [Internet]. Treasure Island (FL) : StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537162/. Multicentric Castleman disease (MCD) is a rare, serious, debilitating, and life-threatening lymphoproliferative disease first described by Castleman and Towne, 1954 that is characterized by systemic manifestations such as fever, night sweats, fatigue, anorexia, and wasting, particularly in patients with the plasma cell or mixed- type variants of the disease. Clinical manifestations may vary, and hepatosplenomegaly, lymph node enlargement, and multiple laboratory abnormalities (eg, anemia, hypoalbuminemia, and hypocholesterolemia) are also common (Nishimoto et al 2005; Casper 2005; Dham and Peterson 2007). Other symptoms include fluid retention; neuropathy; skin abnormalities; and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. Uncontrolled human herpesvirus-8 (HHV-8) infection causes approximately 50% of MCD cases, whereas the etiology is unknown in the remaining HHV-8-negative/idiopathic MCD cases (iMCD).

Interleukin-6 (IL-6) is a pro-inflammatory cytokine that is implicated in iMCD pathology. There are at least two major biological functions of IL-6: mediation of acute phase proteins and acting as a differentiation and activation factor (Avvisti, G. et al., Baillieres Clinical Hematology 8: 815- 829 (1995) and Poli, V. et al., EMBO 13: 1189-1196 (1994). In 2014, the anti-IL-6 therapy siltuximab, licensed as Sylvant®, became the first iMCD treatment approved by the US Food and Drug Administration, for patients who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative, on the basis of a 34% durable response rate. Siltuximab is also authorised for treatment of iMCD in the European Union, Brazil, and elsewhere, and consensus guidelines recommend it as front-line therapy. Siltuximab is a chimeric (humanmurine) immunoglobulin G 1 K (IgGlK) monoclonal antibody having a binding specificity for human IL-6, and is produced in a Chinese hamster ovary (CHO) cell line by recombinant DNA technology. It is described in European Public Assessment Report (EPAR) of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) for Sylvant® (EMEA/H/C/003708, last updated 8 October 2019), and in WO 2004/039826A1. The recommended treatment regimen for iMCD is 11 mg/kg siltuximab given over 1 hour as an intravenous infusion administered every 3 weeks until treatment failure. Tocilizumab, an anti-IL- 6 receptor monoclonal antibody, may be used to treat iMCD if siltuximab is not available, typically at a dose of 8 mg/kg every 2 weeks (van Rhee F, Voorhees P et al. 2018 International, evidencebased consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood. 132(20):2115-2124). Van Rhee, supra, recommends that critically ill iMCD patients should be promptly started on a high-dose steroid regimen (eg, methylprednisolone 500 mg daily) together with siltuximab. For pharmacokinetic reasons, an accelerated, weekly dosing schedule of siltuximab may be used for 1 month. Patients who immediately respond should continue on siltuximab at every 3-week interval indefinitely and slowly taper steroids.

Clinical experience shows that about 50% of iMCD patients do not achieve a satisfactory response to first-line anti-IL-6 therapy. According to Fajgenbaum DC (2018) Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease. Blood. 132(22) :2323-2330, treatment of iMCD patients who do not respond to siltuximab should be tailored by disease severity into nonsevere or severe. Patients with nonsevere disease (no intensive care or progressive organ dysfunction) who fail to adequately respond to siltuximab after 3 to 4 doses should receive rituximab (375 mg/m ² x 4-8 weekly doses) ± corticosteroids ± an immunomodulatory/immunosuppressive agent, such as cyclosporine, sirolimus, anakinra, thalidomide, or bortezomib. According to van Rhee, supra, aggressive intervention with multiagent chemotherapy should be considered for severe iMCD cases as early as necessary (any sign of deterioration or after 1 week of no response to siltuximab, whichever comes first) to ablate the hyperactivated immune system. The subsequent management of severe iMCD patients who fail to respond to anti-IL-6 mAb or the first cytotoxic chemotherapy regimen, or those who relapse, is not well defined and is mostly done on an ad hoc basis taking into account any previous response, clinical status, comorbidities, and cytokine profile.

There remains a need for effective treatments for relapsed, refractory, or resistant iMCD. IL-6 is implicated in pathogenesis of other lymphoproliferative disorders, in addition to iMCD, including high-grade B-cell lymphomas (Emilie D et al. Interleukin-6 production in high-grade B lymphomas: correlation with the presence of malignant immunoblasts in acquired immunodeficiency syndrome and in human immunodeficiency virus-seronegative patients. Blood. 1992;80:498-504) and myelomas (Klein B, Zhang X, Lu Z, Bataille R. Interleukin-6 in human multiple myeloma. Blood. 1995;85:863-872). The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs, as described in Emile JF et al, Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016 Jun 2;127(22):2672-81. IL-6 is implicated in pathogenesis of various histiocytoses, including Rosai-Dorfman disease (Aouba A et al. Dramatic clinical efficacy of cladribine in Rosai-Dorfman disease and evolution of the cytokine profile: towards a new therapeutic approach. Haematologica. 2006 Dec;91(12 Suppl):ECR52).

There remains a need for effective treatments for IL-6 associated histiocytic or lymphoproliferative disorders.

The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

SUMMARY OF THE INVENTION

An object of the invention is to provide a second-line or subsequent therapy for iMCD patients who have relapsed or were refractory or resistant to treatment with a prior IL-6 antagonist therapy.

Another object of the invention is to provide a therapy for IL-6 associated histiocytic and lymphoproliferative disorders. Patients may include those who have never received a prior IL-6 antagonist therapy, and patients who have received a prior IL-6 antagonist therapy, and have relapsed or were refractory or resistant to treatment with the prior IL-6 antagonist therapy.

A first aspect of the invention provides an antibody or fragment thereof which is capable of inhibiting human IL-6 for use in a method of treating relapsed, refractory, or resistant idiopathic multicentric Castleman disease (iMCD) in a patient according to a treatment regimen, wherein the patient has previously been treated by a prior treatment regimen and has relapsed or was refractory or resistant to treatment with the prior treatment regimen; wherein the treatment regimen comprises at least one first intensity treatment cycle comprising intravenously administering the antibody in a first antibody treatment density of > 11 mg/kg per three-week interval or 11 mg/kg per < 3-week interval, or the fragment at an equivalent fragment treatment density having an equivalent antagonistic effect on human IL-6; and wherein the prior treatment regimen comprises intravenously administering an antibody or fragment thereof which is a human IL-6 signalling pathway antagonist, wherein the antibody or fragment is administered at an IL-6 signalling pathway antagonist treatment density that is lower than the first antibody treatment density or equivalent fragment treatment density.

A corresponding aspect of the invention provides a method of treating relapsed, refractory or resistant idiopathic multicentric Castleman disease (iMCD) in a patient according to a treatment regimen, wherein the patient has previously been treated in a prior treatment regimen and has relapsed or was refractory or resistant to treatment with the prior treatment regimen; wherein the treatment regimen comprises at least one first intensity treatment cycle comprising intravenously administering an antibody or fragment thereof which is capable of inhibiting human IL-6 in a first antibody treatment density of > 11 mg/kg per three-week interval or 11 mg/kg per < 3-week interval, or the fragment at an equivalent fragment treatment density having an equivalent antagonistic effect on human IL-6; and wherein the prior treatment regimen comprises intravenously administering an antibody or fragment thereof which is a human IL-6 signalling pathway antagonist, wherein the antibody or fragment is administered at an IL-6 signalling pathway antagonist treatment density that is lower than the first antibody treatment density or equivalent fragment treatment density.

A second aspect of the invention provides an antibody or fragment thereof which is capable of inhibiting human IL-6 for use in a treatment regimen for treating an IL-6 associated histiocytic or lymphoproliferative disorder in a patient, wherein the treatment regimen comprises: at least one first intensity treatment cycle comprising intravenously administering the antibody in a first antibody treatment density of > 11 mg/kg per three-week interval or 11 mg/kg per < 3-week interval, or the fragment at an equivalent fragment treatment density having an equivalent antagonistic effect on human IL-6.

A corresponding aspect of the invention provides a method of treating an IL-6 associated histiocytic or lymphoproliferative disorder in a patient according to a treatment regimen, wherein the treatment regimen comprises: at least one first intensity treatment cycle comprising intravenously administering an antibody or fragment thereof which is capable of inhibiting human IL-6 in a first antibody treatment density of > 11 mg/kg per three-week interval or 11 mg/kg per < 3-week interval, or the fragment at an equivalent fragment treatment density having an equivalent antagonistic effect on human IL-6.

The aspects of the invention are founded on the principle that escalation of the dose of the anti- IL-6 antibody above the standard dose for iMCD can provide further clinical benefit in iMCD and other IL-6 associated histiocytic or lymphoproliferative disorders.

DESCRIPTION OF THE FIGURES

Figure 1. Schematic of IL-6 signalling and sites of action of IL-6 signalling pathway antagonists. Figure 2. Clinical trial study design.

Figure 3. Clinical trial intrapatient dose escalation and dose-limiting toxicity (DLT) assessments. Abbreviations: CDCNRC = Castleman Disease Collaborative Network Response Criteria; CRP = C-reactive protein; DL = dosing level; DLT = dose-limiting toxicity; q3w = every 3 weeks.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method of treating relapsed, refractory, or resistant iMCD in a patient, and compositions for use in the method. iMCD may be diagnosed according to the Castleman Disease Collaborative Network (CDCN) Consensus Diagnostic criteria for iMCD, as described in Fajgenbaum DC, Uldrick TS, Bagg A, et al. (2017) International, evidence-based consensus diagnostic criteria for HHV-8- negative/idiopathic multicentric Castleman disease. Blood. 129(12): 1646-1657. In particular, iMCD diagnosis requires the presence of histopathologic lymph node features consistent with the iMCD spectrum and enlarged lymph nodes (>1 cm in short-axis diameter) in >2 lymph node stations. Histopathologic lymph node features that an experienced histopathologist may take into account include regressive GCs or plasmacytosis at minimum) Regressed/atrophic/atretic germinal centers (GCs), often with expanded mantle zones composed of concentric rings of lymphocytes, follicular dendritic cell (FDC) prominence, vascularity, often with prominent endothelium in the interfollicluar space and vessels penetrating into the GCs with a "lollipop" appearance, sheetlike, polytypic plasmacytosis in the interfollicular space and hyperplastic GCs. Further criteria may be taken into account, such as a finding of at least two further criteria, at least one of which being a laboratory criterion. Further laboratory criteria are: 1. Elevated serum C-reactive protein (CRP) (typically >10 mg/L) or elevated erythrocyte sedimentation rate (ESR) (typically >15 mm/h), 2. Anemia (hemoglobin typically < 12.5 g/dL for males, haemoglobin typically <11.5 g/dL for females), 3. Thrombocytopenia (platelet count typically <150 k/pL) or thrombocytosis (platelet count typically >400 k/pL), 4. Hypoalbuminemia (albumin typically <3.5 g/dL), 5. Renal dysfunction (estimated glomerular filtration rate (eGFR) typically <60 mL/min/1.73 m ² ) or proteinuria (total protein 150 mg/24 h or 10 mg/100 ml), 6. Polyclonal hypergammaglobulinemia (total y globulin or immunoglobulin G >1700 mg/dL). Further clinical criteria are 1. Constitutional symptoms: night sweats, fever (>38°C), weight loss, or fatigue (>2 CTCAE lymphoma score for B-symptoms), 2. Large spleen and/or liver, 3. Fluid accumulation: edema, anasarca, ascites, or pleural effusion, 4. Eruptive cherry hemangiomatosis or violaceous papules, 5. Lymphocytic interstitial pneumonitis. Typically, other diseases may be excluded before a diagnosis of iMCD is reached. Exclusion criteria for diseases which can mimic iMCD are described in the Example.

Infection with HHV-8 or HIV should be excluded in diagnosis of iMCD. These viruses can cause MCD, and produce viral IL-6. Siltuximab and other IL-6 antibodies bind human but not viral IL- 6.

The treatment regimen of the present invention is particularly suitable for iMCD cases for which excessive IL-6 is suspected to be contributing to pathology, i.e. "IL-6-driven iMCD". IL-6 is thought to drive a cytokine storm in some patients, although other cytokines may contribute, and indeed other cytokines may have a predominant role in driving disease in other patients. Evidence for IL-6 as a driver for iMCD is discussed in Fajgenbaum, 2018, supra. IL-6 is the primary inducer of CRP synthesis in the liver (Heinrich et al 1990), and CRP suppression has previously been used as a surrogate for inhibition of IL-6 signaling (Puchalski et al 2010). Patients for which the treatment regimen of the present invention may be particularly suitable may have elevated C-reactive protein (CRP) (such as serum CRP above upper limit of normal for the testing laboratory, typically >10 mg/L) or elevated erythrocyte sedimentation rate (ES, R) (typically >15 mm/h). It is preferred to measure CRP than ES, R. A normal range of serum CRP for a healthy person is from 0.3 to 10 mg/L. iMCD patients for whom IL-6 is suspected of contributing to pathology may have serum CRP levels at diagnosis >10 mg/L. Although serum CRP can rise 1000-fold or more from healthy levels in response to injury, inflammation or tissue death, a level greater than 100 mg/L strongly suggests bacterial infection, according to Chandrashekara S. (2014) Internet J Rheumatol and Clin Immunol 2(S1): SR3. Serum CRP levels in patients having an IL-6-driven iMCD can be expected to be in the range of 11 mg/L to 100 mg/L, although levels above 100 mg/L are not ruled out. Rising serum CRP levels may also be indicative of IL-6-driven disease, particularly in conjunction with elevated serum CRP. For example, serum CRP levels may be observed to rise over a period of weeks or months during a prior or first-line iMCD therapy. Serum CRP levels are typically monitored at between 3 and 12 weeks after the last treatment with a prior IL-6 antagonist therapy, typically in the absence of additional iMCD treatment and/or serum CRP is typically monitored between 1 and 21 days before commencing the first cycle of the first intensity treatment, typically wherein the antibody or fragment is administered on day 1 of the treatment cycle. CRP monitoring is preferred for patients who have received a prior anti-IL-6 antibody therapy because measurement of free serum IL-6 levels will likely be confounded by the prior antibody therapy, because presently available IL-6 diagnostic tests are unable to distinguish free from antibody-bound IL-6. Further pre-treatment parameters that may be predictive of siltuximab response, and hence IL-6-driven iMCD, include fibrinogen, immunoglobulin G, and hemoglobin in addition to CRP, as described in Morra DE, Pierson SK, et al (2019) Predictors of response to anti-IL-6 monoclonal antibody therapy (siltuximab) in idiopathic multicentric Castleman disease: secondary analyses of phase II clinical trial data. Br J Haematol. 2019 Jan; 184(2) :232-241. doi: 10.1111/bjh.15588. CRP may be measured using commercially available enzyme-linked immunosorbent assay kits (e.g. from R8LD Systems, Minneapolis, MN), and other methods known in the art.

A subset of iMCD has recently been identified that involves a constellation of syndromes: thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R) and organomegaly (O), and is referred to as "TAFRO-iMCD" or "TAFRO syndrome" or "iMCD-TAFRO". According to Fajgenbaum, 2018, supra, patients with TAFRO-iMCD present with heterogenous clinical symptoms ranging from intense episodes of thrombocytopenia, anasarca, fever/elevated C- reactive protein (CRP), renal dysfunction/ reticulin myelofibrosis, organomegaly, megakaryocytic hyperplasia, hypervascular or mixed lymph node histopathology, and normal gammaglobulin levels. iMCD patients who do not have the characteristics of TAFRO-iMCD may have a less intense inflammatory syndrome, normal/elevated platelet counts, plasmacytic or mixed lymph node histopathology, and polyclonal hypergammaglobulinemia whose subtype is not otherwise specified (iMCD-NOS). Thus iMCD may be further subdivided into iMCD-TAFRO and iMCD-NOS on the basis of clinical features. Diagnostic criteria for TAFRO-iMCD are further discussed in Igawa T, Sato Y. TAFRO Syndrome. Hematol Oncol Clin North Am. 2018 Feb;32(l) : 107-118. doi: 10.1016/j.hoc.2017.09.009. PMID: 29157612. The treatment regimen of the invention is intended for patients who have TAFRO-iMCD, iMCD or iMCD-NOS. Typically, the patient has IL- 6-driven iMCD or IL-6-driven TAFRO-iMCD. The therapy of the invention is particularly intended for relapsed, refractory or treatment- resistant iMCD patients. By "refractory", or "treatment-refractory" disease, we mean signs or symptoms of disease that never improved or responded to treatment and simply progressed. By "resistant" or "treatment-resistant" disease, we mean signs or symptoms of disease that improved on or responded to treatment then returned. "Resistant" disease includes disease for which there has been at least a partial or minor response to prior nonsurgical treatment, although does not exclude the possibility that the patient had prior surgical treatment. By "relapsed" disease, we include disease that has returned following a complete response to surgical or nonsurgical treatment. The terms "resistant" and "relapsed" may be used interchangeably in some terminologies, as encompassing disease that has progressed or returned following a partial, minor, or complete response to prior therapy.

The antibody or fragment thereof for use of the invention is capable of inhibiting human IL-6. IL-6 can bind to the IL-6 receptor (IL-6R) expressed on mitogen-activated B cells, T cells, peripheral monocytes, and certain tumors (Ishimi, Y. et al., J. Immunology 145: 3297-3303 (1990)). IL-6R has at least two different components and is composed of an alpha chain called gp80, also referred to as soluble IL-6R, that is responsible for IL-6 binding and a cell-membrane bound beta chain designated gpl30 that is needed for signal transduction (Adebanjo, 0. et al., J. Cell Biology 142: 1347-1356 (1998) and Poli, V. et al., EMBO 13: 1189-1196 (1994)). An antibody which is capable of inhibiting human IL-6 must be capable of specifically binding to human IL-6, and of inhibiting its interaction with gp80 (IL-6R) or otherwise preventing gpl30 activation. By "capable of specifically binding", we include the ability of the antibody or antigenbinding fragment to bind at least 10-fold more strongly to the relevant polypeptide, e.g. IL-6, than to any other polypeptide; preferably at least 50-fold more strongly and more preferably at least 100-fold more strongly. Inhibitory antibodies to IL-6 can typically be divided into two groups; and the putative epitopes on the IL-6 molecule designated Site I and Site II. Site I binders prevent binding to the gp80 (IL-6R) and thereby prevent gpl30 activation. The Site I epitope was further characterized as comprising regions of both amino terminal and carboxy terminal portions of the IL-6 molecule. Site II-binders prevent gpl30 activation and therefore may recognize a conformational epitope involved in signalling. Binding of the antibody may be measured by surface plasmon resonance, for example, by immobilizing the antibody on a chip and using recombinant human IL-6 as analyte, as described in WO 2004/039826A1. Suitable antibodies may bind IL-6 with an affinity (Kd) of at least 10 ^-9 M, preferably at least 10 ^{- 10} M, preferably at least 10 ^-11 or 5 x 10 ^-11 M. Epitope mapping to identify Site I or Site II binders may be performed by binding to human IL-6-mutant proteins as described in Brakenhoff, J. et al. (1990) J. Immunology 145: 561-568). Inhibition of IL-6 activity may be measured by assaying proliferation of the murine B myeloma cell line, 7TD1, in response to IL-6, as described in WO 2004/039826A1. Suitable antibodies may inhibit >50%, such as >90%, such as substantially 100% of 7TD1 cell proliferation in response to IL-6.

By "IL-6" we include any natural or synthetic protein with structural and/or functional identity to the human IL-6 protein, such as defined UniProt Accession No. P05231, or natural variants thereof. IL-6 gene and/or amino acid sequences are disclosed in Eur. J. Biochem (1987) 168, 543-550; J. Immunol. (1988)140, 1534-1541; and Agr. Biol. Chem. (1990)54, 2685-2688.

By "antibody" we include substantially intact antibody molecules, as well as chimaeric antibodies, humanised antibodies, human antibodies (wherein at least one amino acid is mutated relative to the naturally occurring human antibodies), single chain antibodies, bi-specific antibodies, antibody heavy chains, antibody light chains, homo-dimers and heterodimers of antibody heavy and/or light chains, and antigen binding fragments and derivatives of the same. The term also includes antibody-like molecules which may be produced using phage-display techniques or other random selection techniques for molecules. The term also includes all classes of antibodies, including IgG, IgA, IgM, IgD, and IgE. Also included for use in the invention are antibody fragments such as Fab, F(ab')2, Fv, Fab', scFv (single-chain variable fragment), or di-scFv and other fragments thereof that retain the antigen-binding site. Similarly, the term "antibody" includes genetically engineered derivatives of antibodies such as single-chain Fv molecules (scFv) and single-domain antibodies (dAbs).

Preferred antibodies are chimaeric, such as mouse-human chimaeric antibodies, CDR-grafted antibodies, humanised antibodies, or human antibodies. Although the antibody may be a polyclonal antibody, it is preferred if it is a monoclonal antibody, or that the antigen-binding fragment is derived from a monoclonal antibody. Suitable monoclonal antibodies may be prepared by known techniques, for example those disclosed in "Monoclonal Antibodies; A manual of techniques", H Zola (CRC Press, 1988) and in "Monoclonal Hybridoma Antibodies: Techniques and Application", SGR Hurrell (CRC Press, 1982). The antibodies may be human antibodies in the sense that they have the amino acid sequence of human antibodies with specificity for the IL-6; however, it will be appreciated that they may be prepared using methods known in the art that do not require immunisation of humans. Suitable antibodies may be prepared from transgenic mice which contain human immunoglobulin loci, as described in Lee, E., Liang, Q., Ali, H. et al. Complete humanization of the mouse immunoglobulin loci enables efficient therapeutic antibody discovery. Nat Biotechnol 32, 356-363 (2014). https://doi.org/10.1038/nbt.2825. Suitably prepared non-human antibodies can be "humanised" in known ways, for example, by inserting the CDR regions of mouse antibodies into the framework of human antibodies. Chimeric antibodies are discussed by Neuberger et al (1998, 8th International Biotechnology Symposium Part 2, 792-799).

It will be appreciated by persons skilled in the art that the binding specificity of an antibody or antigen-binding fragment thereof is conferred by the presence of complementarity determining regions (CDRs) within the variable regions of the constituent heavy and light chains. As discussed below, in a particularly preferred embodiment of the antibodies and antigen-binding fragments, binding specificity for IL-6 is conferred by the presence of one or more and typically all six of the CDR amino acid sequences defined herein.

Preferably, the antibody or antigen-binding fragment comprises an antibody Fc region. It will be appreciated by the skilled person that the Fc portion may be from an IgG antibody, or from a different class of antibody (such as IgM, IgA, IgD, or IgE). For example, the Fc region may be from an IgGl, IgG2, IgG3, or IgG4 antibody. Advantageously, however, the Fc region is from an IgGl antibody. It is preferred that the antibody or antigen-binding fragment is an IgG molecule, or is an antigen-binding fragment or variant of an IgG molecule.

Suitable antibodies and fragments are described in WO 2004/039826A1. Suitably, the antibody or fragment is a chimeric, humanized or CDR grafted antibody or fragment thereof comprising a heavy chain variable region in which CDR1, CDR2, and CDR3 comprise the amino acid sequences SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively; and a light-chain variable region in which CDR1, CDR2, and CDR3 comprise the amino acid sequences SEQ ID NO: 4, SEQ ID NO:, 5 and SEQ ID NO: 6, respectively, and a constant region derived from a human IgG antibody.

VH CDR1 Ser Phe Ala Met Ser (SEQ ID NO. 1)

VH CDR2 Glu He Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Pro Asp Thr Vai Thr Gly (SEQ ID NO. 2)

VH CDR3 Gly Leu Trp Gly Tyr Tyr Ala Leu Asp Tyr (SEQ ID NO. 3)

VL CDR1 Ser Ala Ser Ser Ser Vai Ser Tyr Met Tyr (SEQ ID NO. 4)

VL CDR2 Asp Thr Ser Asn Leu Ala Ser (SEQ ID NO. 5)

VL CDR3 Gin Gin Trp Ser Gly Tyr Pro Tyr Thr (SEQ ID NO. 6)

In a preferred embodiment the antibody is siltuximab, or an antigen-binding fragment thereof. Siltuximab, also known as CNTO328 and CLLB8, with the US FDA UNII Identifier T4H8FMA7IM and the WHO ATC code L04AC11 is a chimeric (human-murine) IgGlK monoclonal antibody that binds to human IL-6. The intact molecule contains 1324 amino acid residues and is composed of two identical heavy chains (approximately 50 kDa each) and two identical light chains (approximately 24 kDa each) linked by inter-chain disulfide bonds. Siltuximab contains the antigen-binding variable region of the murine antibody, CLB-IL-6-8, and the constant region of a human IgGlK immunoglobulin.

The complete amino acid sequences of the heavy and light chains of siltuximab are shown below.

SEQ ID NO. 7 Siltuximab heavy chain amino acid sequence

EVQLVESGGKLLKPGGSLKLSCAASGFTFS SFAMSWFRQS PEKRLEWVAEI S SGGSYTYY PDTVTGRFTI SRDNAKNTLYLEMS SLRSEDTAMYYCARGLWGYYALDYWGQGTSVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMI SRTPEVT C VWD VS H E D P E VK FNW Y VD G VE VHNAKT KPREEQYNS TYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRDEL TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK

SEQ ID NO. 8 Siltuximab light chain amino acid sequence

QIVLIQSPAIMSAS PGEKVTMTCSASS SVSYMYWYQQKPGSSPRLLIYDTSNLASGVPVR FSGSGSGTSYSLTI SRMEAEDAATYYCQQWSGYPYTFGGGTKLEIKRTVAAPSVFI EPPS DEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL SKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC

Siltuximab and methods of preparing it, including by recombinant expression of encoding nucleic acid sequences, are described in WO 2004/039826A1.

Other suitable antibodies include olokizumab, which is a IgG4K antibody humanized from rat, and is described in Shaw, S., Bourne, T., Meier, C., Carrington, B., Gelinas, R., 8L Henry, A., et al. (2014). Discovery and characterization of olokizumab. mAbs, 6(3), 773-781; elsilimomab (also known as B-E8), which is a mouse IgGlK monoclonal antibody described in Wijdenes J, Clement C, Klein B, et al. Human recombinant dimeric IL-6 binds to its receptor as detected by anti-IL-6 monoclonal antibodies. Mol Immunol. 1991;28(11): 1183-1192; or the human monoclonal antibody clone 1339 derived from elsilimomab as described in Fulciniti, M., Hideshima, T., Vermot-Desroches, C., Pozzi, S., Nanjappa, P., Shen, Z.,. 8i Tai, Y. T. (2009). A high-affinity fully human anti-IL-6 mAb, 1339, for the treatment of multiple myeloma. Clinical Cancer Research, 15(23), 7144-7152. Further suitable antibodies include clazakizumab (formerly ALD518 and BMS-945429), which is an aglycosylated, humanized rabbit IgGl monoclonal antibody against interleukin-6, described in Mease PJ, Gottlieb AB, et al. (September 2016). "The efficacy and safety of clazakizumab, an anti-interleukin-6 monoclonal antibody, in a phase lib study of adults with active psoriatic arthritis". Arthritis Rheumatol. 68 (9): 2163-73; sirukumab, which is a human monoclonal IgGl kappa antibody described in Smolen JS, Weinblatt ME, Sheng S, Zhuang Y, Hsu B. Sirukumab, a human anti-interleukin-6 monoclonal antibody: a randomised, 2-part (proof-of-concept and dose-finding), phase II study in patients with active rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis. 2014 Sep;73(9) : 1616-25. doi: 10.1136/annrheumdis-2013-205137. Epub 2014 Apr 3. PMID: 24699939; PMCID: PMC4145446. Further suitable antibodies include the MH166 antibody (Matsuda, T. et al., Eur. J. Immunol. (1988) 18, 951-956) and the SK2 antibody (Sato, K. et al., The abstracts of the 21st Annual Meeting of the Japanese Society for Immunology (1991) 21, 166). Fragments of any of these antibodies may also be used.

The treatment regimen according to the invention comprises at least one first intensity treatment cycle comprising intravenously administering the antibody in a first antibody treatment density of > 11 mg/kg per three-week interval or 11 mg/kg per < 3-week interval, or the fragment at an equivalent fragment treatment density having an equivalent antagonistic effect on human IL- 6.

By "treatment density", we mean the cumulative dose divided by the total duration of antibody therapy at the specified intensity. The "treatment density" is expressed as a dose in mg/kg per time interval. The time interval may or may not be of the same duration as a treatment cycle. Treatment density is conveniently expressed in terms of dose over a three-week interval. However, it is envisaged that the antibody therapy at a specified intensity may occur over a shorter duration than three weeks, and therefore, a corresponding treatment density is also defined over a shorter interval. In particular, a treatment density of > 11 mg/kg per 3-week interval is equivalent to 11 mg/kg per < 3-week interval.

The dose of the antibody or fragment is determined according to the weight in kg of the patient. An antibody fragment is to be administered at an equivalent fragment treatment density having an equivalent antagonistic effect on human IL-6 to the whole antibody from which the fragment is derived. The equivalent fragment treatment density may be calculated according to the fragment molecular weight compared to the molecular weight of the whole antibody, also referred to as parent antibody. For example, if a given antibody has a molecular weight of 150 kD, and a Fab fragment has a molecular weight of 50 kD, then a fragment dose that is one third of the antibody dose should provide an equivalent antagonistic effect on human IL-6. Thus, if the antibody treatment density was 12 mg/kg per three-week interval, then the equivalent fragment treatment density for the Fab fragment would be 4 mg/kg per three-week interval. The equivalent antagonistic effect on human IL-6 may also be determined according to the amount of human IL-6 that the fragment can specifically bind to, compared to the amount of human IL- 6 that the parent antibody can specifically bind to. These amounts may be determined by various assays, including ELISA.

The term "treatment cycle" as used herein means a course of one or more treatments or treatment periods that is repeated on a regular schedule and may encompass a period of rest. For example, a treatment given one day followed by 20 days of rest is 1 treatment cycle of 21 days. The treatment cycle may be repeated, either identically or in an amended form, e.g., with a different dose or schedule, or with different additional treatments. A "treatment interval" is the interval between starting and completing a treatment cycle. By "first intensity treatment cycle", we mean a treatment cycle characterised by the specified treatment density. Second and third intensity treatment cycles are to be understood accordingly, as meaning a treatment cycle characterised by the specified treatment density.

The "overall treatment time" means the time period comprising all treatment cycles. As described above, treatment cycles may comprise time periods of no treatment (intervals in which no treatment is administered to the patient, i.e., no antibody, no other drug). Thus, as used herein, the overall treatment time may also comprise said intervals of no treatment within treatment cycles. A "treatment period" with a specific preparation or treatment as used herein means the period of time in which said specific preparation or treatment is administered to the patient. For example, if an antibody is administered for 1 hour, and there are no further administrations in the subsequent 20 days, then the treatment period with the antibody is 1 hour.

The patient is administered the antibody for at least one first intensity treatment cycle. The number of first intensity treatment cycles may be one or more than one, such as 2, 3, 4, 5, up to 10 or more, or up to 20 more. After the first treatment cycle at the first intensity, the patient may either continue to receive more treatment cycles at the first intensity, or be treated with at least one treatment cycle at an increased intensity, or discontinue antibody therapy. If the patient obtains clinical benefit after receiving one or more treatment cycles at the first intensity, the patient will typically continue with further treatment cycles at that intensity, unless and until further dose escalation is clinically indicated. Further dose escalation may be considered if the patient's disease progresses, or if the response to treatment is suboptimal, as discussed further below. However, if the patient experiences unacceptable toxicity or clinical deterioration during treatment at the first intensity, further dose escalation would typically not be attempted. The decision whether to continue at the same treatment density, escalate to a higher treatment density, or discontinue antibody therapy will generally be the responsibility of the treating physician, taking into account the patient's response to and toleration of antibody therapy at the current treatment density as well as serum CRP levels.

Typically, according to the treatment regimen of the invention, the first antibody treatment density is > 12 mg/kg per three-week interval, such as > 13 mg/kg, such as > 14 mg/kg, such as > 15 mg/kg, such as > 16 mg/kg, such as > 17 mg/kg per three-week interval; or > 11 mg/kg per 2-week interval; or 11 mg/kg per < 2-week interval. The equivalent fragment treatment density would be determined as explained above. A treatment density of > 11 mg/kg per < 3-week interval may include any of the above treatment densities, typically to the nearest mg/kg, wherein the time interval is expressed as less than 3 weeks, for example wherein the time interval is 20 days, 15 days, 14 days, 10 days, or 7 days.

Typically, the first antibody treatment density is 22 ± 5, 4, 3, 2, or 1 mg/kg per three-week interval, or 33 ± 5, 4, 3, 2, or 1 mg/kg per three-week interval or 44 ± 5, 4, 3, 2, or 1 mg/kg per three-week interval, such as wherein the antibody treatment density is 22, 33, or 44 mg/kg per three-week interval; or 15 ± 3, 2, or 1 mg/kg per two-week interval, or 22 ± 3, 2, or 1 mg/kg per two-week interval, or 29 ± 3, 2, or 1 mg/kg per two-week interval; or 7 ± 2 or 1 mg/kg per one-week interval, or 11 ± 2 or 1 mg/kg per one-week interval, or 15 ± 2 or 1 mg/kg per one-week interval. The expression X ± Y is intended to cover the full range of doses within the limits of X ± Y. Hence 22 ± 5, 4, 3, 2, or 1 mg/kg refers to the ranges of 17 to 27, 18 to 26, 19 to 25, 20 to 24, or 21 to 23 mg/kg. The equivalent fragment treatment density would be determined as explained above.

Typically, the first antibody treatment density is 22 ± 5, 4, 3, 2, or 1 mg/kg per three-week interval, such as 22 mg/kg per three-week interval; or 15 ± 3, 2, or 1 mg/kg per two-week interval, such as 15 mg/kg per two-week interval; or 7 ± 2 or 1 mg/kg per one-week interval, such as 7 mg/kg per one-week interval. The equivalent fragment treatment density would be determined accordingly. These treatment densities correspond to about twice the standard treatment density for siltuximab, which is 11 mg/kg per three-week interval. In one embodiment of the invention, after the patient has been treated with the at least one first intensity treatment cycle, the patient is treated with at least one second intensity treatment cycle comprising intravenously administering the antibody in a second antibody treatment density or equivalent fragment density, if clinically indicated; wherein the second antibody treatment density is greater than the first antibody treatment density.

Suitably, if the first antibody treatment density is 22 ± 5 mg/kg per three-week interval, or 15 ± 3 mg/kg per two-week interval, or 7 ± 2 mg/kg per one-week interval, then the second antibody treatment density is 33 ± 5 mg/kg per three-week interval, or 22 ± 3 mg/kg per two- week interval, or 11 ± 2 mg/kg per one-week interval, or 44 ± 5 mg/kg per three-week interval, or 29 ± 3 mg/kg per two-week interval, or 15 ± 2 mg/kg per one-week interval; wherein if the first antibody treatment density is 33 ± 5 mg/kg per three-week interval, or 22 ± 3 mg/kg per two-week interval, or 11 ± 2 mg/kg per one-week interval, then the second antibody treatment density is 44 ± 5 mg/kg per three-week interval, or 29 ± 3 mg/kg per two-week interval, or 15 ± 2 mg/kg per one-week interval. For doses of X ± Y, we include all whole units of Y from 0 to Y. Thus for 22 ± 5 mg/kg, we include 22 ± 5, 4, 3, 2, 1, or 0 mg/kg.

In an embodiment, after the patient is treated with at least one second intensity treatment cycle, the patient is treated with at least one third intensity treatment cycle comprising intravenously administering the antibody in a third antibody treatment density or equivalent fragment density, if clinically indicated; wherein the third antibody treatment density is greater than the second antibody treatment density, such as if the second antibody treatment density is 33 ± 5 mg/kg per three-week interval, or 22 ± 3 mg/kg per two-week interval, or 11 ± 2 mg/kg per one-week interval, then the third antibody treatment density is 44 ± 5 mg/kg per three-week interval, or 29 ± 3 mg/kg per two-week interval, or 15 ± 2 mg/kg per one-week interval. For doses of X ± Y, we include all whole units of Y from 0 to Y. The equivalent fragment treatment density would be determined as described above.

Typically, treatment with the at least one second intensity treatment cycle or treatment with the at least one third intensity treatment cycle is clinically indicated if serum C-reactive protein (CRP) levels rise during treatment with the first intensity treatment cycle or the second intensity treatment cycle respectively. Serum CRP is rapidly suppressed by siltuximab at standard doses (i.e. 11 mg/kg pre three-week interval), as described in van Rhee F et al (2014) Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2014 Aug;15(9):966-74. doi: 10.1016/51470-2045(14)70319-5. Epub 2014 Jul 17. Erratum in: Lancet Oncol. 2014 Sep;15(10):417. PMID: 25042199. However, sustained serum CRP suppression is not always achieved. Therefore, it is envisaged that the treatment density of IL-6 antibody or fragment may be increased for a given patient if suppression of serum CRP to < 10 mg/L is not maintained during treatment at a given treatment density. Serum CRP is typically monitored at least once per treatment cycle, such as on the same day or within three days of administration of the antibody or fragment. Serum CRP may typically be measured once or twice more in a given treatment cycle, particularly if the treatment cycle is at an increased treatment density than the preceding treatment cycle. Typically, the further monitoring may be performed 5±1 and/or 9±1 days after the administration of the antibody or fragment in the treatment cycle. Thus, if the antibody or fragment is administered on day 1, the serum CRP may be monitored on days 1, 6 and 10 of the treatment cycle. More generally, dose escalation to a higher treatment density may be indicated if the patient experiences disease progression, based on biochemical, lymph node and/or symptom parameters according to the Castleman Disease Collaborative Network Response Criteria (CDCNRC), as described in Example 1. Biochemical markers which may be assessed are serum CRP, hemoglobin, albumin and GFR (glomerular filtration rate). Symptoms which may be assessed are fatigue, anorexia, fever, and weight.

Typically, the patient will continue to be administered the antibody or fragment for as long as there is clinical benefit, typically at the same treatment density at which the clinical benefit has been observed. Clinical benefit may include complete response (CR), partial response (PR), or prolonged stable disease (SD). CR, PR, or prolonged SD may be based on evaluation of biochemical, lymph node and/or symptom response, according to the CDCNRC, as described in Example 1. Biochemical markers which may be assessed are serum CRP, hemoglobin, albumin, and GFR (glomerular filtration rate). Symptoms which may be assessed are fatigue, anorexia, fever, and weight. Biochemical or symptoms evaluation may be preferred because lymph node responses may not be observed until the antibody or fragment has been administered for several months. By "prolonged SD", we mean that the disease has been stable for at least 12 weeks.

The patient will typically be monitored for toxicity of the antibody or fragment, typically on the same days as CRP monitoring. If the patient experiences dose-limiting toxicity (DLT), defined as unacceptable Grade >3 treatment-related toxicity or Grade >3 allergic/hypersensitivity reaction per NCI CTCAE version 5.0, the treatment may be modified. Typically, the antibody or fragment would be administered at a lower treatment density; the dosing schedule would be amended, such as by administering the antibody or fragment at a greater frequency and at a lower dose, at the same or lower treatment density; the treatment regimen would be supplemented with best supportive care. In the alternative, the patient who obtains clinical benefit from the antibody or fragment may continue the therapy without modification depending on the nature of the toxicity and its manageability/preventability. Typically, a patient who has experienced DLT at a given treatment density will not be administered the antibody or fragment at a higher treatment density, and it is also possible that treatment at the given treatment density will be permanently discontinued.

Typically, each treatment cycle of the treatment regimen is < three weeks in duration, such as three weeks, two weeks, or one week. For treatment cycles of under two weeks, the timing of CRP monitoring may need to be adjusted accordingly. Typically, the antibody or fragment is administered once per treatment cycle or as two or more divided doses. The addition of a second administration of antibody or fragment to a treatment cycle may particularly be performed when escalating the dose to the next treatment intensity. For example, a patient who has received 22 mg/kg or 33 mg/kg every 3 weeks could be administered an extra 11 mg/kg dose prior to the next 3-week interval. Thus, the first treatment cycle at the increased treatment intensity would involve one 22 mg/kg or 33 mg/kg dose and one 11 mg/kg dose. Such a dosing pattern could be maintained at the increased treatment intensity, or 33 mg/kg or 44 mg/kg could be provided as a single administration. Typically, the treatment cycles are of the same duration from one treatment intensity to the next, e.g., all three-week cycles, or all two-week cycles, although varying the cycle durations between different treatment intensities is also envisaged.

The antibody or fragment is administered intravenously, typically as an intravenous infusion, such as at a dose of 11 ± 3 mg/kg per hour, such as at a dose of 11 mg/kg per hour. Thus, if a dose of 22 mg/kg is to be administered, it will typically be by intravenous infusion over a period of two hours.

The antibody or fragment should be prepared under sterile conditions. The appropriate volume of antibody or fragment should be withdrawn from the vials. It is recommended that the antibody solution is filtered (0.2 to 1.2 pm) before injection into the patient either by using an in-line filter during infusion or by filtering the solution with a particle filter (e.g., filter Nr. MF1830, Impromediform, Germany). The volume of the antibody is typically added to an infusion bag containing 5% dextrose. Siltuximab is available as a single-use vial containing 100 mg or 400 mg siltuximab powder for concentrate for solution for infusion, and should be stored at refrigeration temperature. The siltuximab powder is typically provided with one or more excipients, typically histidine, histidine hydrochloride monohydrate, polysorbate 80, and sucrose. After reconstitution with single-use sterile water for injection, the solution contains 20 mg siltuximab per mL. Antibodies or fragments may be formulated in other ways, as known in the art. The treatment regimen of the invention is intended for a patient whose disease has previously been treated with a prior treatment regimen and has relapsed or was refractory or resistant to treatment with the prior treatment regimen; wherein the prior treatment regimen comprises intravenously administering an antibody or fragment thereof which is a human IL-6 signalling pathway antagonist, wherein the antibody or fragment is administered at an IL-6 signalling pathway antagonist treatment density that is lower than the first antibody treatment density or equivalent fragment treatment density. Thus, the patient has received a prior IL-6 signalling pathway antagonist therapy, typically over one or more treatment cycles, typically over 2, 3, 4, 5, or more, 10 or more, or 20 or more treatment cycles. If the prior treatment has been successful, and the patient has achieved a complete response (CR), there may be an interval between the prior treatment regimen and the treatment regimen of the invention during which the patient does not receive treatment for iMCD. For example, there may be an interval of one or more months, or even years during which the patient does not receive treatment for iMCD. In cases of resistant or refractory disease, there may also be an interval between the prior treatment regimen and the treatment regimen of the invention. However, as the patient has achieved at best a partial or minor response to the prior treatment (resistant disease) or no response (refractory disease), it is preferred that the patient commences the treatment regimen of the invention shortly after resistant or refractory disease has been diagnosed, typically within 3 months of diagnosis of resistant or refractory disease. The prior treatment may include other therapies in addition to therapy with an IL-6 antagonist, such as therapy with a steroid, such as a corticosteroid, chemotherapy or surgery to remove the affected lymph node.

By "human IL-6 signalling pathway antagonist", we include an antibody or fragment which antagonises the activity of human IL-6 in signalling via the IL-6R beta chain gpl30 on the cell surface. A schema for gpl30 signalling in response to IL-6 binding to the IL-6R alpha chain gp80 is shown in Figure 1. By "human IL-6 signalling pathway antagonist" we include an antibody or fragment which is capable of specifically binding to the human IL-6R alpha chain gp80, and thereby prevents gpl30 signalling; or an antibody or fragment which is capable of specifically binding to human IL-6R beta chain gpl30, and thereby prevents gpl30 signalling; or an antibody or fragment which is capable of specifically binding to human IL-6, and of inhibiting its interaction with gp80 (IL-6R) or otherwise preventing gpl30 signalling. Thus, the term "human IL-6 signalling pathway antagonist" includes the antibodies and fragments described above as being capable of inhibiting human IL-6; and additionally antibodies and fragments which bind specifically to IL-6R alpha chain gp80 or beta chain gpl30. An antibody which is capable of inhibiting human IL-6 must be capable of specifically binding to human IL-6, and of inhibiting its interaction with gp80 (IL-6R) or otherwise preventing gpl30 activation. Antagonism of gpl30 signalling can be determined by assaying proliferation of the murine B myeloma cell line, 7TD1, in response to IL-6, as described in WO 2004/039826A1. Suitable antibodies may inhibit >50%, such as >90%, such as substantially 100% of 7TD1 cell proliferation in response to IL-6.

Suitable antibodies for use in the prior treatment regimen are chimaeric, such as mouse-human chimaeric antibodies, CRD-grafted antibodies, humanised antibodies or human antibodies. Although the antibody may be a polyclonal antibody, it is preferred if it is a monoclonal antibody. Suitable fragments are described above in relation to anti-IL-6 antibody fragments.

By "human IL-6R alpha chain gp80" we include any natural or synthetic protein with structural and/or functional identity to the human IL-6R alpha chain gp80, such as defined in UniProt Accession No. P0887, or natural variants thereof. A suitable antibody which is specific for human IL-6R gp80 is tocilizumab, which is a humanised (from mouse) IgGlK monoclonal antibody. The tocilizumab heavy and light chain amino acid sequences are provided in the Canadian DrugBank database Accession No. DB06273 at https://go.drugbank.com/drugs/DB06273, and in US 10,323,095 B2. Another suitable antibody is sarilumab, which is a human monoclonal antibody selective for the human IL-6R alpha chain gp80, produced in Chinese Hamster Ovary cells by recombinant DNA technology and available as Kevzara. The sarilumab heavy and light chain amino acid sequences are provided in the Canadian DrugBank database Accession No. DB11767, available at https://go.drugbank.com/drugs/DB11767. Another suitable antibody is satralizumab, which is a human IgG2K monoclonal antibody selective for the human IL-6R alpha chain gp80, and described at https://go.drugbank.com/drugs/DB15762.

By "human IL-6R beta chain gpl30" we include any natural or synthetic protein with structural and/or functional identity to the human IL-6R beta chain gpl30, such as defined in UniProt Accession No. P40189, or natural variants thereof. Gpl30 may also be referred to as interleukin- 6 signal transducer (IL-6ST) or IL-6-beta. Anti-gpl30 monoclonal antibodies (mAbs) obtained from hybridomas designated 4B11 and 2H4 are described in US5,571,513.

In an embodiment, the prior treatment regimen comprises: (a) intravenously administering siltuximab, such as at a dose of 11 mg/kg per three-week treatment cycle for at least one treatment cycle; or (b) intravenously administering tocilizumab, such as at a dose of 8 mg/kg per two-week treatment cycle for at least one treatment cycle. Siltuximab is the preferred IL-6 antagonist for front-line therapy of iMCD, and is typically administered at a dose of 11 mg/kg per three-week treatment cycle. However, other cycle durations may be envisaged at the same treatment density. It is also possible that individual patients will have received siltuximab at a lower treatment density than 11 mg/kg per three-week interval, such as 10 mg/kg per three- week interval, 9, 8, 7, 6 or 5 mg/kg per three-week interval. An alternative IL-6 signalling pathway antagonist for front-line therapy for iMCD, especially when siltuximab is not available, is tocilizumab (van Rhee F, Voorhees P et al. 2018 International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood. 132(20):2115-2124). Thus, the prior treatment may comprise tocilizumab, typically at a dose of 8 mg/kg per two-week treatment cycle. However, other cycle durations may be envisaged at the same treatment density. It is also possible that individual patients will have received tocilizumab at a lower treatment density than 8 mg/kg per two-week interval, such as 7 mg/kg per two-week interval, 6, 5, or 4 mg/kg per two-week interval.

As discussed above, the patient for whom the treatment regimen of the invention is intended will typically have progressed with elevated and/or rising serum C-reactive protein (CRP) levels during or after treatment with the prior treatment regimen. Typically, the patient has IL-6-driven iMCD or IL-6-driven TAFRO-iMCD.

It will be appreciated that the treatment regimen of the invention, or the prior treatment regimen may comprise treatment with one or more further active agents, such as chemotherapy agents or a corticosteroid. Alternatively, the treatment regimen of the invention, or the prior treatment regimen, may comprise administration of the anti-IL-6 therapy, or IL-6 signalling pathway antagonist respectively, as sole therapeutic agent. The recommend front-line (prior) therapy for iMCD is siltuximab (11 mg/kg every 3 weeks) ± corticosteroids, according to Fajgenbaum, 2018, supra. Patients who respond to siltuximab should taper off corticosteroids and continue receiving siltuximab monotherapy indefinitely or until treatment failure. Among responders, patients with a mild pretreatment disease course may be carefully observed off of treatment, whereas patients with a more intense pretreatment disease course should be maintained on an immunomodulatory/immunosuppressive agent, such as cyclosporine, sirolimus, anakinra, thalidomide, or bortezomib. Thus, relapsed patients in particular may have received various prior therapies in addition to an IL-6 signalling pathway antagonist. Current therapies for refractory or treatment-resistant disease may include chemotherapy eg, rituximab-cyclophosphamide-doxorubicin-vincristine-prednison e, bortezomib-dexamethasone- thalidomide-adriamycin-cyclophosphamide-etoposide-rituximab, cyclophosphamide-etoposide- rituximab) and/or immunomodulators/immunosuppressants. Thus, treatment-resistant or refractory patients may also have received a variety of prior treatments in addition to an IL-6 signalling pathway antagonist. Any or all of the features described above in relation to the first aspect of the invention relating to a composition for use may be applied in relation to the corresponding aspect of the invention, which provides a method of treating relapsed, refractory or resistant multicentric Castleman disease in a patient.

The method may comprise measuring the amount of IL-6 and/or CRP in a serum sample from the patient, and selecting the patient having IL-6 driven iMCD. Typically, serum IL-6 concentration of > 6 pg/mL and/or a serum CRP concentration of > 10 mg/L will be detected in such a patient prior to commencing treatment with the antibody or fragment, typically within one month prior to commencing treatment. Thus, patients may first be diagnosed with IL-6 driven iMCD, and then treated according to the invention.

The present invention also provides a method of treating an IL-6 associated histiocytic or lymphoproliferative disorder in a patient, and compositions for use in the method.

By "histiocytic disorder", we mean a disorder characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells. Diagnosis is on the basis of clinical, radiographic, pathological, phenotypic, genetic, and/or molecular features, as described in Emile JF et al, Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016 Jun 2; 127(22):2672-81. Histological and phenotypic evaluation of tissue biopsies, including immunohistochemistry, is used to identify macrophage, dendritic cell, or monocyte- derived cells. The histiocytoses include H-group histiocytosis, such as primary hemophagocytic lymphohistiocytosis, secondary hemophagocytic lymphohistiocytosis and hemophagocytic lymphohistiocytosis of unknown/uncertain origin; R-group histiocytosis, such as familial Rosai- Dorfman disease, classical Rosai-Dorfman disease, extranodal Rosai-Dorfman disease, neoplasia- associated Rosai-Dorfman disease, immune disease-associated Rosai-Dorfman disease or other non-C non-L non-M non-H histiocytosis; and malignant (M-group) histiocytosis. Any of these forms may be treated according to the invention. Further information on the histiocytoses is provided in Emile et al, 2016, supra.

By "lymphoproliferative disorder", we mean a disorder characterized by uncontrolled production of lymphocytes that cause lymphocytosis and lymphadenopathy. They may involve various immunophenotypes of T, B and NK cells. Analysis of blood samples frequently reveals large quantities of immature lymphocytes that are usually oligoclonal. Lymphoproliferative disorders include lymphoid neoplasms and non-malignant lymphoproliferative disorders. Lymphoid neoplasms may be classified and diagnosed according to the 2016 revision of the World Health Organization classification of lymphoid neoplasms, as described in Swerdlow SH et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016 May 19;127(20):2375-90, and include Waldenstrom macroglobulinemia, non-Hodgkin or Hodgkin lymphoma, and plasma cell myeloma (also known as multiple myeloma). Any of these forms may be treated according to the invention. Further information on lymphoproliferative disorders is provided in Justiz Vaillant AA, Stang CM. Lymphoproliferative Disorders. [Updated 2020 Aug 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537162/. Non-malignant lymphoproliferative disorders may also be treated according to the invention, and include iMCD.

Typically, the patient is negative for infection with HIV, HHV-8 and/or EBV. These viruses may produce viral IL-6. Siltuximab and other IL-6 antibodies bind human but not viral IL-6. However, EBV infection is common, and may be latent in patients. EBV may not be relevant to the pathology to be treated. Thus, the treatment may be appropriate for patients who have EBV infection. In addition, it is also envisaged that diseases for which EBV is relevant to the pathology may be treated, such as EBV-associated hemophagocytic lymphohistiocytosis, as described in Marsh RA. Epstein-Barr Virus and Hemophagocytic Lymphohistiocytosis. Front Immunol. 2018;8: 1902. In addition, HIV or HHV-8 may not be relevant to the pathology to be treated, and so the treatment may be appropriate for patients who have HIV or HHV-8 infection. Typically, the patient is negative for infection with HIV and HHV-8. Diagnosis of HIV, HHV-8 or EBV can be performed by serological analysis or PCR, as known in the art.

By "IL-6 associated" histiocytic or lymphoproliferative disorder, we include the meaning that elevated IL-6, particularly serum IL-6, has been detected in the type of disease in question. For example, elevated IL-6 has been detected in iMCD, as discussed in relation to the first aspect of the invention. Elevated IL-6 has also been detected in high-grade B-cell lymphomas (Emilie D et al. Interleukin-6 production in high-grade B lymphomas: correlation with the presence of malignant immunoblasts in acquired immunodeficiency syndrome and in human immunodeficiency virus-seronegative patients. Blood. 1992;80:498-504), myelomas (Klein B, Zhang X, Lu Z, Bataille R. Interleukin-6 in human multiple myeloma. Blood. 1995;85:863-872) and Rosai-Dorfman disease (Aouba A et al. Dramatic clinical efficacy of cladribine in Rosai- Dorfman disease and evolution of the cytokine profile: towards a new therapeutic approach. Haematologica. 2006 Dec;91(12 Suppl):ECR52). Thus a patient having a disease of a type that may have elevated IL-6 may be considered to have an IL-6 associated disease, and be suitable for the treatment. Typically, the patient will be assessed for elevated IL-6 and/or CRP, to identify that the particular patient's disease is IL-6 associated. Thus, "IL-6 associated" also includes the meaning that the specific patient has elevated IL-6 and/or CRP.

A normal range of serum IL-6 for a healthy person is <5 pg/mL. Patients having an IL-6 associated disease, i.e. for whom IL-6 is suspected of contributing to pathology, may have serum IL-6 levels at diagnosis >6 pg/mL. Serum IL-6 levels in patients having an IL-6-associated histiocytic or lymphoproliferative disease may typically be in the range of 7 pg/mL to 10 ng/mL or greater. IL-6 may be measured using commercially available enzyme-linked immunosorbent assay kits (e.g. from R&D Systems, Minneapolis, MN), and other methods known in the art. Serum CRP levels in patients having an IL-6-associated disease can be expected to be in the range of 11 mg/L to 100 mg/L, although levels above 100 mg/L are not ruled out. Thus, the patient typically has a serum IL-6 concentration of > 6 pg/mL and/or a serum C-reactive protein (CRP) concentration of > 10 mg/L prior to commencing the treatment regimen, typically within one month prior to commencing the treatment regimen. CRP is typically monitored periodically during the treatment regimen, rather than serum IL-6, because measurement of free serum IL- 6 levels will likely be confounded by IL-6 antibody therapy, because presently available IL-6 diagnostic tests are unable to distinguish free from antibody-bound IL-6. If the patient has received a prior IL-6 antagonist therapy or an exploratory intensity treatment cycle with an anti- IL-6 antibody, serum CRP levels are typically monitored at between 3 and 12 weeks after the last treatment with a prior IL-6 antagonist or antibody therapy, and/or serum CRP is typically monitored between 1 and 21 days before commencing the first cycle of the first intensity treatment, typically wherein the antibody or fragment is administered on day 1 of the treatment cycle. CRP monitoring is preferred for patients who have received a prior anti-IL-6 antibody therapy because measurement of free serum IL-6 levels will likely be confounded by the prior antibody therapy.

The antibody or fragment thereof for use of this aspect of the invention is capable of inhibiting human IL-6. Suitable antibodies and their features are described above. In an embodiment, the antibody or fragment thereof which is capable of inhibiting human IL-6 is a chimeric, humanized or CDR grafted antibody or fragment thereof comprising a heavy chain variable region in which CDR1, CDR2 and CDR3 comprise the amino acid sequences SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively; and a light chain variable region in which CDR1, CDR2 and CDR3 comprise the amino acid sequences SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively, and a constant region derived from a human IgG antibody. In a preferred embodiment, the antibody is siltuximab. The treatment regimen of this aspect of the invention comprises: at least one first intensity treatment cycle comprising intravenously administering the antibody in a first antibody treatment density of > 11 mg/kg per three-week interval or 11 mg/kg per < 3-week interval, or the fragment at an equivalent fragment treatment density having an equivalent antagonistic effect on human IL-6. Suitable features and embodiments of treatment cycles and first intensity treatment cycles are described above. Suitably, the first antibody treatment density is > 12 mg/kg per three-week interval, such as > 13 mg/kg, such as > 14 mg/kg, such as > 15 mg/kg, such as > 16 mg/kg, such as > 17 mg/kg per three-week interval; or > 11 mg/kg per 2-week interval; or 11 mg/kg per < 2-week interval. Suitably, the first antibody treatment density is 22 ± 5 mg/kg per three-week interval, or 33 ± 5 mg/kg per three-week interval or 44 ± 5 mg/kg per three-week interval, such as wherein the first antibody treatment density is 22, 33 or 44 mg/kg per three-week interval; or 15 ± 3 mg/kg per two-week interval, or 22 ± 3 mg/kg per two-week interval, or 29 ± 3 mg/kg per two-week interval; or 7 ± 2 mg/kg per one-week interval, or 11 ± 2 mg/kg per one-week interval, or 15 ± 2 mg/kg per one-week interval. For the avoidance of doubt, we note that for all doses of X ± Y specified herein, we include all whole units of Y from 0 to Y. For all such doses, the equivalent fragment treatment density would be determined as described above.

Suitably, after the patient has been treated with the at least one first intensity treatment cycle, the patient is treated with at least one second intensity treatment cycle comprising intravenously administering the antibody or fragment at a second antibody treatment density or equivalent fragment treatment density, if clinically indicated; wherein the second antibody treatment density is greater than the first antibody treatment density.

In an embodiment, (a) if the first antibody treatment density is 22 ± 5 mg/kg per three-week interval, or 15 ± 3 mg/kg per two-week interval, or 7 ± 2 mg/kg per one-week interval, then the second antibody treatment density is: 33 ± 5 mg/kg per three-week interval, or 22 ± 3 mg/kg per two-week interval, or 11 ± 2 mg/kg per one-week interval; or 44 ± 5 mg/kg per three-week interval, or 29 ± 3 mg/kg per two-week interval, or 15 ± 2 mg/kg per one-week interval; or

(b) if the first antibody treatment density is 33 ± 5 mg/kg per three-week interval, or 22 ± 3 mg/kg per two-week interval, or 11 ± 2 mg/kg per one-week interval, then the second antibody treatment density is 44 ± 5 mg/kg per three-week interval, or 29 ± 3 mg/kg per two- week interval, or 15 ± 2 mg/kg per one-week interval. In an embodiment, after the patient is treated with the at least one second intensity treatment cycle, the patient is treated with at least one third intensity treatment cycle comprising intravenously administering the antibody or fragment at a third antibody treatment density or equivalent fragment density, if clinically indicated; wherein the third antibody treatment density is greater than the second antibody treatment density, such as

(a) if the second antibody treatment density is 33 ± 5 mg/kg per three-week interval, or 22 ± 3 mg/kg per two-week interval, or 11 ± 2 mg/kg per one-week interval, then the third antibody treatment density is 44 ± 5 mg/kg per three-week interval, or 29 ± 3 mg/kg per two- week interval, or 15 ± 2 mg/kg per one-week interval.

In an embodiment, prior to the at least one first intensity treatment cycle, the patient is treated with at least one exploratory intensity treatment cycle, comprising intravenously administering the antibody in an exploratory antibody treatment density of < 11 mg/kg per three-week interval or 11 mg/kg per < 3-week interval, or the fragment at an equivalent fragment treatment density having an equivalent antagonistic effect on human IL-6. The "exploratory intensity" treatment cycle may be used to evaluate whether the patient should be considered for dose escalation, and may be used to assess safety and tolerance, for example, before progressing to the first intensity treatment cycle. In an embodiment, the exploratory antibody treatment density is > 5 mg/kg per three-week interval, such as > 6 mg/kg, such as > 7 mg/kg, such as > 8 mg/kg, such as > 9 mg/kg, such as > 10 mg/kg such as 11 mg/kg per three-week interval; or > 5 mg/kg per < three-week interval, such as 8 mg/kg per two-week interval; or 4 mg/kg per one-week interval.

Clinical indications for dose escalation are as discussed in general above for iMCD, as are provisions for toxicity monitoring. Typically, treatment with the at least one second intensity treatment cycle or treatment with the at least one third intensity treatment cycle is clinically indicated if the patient experiences disease progression and/or the serum C-reactive protein (CRP) level rises during treatment with the first intensity treatment cycle or the second intensity treatment cycle respectively, or wherein if the patient is treated with at least one exploratory intensity treatment cycle, the patient experiences disease progression and/or the serum C- reactive protein (CRP) level rises during treatment with the exploratory intensity treatment cycle.

Serum CRP is rapidly suppressed by siltuximab in the treatment of iMCD at standard doses (i.e. 11 mg/kg pre three-week interval), as described in van Rhee F et al, 2014, supra. However, sustained serum CRP suppression is not always achieved. Therefore, it is envisaged that the treatment density of IL-6 antibody or fragment may be increased for a given patient if suppression of serum CRP to < 10 mg/L is not maintained during treatment at a given treatment density. Serum CRP is typically monitored at least once per treatment cycle, such as on the same day or within three days of administration of the antibody or fragment. Serum CRP may typically be measured once or twice more in a given treatment cycle, particularly if the treatment cycle is at an increased treatment density than the preceding treatment cycle. Typically, the further monitoring may be performed 5± 1 and/or 9± 1 days after the administration of the antibody or fragment in the treatment cycle. Thus, if the antibody or fragment is administered on day 1, the serum CRP may be monitored on days 1, 6 and 10 of the treatment cycle. The discussion of CRP monitoring in relation to iMCD is also relevant to the present aspect. More generally, dose escalation to a higher treatment density may be indicated if the patient experiences disease progression, safety permitting.

Typically, the patient will continue to be administered the antibody or fragment for as long as there is clinical benefit, typically at the same treatment density at which the clinical benefit has been observed. Clinical benefit may include objective response (OR), which is defined as complete response (CR) plus partial response (PR) per applicable response criteria. Further measures of clinical benefit may include an improvement in one or more of progression-free survival (PFS), disease progression determined per applicable response criteria, prolonged stable disease (SD) per applicable response criteria, duration of response (DoR), patient-reported outcomes (PROs) and overall survival (OS), compared to patients who receive prior treatments or no treatment. Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST 1.0) may be used as guidelines for systematic and structured assessment of response to therapy with fluorine 18 fluorodeoxyglucose (FDG) PET in patients with cancer, as described in O, Joo 8L Lodge, Martin 8i Wahl, Richard. (2016). Practical PERCIST: A Simplified Guide to PET Response Criteria in Solid Tumors 1.0. Radiology. 280. 142043. 10.1148/radiol.2016142043.

Typically, each treatment cycle of the treatment regimen is of < three weeks, such as three weeks, two weeks, or one week; and/or the antibody or fragment is administered once per treatment cycle or as two or more divided doses. Typically, the antibody or fragment is administered as an intravenous infusion, such as at a dose of 11 ± 3 mg/kg per hour, such as at a dose of 11 mg/kg per hour. Further features and embodiments are as described above.

Increasing the treatment density of the treatment cycle may be appropriate if the patient relapses or is resistant to treatment, or is refractory to treatment at the given treatment density. The meanings of "refractory", "resistant" and "relapsed" are as described above. Features of intervals between lower and increased intensity treatment cycles are as described above in relation to iMCD.

It will be appreciated that the treatment regimen of the invention may be provided in conjunction with one or more other therapies suitable for treatment of the patient's disease. Alternatively, the treatment regimen of the invention may comprise administration of the anti-IL-6 therapy as sole therapeutic agent or intervention.

Patients who have previously received one or more other therapies are eligible for the treatment regimen of the invention. A patient who has received one or more other therapies, and who is treatment-resistant or who has relapsed, or who is refractory to the one or more prior therapies is eligible for the treatment regimen of the invention. Equally, newly diagnosed patients are eligible.

Typically, the patient has not previously been treated for the disease with a human IL-6 signalling pathway antagonist. In an alternative embodiment, the patient has previously been treated for the disease in a prior treatment regimen and has relapsed or was refractory or resistant to treatment with the prior treatment regimen, wherein the prior treatment regimen comprises intravenously administering an antibody or fragment thereof which is a human IL-6 signalling pathway antagonist, wherein the antibody or fragment is administered at an IL-6 signalling pathway antagonist treatment density that is lower than the first antibody treatment density or equivalent fragment treatment density. Features and embodiments of the prior treatment regimen are as described above in relation to iMCD. It should be appreciated that any prior treatment regimen comprising a human IL-6 signalling pathway antagonist would be an experimental therapy for histiocytic and lymphoproliferative disorders other than iMCD. Nevertheless, it is envisaged that such therapies may be clinically developed in time, and that a patient who has received such a therapy in the past may benefit from receiving the antibody or fragment thereof which is capable of inhibiting human IL-6 at a higher treatment density. Thus, it is envisaged that the patient may have progressed with elevated serum C-reactive protein (CRP) levels during or after treatment with the prior treatment regimen comprising the human IL-6 signalling pathway antagonist.

Any or all of the features described above in relation to the second aspect of the invention relating to a composition for use may be applied in relation to the corresponding aspect of the invention, which provides a method of treating an IL-6 associated histiocytic or lymphoproliferative disorder in a patient. The method may comprise measuring the amount of IL-6 and/or CRP in a serum sample from the patient, and selecting the patient having an IL-6 associated histiocytic or lymphoproliferative disorder for treatment. Typically, serum IL-6 concentration of > 6 pg/mL and/or a serum CRP concentration of > 10 mg/L will be detected in such a patient prior to commencing treatment with the antibody or fragment, typically within one month prior to commencing treatment. Thus, patients are first diagnosed with a IL-6 associated histiocytic or lymphoproliferative disorder, and then treated according to the invention.

Preferences and options for a given aspect, feature, or parameter of the invention should, unless the context dictates otherwise, be regarded as having been disclosed in combination with any and all preferences and options for all other aspects, features, and parameters of the invention.

All documents are incorporated by reference in their entirety.

The present invention will be further illustrated in the following examples, without any limitation thereto.

EXAMPLES

Example 1: A Phase 2 Study of Intrapatient Siltuximab Dose Escalation in Patients with Idiopathic Multicentric Castleman Disease that has Progressed after Prior Siltuximab Treatment

SYNOPSIS

IB Investigator's Brochure

ICF informed consent form

ICH International Council for Harmonisation

I EC Independent Ethics Committee

IL-6 interleukin-6 iMCD idiopathic multicentric Castleman disease

IND Investigational New Drug

IRB Institutional Review Board

ITT intent-to-treat

IV intravenous

IWRS interactive web response system

KM Kaplan-Meier mAb monoclonal antibody

MCD multicentric Castleman disease

MCD-SS multicentric Castleman disease symptom scale

MedDRA Medical Dictionary for Regulatory Activities

NCI National Cancer Institute

ORR objective response rate

OS overall survival

PD pharmacodynamics

PFS progression-free survival

PI principal investigator

PK pharmacokinetic

PR partial response

PRO patient-reported outcome

PS performance status q3w every 3 weeks

QoL quality of life

R/R relapsed or refractory

SAE serious adverse event

SAP statistical analysis plan

SD stable disease SUSAR suspected unexpected serious adverse reaction

TDR time to disease response

TEAE treatment-emergent adverse event

WOCBP women of childbearing potential

US United States

5 INTRODUCTION

Siltuximab (Sylvant®) is a chimeric (human-murine) immunoglobulin G1 K (IgGlK) monoclonal antibody (mAb) that specifically binds human IL-6 with high affinity and prevents its interaction with the IL-6 receptor, glycoprotein (GP) 80 (Seideman and Peritt, 2002). The chimeric antibody contains the variable region of a murine anti-human IL-6 mAb and the constant region from a human immunoglobulin gamma (IgG) 1 molecule. The mechanism of action of siltuximab is neutralization of nonviral IL-6 bioactivity, which can be measured indirectly by C-reactive protein (CRP) suppression since IL-6 is the primary inducer of CRP synthesis in the liver (Heinrich et al 1990), and CRP suppression has previously been used as a surrogate for inhibition of IL-6 signaling (Puchalski et al 2010).

For the most accurate and current information regarding the efficacy and safety of siltuximab, refer to the latest version of the Siltuximab Investigator's Brochure (IB) or Sylvant (siltuximab) package insert.

5.1 Multicentric Castleman Disease

Multicentric Castleman disease (MCD) is a rare, serious, debilitating, and life-threatening lymphoproliferative disease first described by Castleman and Towne, 1954 that is characterized by systemic manifestations such as fever, night sweats, fatigue, anorexia, and wasting, particularly in patients with the plasma cell or mixed-type variants of the disease. Clinical manifestations may vary, and hepatosplenomegaly, lymph node enlargement, and multiple laboratory abnormalities (eg, anemia, hypoalbuminemia, and hypocholesterolemia) are also common (Nishimoto et al 2005; Casper 2005; Dham and Peterson 2007). Other symptoms include fluid retention; neuropathy; skin abnormalities; and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. MCD can occur in individuals who are infected with human immunodeficiency virus (HIV) as well as those not infected with HIV, and symptoms are similar. Treatment goals include alleviation of debilitating symptoms that contribute to shortened survival, and reduction of tumor masses. Clinical data have shown that the benefits of siltuximab, an IL-6 antagonist therapy, are clinically meaningful and favorable relative to the safety profile for treatment of patients with MCD. Furthermore, nonclinical and clinical data indicate that IL-6 remains a relevant target for other cancer indications, supportive care, and premalignancy.

5.1.1 Pathologic Classification of Castleman Disease

Among patients suspected as having Castleman disease, diagnosis is confirmed by histopathologic examination of affected lymph nodes. Castleman disease may be classified as hyaline vascular, plasma cell, or mixed on the basis of lymphoid nodal architectural changes.

5.2 Siltuximab

Sylvant is approved in the United States (US), Europe, and several other countries for the treatment of MCD in adults who are HIV and human herpesvirus 8 (HHV-8)-negative at a dosage of 11 mg/kg administered via intravenous (IV) infusion over 1 hour every 3 weeks (q3w).

Neutralization of nonviral IL-6 bioactivity can be measured indirectly by CRP suppression since IL-6 is the primary inducer of CRP synthesis in the liver (Heinrich et al 1990), and CRP suppression is considered a robust surrogate for indicating the efficacy of IL-6 signaling inhibition (Puchalski et al 2010), as available laboratory tests are unable to distinguish free IL-6 from siltuximab-bound IL-6 in the serum after siltuximab treatment is administered.

For the most comprehensive nonclinical and clinical information regarding the efficacy and safety of siltuximab, refer to the latest version of the Siltuximab IB or Sylvant (siltuximab) product label.

5.2.1 Potential Risks and Benefits With Siltuximab

Details of known or anticipated risks and benefits of siltuximab in its approved indication, its approved IV dosage of 11 mg/kg over 1 hour q3w, and reasonably anticipated adverse events (AEs), may be found in the Siltuximab IB or Sylvant (siltuximab) package insert. Risks

The most common adverse reactions (> 10% of patients) are rash, pruritus, upper respiratory tract infection, increased weight, and hyperuricemia. Uncommon but serious adverse reactions include infusion-related reactions, for which siltuximab should be administered in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation, and gastrointestinal perforation, symptoms of which should be promptly reported and evaluated.

Other important adverse reactions reported in MOD clinical studies were: nasopharyngitis, urinary tract infection, neutropenia, dizziness, hypertension, nausea, abdominal pain, vomiting, diarrhea, gastroesophageal reflux disease, and mouth ulceration.

Siltuximab also carries a warning against administering live vaccines to patients receiving siltuximab because IL-6 inhibition may interfere with the normal immune response to new antigens. There are warnings against administering siltuximab to patients with concurrent active severe infections until the infection resolves, and also cautions that siltuximab may mask signs and symptoms of acute inflammation including suppression of fever and of acute phase reactants such as CRP.

Siltuximab was not immunogenic in over 400 patients tested by enzyme immunoassay, and in 4 patients who tested positive for anti-siltuximab antibodies by electrochemiluminescencebased immunoassay methods, none had neutralizing antibodies.

Benefits

The presence of excess bioactive IL-6 is a reasonable hypothesis explaining why a patient with iMCD or iMCD-TAFRO does not respond or stops responding to standard doses of siltuximab. Therefore, it stands to reason that safely increasing the siltuximab dose in these patients with evidence of elevated and rising IL-6 levels measured through its surrogate, CRP, could establish or re-establish disease control.

Taken together, siltuximab has a favorable benefit/ risk profile for its further investigation in patients with iMCD (or iMCD-TAFRO), a serious, life-threatening, IL-6-driven disease without alternate proven safe and effective treatment options, especially after standard-dose siltuximab failure at higher doses, which may be done safely in patients who previously tolerated standard- dose siltuximab as predicted in Section 5.3 below. 5.3 Study and Dose Rationales

This is an open-label, two-stage, Phase 2 study to investigate the safety, tolerability, and efficacy of administering increased siltuximab doses to patients with iMCD that progressed after prior treatment with siltuximab 11 mg/kg q3w without unacceptable toxicity. Patients in both cohorts in Stage 1 will be screened for IL-6-driven disease, marked by elevated and rising CRP levels, as the measurement of free serum IL-6 levels will likely be confounded by prior siltuximab treatment. It was previously determined that elevated CRP, a surrogate marker for IL-6, is a diagnostic measure of naive or relapsed iMCD and a potential predictor of response to siltuximab treatment (Morra et al 2019). Despite the rapid suppression of CRP by siltuximab at standard doses (van Rhee et ai 2014), it was unclear whether this was related to disease response. A likely contributing factor to such uncertainty in CRP suppression and efficacy is inclusion of patients who were later predicted to be non-responders due to low baseline CRP levels. In contrast, this study is designed to better evaluate the efficacy of siltuximab by selecting for patients with IL-6- driven iMCD where baseline CRP levels are elevated and rising.

In a Phase 2 comparison with best supportive care study (Study CNT0328MCD2001), standard siltuximab doses were given to a proportion of patients with IL-6-driven iMCD; however, sustained CRP suppression in those patients was not achieved. This may explain the incomplete ORR of 34% reported, highlighting a need to improve the ORR by sustaining CRP suppression. Based on previous siltuximab dose-finding studies, PK/PD-based simulations demonstrated a dose-dependent increase in response and CRP suppression. This may suggest that siltuximab at increased doses is a viable treatment strategy in sustaining CRP suppression to improve the ORR, taking into account that neither DLT up to 12 mg/kg q2w, antibodies to siltuximab, apparent dose-toxicity relationship, nor maximum tolerated dose of siltuximab was reached in a Phase 1 clinical trial (Kurzrock et a! 2013). In the present study, the proposed strategy of intrapatient dose escalation includes a starting dose of 22 mg/kg q3w with the option to dose escalate to 33 mg/kg q3w then up to 44 mg/kg q3w if clinically indicated without DLT. These dose escalation levels are expected to not only improve ORR but also account for potential patient variability in iMCD response and tolerability. Taken together, this study is focused on optimizing the efficacy of siltuximab in IL-6-driven iMCD patients whose disease progressed after prior standard siltuximab therapy.

Enrolled patients will have iMCD that progressed after prior treatment with siltuximab at 11 mg/kg q3w; therefore, the starting dose will be 22 mg/kg q3w. The increased Siltuximab doses up to 44 mg/kg q3w were conservatively selected by extrapolating the maximum dose tested in cynomolgus monkey to humans and through clinical pharmacological simulations based on available published literature (Mayer et al 2015; Nikanjam et al 2019). This maximum dose in monkeys did not cause treatment-related toxicity despite a Cmax that was 4-fold greater than the Cmax in humans simulated for 44 mg/kg q3w. Both the nonclinical data and PK/PD-based simulations support the expected safety and tolerability of the proposed intrapatient dose escalation regimen. Furthermore, all previously published clinical studies reviewed did not report any significant safety concerns upon administration of siltuximab up to 15 mg/kg q3w.

Among 30 patients with COVID-19-associated acute respiratory distress syndrome who were treated with siltuximab 11 mg/kg IV over 1 hour, 6 (20.0%) safely received a second dose 72 hours after the initial infusion. All siltuximab-treated patients had at least 7 days of followup after siltuximab administration (median: 33.3 days; range: 7 to 58 days). The 30-day mortality rate was lower in patients treated with siltuximab than in the matched-control cohort (hazard ratio: 0.462 [95% CI: 0.221, 0.965], 2-sided p-value=0.0399). After treatment with siltuximab, CRP levels, a marker of systemic inflammation, reduced from a median of 20.7 mg/dL (interquartile range 12.85 to 25.30) at Day 1 to a median of 0.3 mg/dL (interquartile range 0.1 to 3.9) at Day 14 (Gritti et al 2020). Reduction in CRP is considered a robust surrogate for indicating the efficacy of IL-6 inhibition, as available laboratory tests are unable to distinguish free IL-6 from siltuximab-bound IL-6 after siltuximab treatment is administered.

As such, this study is not a higher siltuximab dose-finding study per se, but rather aims to ensure overall patient safety and drug tolerability using an intrapatient siltuximab dose escalation strategy to establish or re-establish responses in patients who experienced failure of prior standard siltuximab therapy that they previously tolerated in the setting of elevated and rising serum CRP levels. These patients are in need of additional IL-6 neutralization to potentially increase the global response rates of siltuximab for this serious, life-threatening disease without alternate proven safe and effective treatment options.

6 STUDY OBJECTIVES AND ENDPOINTS

6.1 Study Objectives

6.1.1 Primary Objective Assess the clinical benefit response (CBR) of increased siltuximab doses in patients with IL-6-driven (C-reactive protein [CRP]-elevated and rising) iMCD after disease progression on the standard siltuximab dose schedule.

6.1.2 Secondary Objectives

• Evaluate the safety and tolerability of increased siltuximab doses.

• Evaluate the pharmacokinetics (PK) of increased siltuximab doses.

• Evaluate the efficacy, immunogenicity, and patient-reported outcomes (PROs) of increased siltuximab doses after disease progression on prior siltuximab treatment.

6.1.3 Exploratory Objectives

• Explore pharmacodynamic (PD) biomarkers that may predict response to increased doses of siltuximab.

• Explore mechanisms of resistance in patients whose disease progresses despite increased doses of siltuximab.

6.2 Study Endpoints

6.2.1 Primary Endpoint

• CBR defined as complete response (CR), partial response (PR), or stable disease (SD) lasting >12 weeks per Castleman Disease Collaborative Network Response Criteria (CDCNRC) (see Appendix 2) based on evaluation of biochemical, lymph node, and symptom response.

6.2.2 Secondary Endpoints

Secondary endpoints include:

• Safety analysis

- Type, incidence, severity, seriousness, and relationship to study medications for AEs, including laboratory abnormalities, treatment-emergent AEs (TEAEs), serious adverse events (SAEs), suspected unexpected serious adverse reactions (SUSARs), and dose-limiting toxicities (DLTs).

• Immunogenicity analysis

- Detection of antibodies against siltuximab.

• Pharmacokinetic analysis

- AUCss, Vd, Cmin, Cmax, Ctrough, Tmax, TI/2, Keip, and clearance (CL) from empirical Bayes estimates.

• Efficacy analysis

- Objective response rate (ORR), time to disease response (TDR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

• PRO/Quality of Life (QoL) assessments

- EuroQol (EQ)-5D-3L

- MCD-symptom scale (MCD-SS)

6.2.3 Exploratory Endpoints

Exploratory endpoints include:

• Laboratory parameters and measures of tumor burden at baseline and at subsequent cycles to monitor ongoing disease status and determine potential biomarker(s) predictive of treatment response.

• Exploratory screening of IL-6-dependent and IL-6-independent biomarkers in available tissue samples of responders and non-responders to uncover potential mechanism(s) of resistance to treatment.

7 INVESTIGATIONAL PLAN

7.1 Description of Overall Study Design and Plan

This is an open-label, two-stage, Phase 2 study to investigate the safety, tolerability, and efficacy of administering increased siltuximab doses to patients with iMCD who progressed with elevated and rising serum CRP levels after prior treatment with siltuximab 11 mg/kg q3w without unacceptable toxicity.

Patients will continue to receive study treatment as long as they derive benefit from the investigational treatment regimen without unacceptable toxicity, withdrawal of consent, investigator decision to stop treatment, or end of study. Patients may be considered for treatment beyond disease progression with or without siltuximab dose escalation at the discretion of the investigator and in consultation with the Medical Monitor.

7.2 Discussion of Study Design

This is an open-label, two-stage, Phase 2 study to investigate the safety, tolerability, and efficacy of administering increased siltuximab doses to patients with iMCD that progressed with elevated and rising serum CRP levels after prior treatment with siltuximab 11 mg/kg q3w without unacceptable toxicity, and is primarily designed to leverage opportunities for intrapatient dose escalation with available clinical, nonclinical, and PK justification as a means to restore or enable disease control.

Enrolled patients with iMCD that progressed after prior treatment with siltuximab at 11 mg/kg q3w will have a starting dose in both stages (Stage 1 and Stage 2) of the study of 22 mg/kg q3w. The dose of siltuximab may be escalated, if clinically indicated, to 33 mg/kg q3w and up to 44 mg/kg q3w. Based on previous siltuximab dose-finding studies, PK/PD-based simulations demonstrated a dose-dependent increase in response and CRP suppression suggesting that siltuximab at increased doses is a viable treatment strategy in sustaining CRP suppression to improve the ORR.

7.3 End of Study

A patient will have fulfilled the requirements for study completion if/when the patient has completed all study periods, including post-treatment follow-up (up to 3 years after last dose).

8 SELECTION OF STUDY POPULATION

Section 7.1 provides information regarding number of patients planned to be enrolled.

8.1 Inclusion Criteria

Patients are eligible for the study if they meet the following criteria :

1. Documented history of consensus histologic, laboratory, and clinical diagnostic criteria of iMCD (Appendix 1).

2. Archival and/or baseline incisional/excisional biopsy for retrospective central histologic confirmation of iMCD (see Section 11.4.1) is required. Of note, if prior diagnostic material relating to the patient's Castleman disease is not available, or if histologic diagnosis was made >5 years prior to study enrollment, or if histologic diagnosis was based on fine-needle aspiration cytology and/or core needle biopsy only, then a baseline incisional/excisional lymph node biopsy must be performed to confirm histologic diagnosis of Castleman disease prior to enrollment.

3. CDCNRC-defined disease progression on or after prior treatment with siltuximab at 11 mg/kg q3w without unacceptable toxicity within 12 weeks between the last dose of siltuximab and the date of signed patient informed consent form (ICF) to participate in this study.

4. At least 1 measurable abnormal lymph node mass that is >1 cm in its longest transverse diameter as assessed by computerized tomography (CT) scan that has not been previously irradiated.

5. Elevated (>10 mg/L) and rising serum CRP levels between 3 to 12 weeks after the last siltuximab dose in the absence of additional iMCD treatment.

6. Evidence of at least an additional one of the following laboratory or clinical signs of iMCD per international, evidence-based consensus diagnostic criteria for HIV or HHV-8 negative iMCD (Appendix 1)

- Anemia, thrombocytopenia, hypoalbuminemia, renal dysfunction, or polyclonal hypergammaglobulinemia.

- Constitutional symptoms (night sweats, fever (>38°C), weight loss, or fatigue (CTCAE lymphoma B-symptoms score >2), large spleen and/or liver, fluid accumulation, eruptive cherry hemangiomatosis/violaceous papules, or lymphocytic interstitial pneumonitis.

7. Adequate clinical laboratory measurements within 3 weeks prior to study entry in all parameters below:

- Absolute neutrophil count >1.0 x 109/L, hemoglobin >6.5 g/dL, and platelets >50 x 109/L without transfusion, hematopoietic growth factors, or both for >7 days prior to measurement.

- AST, ALT, total bilirubin, and alkaline phosphatase <5 x ULN.

- Fasting cholesterol <300 mg/dL and fasting triglyceride <400 mg/dL.

8. Age >12 years.

9. Women of childbearing potential (WOCBP) require negative serum pregnancy test at screening and agreement to use appropriate contraception methods from study entry to 3 months after the last day of treatment. 10. Male patients agree to use contraception methods from study entry to 3 months after the last date of treatment.

11. Evidence of a personally signed and dated ICF indicating that the patient (or a legally authorized representative) has been informed of all pertinent aspects of the study prior to enrollment.

12. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

8.2 Exclusion Criteria

Patients are not eligible for the study if they meet any of the following criteria :

1. Documentation of HIV or HHV-8 infection or presence of other infection-related disorders that resemble clinical or histological features of iMCD (eg, Epstein-Barrvirus- lymphoproliferative disorders, acute or uncontrolled cytomegalovirus, toxoplasmosis, active tuberculosis)

2. Diagnosis of any malignant/benign lymphoproliferative disorders (eg, lymphoma, multiple myeloma, primary lymph node plasmacytoma, follicular dendritic cell sarcoma, and POEMS syndrome)

3. Diagnosis of autoimmune/autoinflammatory disease

4. Treatment with corticosteroids (prednisone dose-equivalent >1 mg/kg/day) within 7 days prior to study entry.

5. History of solid organ transplant, allogeneic bone marrow transplant, or allogeneic peripheral blood stem cell transplant.

- Patients with prior history of autologous transplant will not be excluded.

6. Patients with a previous malignancy with the following exceptions:

- Past malignancy with treatment that was completed at least 2 years before signing informed consent and the patient has no evidence of disease, or

- Concurrent malignancy that is clinically stable and does not require tumor- directed treatment (eg, nonmelanoma skin cancer and carcinoma in situ)

7. Other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that, in the judgment of the investigator, would render the patient inappropriate for study participation or study drug administration.

8.3 Study Withdrawal and Replacement of Patients

If a patient discontinues study treatment or is withdrawn from the study for any reason, the study site must immediately notify the Medical Monitor. The date and the reason for discontinuing study treatment or overall study discontinuation must be recorded on the electronic case report form (eCRF). Patients who complete or discontinue early from study treatment will be asked to return to the study site within 14 days of the last administration of study drug to complete end of treatment (EOT) assessments as indicated in the Schedule of Assessments (Table 2).

In the event that a patient discontinues prematurely from study treatment or the study because of a treatment-emergent adverse event (TEAE) or serious TEAE, the TEAE or serious TEAE should be followed up until it resolves (returns to normal or baseline values) or stabilizes, or until it is judged by the investigator to no longer be clinically significant.

In the event a patient is deemed non-evaluable in Stage 1 for efficacy or DLT, or for reasons other than toxicity, the patient will be replaced.

Once a patient is withdrawn from the study, the patient may not re-enter the study.

Patients may be voluntarily discontinued, or withdrawn from study treatment at any time for the following reasons, including, but not limited to:

• patient withdrawal of consent: at any time, a patient's participation in the study may be terminated at his/her request. The reason for patient withdrawal will be noted on the eCRF.

• uncontrollable disease progression (worsened ECOG performance status [PS] from baseline)

• unacceptable toxicity (DLT)

• investigator decision: at any time, a patient's participation in the study may be terminated on the basis of the investigator's clinical judgment. The reason for patient withdrawal will be noted on the eCRF.

• intercurrent illness: a condition, injury, or disease unrelated to the primary diagnosis that became apparent during treatment and necessitated the patient's termination from the study.

• general or specific changes in the patient's condition that renders him/her ineligible for further treatment according to the inclusion/exclusion criteria.

• patient fails to adhere to the protocol requirements (eg, drug noncompliance, failure to return for defined number of visits).

• lost to follow-up: the patient stopped coming for visits, and study personnel were unable to contact the patient. pregnancy, as indicated in Section 12,6.6.

Additionally, the Sponsor may stop the study at any time for safety, regulatory, legal, or other reasons aligned with GCP. This study may be terminated at the discretion of the Sponsor or any regulatory agency. An investigator may elect to discontinue or stop the study at his or her study site for any reason, including safety. See also Section 9.1.

9 TREATMENTS

9.1 Details of Study Treatments

Enrolling in Stage la and Stage lb of this study in parallel will be up to 6 patients each with siltuximab-relapsed or refractory IL-6-driven iMCD and TAFRO-iMCD patients, respectively, who will undergo intrapatient dose escalation of siltuximab beginning with 22 mg/kg q3w, then possibly dose escalating to 33 mg/kg q3w then 44 mg/kg q3w if clinically indicated in the absence of DLT. The justifications for escalating siltuximab doses up to 44 mg/kg q3w will be based on intrapatient dose escalation and DLT assessments as described in Section 9.1.1 below.

Upon enrollment of 6 evaluable patients in either the Stage la or the Stage lb cohort, the Data Monitoring Committee (DMC) will review the combined enrolled patients for safety, DLT, and efficacy. If at least 1 patient achieves CBR (defined as CR, PR, or stable disease [SD]) >12 weeks according to the CDCNRC (Appendix 2) without >33% of Stage 1 patients experiencing DLT, as defined below, the study will proceed to enroll Stage 2.

A DMC review will be completed after enrollment of 6 patients in Stage la and again after enrollment of 6 patients in Stage lb to determine if and when one or both iMCD cohorts may be enrolled in Stage 2.

The study will be terminated if no CBR is reported throughout Stage 1, or if >33% of patients across both Stage la and lb cohorts experience DLT at the 22 mg/kg q3w dose level.

Stage 2 of the study will expand the patient sample size by at least 10 patients to better evaluate the efficacy and safety of the proposed intrapatient siltuximab dose escalation regimen. As in Stage 1, siltuximab will be administered at 22 mg/kg q3w with the option to dose escalate to 33 mg/kg q3w ± 44 mg/kg q3w to account for potential patient variability in safety and efficacy, excluding dose levels at or above where >33% patients experienced DLT in one or both Stage 1 cohorts. (See Section 9.1.1 for details on evaluating DLTs during stage procession). The pharmacodynamics of the treatment will be investigated by laboratory testing to monitor ongoing disease status and determine potential predictor(s) of efficacy and mechanism(s) of resistance.

Stage 2 need not enroll and treat a minimum number of iMCD or TAFRO-iMCD patients, so 0 to 10 patients from each Stage 1 cohort could be enrolled and treated with higher-dose siltuximab in Stage 2, if Stage 2 procession criteria from at least one Stage 1 cohort are met.

Treatment of first and second patients at the 22 mg/kg dose level will be staggered by 24 to 72 hours to allow real-time updates regarding patient status prior to treatment of subsequent patients with a previously untested dose. If the first patient does not experience DLT during this time after the initial dose, then subsequently enrolled patients will start treatment as scheduled (see Visit Schedule).

The pharmacodynamics of the treatment will be investigated by laboratory testing to monitor ongoing disease status and determine potential predictor(s) of efficacy and mechanism(s) of resistance.

9.1.1 Intrapatient Dose Escalation and DLT Assessments

Re-emergence of CDCNRC-defined disease progression in the absence of DLT defined by Grade >3 allergic/hypersensitivity reaction or unacceptable Grade >3 treatment-related toxicity per NCI CTCAE version 5.0 will provide the opportunity for further intrapatient siltuximab dose escalation according to Table 1 :

Table 1. Intrapatient Siltuximab Dose Escalation Levels

If a patient's disease progresses without experiencing a DLT, then the investigator may have the option to escalate a patient's siltuximab dose to the next dose level and treat beyond initial signs of CDCN RC-defined disease progression. Patients must document elevated (>10 mg/L) and rising CRP and continue to meet safety inclusion criteria for this study prior to any potential intrapatient dose escalation.

Following the start of Cycle 2, if a patient is identified with CDCNRC-defined disease progression after Day 1 dosing of a cycle, a single "rescue dose" of siltuximab 11 mg/kg may be administered at the investigator's discretion in consultation with the Medical Monitor up to 7 days prior to dose escalation on Day 1 of the next treatment cycle. However, no patient may receive an excess of the next dose escalation level during a given cycle, and no patients may be treated with greater than 44 mg/kg cumulative siltuximab dose in any given 3-week period.

9.1.1.1 Stage 2 Procession

DLT assessments will be made for each Stage 1 cohort dose level at the time of Stage 2 procession. For example, if at least 1 CBR is observed in the Stage la cohort, and <33% of DLT-evaluable patients experience DLT at the 22 mg/kg q3w dose level across both Stage la and Stage lb cohorts at the time of Stage la cohort completion, then Stage 2 may proceed at least at the 22 mg/kg q3w dose level.

DLT assessments need to be independently made by dose level at the time of Stage 2 procession criteria assessment for each Stage 1 cohort.

9.1.2 Visit Schedule

Prior to study treatment on Day 1 of Cycle 1, enrolled patients will be evaluated for efficacy and safety to establish baseline measurements via assessments listed in Table 2. Siltuximab will be administered on Day 1 of each cycle, with the exception of "rescue doses" or amended dosing schedules approved by the Medical Monitor.

Patient blood samples will be collected for rich PK during Cycle 1 on Days 1, 6, and 10 at predose (hour 0), and at 2 and 4 hours after siltuximab infusion. This schedule of PK blood sample collection will be repeated for individual patients during the study at the time of intrapatient dose escalation to Dose Level 2 (33 mg/kg q3w) or Dose Level 3 (44 mg/kg q3w). Blood samples for sparse PK will be collected during Cycles >2 on Day 1 at predose (hour 0) and 2 hours after siltuximab infusion. Dose amount, administration time, and infusion duration will also be reported for each cycle during the study. On Day 1 of each cycle starting with Cycle 2, the investigator will collect patient blood samples for biochemical testing and assess disease-related clinical symptoms. Every 3 to 6 months, radiologic imaging and clinical assessment of skin manifestations (from physical examination) will be performed and reviewed locally and/or centrally to assess lymph node response. The results from biochemical testing, symptom response, and lymph node response (when available) will be combined for CBR at every cycle beginning with Cycle 2.

Safety (DLTs and AEs/SAEs) will be monitored throughout the treatment period. Both CBR criteria and safety assessments will be evaluated every cycle, normalized to baseline measurements, to determine patient eligibility for dose escalation. Patients will end study treatment upon withdrawal of consent, uncontrolled disease progression, and unacceptable toxicity (worsened ECOG PS from baseline) are observed, or at the investigator's discretion. Patient blood samples collected throughout the study will be performed in accordance with the Laboratory Manual and will be analyzed by local and/or central laboratories. At the conclusion of the study, the laboratory results will help determine potential biomarker(s) for predicting response to siltuximab. Tissue samples, if available, will be used to screen for IL-6-dependent and IL-6-independent signaling pathways to uncover novel mechanism(s) of resistance against siltuximab.

9.2 Investigational Product

Siltuximab was originally developed by Janssen Research & Development LLC. On 21 December 2018, EUSA Pharma (UK) Ltd. acquired the development rights to siltuximab (ie, the current sponsor).

9.2.1 Physical and Chemical Properties

The siltuximab mAb has an approximate molecular weight of 147,750 daltons. A lyophilized formulation contains siltuximab at pH 4.7 to 5.7 after reconstitution of the lyophile.

9.2.2 Packaging and Labeling

The investigational supplies will be uniquely packaged to assure that they are appropriately managed throughout the supply chain process. Drug labels will contain information to meet the applicable regulatory requirements required by local regulations. 9.2.3 Supplies and Storage

Siltuximab must be stored at controlled temperatures ranging from 35.6°F to 46.4°F (2°C to 8°C).

Study agent vials should be stored in a secured refrigerator at 2°C to 8°C. During extended storage, study agent vials should be stored refrigerated at 2 °C to 8°C and protected from light. Protection from light is not required during dose preparation or administration. All drug supplies will be provided by the Sponsor.

9.3 Dosing Schedule

Siltuximab will be administered at a starting dose of 22 mg/kg q3w administered over 2 hours by IV infusion. For intrapatient dose escalations, 33 mg/kg will be administered over 3 hours by IV infusion, and 44 mg/kg will be administered over 4 hours by IV infusion.

9.3.1 Dosage Forms and Strengths

Siltuximab for injection is available as:

• 100 mg of lyophilized powder in a single-dose vial

• 400 mg of lyophilized powder in a single-dose vial

9.3.2 Warnings and Precautions

Refer to siltuximab package insert for further details. Hypersensitivity reactions, including anaphylactic reaction, hypersensitivity, and drug hypersensitivity have been reported in patients treated with siltuximab.

9.3.2.1 Concurrent Active Severe Infections

Siltuximab should not be administered to patients with severe infections until the infection resolves; monitor patients closely for infections, and do not administer siltuximab until the infection resolves. 9.3.2.2 Vaccinations

Do not administer live vaccines to patients receiving siltuximab because IL-6 inhibition may interfere with the normal immune response to new antigens.

9.3.2.3 Infusion-Related Reactions and Hypersensitivity

Although rare in occurrence, siltuximab may cause infusion-related reactions and anaphylaxis. The infusion of siltuximab should be stopped if the patient develops signs of anaphylaxis and further therapy with siltuximab discontinued. If the reaction resolves, the therapy may be restarted at a lower infusion rate. Consider medication with antihistamines, acetaminophen, and corticosteroids (see also Section 9.6). Discontinue siltuximab if the patient does not tolerate the infusion following these interventions.

9.3.3 Drug Interactions

Caution should be taken when siltuximab is co-administered with CYP3A4 substrate drugs where a decrease in effectiveness would be undesirable (eg, oral contraceptives, lovastatin, and atorvastatin).

Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in patients treated with siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment with siltuximab.

Upon initiation or discontinuation of siltuximab, in patients being treated with CYP450 substrates with a narrow therapeutic index, perform therapeutic monitoring of effect (eg, warfarin) or drug concentration (eg, cyclosporine or theophylline) as needed and adjust dose. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.

9.3.4 Blinding

This is an open-label study; therefore, blinding is not applicable. 9.4 Dose Modification

Investigators, at their discretion, may elect to reduce the siltuximab dose, amend the dosing schedule, and/or add best supportive care in consultation with the Medical Monitor in patients who experience DLT, including treatment-related Grade >3 AEs or SAEs.

9.5 Treatment Accountability and Compliance

Administration of siltuximab will be supervised by study site personnel to ensure compliance.

9.6 Concomitant Medications and Treatments

Restricted prior therapies are provided in Section 8.2 and will apply throughout the study. Concomitant medication review should be conducted at screening, and all medications, vitamins, supplements, or other treatments should be recorded. Concomitant medications should be reviewed regularly with patients as part of clinic visits and at least as part of assessments prior to Day 1 for each cycle.

Patients may continue stable or decreasing dose of corticosteroids (no more than 1 mg/kg/day prednisone dose-equivalent) while on treatment. Any increase from baseline or a new course of corticosteroids is not allowed except to treat treatment-emergent reactions and comorbid conditions, which the Medical Monitor should be consulted. For any other changes in corticosteroid dosing, the Medical Monitor must be consulted.

Use of other immunosuppressive agents, biologic treatments, IL-6 pathway inhibitors, antitumor or cytotoxic treatments, and erythropoietin-stimulating agents are not permitted. All medications and other treatments taken by the patient during the study, including those treatments initiated before the start of the study, must be recorded on the eCRF.

Medications taken by or administered to the patient for the time period before screening will be recorded on the eCRF. After the baseline visit, any concomitant medication or therapy that is taken by or administered to the patient during the course of the study must be recorded on the eCRF. The entry must include the dose, regimen, route, indication, and dates of use. 10 STUDY PROCEDURES

5 Table 2 provides an overview of the timing of procedures and assessments to be performed throughout the study. Refer to Sections 11 and 12 for detailed information on each procedure and assessment required for protocol compliance.

The investigator may schedule unplanned visits in addition to those listed in Table 2 in order to perform evaluations or assessments required to protect the well-being of the patient.

Table 2. Schedule of Assessments

n Abbreviations: AE = adverse event; CBR = clinical benefit response; CT/PET = computerized tomography/positron emission tomography; CTCAE = Common Terminology Criteria for Adverse Events; CRP = C-reactive protein; d = day(s); DLT = dose-limiting toxicity; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EQ-5D-3L = EuroQoL EQ-

5 5D-3L questionnaire; EOT = end of treatment; hCG = human chorionic gonadotropin; iMCD = idiopathic multicentric

Castleman disease; IV = intravenous; MCD-SS = multicentric Castleman disease symptom scale; mos. = months; PE = physical examination; PK = pharmacokinetics; PROs = patient-reported outcomes; PS = performance status.

Informed consent: Must be obtained prior to conducting any study-specific assessments, and any time an updated, approved informed consent form is implemented at a study site.

Inclusion/exclusion review; confirmation of iMCD: Verification by the investigator or sub-investigator must be completed to confirm patient meets all inclusion criteria and no exclusion criteria; includes iMCD-related history and histologic diagnosis based on incisional/excisional lymph node biopsy performed <5 years prior to study enrollment; archival (paraffin-embedded blocks or recut slides from formalin-fixed archival specimens) or fresh lymph node biopsy collected during screening is required to be sent to central or local laboratory for independent diagnostic pathology confirmation of iMCD.

Demographics/Medical history: Patient demographics includes year of birth (age), gender, race, ethnicity, height, and childbearing status. Medical history includes all prior therapies, start/end dates and best response; history of other malignancies and any clinically significant medical/psychiatric or surgical history or current medical conditions (not related to primary iMCD diagnosis); includes onset/end dates and treatments.

Physical examination/ECOG PS: A complete physical examination (head, eyes, ears, nose and throat, heart, lungs, abdomen, skin, cervical and axillary lymph nodes, and neurological and musculoskeletal systems) will be performed at screening. Body weight (without shoes) will be recorded whenever vital signs are recorded; height (without shoes) will be recorded at screening only. Symptom-driven, limited physical examinations, and ECOG PS will be performed as clinically indicated during any study visit.

Vital signs: Includes systolic and diastolic blood pressure, heart rate, respiratory rate, and oral body temperature. All vital signs will be measured after the patient has been resting in a sitting position for at least 5 minutes. BP measurements are to be taken in the same arm for the duration of the study.

Clinical laboratory assessments: Patient blood samples collected throughout the study will be analyzed by local laboratory in accordance with the study Laboratory Manual; see also list of assessments in Section 12.5.

CRP: CRP measurements required for eligibility criterion may be performed by a local laboratory to meet screening timeline. Urinalysis: Dipstick urinalysis and microscopic examination: perform only when clinically indicated during the Treatment Period.

Clinical chemistry: Tests will be performed at screening and throughout the study to assess organ function and safety and identification of biochemical signs of response or disease progression.

Hematology: Tests will be performed at screening and throughout the study to assess safety and early identification of clinical signs of response or disease progression.

Pregnancy testing: Serum test performed at screening for all WOCBP; urine test performed thereafter. If a urine pregnancy test (hCG) is positive, it must be confirmed by a blood pregnancy test.

Lymph node sample: Tumor biopsy tissue is requested and/or collected during screening (archival and/or fresh) before the first dose of study treatment (mandatory) and optional (but strongly recommended) at time of EOT to evaluate potential for gene and protein biomarkers to understand mechanisms of resistance to study treatment (core needle biopsy may be accepted for this purpose).

PK sampling: Blood samples for rich PK sampling will be collected during Cycle 1 on Day 1 predose and 0, 2, and 4 hours post-infusion, and Days 6 and 10 after siltuximab infusion (6 samples) and blood samples for sparse PK sampling will be collected during Cycles > 2 on Day 1 predose and immediately after siltuximab infusion (2 samples), and once again at EOT visit (1 sample).

*Rich PK blood sample collection will also occur on Day 1 predose and 0, 2, and 4 hours postinfusion, and Days 6 and 10 after siltuximab infusion during any cycle for patients who have their dose escalated to Dose Level 2 (33 mg/kg q3w) or Dose Level 3 (44 mg/kg q3w).

Pharmacodynamic biomarkers: Serum samples for other biomarker analysis will be collected from all patients on Day 1, before administration of any new dose level of siltuximab including 22 mg/kg, and before administration of siltuximab on Day 1 in Cycles 2, 3, and 4 (after any new dose level of siltuximab) and EOT. See list of assessments in Section 12.5. Additional details will be provided in the Laboratory Manual. Immunogenicity analysis: Detection of antibodies against siltuximab will be conducted via immunoassay ± serum IL-6 levels on Day 1 of Cycle 1, 3, 6 and every 4 cycles thereafter, before administration of siltuximab.

Drug administration: Siltuximab will be administered at a starting dose of 22 mg/kg q3w over 2 hours by IV infusion. Safety eligibility criteria will be reassessed for patients considered for potential intrapatient dose escalation. For intrapatient dose escalations, 33 mg/kg will be administered over 3 hours by IV infusion, and 44 mg/kg will be administered over 4 hours by IV infusion. Single "rescue doses" of siltuximab (11 mg/kg) may be administered at the investigator's discretion in consultation with the Medical Monitor up to 7 days prior to dose escalation on Day 1 of the next treatment cycle.

CBR assessment: Based on CDCNRC-defined biochemical (including Hgb, CRP, albumin, eGFR [creatinine]), lymph node, and symptom response assessments (Appendix 2). CBR criteria will be evaluated each cycle, except for radiological imaging and skin manifestations assessments which will be completed approximately every 3-6 months.

Disease assessments will be performed every 6 months if a patient permanently discontinues study treatment for reasons other than tumor progression until tumor progression is documented or subsequent treatment for MCD is started.

Radiologic lymph node and skin manifestation responses: Diagnostic CT or CT-PET scan of neck/chest/abdomen/pelvis to confirm measurable lymph node disease for eligibility criteria and ongoing efficacy evaluation during screening and then every 3 to 6 months starting Cycle 5 (CT scanning every 3 months until maximum response has occurred, after which the frequency of imaging may be reduced to 6 months); assessment of measurable cutaneous lesions for ongoing efficacy evaluation at baseline during screening and then every 3 months. Disease assessments will be performed every 6 months if a patient permanently discontinues study treatment for reasons other than tumor progression until tumor progression is documented or subsequent treatment for MCD is started.

AEs per CTCAE/Concomitant medication review: Should be conducted at screening; all medications, vitamins, supplements, or other treatments should be recorded. Review concomitant medications regularly as part of assessments prior to Day 1 for each cycle; record AEs at each cycle. Safety/DLT assessments as defined in Section 12.6.4 and NCI-CTCAE v5.0.

ECGs: To be performed in triplicate. 12-lead ECGs should be performed within a 5-minute time window following 10 minutes of rest in the supine position. Clinically significant abnormalities will be reported as AEs.

EQ-5D-3L: Patient-reported evaluation based on 5 dimensions describing the patient's health state at predose in Cycle 1 (baseline) and every 3 months starting Cycle 5 (refer to Section

11.3.1 and Appendix 4).

MCD-SS: Patient-reported evaluation based on sum of the severity of 16 disease-related symptoms at predose in Cycle 1 (baseline) and every 3 months starting Cycle 5 (refer to Section 11.3.2 and Appendix 5).

Survival: Patients will be contacted every 3 months (up to 3 years) after their last treatment until the end of study for survival and other assessments.

10.1 Informed Consent

Before performing any study-related procedures, the investigator (or designee) will obtain signed informed consent from the patient. For adolescent patients in the study, they will assent to treatment with their parent or guardian's consent.

10.2 Study Procedures

Assessments and their timing are to be performed as outlined in Table 2. Section 12.5 specifies laboratory assessment samples to be obtained.

Assessments and procedures scheduled at a visit where siltuximab is administered should be performed before administration of treatment (predose) unless otherwise indicated in Table 2.

Efficacy assessments are described in Section 11 and include CDCNRC-defined CBR, ORR, TDR, DOR, PFS (disease response includes CR, PR, or SD lasting >12 weeks per CDCNRC based on evaluation of biochemical, lymph node, and symptom response); clinical response as defined by MCD-related overall symptom score; and laboratory measurement of PD markers of disease status and efficacy normalized to baseline over time.

Safety assessments are described in Section 12 and include vital signs, physical examinations, electrocardiograms (ECGs), laboratory assessments, AEs, and immunogenicity (incidence of antibodies to siltuximab).

Pharmacokinetic blood sampling is described in Section 13.

The investigator may, at his/her discretion, arrange for a patient to have an unscheduled assessment, especially in the case of AEs that require follow-up or are considered by the investigator to be possibly related to the use of siltuximab. The unscheduled visit page on the eCRF must be completed.

Study discontinuation procedures are described in Section 8.3.

Patients will be contacted for follow-up every 3 months for up to 3 years after their last dose of siltuximab for survival, CBR, AEs, and additional assessments as noted as in Table 2.

10.2.1 Screening

After the ICF is signed, a Screening number will be assigned and enrolled patients will be evaluated for efficacy and safety to establish baseline measurements via assessments listed in Table 2. If prior diagnostic material relating to the patient's Castleman disease is not available, or if histologic diagnosis was based on fine-needle aspiration cytology and/or core needle biopsy only, or if histologic diagnosis was made >5 years prior to study enrollment, then a baseline incisional/excisional lymph node biopsy must be performed to confirm histologic diagnosis of Castleman disease prior to enrollment.

10.2.2 Treatment Period

Siltuximab will be administered on Day 1 of each cycle, with the exception of "rescue doses" or amended dosing schedules approved by the Medical Monitor.

On Day 1 of each cycle starting with Cycle 2, the investigator will collect patient blood samples for biochemical testing and assess disease-related clinical symptoms. Every 3 to 6 months, radiologic imaging and assessment of skin manifestations (from physical examination) will be performed and reviewed locally and/or centrally to assess lymph node response. The results from biochemical testing, symptom response, and lymph node response (when available) will be combined for CBR assessment at every cycle beginning with Cycle 2.

Patient blood samples for PK sampling will be collected on Day 1 in Cycle 1 predose and after siltuximab infusion (0, 2, 4 hours, Day 6, and Day 10). Patient blood samples will also be collected at Cycles >2 predose (0 hours) and after siltuximab infusion (2 hours). This schedule of PK blood sample collection will be repeated (eg, back to Day 1 of the cycle) for patients at the time of intrapatient dose escalation to Dose Level 2 (33 mg/kg q3w) or Dose Level 3 (44 mg/kg q3w). Dose amount, administration time, and infusion duration will also be reported for each cycle during the study.

Safety (DLTs and AEs/SAEs) will be monitored throughout the treatment period. Both assessments for CBR and safety, normalized to baseline measurements, will be evaluated every cycle to determine patient eligibility for dose escalation.

10.2.3 End of Treatment

An EOT visit will be completed 14 days (+/-7 days) after the last administration of study treatment for a patient discontinuing treatment for any reason, or before subsequent treatment for MCD is started. If a patient is unable to return to the site for the EOT procedures, then the patient should be contacted to collect AEs that occur within 30 days after their last dose of study treatment.

10.2.4 Follow-up

Patients will be contacted every 3 months after their last study drug administration for survival status, occurrence of malignancies, and subsequent systemic treatment for MCD, including best overall response to subsequent treatment, and additional assessments (Table 2). Whenever possible, CBR assessments will be performed if a patient permanently discontinues study treatment for reasons other than disease progression until subsequent treatment for MCD is started. This includes tumor imaging and skin lesions if part of the index lesions for response assessments. 11 EFFICACY ASSESSMENTS

Table 2 provides an overview of the efficacy assessments to be performed throughout the study and their timing.

11.1 Clinical Benefit Response

CBR will be evaluated based on the combination of efficacy results from laboratory testing, radiologic disease assessment, and clinical response per symptoms scores. CBR assessments will be evaluated each cycle (q3w), except for radiological assessments which will be completed approximately every 3 months. See also Appendix 2.

11.2 Lymph Node Response Assessment

Tumor response will be evaluated every 3 to 6 months using Cheson (1999) criteria (Appendix 2) modified to include the additional assessment of measurable cutaneous lesions.

Lymph node assessment will be completed radiologica lly via diagnostic CT or CT-PET. Lymph node response may take several months in patients treated with anti-IL-6 monoclonal antibodies.

11.3 Patient-Reported Outcomes

PROs are based on the sum of the severity of MCD disease-related symptoms (graded per NCI CTCAE v5.0) during intermediate time points and at end of treatment, and compared to baseline.

11.3.1 EQ-5D-3L Health Questionnaire

The EQ-5D-3L is a patient-reported evaluation based on the patient's health will be conducted predose on Day 1 of Cycle 1 (baseline) and every 3 months starting Cycle 5.

The EQ-5D-3L (Appendix 4) questionnaire consists of 2 pages and has the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the 5 dimensions. This decision results into a 1-digit number that expresses the level selected for that dimension. The digits for the 5 dimensions can be combined into a 5-digit number that describes the patient's health state.

11.3.2 Multicentric Castleman Disease - Symptom Scale

The MCD-SS will be conducted predose on Day 1 of Cycle 1 (baseline) and every 3 months starting cycle 5.

The MCD-SS (Appendix 5) is a 16-item questionnaire consisting of 4 items in the Fatigue domain (tiredness, fatigue, lack of energy, feeling weak), 2 items in the Rash/Itching domain (sores/rash on skin, itch), 2 items in the Sweats domain (night sweats, daytime sweating), and 8 items that are not categorized to a domain (cough, shortness of breath, fever, loss of appetite, numbness or tingling, pain, swollen lymph nodes, swelling or edema). The MCD-SS was developed to assess a patient's perception of severity of MCD-related symptoms. The instrument design was based on literature reviews, concept elicitation, and cognitive debriefing interviews conducted in patients with a confirmed diagnosis of MCD, and feedback from clinical topic experts (van Rhee F el al 2015).

11.4 Other Assessments

11.4.1 Incisional/Excisional Surgical Lymph Node Biopsy

Patients who do not have recent or archival diagnostic lymph node biopsy tissue obtained by incisional/excisional surgical biopsy <5 years prior to enrollment available for central retrospective confirmation of histologic diagnosis of Castleman disease and exploratory biomarker analysis will require a baseline incisional/excisional surgical lymph node biopsy. (Refer to Section 8.1 [inclusion criterion #2]). In addition, an optional repeat lymph node biopsy (surgical or core needle biopsy is acceptable) is strongly recommended as part of the EOT assessments to screen for mechanism(s) of resistance.

12 SAFETY ASSESSMENTS

Safety assessments (vital signs, physical examinations, ECGs, AEs, SAEs, clinical laboratory results [routine hematology and biochemistry]) are to be performed at protocol-specified visits, as described in Table 2. 12.1 Medical History

Investigators should document the occurrence, signs, and symptoms of the patient's preexisting conditions, including all prior significant illnesses and surgeries, during screening.

Additional pre-existing conditions present at the time informed consent is given and up to the study entry are to be regarded as concomitant. Medical history will include patients that "initially responded then progressed" versus "progressed without any response" after prior standard-dose siltuximab therapy, including all prior therapies, start/end dates, and best response; history of other malignancies, and any clinically significant medical/psychiatric or surgical history or current medical conditions (not related to primary iMCD diagnosis) including onset/end dates and treatments.

Illnesses first occurring or detected during the study and/or worsening of a concomitant illness during the study are to be documented as AEs on the eCRF in accordance with Section 12.6. All changes not present at baseline or described in the past medical history and identified as clinically noteworthy must be recorded as AEs.

Additionally, demographic data will be collected for all patients and include year of birth (age) at study entry, gender, race, ethnicity, weight, and height, according to applicable regulations.

12.2 Vital Signs

Vital signs include systolic and diastolic blood pressure (BP), heart rate, respiratory rate, and oral body temperature. All vital signs will be measured after the patient has been resting in a sitting position for at least 5 minutes. BP measurements are to be taken in the same arm for the duration of the study.

Vital sign measurements will be repeated if clinically significant or machine/equipment errors occur. Out-of-range BP or heart rate measurements will be repeated at the investigator's discretion. Any confirmed clinically significant vital sign measurements must be recorded as AEs. 12.3 Physical Examination

Physical examination will be performed by a physician or licensed practitioner and include head, eyes, ears, nose and throat, heart, lungs, abdomen, skin, cervical and axillary lymph nodes, and neurological and musculoskeletal systems. Body weight (without shoes) will be recorded whenever vital signs are recorded; height (without shoes) will be recorded at screening only.

A limited physical examination to follow up on any change in medical condition will be performed at subsequent visits. Symptom-driven, limited physical examinations, and ECOG PS will be performed as clinically indicated during any study visit.

Physical Examination for iMCD

Targeted physical examination to assess clinical signs of iMCD as part of eligibility criteria are identified in Table 2.

12.4 Electrocardiograms

A 12-lead resting ECG will be obtained at screening and at subsequent cycles shown in Table 2. At screening, the investigator will examine the ECG traces for signs of cardiac disease that could exclude the patient from the study. An assessment of normal or abnormal will be recorded; if the ECG is considered abnormal, the abnormality will be documented on the eCRF. ECGs will be repeated if clinically significant abnormalities are observed or artifacts are present.

All ECGs are to be performed in triplicate. Clinically significant abnormalities will be reported as AEs.

12.5 Laboratory Assessments

Laboratory assessment samples will be obtained at designated visits as shown in Table 2. Normal ranges for the study laboratory parameters must be supplied to the Sponsor before the study starts.

A full list of clinical laboratory tests to be performed is provided in accordance with the study Laboratory Manual.

The investigator must review the laboratory report, document this review, and record any clinically relevant changes occurring during the study in the AE section of the eCRF. The laboratory reports must be filed with the source documents. Clinically significant (CS) abnormal laboratory findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

• In the event of unexplained abnormal CS laboratory test results, the tests should be repeated immediately and followed up until they have returned to the normal range and/or an adequate explanation of the abnormality is found.

• If these laboratory abnormalities do not return to normal/baseline within a period of time judged reasonable by the investigator, then the etiology should be identified and the Sponsor notified.

• If laboratory abnormalities from non-protocol-specified laboratory assessments performed at the local laboratory require a change in participant management or are considered CS by the investigator (eg, SAE or AE or dose-modification), then the results must be recorded as a comment on the eCRF.

Additional blood or urine samples may be taken at the discretion of the investigator if the results of any test fall outside the reference ranges, or clinical symptoms necessitate additional testing to monitor participant safety.

Where the clinical significance of abnormal laboratory test results is considered uncertain, screening laboratory tests may be repeated before randomization to confirm eligibility. Local laboratory results are only required in the event that the central laboratory results are not available in time for either study treatment administration and/or response evaluation. If a local sample is required, it is important that the sample for central analysis is obtained at the same time. Additionally, if the local laboratory results are used to make either a study treatment decision or response evaluation, the results must be captured in source documentation and entered as a comment into the eCRF.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in Sections 8.1 and 8,2, respectively.

Additional tests may be performed at any time during the study as deemed necessary by the investigator or required by local regulations.

Laboratory Parameters Assessments

Hematology CBC with WBC differential (hemoglobin, RBC, hematocrit, WBC, platelet count, ANC, absolute lymphocyte count, absolute monocyte count, absolute basophil count, absolute eosinophil count)

Clinical chemistry AST, ALT, T. bilirubin, ALK, albumin, GGT, BMP (sodium, potassium, chloride, glucose, creatinine/eGFR)

Serology HIV screen = per local guidelines; Hepatitis B screen = HBsAg, HBsAb, HBcAb; Hepatitis C screen = HCV Ab

Lipids Cholesterol, triglycerides

Markers for response CRP

Fibrinogen, hemoglobin, ESR, ferritin, iron/TIBC, IgG/IgA/IgM, sIL2R,VEGF, IgE, LDH, B2M

Pregnancy test All WOCBP— blood pregnancy test at screening. Urine pregnancy tests at specified subsequent visits. If a urine hCG pregnancy test is positive, it must be confirmed by a blood pregnancy test.

Urinalysis Dipstick UA/urine protein

Pharmacodynamic IL-ip, IL-4, IL-5, IL-8, IL-10, IL-12, IL-13, TNF-o, GM- biomarkers CSF, IFN-y, hepcidin

12.5.1 Immunogenicity

Detection of antibodies against siltuximab will be conducted via immunoassay on Day 1 of Cycles 1, 3, 6 and every 4 cycles thereafter, before administration of siltuximab.

All samples collected for detection of antibodies to siltuximab will also be evaluated for siltuximab serum concentration to interpret antibody response data. Serum samples will be screened for antibodies binding to siltuximab, and the serum titer of confirmed positive samples will be reported. Other immunogenicity analyses may be performed to further characterize the immune responses.

12.6 Adverse Events

An AE is any symptom, physical sign, syndrome, or disease that either emerges during the study or, if present at screening, worsens during the study, regardless of the suspected cause of the event. All medical and psychiatric conditions (except those related to the indication under study) present at screening will be documented in the medical history eCRF. Changes in these conditions and new symptoms, physical signs, syndromes, or diseases should be noted on the AE eCRF during the rest of the study. Newly occurring CS laboratory abnormalities should also be recorded as AEs.

Additionally, anticipated AEs for this study population listed below in Table 3 must be reported by investigators to the Sponsor but will not be expedited on an individual basis. Instead, these AEs will be reviewed in aggregate on a regular basis by a DMC which will be defined in the DMC charter. This aggregate review may result in an expedited safety report.

The most frequent adverse drug reactions (>20% of patients) during treatment with siltuximab in the MCD clinical trials were upper respiratory tract infection, pruritus, rash, arthralgia, and diarrhea (see Siltuximab IB). The most serious ADR associated with the use of siltuximab was anaphylactic reaction.

Table 3. List of Anticipated Adverse Reactions for this Study

Rash, pruritus, upper respiratory tract Most common adverse reactions (>10% of infection, increased weight, hyperuricemia, patients) hypertriglyceridemia, localized edema, headache, oropharyngeal pain, thrombocytopenia, eczema, Nasopharyngitis, urinary tract infection, Other important, common adverse neutropenia, dizziness, hypertension, reactions reported in MOD clinical nausea, abdominal pain, vomiting, diarrhea, gastroesophageal reflux disease, mouth ulceration, pain in extremity, renal impairment

Abbreviation: MCD=multicentric Castleman disease

Source: Siltuximab IB; SYLVANT® (siltuximab) package insert

Investigators will be instructed to report AEs at each study visit. All AEs are to be followed up until resolution or a stable clinical endpoint is reached.

Each AE is to be documented on the eCRF. As a minimum requirement, the initial notification must provide the following information, and reporting must not be delayed if all of the required information is not available; however, all of the following information must be provided within 2 calendar days:

• Patient study number

• Patient sex

• Date of birth or age

• Name of treating physician and hospital address

• Details of SAE including onset date and time

• Concomitant medications

• Therapy start and stop dates, dose given

• Product batch number

• Causality assessment (see Table 2)

Furthermore, each AE is to be classified as being serious or nonserious. Changes in AEs and resolution dates are to be documented on the eCRF.

For the purposes of this study, the period of observation for collection of AEs extends from the time the patient gives informed consent until the follow-up visit. Follow-up of the AE, even after the date of therapy discontinuation, is required if the AE persists until the event resolves or stabilizes at a level acceptable to the investigator.

When changes in the intensity of an AE occur more frequently than once a day, the maximum intensity for the event should be noted. If the intensity category changes over a number of days, then those changes should be recorded separately (with distinct onset dates). The severity of AEs will be graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events, version 5.0 (NCI-CTCAE v5.0) (Grades 1 through 5).

The relationship of AEs to study drug will be defined as described in Table 4:

Table 4. Classification of Adverse Events by Relationship to Study Drug

Abbreviation: AE=adverse event.

12.6.1 Serious Adverse Events

An SAE is any untoward medical occurrence, in the view of either the investigator or Sponsor, that:

• results in death,

• is life-threatening,

• results in inpatient hospitalization or prolongation of existing hospitalization,

• results in persistent or significant disability/incapacity, and/or

• is a congenital anomaly/birth defect.

Other important medical events that may not be immediately life-threatening or result in death or hospitalization, based upon appropriate medical judgment, are considered SAEs if they are thought to jeopardize the patient and/or require medical or surgical intervention to prevent one of the outcomes defining an SAE. SAEs are critically important for the identification of significant safety problems; therefore, it is important to take into account both the investigator's and the Sponsor's assessment. If either the Sponsor or the investigator believes that an event is serious, the event must be considered serious and evaluated by the Sponsor for expedited reporting. 12.6.2 Serious Adverse Event Reporting

An SAE occurring from the time informed consent is obtained, during the study, or within 4 weeks (±7 days) of stopping the treatment must be reported to the EUSA Pharma Safety group and will be communicated to the Sponsor. Any such SAE due to any cause, whether or not related to the study drug, must be reported within 24 hours of occurrence or when the investigator becomes aware of the event.

The event must also be recorded on the standard AE eCRF. Preliminary reports of SAEs must be followed up by detailed follow-up reports, which will be sent by the treating physician to EUSA Pharma on the SAE form within 24 hours of the initial report. EUSA Pharma may request, and the investigator will provide, further information to allow the assessment of the SAE. Follow-up reports will include clear and anonymized photocopies of hospital case reports, consultant reports, autopsy reports, and other documents when requested and applicable. SAE reports must be made whether or not the investigator considers the event to be related to the investigational drug.

Appropriate remedial measures should be taken to treat the SAE, and the response should be recorded. Clinical, laboratory, and diagnostic measures should be employed as needed in order to determine the etiology of the problem. The investigator must report all additional followup evaluations to EUSA Pharma Safety group within 24 hours of becoming aware of the additional information. All SAEs will be followed up until the investigator and Sponsor agree the event is satisfactorily resolved.

Any SAE that is not resolved by the end of the study or upon discontinuation of the patient's participation in the study is to be followed up until it either resolves, stabilizes, returns to baseline values (if a baseline value is available), or is shown to not be attributable to the study drug or procedures.

The following outcome categories will be used in the follow-up reports for all AEs:

• Recovered without sequelae: The patient has fully recovered from the event or the condition has returned to the level observed at baseline.

• Recovering : The event is improving but the patient is still not fully recovered. • Not recovered: The event is ongoing at the time of reporting and the patient has still not recovered.

• Recovered with sequelae: As a result of the AE, the patient suffered persistent and significant disability/incapacity (eg, became blind, deaf, or paralyzed).

• Fatal: The patient died due to the event. If the patient died due to other circumstances than the event, the outcome should be stated otherwise (eg, not recovered or recovering).

• Unknown: If outcome is not known or not reported.

12.6.3 Suspected Unexpected Serious Adverse Reactions

AEs that meet all of the following criteria will be classified as SUSARs and reported to the appropriate regulatory authorities in accordance with applicable regulatory requirements for expedited reporting:

• serious

• unexpected (ie, the event is not consistent with the safety information in the IB)

• there is at least a reasonable possibility that there is a causal relationship between the event and the study treatment

The investigator will assess whether an event is causally related to study treatment. The Sponsor will consider the investigator's assessment and determine whether the event meets the criteria for being reportable as a 7-day or 15-day safety report. SUSARs that are fatal or life-threatening must be reported to the regulatory authorities and the lEC/IRBs (where required) within 7 days after the Sponsor has first knowledge of them, with a follow-up report submitted within a further 8 calendar days. Other SUSARs must be reported to the relevant regulatory authorities and the lEC/IRBs within 15 calendar days after the Sponsor first has knowledge of them.

The Sponsor or designee is responsible for reporting SUSARs and any other events required to be reported in an expedited manner to the regulatory authorities and for informing investigators of reportable events, in compliance with applicable regulatory requirements within specific timeframes. Investigators will notify the relevant lEC/IRBs of reportable events within the applicable timeframes and confirm notification. 12.6.4 Definition of Dose-Limiting Toxicity

DLTs as defined by treatment-related toxicity Grade >3, allergic/hypersensitivity reaction Grade >2; AEs/SAEs as part of CBR assessment: >1 grade decrease in fatigue, >1 grade decrease in anorexia, >2°C decrease in fever or return to 37°C, or improvement in night sweats per CTCAE version 5.0; DLTs, AEs, and SAEs will be evaluated as part of the intrapatient dose escalation assessments described in Section 9.1.1.

12.6.5 Pregnancy

WOCBP will have pregnancy testing performed at screening. All WOCBP must follow contraception guidance and will be strongly advised that they should not become pregnant while on study treatment and for 3 months after the last dose. WOCBP will be advised that they must report immediately to the study site for pregnancy testing and appropriate management in the event they become pregnant.

If a patient is known to be pregnant at the time of study enrollment, a pregnancy report must be submitted to the Sponsor within 24 hours of enrollment with details of the planned treatment regimen. A second pregnancy form must be submitted once treatment commences.

Any reports of pregnancy that occur following administration of study drug will be reported until the patient completes or withdraws from the study. Pregnancy will be reported immediately by faxing/emailing a completed pregnancy report to the Sponsor within 24 hours of knowledge of the event. The investigator will follow up with the patient until completion of the pregnancy and must assess the outcome in the shortest possible time but not more than 30 days after completion of the pregnancy. The investigator should notify the Sponsor of the pregnancy outcome by submitting a follow-up pregnancy report. If the outcome of the pregnancy involved spontaneous or therapeutic abortion (any congenital anomaly detected in an aborted fetus is to be documented), stillbirth, neonatal death, or congenital anomaly, the investigator will report the event by faxing/emailing a completed pregnancy report form to the Sponsor within 24 hours of knowledge of the event.

If the investigator becomes aware of a pregnancy occurring in the partner of a patient participating in the study, the pregnancy should be reported to the Sponsor within 24 hours of knowledge of the event. Information regarding the pregnancy must only be submitted after obtaining written consent from the pregnant partner. The investigator will arrange counseling for the pregnant partner by a specialist to discuss the risks of continuing with the pregnancy and the possible effects on the fetus.

Upon discontinuation from the study, only those procedures that would not expose the patient to undue risk will be performed. The investigator should also be notified of pregnancy occurring during the study but confirmed after completion of the study. In the event that a patient is subsequently found to be pregnant after inclusion in the study, any pregnancy will be followed to term, and the status of mother and child will be reported to the Sponsor after delivery.

12.6.6 Overdose

No confirmed case of overdose has been reported. Any cases of overdose should be reported on the SAE form following the SAE reporting process described above.

13 PHARMACOKINETICS

13.1 Pharmacokinetic Sampling

13.1.1 Blood Samples

Patient blood samples will be collected for rich PK during Cycle 1 on Days 1, 6, and 10 at predose (hour 0), and at 2 and 4 hours after siltuximab infusion. This schedule of PK blood sample collection will be repeated for individual patients during the study at the time of intra patient dose escalation to Dose Level 2 (33 mg/kg q3w) or Dose Level 3 (44 mg/kg q3w). Blood samples for sparse PK will be collected during Cycles >2 on Day 1 at predose (hour 0) and 2 hours after siltuximab infusion.

Dose amount, administration time, and infusion duration time will be also reported for each cycle during the study as indicated in Table 2. The actual date and time of each blood sample collection will be recorded. Patient blood samples collected throughout the study will be analyzed by central laboratories. The timing of PK samples may be altered, and PK samples may be obtained at additional time points to ensure thorough PK monitoring.

Details of PK blood sample collection, processing, storage, and shipping procedures are provided in a separate Laboratory Manual. 13.2 Pharmacokinetic Analytical Methodology

The concentration of siltuximab will be determined from the plasma and using a validated analytical method. Details of the method validation and sample analysis will be included with the final clinical study report.

14 OTHER ASSESSMENTS

14.1 Pharmacodynamics

The PD of the treatment will be investigated by laboratory testing to monitor ongoing disease status and determine potential predictor(s) of efficacy and mechanism(s) of resistance. Serum samples for other biomarker analysis will be collected from all patients on Day 1, before administration of any new dose level of siltuximab, including 22 mg/kg, and before administration of siltuximab on Day 1 in Cycles 2, 3, and 4 (after any new dose level of siltuximab) and EOT.

14.2 Pharmacogenomics

Not applicable.

14.3 Biomarkers

Participation in the exploratory biomarker research component of the study is mandatory. Biological samples (eg, plasma, serum) will be collected and analyzed for exploratory biomarkers to assess correlations with disease activity, effects of siltuximab, and clinical outcomes.

The results of this exploratory biomarker research will be reported separately and may or may not form part of the clinical study report.

The results of this exploratory biomarker research may be pooled with biomarker data from other studies with siltuximab to generate hypotheses to be tested in future studies. 15 STATISTICAL ANALYSIS

A statistical analysis plan (SAP) will be prepared after the protocol is approved. This document will provide further details regarding the definition of analysis variables and analysis methodology to address all study objectives. The SAP will document all changes in statistical analysis methods from the protocol.

The statistical evaluation will be performed using SAS® software version 9.4 or higher (SAS Institute, Cary, NC). All data will be listed, and summary tables will be provided.

Descriptive summaries of data will be presented (n, means, SE, median, QI and Q3, quartiles, minimum and maximum) for continuous parameters and number, and percentages for categorical data, at the conclusion of Stage 1 and at the approved data cutoff date.

15.1 Determination of Sample Size

This study follows a modified Simon's optimal two-stage design. Based on 80% power with a one-sided type 1 error rate (alpha) of 10%, assuming a 2% CBR rate null hypothesis with target CBR rate of 25%, the estimated sample size is 22 patients, with 6 patients each in Stage la and Stage lb and 10 patients in Stage 2.

If at least 1 of 6 patients achieve CBR in either or both first-stage cohorts (Stages la or lb), and <33% of all patients (at least 6, and up to 12 patients) across Stages la and lb experience DLT at 22 mg/kg, then the study will continue to the second-stage cohort (Stage 2) at a starting dose of 22 mg/kg.

15.2 Analysis Populations

The study will enroll patients whose iMCD either initially responded then progressed, or patients whose iMCD progressed without any response, after standard-dose siltuximab therapy.

As-Treated Population: The As-Treated population will consist of patients who have been previously treated with siltuximab 11 mg/kg q3w and received at least 1 siltuximab dose in this study. The same As-Treated population will be used for all summaries of demographic, baseline, safety, and efficacy, plus immunogenicity data. Pharmacokinetic Population: The PK population will comprise all patients in the As-Treated population who have at least 1 PK parameter available. The PK population will be used for summary of plasma concentrations and PK parameters.

15.3 Efficacy Analysis

15.3.1 Analysis of Primary Efficacy Endpoint

The primary efficacy endpoint is CBR defined as CR, PR, or SD lasting > 12 weeks per CDCNRC based on evaluation of biochemical, lymph node, and symptom response (see Appendix.2). The proportion of patients with CBR and the corresponding 95% exact (Clopper- Pearson) confidence interval will be reported.

15.3.2 Analysis of Secondary Efficacy Endpoints

The secondary efficacy endpoints include:

• ORR: defined as the proportion of patients with sum of PRs or CRs per CDCNRC

• TDR: defined as time from Cycle 1 Day 1 (C1D1) to CR or PR per CDCNRC

• DOR: defined as time from documentation of disease response (CR or PR per CDCNRC) to disease progression

• PFS: defined as the time from C1D1 until disease progression per CDCNRC or death, whichever occurs first

• OS: defined as the time from C1D1 to death from any cause

• Laboratory evaluation of biomarkers for disease status and efficacy over time

• PROs/QoL assessments

- EuroQol (EQ)-5D-3L

- MCD-symptom scale (MCD-SS)

Investigators will assess disease status as outlined in Table 2. CBR and ORR will be summarized in frequency and percentage. Time-to-event parameters (TDR, PFS, and OS) will be summarized by Kaplan-Meier (KM) estimates and will be presented by KM figures. DOR will be summarized descriptively based on objective disease response assessments. Descriptive summaries of the actual values and changes from baseline will be provided for the overall symptom score, efficacy biomarkers, and PRO/QoL assessments. The analyses of efficacy will be presented by combining all patients in both stages of the study. The results may also be reported separately for all siltuximab-relapsed or refractory (R/R) iMCD patients and all siltuximab-R/R TAFRO-iMCD patients across both stages.

15.3.3 Analysis of Exploratory Endpoints

Exploratory endpoints include:

• Laboratory parameters and measures of tumor burden at baseline and at subsequent cycles to monitor ongoing disease status and determine potential biomarker(s) predictive of treatment response.

• Exploratory screening of IL-6-dependent and IL-6-independent biomarkers in available tissue samples of responders and non-responders to uncover potential mechanism(s) of resistance to treatment.

The exploratory endpoints will be summarized descriptively by combining all patients across both stages of the study.

15.4 Safety Analysis

Investigators will monitor and record AEs at each patient visit. Safety analyses will include type, incidence, severity, seriousness, and relationship to study drug for reported AEs, including laboratory abnormalities, SAEs, SUSARs, DLTs, and treatment-related AEs and SAEs which will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 21.0, or current version at time of processing, and summarized by system organ class and preferred term for each siltuximab dose level and overall. Summary tables will present the number and percentage of patients and number of events. In addition, separate summaries will be provided for AEs by maximum severity and maximum relationship to study drug. SAEs and all AEs associated with permanent treatment discontinuation will be summarized and listed separately.

All AEs will be listed by patient, along with information regarding onset, duration, relationship and severity to study drug, action taken with study drug, treatment of event, and outcome. The incidence of TEAEs (events with onset dates on or after the start of the study drug) will be included in incidence tables. Events with missing onset dates will be included as treatment- emergent. If a patient experiences more than 1 occurrence of the same AE, then the occurrence with the greatest severity and the closest association with the study drug will be used in the summary tables.

Clinical laboratory data, vital signs, and ECGs will be summarized at each protocol-scheduled time point considering actual values and changes from baseline by combining all patients in both stages of the study. The summaries of AEs, clinical laboratory, vital signs, and ECGs may also be reported separately for all siltuximab-R/R iMCD patients and all siltuximab-R/R TAFRO- iMCD patients across both stages.

The number (percentage) of patients who develop antibodies against siltuximab (immunogenicity) will also be provided.

Concomitant medications will be summarized by siltuximab dose level and overall.

Demographics and prior medications of each patient will be summarized.

15.5 Pharmacokinetic Analysis

Blood sample collection for PK analysis will be performed at scheduled time points as outlined in Table 2. Siltuximab will be administered on Day 1 of each cycle, with the exception of "rescue doses" or amended dosing schedules approved by the Medical Monitor.

Blood samples for rich PK sampling will be collected during Cycle 1 on Days 1, 6, and 10 at hour 0 (predose), and at 2 and 4 hours after siltuximab infusion. Blood samples for sparse PK will be collected during Cycles >2 on Day 1 at predose (hour 0) and 2 hours after siltuximab infusion. Note: Rich PK blood sample collection will also occur on Days 1, 6, and 10 at hour 0 (predose) and hours 0, 2, and 4 after siltuximab infusion during any cycle for patients with intra patient dose escalation to Dose Level 2 (33 mg/kg q3w) or Dose Level 3 (44 mg/kg q3w).

Dose amount, administration time, and infusion duration will also be reported for each cycle during the study.

PK parameters will be derived using a non-linear mixed-effects modeling approach with NONMEM. A complete description of the population PK approach will be presented in a separate PK Modeling Analysis Plan. From the developed population PK model, PK parameters such as volume of distribution (Vd) and clearance (CL) will be estimated. Additional PK parameters (eg, AUCss, Cmin, Cmax, Ctrough, Tmax, TI/2, Keip) will be derived from the individual Bayes estimates from the population PK model.

PK concentrations and PK parameters will be summarized descriptively by combining all patients across both stages of the study. These summaries may also be reported separately for all R/R TAFRO-iMCD patients across both stages of the study.

In addition, for PK parameters, the geometric mean and the coefficient of variation will also be provided.

15.6 Other Analyses

Any other analyses will be fully described in the SAP.

15.7 Interim Analysis

An informal interim analysis is planned after completion of Stage la and/or Stage lb to determine if the study may continue to Stage 2.

15.8 Data Monitoring Committee

A DMC will monitor the safety and efficacy of the patients on a periodic basis and determine whether the trial should be terminated based on ongoing reviews of safety data. The DMC will also evaluate efficacy data after completion of Stage la and Stage lb and make a recommendation about whether or not enrollment of each iMCD subgroup may proceed to Stage 2 based on the criteria described in Section 9.1. The DMC membership and governance are outlined in a separate charter.

16 STUDY MANAGEMENT

16.1 Approval and Consent

16.1.1 Regulatory Guidelines This study will be conducted in accordance with the accepted version of the Declaration of Helsinki and/or all relevant regulations, as set forth in Parts 50, 56, 312, Subpart D, of Title 21 of the US Code of Federal Regulations (CFR), in compliance with International Council for Harmonisation (ICH) and good clinical practice (GCP) guidelines, and according to the appropriate regulatory requirements in the countries where the study is conducted.

16.1.2 Institutional Review Board/Independent Ethics Committee

Conduct of the study must be approved by an appropriately constituted independent ethics committee (IEC)/institutiona I review board (IRB). Approval is required for the study protocol, protocol amendments (if applicable), IB, ICFs, recruitment material, and patient information sheets and other patient-facing material. IEC/IRB approval of the protocol, ICFs and other study- related materials, as relevant, must be obtained prior to the authorization of drug shipment to a study site.

16.1.3 Informed Consent

For each patient enrolled in the study, signed informed consent will be obtained before any protocol-related activities are performed. For patients who are minors, informed consent will be agreed to and signed by a parent or guardian. As part of this procedure, the principal investigator (PI) or designee must explain orally and in writing the nature of the study, its purpose, procedures, expected duration, alternative therapy available, and the benefits and risks involved in study participation. A copy of the signed ICF should be provided to the patient and the original filed in the patient's medical records/study documents. The patient should be informed that he/she may withdraw from the study at any time, and the patient will receive all information that is required by local regulations and guidelines for ICH. The PI will provide the Sponsor or its representative with a copy of the lEC/IRB-approved ICF before the start of the study.

In the event a patient withdraws consent for study participation, stored biomarker and research samples will continue to be used for research and analysis as allowed per local and federal regulations. If a patient would like to withdraw consent for these samples to be used to support this research, the patient should request in writing for their samples to be withdrawn and upon receiving this request, the study team will ensure destruction of remaining samples. However, if the patient withdraws consent and the samples have already been tested, the results will still remain as part of the overall research data. 16.2 Data Handling

Any data to be recorded directly on the eCRFs (to be considered as source data) will be identified at the start of the study. Data reported on the eCRF that are derived from source documents should be consistent with the source documents, or the discrepancies must be explained. See also Section 16.3.

Clinical data will be entered by site personnel on eCRFs for transmission to the Sponsor. Data on eCRFs transmitted via the web-based data system must correspond to and be supported by source documentation maintained at the study site, unless the study site makes direct data entry to the databases for which no other original or source documentation is maintained. In such cases, the study site should document which eCRFs are subject to direct data entry and should have in place procedures to obtain and retain copies of the information submitted by direct data entry.

All study forms and records transmitted to the Sponsor must only include coded identifiers such that directly identifying personal patient information is not transmitted. The primary method of data transmittal is via the secure, internet-based electronic data capture (EDC) system maintained by Syneos Health. Access to the EDC system is available to only authorized users via the study's internet website, where a user unique assigned username and password are required for access.

Any changes made to data after collection will be made through the use of EDC system. eCRFs will be considered complete when all missing and/or incorrect data have been resolved.

16.3 Source Documents

Source documents are considered to be all information in original records and certified copies of original records of clinical findings, observations, data, or other activities in a clinical study necessary for the reconstruction and evaluation of the study. The investigator will provide direct access to source documents and/or source data in the facilitation of trial-related monitoring, audits, review by lECs/IRBs, and regulatory inspections.

The investigator/institution should maintain adequate and accurate source documents and trial records that include all pertinent observations on each of the site's trial patients. Source data should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data should be traceable, not obscure the original entry, and be explained if necessary.

16.4 Monitoring

The study will be monitored according to the Sponsor's Clinical Monitoring Plan to ensure that it is conducted and documented properly according to the protocol, GCP, and all applicable regulatory requirements.

Monitoring visits, on-site and/or remote (telephone), as per the Clinical Monitoring Plan, and email/telephone contacts will be made at appropriate times during the study. The PI will ensure he/she and adequate site personnel are available throughout the study to collaborate with clinical monitors. Clinical monitors must have direct access to source documentation in order to check the completeness, clarity, and consistency of the data recorded on the eCRFs for each patient.

The investigator will make available to the clinical monitor all source documents and medical records necessary to review protocol adherence and eCRFs. In addition, the investigator will work closely with the clinical monitor and, as needed, provide them appropriate evidence that the study is being conducted in accordance with the protocol, applicable regulations, and GCP guidelines.

16.5 Quality Control and Quality Assurance

The Sponsor or its designee will perform quality assurance and quality control activities during this study; however, responsibility for the accuracy, completeness, security, and reliability of the study data presented to the Sponsor lies with the investigator generating the data.

The Sponsor may arrange audits as part of the implementation of quality assurance to ensure that the study is being conducted in compliance with the protocol, standard operating procedures, GCP, and all applicable regulatory requirements. Audits will be independent of and separate from the routine monitoring and quality control functions.

Quality assurance procedures will be performed at study sites and during data management to assure that safety and efficacy data are adequate and well documented. 16.6 Protocol Amendment(s) and Protocol Deviation(s)

16.6.1 Protocol Amendment(s)

Amendments to the protocol that entail corrections of typographical errors, clarifications of confusing wording, changes in study personnel, and minor modifications that have no effect on the safety of patients or the conduct of the study will be classified as administrative amendments and will be submitted to the IEC/IRB for informational purposes only. The Investigator will ensure that IEC/IRB acknowledgement is received and filed and available for Sponsor review.

Amendments that are classified as substantial amendments must be submitted to the appropriate regulatory authorities and lECs/IRBs for approval, and will not be implemented at sites until such approvals are received.

16.6.2 Protocol Deviation(s)

If a protocol deviation is identified or recorded at a study site, the Sponsor should be informed as outlined in the Clinical Monitoring Plan or Protocol Deviation Plan, as applicable. Protocol deviations and/or violations and the reasons they occurred will be included in the clinical study report. Pls are responsible for accurate and timely reporting of protocol deviations to their IRB/IEC in accordance with applicable regulatory guidelines.

The Sponsor will not grant protocol waivers as part of the conduct of this study.

16.7 Ethical Considerations

This study will be conducted in accordance with this protocol, the accepted version of the Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, Subpart D, of Title 21 of the CFR; and in compliance with GCP guidelines. lECs/IRBs will review and approve this protocol and the ICFs. All patients are required to provide voluntary written informed consent before participation in the study. REFERENCES Brighton TA, Khot A, Harrison ST, et al. Randomized, double-blind, placebo-controlled, multicenter study of siltuximab in high-risk smoldering multiple myeloma. Clin Cancer Res; 25(13) July 1, 2019. FDA. Center for Drug Evaluation and Research. Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Vo I u ntee rs . http://www.fda.gov/cder/quidance/index.htm Cheson B, Fisher R, Barrington S, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma : The Lugano Classification.

J Clin Oncol 2014;32:3059-3067. Cheson BD, Horning SJ, Coiffier B, et al. NCI Sponsored International Working Group. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. J Clin Oncol. 1999; 17(4): 1244-1253. Fajgenbaum DC, Uldrick TS, Bagg A, et al. International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood. 2017 Mar 23; 129(12) : 1646-1657. https://www.ncbi.nSm.nih.qov/pubmed/28087540 Garbers C, Heink S, Korn T, Rose-John S. Interleukin-6: designing specific therapeutics for a complex cytokine. Nat Rev Drug Discov. 2018 Jun; 17(6) :395-412. Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J 1990. 265(3):621-636. Gritti G, Raimondi F, Ripamonti D, et al. Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support. medRxiv 2020. Janssen, MF, Bonsel, GJ, Luo, N. Is EQ-5D-5L Better Than EQ-5D-3L? A Head-to-Head Comparison of Descriptive Systems and Value Sets from Seven Countries. PharmacoEconomics 36, 675-697 (2018). https://doi.org/10.1007/s40273-018-Q623-8.Kurzrock R, Voorhees PM, Casper C, et al. A phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease. Clin Cancer Res. 2013 Jul l; 19(13):3659-70. https://www.ncbi.nim.nih.gov/pubmed/23659971 Mayer CL, Xie L, Bandekar R, et al. Dose selection of siltuximab for multicentric Castleman's disease. Cancer Chemother Pharmacol. 2015 May;75(5): 1037-45. Morra DE, Pierson SK, Shilling D, et al. Predictors of response to anti-IL-6 monoclonal antibody therapy (siltuximab) in idiopathic multicentric Castleman disease: secondary analyses of phase II clinical trial data. Br J Haematol. 2019 Jan; 184(2):232-241. National Comprehensive Cancer Network, NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. Version 1.2020. Published January 22, 2020. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Invest. 113: 1271- 1276 (2004). Nikanjam M, Yang J, Capparelli EV. Population pharmacokinetics of siltuximab: impact of disease state. Cancer Chemother Pharmacol. 84(5):993-1001 (2019). Protocol CNT0328MCD2001; A randomized, double-blind, placebo-controlled Phase 2 study to assess the efficacy and safety of CNTO 328 (anti-IL-6 monoclonal antibody) plus best supportive care compared with best supportive care in subjects with multicentric Castleman's disease. Addendum to 48-week Clinical Study Report dated 20 June 2013 - Follow-up analyses until end-of-study. Janssen Research 8L Development. Puchalski T, Prabhakar U, Jiao Q, Berns B, Davis HM. Pharmacokinetic and pharmacodynamic modeling of an antiinterleukin-6 chimeric monoclonal antibody (siltuximab) in patients with metastatic renal cell carcinoma. Clin Cancer Res. 2010. 16(5): 1652-1661. Orlowski RZ, Gercheva L, Williams C., et al. A phase II, randomized, double-blind, placebo- controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. Am J Hematol. 2015 January 90(1): 42-49. Shah JJ, Feng L, Thomas SK, et al. Siltuximab (CNTO 328) with lenalidomide, bortezomib and dexamethasone in newly diagnosed, previously untreated multiple myeloma : an open- label phase I trial. Blood Cancer Journal (2016) 6, e396. Siltuximab Investigator Brochure. Edition 13, June 2020. Sylvant (siltuximab) package insert. Tonialini L, Bonfichi M, Ferrero S, et al. Siltuximab in relapsed/ refractory multicentric Castleman disease: Experience of the Italian NPP program. Hematological Oncology. 2018;36:689-692. US Department of Health and Human Services. National Institutes of Health. National

Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v5.0. November 27, 2017. https://ctep.cancer.gov/protocolDevelopment/eiectronic applications/docs/CTCAE v5 Q uic k Reference 8.5xll.pdf van Rhee F, Rothman M, Ho KF, et al. Patient-reported outcomes for multicentric Castleman's disease in a randomized, placebo-controlled study of siltuximab. Patient. 2015 Apr;8(2):207-16. ] it t ps j 2 / www . j icb Ln Im, n 1 h,j a Q v/pu lb n is d/25736164

25. van Rhee F, Voorhees P, Dispenzieri A, et al. International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood. 2018 Nov 15; 132(20) : 2115-2124. https ://www.ncbi.nim, nih.gov/pmc/articles/PMC6238190/# !po=45.1220; https://ashpubiications.orq/blood/articie-lookup/doi/10.1182 /biood-2018-07-862334

26. van Rhee F, Fayad L, Voorhees P, et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody for Castleman disease. J Clin Oncol. 2010;28(23) :3701-3708. doi: 10.1200/JC0.2009.27.2377.

27. van Rhee F, Wong RS, Munshi N, et al. Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2014 Aug; 15(9):966- 74. Erratum in Lancet Oncol. 2014 Sep; 15(10):417.

18 APPENDICES

Appendix 1. Castleman Disease Collaborative Network (CDCN) Consensus Diagnostic Criteria for iMCD

I. Major Criteria (need both):

1. Histopathologic lymph node features consistent with the iMCD spectrum. Features along the iMCD spectrum include (need grade 2-3 for either regressive GCs or plasmacytosis at minimum) :

Regressed/atrophic/atretic germinal centers, often with expanded mantle zones composed of concentric rings of lymphocytes in an "onion skinning" appearance

FDC prominence

Vascularity, often with prominent endothelium in the interfollicluar space and vessels penetrating into the GCs with a "lollipop" appearance

Sheetlike, polytypic plasmacytosis in the interfollicular space Hyperplastic GCs

2. Enlarged lymph nodes (> 1 cm in short-axis diameter) in >2 lymph node stations

II. Minor Criteria (need at least 2 of 11 criteria with at least 1 laboratory criterion) Laboratory*

1. Elevated CRP (> 10 mg/L) or ESR (>15 mm/h) ⁺

2. Anemia (hemoglobin < 12.5 g/dL for males, hemoglobin < 11.5 g/dL for females) 3. Thrombocytopenia (platelet count <150 k/pL) or thrombocytosis (platelet count >400 k/pL)

4. Hypoalbuminemia (albumin <3.5 g/dL)

5. Renal dysfunction (eGFR <60 mL/min/1.73m ² ) or proteinuria (total protein 150 mg/24 h or 10 mg/100 ml)

6. Polyclonal hypergammaglobulinemia (total y globulin or immunoglobulin G >1700 mg/dL)

Clinical

1. Constitutional symptoms: night sweats, fever (>38°C), weight loss, or fatigue (>2 CTCAE lymphoma score for B-symptoms)

2. Large spleen and/or liver

3. Fluid accumulation: edema, anasarca, ascites, or pleural effusion

4. Eruptive cherry hemangiomatosis or violaceous papules

5. Lymphocytic interstitial pneumonitis

III. Exclusion Criteria (must rule out each of these diseases that can mimic iMCD)

Infection-related disorders

1. HHV-8 (infection can be documented by blood PCR, diagnosis of HHV-8-associated MCD requires positive LANA-1 staining by IHC, which excludes iMCD)

2. Clinical EBV-lymphoproliferative disorders such as infectious mononucleosis or chronic active EBV (detectable EBV viral load not necessarily exclusionary)

3. Inflammation and adenopathy caused by other uncontrolled infections (eg, acute or uncontrolled CMV, toxoplasmosis, HIV, active tuberculosis)

Autoimmune/autoinflammatory diseases (requires full clinical criteria, detection of autoimmune antibodies alone is not exclusionary)

1. Systemic lupus erythematosus

2. Rheumatoid arthritis

3. Adult-onset Still disease

4. Juvenile idiopathic arthritis

5. Autoimmune lymphoproliferative syndrome

Malignant/lymphoproliferative disorders (these disorders must be diagnosed before or at the same time as iMCD to be exclusionary):

1. Lymphoma (Hodgkin and non-Hodgkin)

2. Multiple myeloma 3. Primary lymph node plasmacytoma

4. FDC sarcoma

5. POEMS syndrome*

Select additional features supportive of, but not required for diagnosis

Elevated IL-6, SIL-2R, VEGF, IgA, IgE, LDH, and/or B2M

Reticulin fibrosis of bone marrow (particularly in patients with TAFRO syndrome) Diagnosis of disorders that have been associated with iMCD: paraneoplastic pemphigus, bronchiolitis obliterans organizing pneumonia, autoimmune cytopenias, polyneuropathy (without diagnosing POEMS*), glomerular nephropathy, inflammatory myofibroblastic tumor B2M, p-2-microglobulin; CMV, cytomegalovirus; CTCAE, common terminology for adverse events; eGFR, estimated glomerular filtration rate; GC, germinal center; IHC, Immunohistochemistry; LANA-1, latency-associated nuclear antigen; LDH, lactate dehydrogenase.

*We have provided laboratory cutoff thresholds as guidance, but we recognize that some laboratories have slightly different ranges. We suggest that you use the upper and lower ranges from your particular laboratory to determine if a patient meets a particular laboratory Minor Criterion.

"Evaluation of CRP is mandatory and tracking CRP levels is highly recommended, but ESR will be accepted if CRP is not available.

*POEMS is considered to be a disease "associated" with CD. Because the monoclonal plasma cells are believed to drive the cytokine storm, we do not consider it iMCD, but rather "POEMS- associated MCD."

Source: Fajgenbaum DC, Uldrick TS, Bagg A, et al. International, evidence-based consensus diagnostic criteria for HHV-8- negative/idiopathic multicentric Castleman disease. Blood. 2017 Mar 23; 129(12): 1646-1657. https://www.ncbi,nlm,mh,gov/pubmed/28087540

Appendix 2. Castleman Disease Collaborative Network Response Criteria (CDCNRC)

CDCNRC based on evaluation of biochemical, lymph node, and symptom response. A biochemical CR requires normalization of all values compared with baseline. In a PR, there is 50% to 99% improvement in all laboratory values. In patients with SD, there is a <50% improvement in all laboratory values or <25% worsening in any laboratory indicators. Progressive disease (PD) indicates a >25% worsening in any of the laboratory markers. Lymph node response is assessed using Cheson criteria as previously published (Cheson et al 1999) and modified to include assessment of skin manifestations (van Rhee et al. 2010). Last, 4 important clinical symptoms are assessed using the National Cancer Institute Common Terminology Criteria of Adverse Events (version 4). A symptomatic CR requires normalization of all symptoms. PR requires improvement in the grades of all 4 symptoms, but they do not have to return to baseline. SD requires not meeting the criteria for PR or PD, which occurs if any symptoms worsen on >2 assessments 4 weeks apart. An overall CR requires a complete biochemical, lymph node, and symptomatic response. An overall PR requires nothing less than a PR across all categories, but not meeting criteria for CR. Overall SD requires no PD in any of the categories and not meeting the criteria for CR or PR. An overall PD occurs when any category has a PD. Lymph node response may take several months in patients treated with anti-IL-6 mAbs.

Source: van Rhee, et al

2018.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238190 /#!po=45.1220; https://ashpublications.org/blood/article-lookup/doi/10.1182 /blood-2018-07-862334

Appendix 3. Eastern Cooperative Oncology Group (ECOG) Performance Status Scale

Reference: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. AM J Clin Oncol. 1982;5(6):649-655.

Appendix 4. EQ-5D-3L Health Questionnaire

By placing a tick in one box in each group below, please indicate which statements describe your own health state today.

Mobility

I have no problems in walking about >

I have some problems in walking about

I am confined to bed

Self-Care

I have no problems with self-care >

I have some problems washing or dressing myself

I am unable to wash or dress myself

Usual Activities (e.g. work, study, housework, family or leisure activities)

I have no problems with performing my usual activities

I have some problems with performing my usual activities

I am unable to perform my usual activities

Pain / Discomfort

I have no pain or discomfort

I have moderate pain or discomfort

I have extreme pain or discomfort

Anxiety / Depression

I am not anxious or depressed

I am moderately anxious or depressed

I am extremely anxious or depressed Appendix 5. Multicentric Castleman Disease Symptom Scale (MCD-SS)

Multicentric Castleman's Disease Symptom Scale

When filling out this questionnaire, please consider your experiences with Castleman's Disease Symptoms during the past 24 hours. Choose the response that best describes your experiences with Castleman's Disease symptoms by marking the correspondence box (S).

Please rate the severity of the following Did not Very Very

Mild Moderate Severe symptoms during the past 24 hours. experience Mild Severe

1. Cough

2. Shortness of breath

3. Loss of appetite

4. Tiredness

5. Fatigue

6. Lack of Energy

7. Feeling Weak

8. Sores or rash on your skin (skin lesions)

9. Itching

10. Numbness or Tingling

11. Pain

12. Fever

13. Swollen lymph nodes (swollen lumps in neck area, under arms, or groin area)

14. Swelling or edema in other body areas (face, chest, abdomen, arms, hands, legs, or feet)

15. Night Sweats

16. Excessive daytime sweating