COMBINATION THERAPY

FIELD OF THE INVENTION

The present invention relates to combination therapies of radiolabelled somatostatin receptor binding compounds with PARP inhibitors.

BACKGROUND

Neuroendocrine tumors (NETs) of the gastrointestinal tract and pancreas are a rare and heterogeneous, but clinically important group of neoplasms with unique tumor biology, natural history, and clinical management issues.

While the treatment of localized NETs is surgical resection, a variety of therapeutic options are available for patients with advanced NETs. These include medical control of excess hormone levels and associated symptoms, cytoreductive surgery for patients with advanced disease, radioembolization, chemoembolization, systemic chemotherapy, interferon, long- acting somatostatin analogs, receptor-targeted radionuclide therapy, and or liver transplantation.

Somatostatin receptors (SSTR) have been shown to be overexpressed in a number of human tumors, including neuroblastoma, prostate cancer, pheochromocytomas, paragangliomas, and NETs, among many others.

Lu-177-DOTATATE is a SSTR-agonist agent which emits ionizing radiation which causes DNA damage to its target cells through both direct and indirect mechanisms. In addition, ionizing radiation has also been shown to induce cell death through what is known as the bystander effect, a phenomenon where cellular signaling from irradiated cells towards non- irradiated cells induces cellular damage and eventually death in nearby surrounding cells.

Olaparib (AZD2281 , KU-0059436) is a potent polyadenosine 5’diphosphoribose [poly (ADP ribose] polymerisation (PARP) inhibitor (PARP-1 , -2 and -3) that is being developed as an oral therapy, both as a monotherapy (including maintenance) and for combination with chemotherapy and other anti-cancer agents. Although there has been previous work specifically looking at olaparib such as a radiosensitizer [Verhagen, C.V. , et al. , Radiother Oncol, 2015. 116(3): p. 358-65.]; pre- clinical studies with olaparib and Lutathera on live human GEP-NET tumor slices [Nonnekens, J., et al. , Theranostics, 2016. 6(1 1 ): p. 1821 -32]; and the ability of PARP inhibitors to potentiate the cytotoxic effects of Lutathera on 2D monolayer and 3D spheroid models of two types of NET cells (Purohit et al 2018, Oncotarget Vol 9(37) pp: 24693- 24709), no clinically relevant information regarding the therapeutic efficacy of a combination of an SSTR-targeting Peptide Receptor Radiotherapy Therapy and PARP inhibitors has been attempted or described previously.

SUMMARY

The present disclosure provides a combination therapy approach for treating treating neuro- endocrine tumors (NETs) with a combination of SSTR-targeting Peptide Receptor Radiotherapy Therapy and PARP inhibitors.

More specifically, the disclosure relates to a radiolabelled somatostatin receptor binding compound, for use in treating cancer in a subject in need thereof, wherein said radiolabelled somatostatin receptor binding compound is administered in combination, simultaneously, separately or sequentially, with a PARP inhibitor.

In a specific embodiment, said somatostatin receptor binding compound is a compound of formula

M-C-S-P wherein :

M is a radionuclide;

C is a chelating agent capable of chelating said radionuclide;

S is an optional spacer covalently linked between C and P;

P is a somatostatin receptor binding peptide covalently linked to C, either directly or indirectly via S.

In a specific embodiment, M is selected from ⁹⁰ Y, ^{1 14m} ln, ^{1 17} mSn, ¹⁸⁶ Re, ¹⁸⁸ Re, ⁶⁴ Cu, ⁶⁷ Cu, ⁵⁹ Fe, ⁸⁹ Sr, ¹⁹⁸ AU , ²⁰³ Hg, ²¹² Pb, ¹⁶⁵ Dy, ¹⁰³ Ru, ¹⁴⁹ Tb, ¹⁶¹ Tb, ²¹² Bi, ¹⁶⁶ Ho, ¹⁶⁵ Er, ¹⁵³ Sm, ¹⁷⁷ Lu, ²¹³ Bi, ²²³ Ra, ²²⁵ AC, ²²⁷ Th, ²¹¹ At, ⁶⁷ Cu, ¹⁸⁶ Re, ¹⁸⁸ Re, ¹⁶¹ Tb, ¹⁷⁵ Yb, ¹⁰⁵ Rh, ¹⁶⁶ Dy, ¹⁹⁸ Au, ⁴⁴ Sc and ⁴⁷ Sc, preferably is ¹⁷⁷ l_u.

In a specific embodiment, C is selected from DOTA, DTPA, NTA, EDTA, D03A, NOC and NOTA chelating agent, preferably is DOTA, NOTA or DTPA chelating agent, and more preferably is DOTA chelating agent.

In a specific embodiment, P is selected from octreotide, octreotate, lanreotide, vapreotide, and pasireotide, preferably selected from octreotide and octreotate.

More specifically, said somatostatin receptor binding compound is selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA-LAN, and DOTA-VAP, preferably selected from DOTA-TOC and DOTA-TATE, more preferably is DOTA-TATE.

In a preferred embodiment, the radiolabelled somatostatin receptor binding compound is ¹⁷⁷ LU-DOTA-TOC ( ¹⁷⁷ l_u-edotreotide) or ¹⁷⁷ Lu-DOTA-TATE ( ¹⁷⁷ l_u-oxodotreotide), more preferably ¹⁷⁷ Lu-DOTA-TATE ( ¹⁷⁷ l_u-oxodotreotide).

In a specific embodiment, said PARP inhibitor is selected from Olaparib, Niraparib and Rucaparib, preferably Olaparib.

Typically, said cancers are neuroendocrine tumors of the gastrointestinal tract and pancreas tumors, gastroenteropancreatic neuroendocrine tumors (GEP-NET), and more typically SSTR-positive GEP-NET tumors.

In a specific embodiment, 2-4 doses of 7.4 GBq of ¹⁷⁷ Lu-DOTA-TATE are administered to the subject. More specifically, ¹⁷⁷ Lu-DOTA-TATE is administered every 6-10 weeks, typically every 8 weeks.

In specific embodiments, the combined effect of the somatostatin receptor binding compound and PARP inhibitor therapies increases the overall response rate to at least 10%, 20%, 30%, 40%, or at least 50% as compared to single PPRT.

In a preferred embodiment, said cancer is a neuroendocrine tumor. More specifically, said neuroendocrine tumor is selected from the group consisting of gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor, or a pancreatic neuroendocrine tumor, pituitary adenoma, adrenal gland tumors, Merkel cell carcinoma, breast cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, head and neck tumor, urothelial carcinoma (bladder), renal cell carcinoma, hepatocellular carcinoma, GIST, neuroblastoma, bile duct tumor, cervix tumor, Ewing sarcoma, osteosarcoma, small cell lung cancer, prostate cancer, melanoma, meningioma, glioma, medulloblastoma, hemangioblastoma, supratentorial primitive, neuroectodermal tumor, and esthesioneuroblastoma.

Alternatively, said neuroendocrine tumor may be selected from the group consisting of functional carcinoid tumor, insulinoma, gastrinoma, vaso active intestinal pepetide (VI P)oma, glucagonoma, serotoninoma, histaminoma, ACTHoma, pheocromocytoma, and somatostatinoma.

More specifically, said neuroendocrine tumor is a low grade, medium grade or high grade neuroendocrine tumor. Typically, said neuroendocrine tumor is an inoperable GEP-NET.

In a more specific embodiment, said neuroendocrine tumor is SSTR positive disease as shown by ⁶⁸ Ga-DOTA-TATE PET scan.

The disclosure further relates to a method of treating a subject that has a cancer comprising administering to said subject a combination of Peptide Receptor Radionuclide Therapy and a PARP inhibitor therapy.

BRIEF DESCRIPTION OF THE FIGURE

Figure 1 : In vivo therapy of PRRT +/- Olaparib. The figure 1A presents the tumor volume after injection in the presence of the vehicle (square), olaparib alone (full circle), PRRT alone (empty circle) or in combination with PARP inhibitor (triangle). The survival proportions are also shown in Figure 1 B after injection in the presence of the vehicle, olaparib alone, PRRT alone or in combination with PARP inhibitor.

DETAILED DESCRIPTION

The present disclosure includes methods of treating a subject that has a cancer comprising administering to said subject a combination of Peptide Receptor Radionuclide Therapy (PRRT) and a PARP inhibitor therapy. The disclosure thus relates to a radiolabelled somatostatin receptor binding compound, for use in treating cancer in a subject in need thereof, wherein said radiolabelled somatostatin receptor binding compound is administered as a PRRT in combination, simultaneously, separately or sequentially, with a PARP inhibitor.

The disclosure also relates to the use of a radiolabelled somatostatin receptor binding compound, in the preparation of a drug for treating cancer in a subject in need thereof, wherein said radiolabelled somatostatin receptor binding compound is administered in combination, simultaneously, separately or sequentially, with a PARP inhibitor.

General Definitions

The use of the articles“a”, “an”, and “the” in both the description and claims are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms“comprising”, “having”, “being of” as in e.g., a complex“of a radionuclide and a cell receptor binding organic moiety linked to a chelating agent”, “including”, and “containing” are to be construed as open terms (i.e. , meaning “including but not limited to”) unless otherwise noted. Additionally, whenever“comprising” or another open-ended term is used in an embodiment, it is to be understood that the same embodiment can be more narrowly claimed using the intermediate term “consisting essentially of” or the closed term“consisting of”.

The term“about” or“ca.” has herein the meaning that the following value may vary for ± 20%, preferably ± 10%, more preferably ± 5%, even more preferably ± 2%, even more preferably ± 1 %.

Unless otherwise defined,“%” has herein the meaning of weight percent (wt%), also refered to as weight by weight percent (w/w%).

“total concentration” refers to the sum of one or more individual concentrations.

“aqueous solution” refers to a solution of one or more solute in water.

The phrase“treatment of” and“treating” includes the amelioration or cessation of a disease, disorder, or a symptom thereof. In particular, with reference to the treatment of a tumor, the term "treatment" may refer to the inhibition of the growth of the tumor, or the reduction of the size of the tumor.

As used herein, the terms “effective amount” or “therapeutically efficient amount” of a compound refer to an amount of the compound that will elicit the biological or medical response of a subject, for example, ameliorate the symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease.

The terms“patient” and“subject” which are used interchangeably refer to a human being, including for example a subject that has cancer.

As used herein, the term“PRRT” or“Peptide Receptor Radionuclide Therapy” refers to a therapy using a peptide with high affinity to a well-defined receptor, e.g. somatostatin receptors (SSTRs), said peptide being conjugated to a complex carrying a radioactive isotope emitting ionizing radiations (such as beta particles emitted by Lu-177) and thereby causing damages to the target cells.

The peptide gives the specificity to a particular tumor type and is often referred to as a cell binding receptor moiety or peptide. The radioactive isotope complexed, for example, to a chelator provides the cytotoxic effect. In many embodiments of the disclosure, the cell receptor binding moiety linked to a chelator is the SSTR-agonist DOTA-TATE. In these and other embodiments, the radioactive isotope is ¹⁷⁷ Lu.

As used herein, the terms "cancer" refer to cells having the capacity for autonomous growth, i.e., an abnormal state or condition characterized by rapidly proliferating cell growth. Hyperproliferative and neoplastic disease states may be categorized as pathologic, i.e., characterizing or constituting a disease state, or may be categorized as non-pathologic, i.e., a deviation from normal but not associated with a disease state. Unless specified otherwise, the term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness.

“for commercial use” refers to the drug product, e.g. a pharmaceutical aqueous solution, is able to obtain (preferably has obtained) marketing authorization by health authorities, e.g. US-FDA or EMA, by complying with all drug product quality and stability requirements as demanded by such health authorities, is able to be manufactured (preferably is manufactured) from or at a pharmaceutical production site at commercial scale followed by a quality control testing procedure, and is able to be supplied (preferably is supplied) to remotely located end users, e.g. hospitals or patients.

“Combination” refers to either a fixed combination in one dosage unit form, or a combined administration where a compound of the present disclosure and a combination partner (e.g. another drug as explained below, also referred to as“therapeutic agent” or“co-agent”) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a coope- rative, e.g. synergistic effect. The single components may be packaged in a kit or separately. One or both of the components (e.g., powders or liquids) may be reconstituted or diluted to a desired dose prior to administration. The terms “co-administration” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

The term“pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one therapeutic agent and includes both fixed and non-fixed combinations of the therapeutic agents. The term“fixed combination” means that the therapeutic agents, e.g. the radiolabelled somatostatin binding receptor compound and a combination partner, e.g. the PARP inhibitor, are both administered to a patient simultaneously in the form of a single entity or dosage. The term“non-fixed combination” means that the therapeutic agents, e.g. the radiolabelled somatostatin binding receptor compound and the combination partner, e.g. the PARP inhibitor, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more therapeutic agents. The radiolabelled somatosatin receptor binding compound as used in the Peptide Receptor

Radionuclide Therapy

As used herein the term “radiolabelled” refers to a compound which is labelled with a radionuclide element, typically of metallic nature. Accordingly, a radiolabelled somatostatin receptor binding compound is a compound which comprises a radionuclide and which has specific binding affinity to somatostatin receptor. In some embodiments of the disclosure, said radiolabelled somatostatin receptor binding compound with specific binding affinity to at least SSTR2 receptor.

In these and other embodiments of the disclosure, said somatostatin receptor binding compound is a compound of formula

M-C-S-P wherein :

• M is a radionuclide;

• C is a chelating agent capable of chelating said radionuclide;

• S is an optional spacer covalently linked between C and P;

• P is a somatostatin receptor binding peptide covalently linked to C, for example via its N-terminal end, either directly or indirectly via S.

As used herein, the term“somatostatin receptor binding peptide” refers to a peptidic moiety with specific binding affinity to somatostatin receptor. Such somatostatin receptor binding peptide may be selected from octreotide, octreotate, lanreotide, vapreotide, and pasireotide, preferably selected from octreotide and octreotate.

As used herein, the term“chelating agent” refers to an organic moiety comprising functional groups that are able to form non-covalent bonds with the radionuclide and, thereby, form stable radionuclide complex. The chelating agent in the context of the present disclosure may be 1 ,4,7, 10-Tetraazacyclododecane-1 ,4,7, 10-tetraacetic acid (DOTA), diethylentriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1 ,4,7,10-tetraazacyclododecane-1 ,4,7-triacetic acid (D03A), 1 ,4,7-triazacyclononane-1 ,4,7-triacetic acid (NOTA). In many embodiments of the disclosure, the chelating agent is DOTA.

Such chelating agents are either directly linked to the somatostatin receptor binding peptide or connected via a linker molecule, preferably it is directly linked. The linking bond(s) is (are) either covalent or non-covalent bond(s) between the cell receptor binding organic moiety (and the linker) and the chelating agent, preferably the bond(s) is (are) covalent.

In some embodiments of the disclosure, the radionuclide M is selected radionuclide isotope suitable for PRRT.

Examples of such suitable radionuclide M includes without limitation ⁹⁰ Y, ^{1 14m} ln, ^{1 17} mSn,

166

¹⁸⁶ Re, ¹⁸⁸ Re, ⁶⁴ Cu, ⁶⁷ Cu, ⁵⁹ Fe, ⁸⁹ Sr, ¹⁹⁸ Au, ²⁰³ Hg, ²¹² Pb, ¹⁶⁵ Dy, ¹⁰³ Ru, ¹⁴⁹ Tb, ¹⁶¹ Tb, ²¹² Bi, Ho,

105

¹⁶⁵ Er, ¹⁵³ Sm, ¹⁷⁷ LU, ²¹³ Bi, ²²³ Ra, ²²⁵ Ac, ²²⁷ Th, ²¹¹ At, ⁶⁷ Cu, ¹⁸⁶ Re, ¹⁸⁸ Re, ¹⁶¹ Tb, ¹⁷⁵ Yb, Rh,

¹⁶⁶ Dy, ¹⁹⁸ AU, ⁴⁴ SC and ⁴⁷ Sc . Preferably is M is ¹⁷⁷ l_u. According to many embodiments of the methods of the present disclosure, the somatostatin receptor binding peptide linked to the chelating agent is selected from DOTA-OC, DOTA- TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA-LAN, and DOTA-VAP. In many of these embodiments, the somatostatin receptor binding peptide is DOTA-TOC or DOTA-TATE. In many such embodiments, the somatostatin receptor binding peptide is DOTA-TATE.

Many embodiments of the disclosure encompass combination therapy with 177Lu-DOTA- TOC (177Lu-edotreotide) or ¹⁷⁷ Lu-DOTA-TATE ( ¹⁷⁷ l_u-oxodotreotide), with many of these embodiments being ¹⁷⁷ Lu-DOTA-TATE ( ¹⁷⁷ Lu-oxodotreotide).

Accordingly, the cell receptor binding moiety and the chelating agent may form together the following molecules:

DOTA-OC: [DOTA°, D-Phe ¹ ]octreotide,

DOTA-TOC: [DOTA°, D-Phe ¹ ,Tyr ³ ]octreotide, edotreotide (INN),

represented by the following formulas:

DOTA-LAN: [DOTA°,D-3-Nal ¹ ]lanreotide, DOTA-VAP: [DOTA ⁰ , D-Phe ¹ ,Tyr ³ ]vapreotide. Satoreotide trizoxetan ₂

Satoreotide tetraxetan

Common “cell receptor binding moiety linked to the chelating agent” molecules of the disclosure for use in the combination therapy are DOTA-TOC, DOTA-TATE, and Satoreotide tetraxetan, more preferably the molecule is DOTA-TATE.

More specifically, in many embodiments of the disclosure, the complex formed by the radionuclide and the cell receptor binding moiety linked to the chelating agent according to the present invention is ¹⁷⁷ Lu-DOTA-TATE, which is also referred to as Lutetium (177Lu) oxodotreotide (INN), i.e. hydrogen [N-{[4,7, 10-tris(carboxylato-KO-methyl)-1 ,4,7, 10- tetraazacyclododecan-1-yl-K ⁴ N ¹ ,N ⁴ ,N ⁷ ,N ¹⁰ ]acetyl-KO}-D-phenylalanyl-L-cysteinyl-tyrosyl-D- tryptophyl-L-lysyl-L-threonyl-L-cysteinyl-L-threoninato cyclic (2 7)-disulfide(4-

)](177Lu)lutetate(1 -)

and is represented by the following formulas:

Said radiolabelled somatostatin receptor binding compound is typically formulated for administration of a therapeutically efficient amount in the subject in need thereof.

The radiolabelled somatostatin receptor binding compound can be present in a concentration providing a volumetric radioactivity of 100 MBq/mL or higher. In many embodiments of the disclosure, the volumetric radioactivity is 250 MBq/mL or higher.

In many embodiments of the disclosure, the radiolabeled somatostatin receptor binding compound can be present in a concentration providing a volumetric radioactivity comprised between 100 MBq/mL and 1000 MBq/mL, including between 250 MBq/mL and 500 MBq/mL, for example, at a concentration of about 370 MBq/mL (10mCi/mL). The pharmaceutically acceptable excipient can be any of those conventionally used, and is limited only by physico-chemical considerations, such as solubility and lack of reactivity with the active compound(s).

In particular, the one or more pharmaceutically acceptable excipient(s) can be selected from numerous different classes of such pharmaceutcially acceptable excipients. Examples of such classes include stabilizers against radiolytic degradation, buffers, sequestering agents and mixtures thereof.

As used herein, “stabilizer against radiolytic degradation” refers to stabilizing agent which protects organic molecules against radiolytic degradation, e.g. when a gamma ray emitted from the radionuclide is cleaving a bond between the atoms of an organic molecules and radicals are forms, those radicals are then scavenged by the stabilizer which avoids the radicals undergo any other chemical reactions which might lead to undesired, potentially ineffective or even toxic molecules. Therefore, those stabilizers are also referred to as“free radical scavengers” or in short “radical scavengers”. Other alternative terms for those stabilizers are“radiation stability enhancers”,“radiolytic stabilizers”, or simply“quenchers".

As used herein, “sequestering agent” refers to a chelating agent suitable to complex free radionuclide metal ions in the formulation (which are not complexed with the radiolabelled peptide).

Buffers include acetate buffer, citrate buffer and phosphate buffer.

According to many embodiments of the disclosure, the pharmaceutical composition is an aqueous solution, for example an injectable formulation. According to a particular embodiment, the pharmaceutical composition is a solution for infusion.

The requirements for effective pharmaceutical carriers for injectable compositions are well- known to those of ordinary skill in the art (see, e.g., Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982), and ^A SHP Handbook on Injectable Drugs, Trissel, 15th ed., pages 622-630 (2009)). The following clauses refer to various embodiments of suitable pharmaceutical aquesous solution for use in the combination methods of the present disclosure. The following clauses provided are non-limiting.

1. A pharmaceutical aqueous solution comprising

(a) a complex formed by

(ai) a radionuclide, and

(aii) a cell receptor binding organic moiety linked to a chelating agent; and

(b) at least one stabilizer against radiolytic degradation;

wherein

said radionuclide is present in a concentration that it provides a volumetric radioactivity of at least 100 MBq/mL, preferably of at least 250 MBq/mL.

2. The pharmaceutical aqueous solution according to embodiment 1 ,

wherein said stabilizer(s), component (b), is (are) present in a total concentration of at least 0.2 mg/mL, preferably at least 0.5 mg/mL, more preferably at least 1.0 mg/mL, even more preferably at least 2.7 mg/mL.

3. The pharmaceutical aqueous solution according to any one of the preceding embodiments, wherein said radionuclide is present in a concentration that it provides a volumetric radioactivity of from 100 to 1000 MBq/mL, preferably from 250 to 500 MBq/mL.

4. The pharmaceutical aqueous solution according to any one of the preceding embodiments, wherein said stabilizer(s) is (are) present in a total concentration of from 0.2 to 20.0 mg/mL, preferably from 0.5 to 10.0 mg/mL, more preferably from 1.0 to 5.0 mg/mL, even more preferably from 2.7 to 4.1 mg/mL.

5. The pharmaceutical aqueous solution according to any one of the preceding embodiments, wherein the component (b) is only one stabilizers against radiolytic degradation, i.e. only a first stabilizer.

6. The pharmaceutical aqueous solution according to any one of the preceding embodiments,

wherein the component (b) are at least two stabilizers against radiolytic degradation, i.e. at least a first and a second stabilizer, preferably only two stabilizers, i.e. only a first and a second stabilizer.

7. The pharmaceutical aqueous solution according to any one of the embodiments 5 to 6, wherein the first stabilizer is present in a concentration of from 0.2 to 5 mg/mL, preferably from 0.5 to 5 mg/mL, more preferably from 0.5 to 2 mg/mL, even more preferably from 0.5 to 1 mg/mL, even more preferably from 0.5 to 0.7 mg/mL.

8. The pharmaceutical aqueous solution according to embodiment 6 or 7, wherein the second stabilizer is present in a concentration of from 0.5 to 10 mg/mL, more preferably from 1.0 to 8.0 mg/mL, even more preferably from 2.0 to 5.0 mg/mL, even more preferably from 2.2 to 3.4 mg/mL.

9. The pharmaceutical aqueous solution according to any one of the preceding embodiments, wherein the stabilizer(s) is (are) selected from gentisic acid (2,5- dihydroxybenzoic acid) or salts thereof, ascorbic acid (L-ascorbic acid, vitamin C) or salts thereof (e.g. sodium ascorbate), methionine, histidine, melatonin, ethanol, and Se-methionine, preferably selected from gentisic acid or salts thereof and ascorbic acid or salts thereof.

10. The pharmaceutical aqueous solution according to any one of the embodiments 5 to 9, wherein the first stabilizer is selected from gentisic acid and ascorbic acid, preferably the first stabilizer is gentisic acid. 1 1 . The pharmaceutical aqueous solution according to any one of the embodiments 6 to 10, wherein the second stabilizer is selected from gentisic acid and ascorbic acid, preferably the second stabilizer is ascorbic acid.

12. The pharmaceutical aqueous solution according to any one of the embodiments 6 to 8, wherein the first stabilizer is gentisic acid or a salt thereof and the second stabilizer is ascorbic acid or a salt thereof, and the ratio of the concentration (in mg/mL) of the first stabilizer to the concentration (in mg/mL) of the second stabilizer is from 1 :3 to 1 :7, preferably from 1 :4 to 1 :5.

13. The pharmaceutical aqueous solution according to any one of the preceding

186 embodiments, wherein the radionuclide is selected from ⁹⁰ Y, ^{1 14m} ln, ^{1 17} mSn, Re,

166

¹⁸⁸ Re,“Cu, ⁶⁷ Cu, ⁵⁹ Fe, ⁸⁹ Sr, ¹⁹⁸ Au, ²⁰³ Hg, ²¹² Pb, ¹⁶⁵ Dy, ¹⁰³ RU, ¹⁴⁹ Tb, ¹⁶¹ Tb, ²¹² Bi, Ho,

105 1 ⁶⁵ Er, ¹⁵³ Sm, ¹⁷⁷ LU, ²¹³ Bi, ²²³ Ra, ²²⁵ Ac, ²²⁷ Th, ^{21 1} At, ⁶⁷ Cu, ¹⁸⁶ Re, ¹⁸⁸ Re, ¹⁶¹ Tb, ¹⁷⁵ Yb, Rh, 1 ⁶⁶ Dy, ¹⁹⁸ AU, ⁴⁴ SC and ⁴⁷ Sc, preferably is ¹⁷⁷ Lu.

14. The pharmaceutical aqueous solution according to any one of the preceding embodiments, wherein the cell receptor binding moiety is a somatostatin receptor binding peptide, preferably said somatostatin receptor binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide and pasireotide, preferably selected from octreotide and octreotate.

15. The pharmaceutical aqueous solution according to any one of the preceding embodiments, wherein the chelating agent is selected from DOTA, DTPA, NTA, EDTA, D03A, NOC and NOTA, preferably is DOTA.

16. The pharmaceutical aqueous solution according to any one of the preceding embodiments, wherein the cell receptor binding moiety and the chelating agent form together molecules selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA-LAN, and DOTA-VAP, preferably selected from DOTA-TOC and DOTA-TATE, more preferably is DOTA-TATE. 17. The pharmaceutical aqueous solution according to any one of the preceding embodiments, wherein the radionuclide, the cell receptor binding moiety and the chelating agent form together the complex ¹⁷⁷ Lu-DOTA-TOC ( ¹⁷⁷ l_u-edotreotide) or 1 ⁷⁷ LU-DOTA-TATE ( ¹⁷⁷ l_u-oxodotreotide), preferably ¹⁷⁷ Lu-DOTA-TATE.

18. The pharmaceutical aqueous solution according to any one of the preceding embodiments, further comprising a buffer, preferably said buffer is an acetate buffer, preferably in an amount to result in a concentration of from 0.3 to 0.7 mg/mL (preferably about 0.48 mg/mL) acetic acid and from 0.4 to 0.9 mg/mL (preferably about 0.66 mg/mL) sodium acetate.

19. The pharmaceutical aqueous solution according to any one of the preceding embodiments, further comprising a sequestering agent, preferably said sequestering agent is diethylentriaminepentaacetic acid (DTPA) or a salt thereof, preferably in an amount to result in a concentration of from 0.01 to 0.10 mg/mL (preferably about 0.05 mg/mL).

20. The pharmaceutical aqueous solution according to any one of the preceding embodiments, which has a shelf life of at least 24 hours (h) at < 25 °C, at least 48 h at

< 25 °C, at least 72 h at < 25 °C, of from 24 h to 120 h at < 25 °C, from 24 h to 96 h at

< 25 °C, from 24 h to 84 h at < 25 °C, from 24 h to 72 h at < 25 °C, in particular has a shelf life of 72 h at < 25 °C.

21. The pharmaceutical aqueous solution according to any one of the preceding embodiments, wherein said solution is produced at commercial scale manufacturing, in particular is produced at a batch size of at least 20 GBq, at least 50 GBq, or at least 70 GBq.

22a. The pharmaceutical aqueous solution according to any one of the preceding embodiments, which is ready-to-use. 22b. The pharmaceutical aqueous solution according to any one of the preceding embodiments, which is for commercial use.

23. A pharmaceutical aqueous solution, comprising

(a) a complex formed by

(ai) the radionuclide ¹⁷⁷ l_utetium (Lu-177), present in a concentration that it provides a volumetric radioactivity of from 250 to 500 MBq/mL , and

(aii) the chelating agent linked somatostatin receptor binging organic moiety DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide);

(bi) gentisic acid or a salt thereof as the first stabilizer against radiolytic degradation present in a concentration of from 0.5 to 1 mg/mL;

(bii) ascorbic acid or a salt thereof as the second stabilizer against radiolytic degradation present in a concentration of from 2.0 to 5.0 mg/mL.

24. The pharmaceutical aqueous solution according to embodiment 23, further comprising:

(c) Diethylentriaminepentaacetic acid (DTPA) or a salt thereof in a concentration of from 0.01 to 0.10 mg/mL.

25. The pharmaceutical aqueous solution according to embodiments 23 or 24, further comprising:

(d) acetic acid in a concentration of from 0.3 to 0.7 mg/mL and sodium acetate in a concentration from 0.4 to 0.9 mg/mL.

26. The pharmaceutical aqueous solution according to any one of the preceding embodiments wherein the stabilizer(s) is (are) present in the solution during the complex formation of components (ai) and (aii).

27. The pharmaceutical aqueous solution according to any one of embodiments 5 to 26 wherein only the first stabilizer is present during the complex formation of components (ai) and (aii), preferably in an amount to result in a concentration of from 0.5 to 5 mg/ml_, more preferably from 0.5 to 2 mg/ml_, even more preferably from 0.5 to 1 mg/ml_, even more preferably from 0.5 to 0.7 mg/ml_, in the final solution.

28. The pharmaceutical aqueous solution according to any one of embodiments 6 to 27 wherein a part of the amount of the second stabilizer is already present in the solution during the complex formation of components (ai) and (aii) and another part of the amount of the second stabilizer is added after the complex formation of components (ai) and (aii).

29. The pharmaceutical aqueous solution according to any one of embodiments 6 to 28 wherein the second stabilizer is added after the complex formation of components (ai) and (aii).

30. The pharmaceutical aqueous solution according to embodiment 6 or 29 wherein the second stabilizer is added after the complex formation of components (ai) and (aii), preferably in an amount to result in a concentration of from 0.5 to 10 mg/ml_, more preferably from 1.0 to 8.0 mg/ml_, even more preferably from 2.0 to 5.0 mg/ml_, even more preferably from 2.2 to 3.4 mg/ml_, in the final solution.

31. The pharmaceutical aqueous solution according to any one of the preceding embodiments, further comprising a sequestering agent, added after the complex formation of components (ai) and (aii), for removing any uncomplexed Lu, preferably said sequestering agent is diethylentriaminepentaacetic acid (DTPA) or a salt thereof, preferably in an amount to result in a concentration of from 0.01 to 0.10 mg/ml_ (preferably about 0.05 mg/ml_) in the final solution.

Often, a solution for infusion of 177Lu-DOTA-TATE or 177Lu-DOTA-TOC such as one with specific activity concentration of 370 MBq/mL (± 5%) is used in the combination methods of the present disclosure.

A particular process for manufacturing the pharmaceutical aqueous solution as defined in any one of the preceding embodiments, may comprise the process steps: (1 ) Forming a complex of the radionuclide and the chelating agent linked cell receptor binding organic moiety by

(1.1 ) preparing an aqueous solution comprising the radionuclide;

(1.2) preparing an aqueous solution comprising the chelating agent linked cell receptor binding organic moiety, a first stabilizer, optionally a second stabilizer; and

(1.3) mixing the solutions obtained in steps (1.1 ) and (1.2) and heating the resulting mixture;

(2) Diluting the complex solution obtained by step (1 ) by

(2.1 ) preparing an aqueous dilution solution optionally comprising a second stabilizer; and

(2.2.) mixing the complex solution obtained by step (1 ) with the dilution solution obtained by the step (2.1 ).

Said radiolabelled somatostatin receptor binding compound is administered to said subject at a therapeutically efficient amount comprised between 1.85 to 18.5 GBq (50-500 mCi). In specific embodiments, a therapeutically efficient amount of the composition is administered to said subject 1 to 8 times per treatment, for example 2 to 4 times.

In many embodiments of the disclosure, the PRRT consists of 2-4 doses of 7.4 GBq of 177Lu-DOTA-TATE administered to the subject.

The PARP inhibitor as used in the combination therapy

As used herein, PARP inhibitor refers to a pharmacological inhibitor of the enzyme poly ADP ribose polymerase.

PARP inhibitors have been developed for multiple indications, including the treatment of cancers.

PARP1 is a protein that is important for repairing single-strand breaks ('nicks' in the DNA). If such nicks persist unrepaired until DNA is replicated (which must precede cell division), then the replication itself can cause double strand breaks to form. Drugs that inhibit PARP1 cause multiple double strand breaks to form in this way, and h certain tumours such as tumors with BRCA1 , BRCA2 or PALB2 mutations, these double strand breaks cannot be efficiently repaired, leading to the death of the cells. Normal cells that do not replicate their DNA as often as cancer cells, and that lack any mutated BRCA1 or BRCA2 still have homologous repair operating, which allows them to survive the inhibition of PARP. PARP inhibitors lead to trapping of PARP proteins on DNA in addition to blocking their catalytic action. This interferes with replication, causing cell death preferentially in cancer cells, which grow faster than non-cancerous cells.

PARP inihibitors include without limitation talazoparib, veliparib, pamiparib, olaparib, rucaparib, CEP9822, niraparib, E7016, iniparib and 3-aminobenzamide.

More specifically, rucaparib (US brand name“Rubraca”) has the following formula:

or a pharmaceutically acceptable salt thereof.

Talazoparib has the following formula:

or a pharmaceutically acceptable salt thereof. Veliparib has the following formula:

or a pharmaceutically acceptable salt thereof. Olaparib (US brand name“Lynparza”) has the following formula:

or a pharmaceutically acceptable salt thereof.

In specific embodiments of the combination therapy of the present disclosure, said PARP inhibitor is selected from Olaparib, Niraparib and Rucaparib, preferably Olaparib. These PARP inhibitors are commercially available.

The PARP inhibitors may be administered by the oral, intravenous, topical, intraperitoneal or nasal route, preferably is administered by the oral route.

The PARP inhibitors may be formulated depending on the route of administration. In specific embodiments, they are formulated as oral formulations, typically tablets. For example, they can be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present.

The PARP inhibitors can also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1 ) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.

Olaparib is typically administered to a patient at a dosage of 300 mg, 400 mg or 800 mg once per day or at a dosage of 50 mg to 400 mg administered twice daily.

Olaparib is available in the form of 100 mg or 150 mg tablets. The recommended dose of Olaparib is 300 mg (two 150 mg tablets) taken twice daily, equivalent to a daily dose of 600 mg. A 100 mg tablet is available for dose reduction.

Olaparib is also available in the form of 50 mg capsules with a recommended dose of 400 mg (eight 50 mg capsules) taken twice daily, equivalent to a daily dose of 800 mg.

Lynparza® is a brandname of olaparib.

The recommended dose of rucaparib is 600 mg (two 300 mg tablets) taken orally twice daily. It is is available in the form of 200 mg, 250 mg or 300 mg tablets.

Rubraca® is a brandname of rucaparib.

The recommended dose of niraparib is 300 mg taken once daily. It is is available in the form of 100 mg capsules.

Zejula® is a brandname of niparib.

Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compounds employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound for the combination therapy as disclosed herein o can be ascertained by those skilled in the art using conventional treatment tests. Suitable dose(s), administration regime(s) and administration route(s) for PARP inhibitors, particularly olaparib, rucaparib, niraparib, veliparib and talazoparib, may be readily determined by standard techniques known to the skilled person. The dose(s), administration regime(s) and administration route(s) may have to be adapted according to, inter alia, the indication, the indication stage, the patient age and/or the patient gender, among other factors. Such adaptations can be readily determined by standard techniques known to the skilled person.

The combination therapy

The present disclosure is directed to methods of treating a subject that has a cancer comprising administering to said subject a combination of Peptide Receptor Radionuclide Therapy (PRRT) and a PARP inhibitor therapy.

In certain embodiments of the disclosure, the combination therapy of the present disclosure is preferably provided for treating subject with neuroendocrine tumors.

In particular, said neuroendocrine tumor is selected from the group consisting of gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor, or a pancreatic neuroendocrine tumor, pituitary adenoma, adrenal gland tumors, Merkel cell carcinoma, breast cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, head and neck tumor, urothelial carcinoma (bladder), renal cell carcinoma, hepatocellular carcinoma, GIST, neuroblastoma, bile duct tumor, cervix tumor, Ewing sarcoma, osteosarcoma, small cell lung cancer, prostate cancer, melanoma, meningioma, glioma, medulloblastoma, hemangioblastoma, supratentorial primitive, neuroectodermal tumor, and esthesioneuroblastoma.

In other embodiments of the disclosure, said neuroendocrine tumor is selected from the group consisting of functional carcinoid tumor, insulinoma, gastrinoma, vaso active intestinal peptide (VlP)oma, glucagonoma, serotoninoma, histaminoma, ACTHoma, pheocromocytoma, and somatostatinoma.

Said cancers are often neuroendocrine tumors of the gastrointestinal tract and pancreas tumors, gastroenteropancreatic neuroendocrine tumors (GEP-NET), and more typically SSTR-positive GEP-NET tumors. In certain embodiments of the disclosure, said neuroendocrine tumor is SSTR positive disease as shown by ⁶⁸ Ga-DOTA-TATE PET scan.

The disclosure thus relates to a radiolabelled somatostatin receptor binding compound, for use in treating cancer in a subject in need thereof, wherein said radiolabelled somatostatin receptor binding compound is administered as a PRRT in combination, simultaneously, separately or sequentially, with a PARP inhibitor.

The disclosure also relates to the use of a radiolabelled somatostatin receptor binding compound, in the preparation of a drug for treating cancer in a subject in need thereof, wherein said radiolabelled somatostatin receptor binding compound is administered in combination, simultaneously, separately or sequentially, with a PARP inhibitor.

In various embodiments of the disclosure, the combination therapy comprises administering to a subject in need thereof jointly therapeutically efficient amounts of (i) a pharmaceutical composition comprising a PARP inhibitor and (ii) a pharmaceutical composition comprising a radiolabelled somatostatin receptor binding compound.

As used herein, the term“jointly therapeutically effective” means that the therapeutic agents may be given separately (in a chronologically staggered manner, especially a sequence- specific manner) in such time intervals to show a (preferably synergistic) interaction (i.e. joint therapeutic effect).

In various embodiments of the disclosure, a combined administration where a PARP inhibitor (e.g. Olaparib) and the radiolabelled somatostatin receptor binding compound (e.g. ¹⁷⁷ LU-DOTA-TATE) is administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect.

Suitable dose(s), administration regime(s) and administration route(s) for olaparib include those described in NCCN clinical practice guidelines (NCCN guidelines). In certain embodiments, said PARP inhibitor, e.g. Olaparib, is first administered within 7 to 2 days prior to the first administration of the radiolabelled somatostatin receptor binding peptide compound, and prior to each cycle of PRRT.

In parallel with the above dose regimen for Olaparib, said radiolabelled somatostatin receptor binding compound is administered to said subject at a therapeutically efficient amount comprised between 1.85 to 18.5 GBq (50-500 mCi). In specific embodiments, a therapeutically efficient amount of the composition is administered to said subject 1 to 8 times per treatment, for example 2 to 4 times. In preferred embodiments, the PRRT administered in combination with the above dose regimen for Olaparib consists of 2-4 doses of 7.4 GBq of ¹⁷⁷ Lu-DOTA-TATE administered to the subject.

Administration of ¹⁷⁷ Lu-DOTA-TATE may be performed every 6-10 weeks, typically every 8 weeks.

Advantageously, the combined effect of the somatostatin receptor binding compound and PARP inhibitor therapies increases the overall response rate to at least 10%, 20%, 30%, 40%, or at least 50% as compared to single PPRT.

The single components or their precursor, typically non-labelled DOTATE, may be packaged in a kit or separately. One or both of the components (e.g., powders or liquids) may be reconstituted or diluted to a desired dose prior to administration.

In certain aspects, the administration of the composition comprising radiolabeled somatostatin receptor binding compound to a subject eligible for said treatment can inhibit, delay, and/or reduce tumor growth in the subject. In certain aspects, the growth of the tumor is delayed by at least 50%, 60%, 70% or 80% in comparison to an untreated control subject. In certain aspects, the growth of the tumor is delayed by at least 80% in comparison to an untreated control subject. In certain aspects, the growth of the tumor is delayed by at least 50%, 60%, 70% or 80% in comparison to the predicted growth of the tumor without the treatment. In certain aspects, the growth of the tumor is delayed by at least 80% in comparison to the predicted growth of the tumor without the treatment. In certain aspects, the administration of the composition comprising radiolabeled somatostatin receptor binding compound to a subject eligible for said treatment can increase the length of survival of the subject. In certain aspects, the increase in survival is in comparison to an untreated control subject. In certain aspects, the increase in survival is in comparison to the predicted length of survival of the subject without the treatment. In certain aspects, the length of survival is increased by at least 3 times, 4 times, or 5 times the length in comparison to an untreated control subject. In certain aspects, the length of survival is increased by at least 4 times the length in comparison to an untreated control subject. In certain aspects, the length of survival is increased by at least 3 times, 4 times, or 5 times the length in comparison to the predicted length of survival of the subject without the treatment. In certain aspects, the length of survival is increased by at least 4 times the length in comparison to the predicted length of survival of the subject without the treatment. In certain aspects, the length of survival is increased by at least one week, two weeks, one month, two months, three months, six months, one year, two years, or three years in comparison to an untreated control subject. In certain aspects, the length of survival is increased by at least one month, two months, or three months in comparison to an untreated control subject. In certain aspects, the length of survival is increased by at least one week, two weeks, one month, two months, three months, six months, one year, two years, or three years in comparison to the predicted length of survival of the subject without the treatment. In certain aspects, the length of survival is increased by at least one month, two months, or three months in comparison to the predicted length of survival of the subject without the treatment.

Other possible combination

The present invention further provides the combination or combination therapy of the complex formed by the radionuclide ¹⁷⁷ l_u (Lutetium-177), and a somatostatin receptor binding peptide linked to the chelating agent as defined herein, or the combination or combination therapy of the pharmaceutical aqueous solution as defined herein, together with one of more therapeutic agents as outlined in the following:

In certain instances, pharmaceutical aqueous solution of the present invention are combined with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti- nausea agents (or anti-emetics), pain relievers, cytoprotective agents, and combinations thereof.

General Chemotherapeutic agents considered for use in combination therapies include anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4- pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), nab-paclitaxel (Abraxane ^® ), phoenix (Yttrium90/MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

Anti-cancer agents of particular interest for combinations with the pharmaceutical aqueous solution of the present invention include:

Tyrosine kinase inhibitors: Erlotinib hydrochloride (Tarceva®); Linifanib (N-[4-(3-amino- 1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, available from Genentech); Sunitinib malate (Sutent®); Bosutinib (4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl) propoxy]quinoline-3- carbonitrile, also known as SKI-606, and described in US Patent No. 6,780,996); Dasatinib (Sprycel®); Pazopanib (Votrient®); Sorafenib (Nexavar®); Zactima (ZD6474); and Imatinib or Imatinib mesylate (Gilvec® and Gleevec®).

Vascular Endothelial Growth Factor (VEGF) receptor inhibitors: Bevacizumab (Avastin®), axitinib (Inlyta®); Brivanib alaninate (BMS-582664, (S)-((R)-1-(4-(4-Fluoro-2- methyl-1 /-/-indol-5-yloxy)-5-methylpyrrolo[2, 1 -f\[ 1 ,2,4]triazin-6-yloxy)propan-2-yl)2- aminopropanoate); Sorafenib (Nexavar®); Pazopanib (Votrient®); Sunitinib malate (Sutent®); Cediranib (AZD2171 , CAS 288383-20-1 ); Vargatef (BIBF1 120, CAS 928326-83- 4); Foretinib (GSK1363089); Telatinib (BAY57-9352, CAS 332012-40-5); Apatinib (YN968D1 , CAS 81 1803-05-1 ); Imatinib (Gleevec®); Ponatinib (AP24534, CAS 943319-70- 8); Tivozanib (AV951 , CAS 475108-18-0); Regorafenib (BAY73-4506, CAS 755037-03-7); Vatalanib dihydrochloride (PTK787, CAS 212141 -51-0); Brivanib (BMS-540215, CAS 649735-46-6); Vandetanib (Caprelsa® or AZD6474); Motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1 H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3- pyridinecarboxamide, described in PCT Publication No. WO 02/066470); Dovitinib dilactic acid (TKI258, CAS 852433-84-2); Linfanib (ABT869, CAS 796967-16-3); Cabozantinib (XL184, CAS 849217-68-1 ); Lestaurtinib (CAS 1 1 1358-88-4); N-[5-[[[5-(1 ,1 -Dimethylethyl)- 2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (BMS38703, CAS 345627-80-7); (3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1 -f][1 ,2,4]triazin-5- yl)methyl)piperidin-3-ol (BMS690514); A/-(3,4-Dichloro-2-fluorophenyl)-6-methoxy-7- [[(3aa,53,6aa)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]me thoxy]- 4-quinazolinamine (XL647, CAS 781613-23-8); 4-Methyl-3-[[1-methyl-6-(3-pyridinyl)-1 H-pyrazolo[3,4- c]pyrimidin-4-yl]amino]-A/-[3-(trifluoromethyl)phenyl]-benza mide (BHG712, CAS 940310-85- 0); . and Aflibercept (Eylea®), sulfatinib, surufatinib.

Platelet-derived Growth Factor (PDGF) receptor inhibitors: Imatinib (Gleevec®); Linifanib (N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, available from Genentech); Sunitinib malate (Sutent®); Quizartinib (AC220, CAS 950769-58-1 ); Pazopanib (Votrient®); Axitinib (Inlyta®); Sorafenib (Nexavar®); Vargatef (BIBF1 120, CAS 928326-83-4); Telatinib (BAY57-9352, CAS 332012-40-5); Vatalanib dihydrochloride (PTK787, CAS 212141 -51-0); and Motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1 H-indol-6-yl)-2-[(4- pyridinylmethyl)amino]-3-pyridinecarboxamide, described in PCT Publication No. WO 02/066470).

Fibroblast Growth Factor Receptor (FGFR) Inhibitors: Brivanib alaninate (BMS-582664, (S)-((R)-1 -(4-(4-Fluoro-2-methyl-1 /-/-indol-5-yloxy)-5-methylpyrrolo[2, 1 -f\[ 1 ,2,4]triazin-6- yloxy)propan-2-yl)2-aminopropanoate); Vargatef (BIBF1 120, CAS 928326-83-4); Dovitinib dilactic acid (TKI258, CAS 852433-84-2); 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1 -{6-[4-(4- ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl- urea (BGJ398, CAS 87251 1-34- 7); Danusertib (PFIA-739358); and N-[2-[[4-(Diethylamino)butyl]amino]-6-(3,5- dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1 , 1-dimethylethyl)-urea (PD173074, CAS 219580-1 1 -7). sulfatinib, surufatinib.

Aurora kinase inhibitors: Danusertib (PFIA-739358); A/-[4-[[6-Methoxy-7-[3-(4- morpholinyl)propoxy]-4-quinazolinyl]amino]phenyl]benzamide (ZM447439, CAS 331771-20- 1 ); 4-(2-Amino-4 -methyl-5-thiazolyl)-N-[4-(4-morpholinyl)phenyl]-2-pyrimidin amine

(CYC1 16, CAS 693228-63-6); Tozasertib (VX680 or MK-0457, CAS 639089-54-6); Alisertib (MLN8237); (N-{2-[6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidine-2-y lamino)-(1 S,4R)- 1 ,2,3,4-tetrahydro-1 ,4-epiazano-naphthalen-9-yl]-2-oxo-ethyl}-acetamide) (PF-03814735); 4-[[9-Chloro-7-(2,6-difluorophenyl)-5/-/-pyrimido[5,4-d][2]b enzazepin-2-yl]amino]-benzoic acid (MLN8054, CAS 869363-13-3); Cenisertib (R-763); Barasertib (AZD1 152); and N- cyclopropyl-N'-[3-[6-(4-morpholinylmethyl)-1 FI-benzimidazol-2-yl]-1 FI-pyrazol-4-yl]-urea (AT9283).

Cyclin-Dependent Kinase (CDK) inhibitors: Aloisine A; Alvocidib (also known as flavopiridol or FIMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-meth yl-4- piperidinyl]-4-chromenone, and described in US Patent No. 5,621 ,002); Crizotinib (PF- 02341066, CAS 877399-52-5); 2-(2-Chlorophenyl)-5,7-dihydroxy-8-[(2R,3S)-2-

(hydroxymethyl)-1 -methyl-3-pyrrolidinyl]- 4H-1-benzopyran-4-one, hydrochloride (P276-00, CAS 9201 13-03-7); Indisulam (E7070); Roscovitine (CYC202); 6-Acetyl-8-cyclopentyl-5- methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8/-/-pyrido[2, 3-d]pyrimidin-7-one, hydrochloride (PD0332991 ); Dinaciclib (SCH727965); N-[5-[[(5-ferf-Butyloxazol-2-yl)methyl]thio]thiazol-2- yl]piperidine-4-carboxamide (BMS 387032, CAS 345627-80-7); 4-[[9-Chloro-7-(2,6- difluorophenyl)-5/-/-pyrimido[5,4-cf][2]benzazepin-2-yl]amin o]-benzoic acid (MLN8054, CAS 869363-13-3); 5-[3-(4,6-Difluoro-1 H-benzimidazol-2-yl)-1 H-indazol-5-yl]-N-ethyl-4-methyl-3- pyridinemethanamine (AG-024322, CAS 837364-57-5); 4-(2,6-Dichlorobenzoylamino)-1 H- pyrazole-3-carboxylic acid N-(piperidin-4-yl)amide (AT7519, CAS 844442-38-2); 4-[2-

Methyl-1-(1-methylethyl)-1 /-/-imidazol-5-yl]-A/-[4-(methylsulfonyl)phenyl]- 2-pyrimidinamine (AZD5438,CAS 602306-29-6); Palbociclib (PD-0332991 ); and (2R,3R)-3-[[2-[[3-[[S(R)]-S- cyclopropylsulfonimidoyl]-phenyl]amino]-5-(trifluoromethyl)- 4-pyrimidinyl]oxy]-2-butanol (BAY 10000394), ribociclib.

Checkpoint Kinase (CHK) inhibitors: 7-Hydroxystaurosporine (UCN-01 ); 6-Bromo-3-(1- methyl-1 /-/-pyrazol-4-yl)-5-(3R)-3-piperidinyl-pyrazolo[1 ,5-a]pyrimidin-7-amine (SCH900776, CAS 891494-63-6); 5-(3-Fluorophenyl)-3-ureidothiophene-2 -carboxylic acid N-[(S)-piperidin- 3-yl]amide (AZD7762, CAS 860352-01-8); 4-[((3S)-1-Azabicyclo[2.2.2]oct-3-yl)amino]-3-

(1 H-benzimidazol-2-yl)-6-chloroquinolin-2(1 H)-one (CHIR 124, CAS 405168-58-3); 7-

Aminodactinomycin (7-AAD), Isogranulatimide, debromohymenialdisine; N-[5-Bromo-4- methyl-2-[(2S)-2-morpholinylmethoxy]-phenyl]-N'-(5-methyl-2- pyrazinyl)urea (LY2603618, CAS 91 1222-45-2); Sulforaphane (CAS 4478-93-7, 4-Methylsulfinylbutyl isothiocyanate); 9, 10, 1 1 , 12-Tetrahydro- 9, 12-epoxy-1 /-/-diindolo[1 ,2,3-fg:3',2', 1 '-/c/]pyrrolo[3,4-

/][1 ,6]benzodiazocine-1 ,3(2H)-dione (SB-218078, CAS 135897-06-2); and TAT-S216A (YGRKKRRQRRRLYRSPAMPENL), and CBP501 ((d-Bpa)sws(d-Phe-F5)(d-Cha)rrrqrr); and (aR)-a-amino-N-[5,6-dihydro-2-(1 -methyl-1 H-pyrazol-4-yl)-6-oxo-1 H-pyrrolo[4,3,2- ef][2,3]benzodiazepin-8-yl]-Cyclohexaneacetamide (PF-0477736).

3-Phosphoinositide-dependent kinase-1 ( PDK1 or PDPK1) inhibitors: 7-2-Amino-A/-[4- [5-(2-phenanthrenyl)-3-(trifluoromethyl)-1 /-/-pyrazol-1-yl]phenyl]-acetamide (OSU-03012, CAS 7421 12-33-0); Pyrrolidine-1 -carboxylic acid (3-{5-bromo-4-[2-(1 H-imidazol-4-yl)- ethylamino]-pyrimidin-2-ylamino}-phenyl)-amide (BX912, CAS 702674-56-4); and 4- Dodecyl-A/-1 ,3,4-thiadiazol-2-yl-benzenesulfonamide (PHT-427, CAS 1 191951 -57-1 ).

Protein Kinase C (PKC) activators: Bryostatin I (bryo-1 ) and Sotrastaurin (AEB071 ). B-RAF inhibitors: Regorafenib (BAY73-4506, CAS 755037-03-7); Tuvizanib (AV951 , CAS 475108-18-0); Vemurafenib (Zelboraf®, PLX-4032, CAS 918504-65-1 ); 5-[1 -(2-

Hydroxyethyl)-3-(pyridin-4-yl)-1 H-pyrazol-4-yl]-2,3-dihydroinden-1-one oxime (GDC-0879, CAS 905281-76-7); 5-[2-[4-[2-(Dimethylamino)ethoxy]phenyl]-5-(4-pyridinyl)-1 /-/-imidazol-4- yl]-2,3-dihydro-1 H-lnden-1-one oxime (GSK21 18436 or SB590885); (+/-)-Methyl (5-(2-(5- chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1 H-isoindol-1 -yl)-1 H-benzimidazol-2- yl)carbamate (also known as XL-281 and BMS908662) and N-(3-(5-chloro-1 H-pyrrolo[2,3- b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1 -sulfonamide (also known as PLX4720).

C-RAF Inhibitors: Sorafenib (Nexavar®); 3-(Dimethylamino)-A/-[3-[(4- hydroxybenzoyl)amino]-4-methylphenyl]-benzamide (ZM336372, CAS 208260-29-1 ); and 3- (1-cyano-1 -methylethyl)-A/-[3-[(3,4-dihydro-3-methyl-4-oxo-6-quinazoli nyl)amino]-4- methylphenyl]-benzamide (AZ628, CAS 1007871 -84-2).

Human Granulocyte colony-stimulating factor (G-CSF) modulators: Filgrastim (Neupogen®); Sunitinib malate (Sutent®); Pegilgrastim (Neulasta®) and Quizartinib (AC220, CAS 950769-58-1 ).

RET Inhibitors: Sunitinib malate (Sutent®); Vandetanib (Caprelsa®); Motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1 H-indol-6-yl)-2-[(4- pyridinylmethyl)amino]-3-pyridinecarboxamide, described in PCT Publication No. WO 02/066470); Sorafenib (BAY 43-9006); Regorafenib (BAY73-4506, CAS 755037-03-7); and Danusertib (PHA-739358).

FMS-like Tyrosine kinase 3 (FLT3) Inhibitors or CD135: Sunitinib malate (Sutent®); Quizartinib (AC220, CAS 950769-58-1 ); A/-[(1-Methyl-4-piperidinyl)methyl]-3-[3- (trifluoromethoxy)phenyl]- lmidazo[1 ,2-5]pyridazin-6-amine sulfate (SGI-1776, CAS 1 173928-26-1 ); and Vargatef (BIBF1 120, CAS 928326-83-4).

c-KIT Inhibitors: Pazopanib (Votrient®); Dovitinib dilactic acid (TKI258, CAS 852433-84- 2); Motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1 FI- indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxami de, described in PCT Publication No. WO 02/066470); Masitinib (Masivet®); Regorafenib (BAY73-4506, CAS 755037-03-7); Tivozanib (AV951 , CAS 475108-18-0); Vatalanib dihydrochloride (PTK787, CAS 212141- 51-0); Telatinib (BAY57-9352, CAS 332012-40-5); Foretinib (GSK1363089, formerly XL880, CAS 849217-64-7); Sunitinib malate (Sutent®); Quizartinib (AC220, CAS 950769- 58-1 ); Axitinib (Inlyta®); Dasatinib (BMS-345825); and Sorafenib (Nexavar®).

Bcr/Abl kinase inhibitors: Imatinib (Gleevec®); Inilotinib hydrochloride; Nilotinib (Tasigna®); Dasatinib (BMS-345825); Bosutinib (SKI-606); Ponatinib (AP24534); Bafetinib (INNO406); Danusertib (PHA-739358), AT9283 (CAS 1 133385-83-7); Saracatinib (AZD0530); and A/-[2-[(1 S,4R)-6-[[4-(Cyclobutylamino)-5-(trifluoromethyl)-2- pyrimidinyl]amino]-1 ,2,3,4-tetrahydronaphthalen-1 ,4-imin-9-yl]-2-oxoethyl]-acetamide (PF- 03814735, CAS 942487-16-3).

IGF-1R inhibitors: Linsitnib (OSI-906); [7-[frans-3-[(Azetidin-1-yl)methyl]cyclobutyl]-5-(3- benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine (AEW541 , CAS 475488-34-7); [5- (3-Benzyloxyphenyl)-7-[frans-3-[(pyrrolidin-1 -yl)methyl]cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin- 4-yl]amine (ADW742 or GSK552602A, CAS 475488-23-4); (2-[[3-Bromo-5-(1 , 1- dimethylethyl)-4-hydroxyphenyl]methylene]-propanedinitrile (Tyrphostin AG1024, CAS 65678-07-1 ); 4-[[(2S)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-3-[7-methy l-5-(4- morpholinyl)-1 /-/-benzimidazol-2-yl]- 2(1 /-/)-pyridinone (BMS536924, CAS 468740-43-4); 4- [2-[4-[[(2S)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-1 ,2-dihydro-2-oxo-3-pyridinyl]-7- methyl-1 /-/-benzimidazol-5-yl]- 1-piperazinepropanenitrile (BMS554417, CAS 468741 -42-6); (2S)-1-[4-[(5-Cyclopropyl-1 /-/-pyrazol-3-yl)amino]pyrrolo[2, 1-/][1 ,2,4]triazin-2-yl]-A/-(6-fluoro-3- pyridinyl)-2-methyl-2-pyrrolidinecarboxamide (BMS754807, CAS 1001350-96-4); Picropodophyllotoxin (AXL1717); and Nordihydroguareacetic acid.

IGF-1 R antibodies: Figitumumab (CP751871 ); Cixutumumab (IMC-A12); Ganitumab (AMG-479); Robatumumab (SCH-717454); Dalotuzumab (MK0646); R1507 (available from Roche); BIIB022 (available from Biogen); and MEDI-573 (available from Medlmmune).

MET inhibitors: Cabozantinib (XL184, CAS 849217-68-1 ); Foretinib (GSK1363089, formerly XL880, CAS 849217-64-7); Tivantinib (ARQ197, CAS 1000873-98-2); 1-(2-

Hydroxy-2-methylpropyl)-A/-(5-(7-methoxyquinolin-4-yloxy) pyridin-2-yl)-5-methyl-3-oxo-2- phenyl-2,3-dihydro-1 /-/-pyrazole-4-carboxamide (AMG 458); Cryzotinib (Xalkori®, PF- 02341066); (3Z)-5-(2,3-Dihydro-1 H-indol-1-ylsulfonyl)-3-({3,5-dimethyl-4-[(4- methylpiperazin-1-yl)carbonyl]-1 H-pyrrol-2-yl}methylene)-1 ,3-dihydro-2H-indol-2-one

(SU1 1271 ); (3Z)-N-(3-Chlorophenyl)-3-({3,5-dimethyl-4-[(4-methylpiperaz in-1-yl)carbonyl]- 1 H-pyrrol-2-yl}methylene)-N-methyl-2-oxoindoline-5-sulfonamid e (SU1 1274); (3Z)-N-(3-

Chlorophenyl)-3-{[3,5-dimethyl-4-(3-morpholin-4-ylpropyl) -1 H-pyrrol-2-yl]methylene}-N- methyl-2-oxoindoline-5-sulfonamide (SU1 1606); 6-[Difluoro[6-(1 -methyl-1 H-pyrazol-4-yl)- 1 ,2,4-triazolo[4,3-b]pyridazin-3-yl]methyl]-quinoline (JNJ38877605, CAS 943540-75-8); 2-[4- [1 -(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl]-1 H-pyrazol-1-yl]ethanol (PF04217903, CAS 956905-27-4); N-((2R)-1 ,4-Dioxan-2-ylmethyl)-N-methyl-N'-[3-(1-methyl- 1 H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1 ,2-b]pyridin-7-yl]sulfamide

(MK2461 , CAS 917879-39-1 ); 6-[[6-(1 -Methyl-1 H-pyrazol-4-yl)-1 ,2, 4-triazolo[4,3-b]pyridazin- 3-yl]thio]-quinoline (SGX523, CAS 1022150-57-7); and (3Z)-5-[[(2,6-

Dichlorophenyl)methyl]sulfonyl]-3-[[3,5-dimethyl-4-[[(2R) -2-(1-pyrrolidinylmethyl)-1- pyrrolidinyl]carbonyl]-1 /-/-pyrrol-2-yl]methylene]-1 ,3-dihydro-2/-/-indol-2-one (PHA665752, CAS 477575-56-7).

Epidermal growth factor receptor (EGFR) inhibitors: Erlotinib hydrochloride (Tarceva®), Gefitnib (Iressa®); N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3"S")-tetrahydro- 3- furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide, Tovok®); Vandetanib

(Caprelsa®); Lapatinib (Tykerb®); (3R,4R)-4-Amino-1-((4-((3- methoxyphenyl)amino)pyrrolo[2, 1-f][1 ,2,4]triazin-5-yl)methyl)piperidin-3-ol (BMS690514); Canertinib dihydrochloride (CI-1033); 6-[4-[(4-Ethyl-1-piperazinyl)methyl]phenyl]-A/-[(1 R)-1- phenylethyl]- 7/-/-Pyrrolo[2,3-cf]pyrimidin-4-amine (AEE788, CAS 497839-62-0); Mubritinib (TAK165); Pelitinib (EKB569); Afatinib (BIBW2992); Neratinib (HKI-272); A/-[4-[[1-[(3- Fluorophenyl)methyl]-1 /-/-indazol-5-yl]amino]-5-methylpyrrolo[2, 1-/][1 ,2,4]triazin-6-yl]- carbamic acid, (3S)-3-morpholinylmethyl ester (BMS599626); A/-(3,4-Dichloro-2- fluorophenyl)-6-methoxy-7-[[(3aa,53,6aa)-octahydro-2-methylc yclopenta[c]pyrrol-5- yl]methoxy]- 4-quinazolinamine (XL647, CAS 781613-23-8); and 4-[4-[[(1 R)-1- Phenylethyl]amino]-7/-/-pyrrolo[2,3-cf]pyrimidin-6-yl]-pheno l (PKI 166, CAS 187724-61-4). EGFR antibodies: Cetuximab (Erbitux®); Panitumumab (Vectibix®); Matuzumab (EMD- 72000); Trastuzumab (Herceptin®); Nimotuzumab (hR3); Zalutumumab; TheraCIM h-R3; MDX0447 (CAS 339151-96-1 ); and ch806 (mAb-806, CAS 946414-09-1 ). mTOR inhibitors: Temsirolimus (Torisel®); Ridaforolimus (formally known as deferolimus, (1 R,2R,4S)-4-[(2R)-2 [(1 R,9S, 12S, 15R, 16 E, 18R, 19R,21 R, 23S,24E,26E,28Z,30S,32S,35R)-

I , 18-dihydroxy-19,30-dimethoxy-15, 17,21 ,23, 29,35-hexamethyl-2,3, 10,14,20-pentaoxo-

I I ,36-dioxa-4-azatricyclo[30.3.1.0 ^4,9 ] hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2- methoxycyclohexyl dimethylphosphinate, also known as AP23573 and MK8669, and described in PCT Publication No. WO 03/064383); Everolimus (Afinitor® or RAD001 ); Rapamycin (AY22989, Sirolimus®); Simapimod (CAS 164301 -51-3); (5-{2,4-Bis[(3S)-3- methylmorpholin-4-yl]pyrido[2,3-c]pyrimidin-7-yl}-2-methoxyp henyl)methanol (AZD8055); 2- Amino-8-[frans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3 -pyridinyl)-4-methyl- pyrido[2,3-c]pyrimidin-7(8H)-one (PF04691502, CAS 1013101-36-4); ^-[1 ,4-dioxo-4-[[4-(4- oxo-8-phenyl-4/-/-1-benzopyran-2-yl)morpholinium-4-yl]methox y]butyl]-L-arginylglycyl-L-a- aspartylL-serine-, inner salt (SF1 126, CAS 936487-67-1 ); and N-[4-[[[3-[(3,5- dimethoxyphenyl)amino]-2-quinoxalinyl]amino]sulfonyl]phenyl] -3-methoxy-4-methyl- benzamide (XL765, also known as SAR245409); and (1 r,4r)-4-(4-amino-5-(7-methoxy-1 FI- indol-2-yl)imidazo[1 ,5-f][1 ,2,4]triazin-7-yl)cyclohexanecarboxylic acid (OSI-027).

Mitogen-activated protein kinase (MEK) inhibitors: XL-518 (also known as GDC-0973, Cas No. 1029872-29-4, available from ACC Corp.); Selumetinib (5-[(4-bromo-2- chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1 -methyl-1 FI-benzimidazole-6- carboxamide, also known as AZD6244 or ARRY 142886, described in PCT Publication No. W02003077914); 2-[(2-Chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4- difluoro- benzamide (also known as CI-1040 or PD184352 and described in PCT Publication No. W02000035436); N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]- benzamide (also known as PD0325901 and described in PCT Publication No. W02002006213); 2,3-Bis[amino[(2-aminophenyl)thio]methylene]- butanedinitrile (also known as U0126 and described in US Patent No. 2,779,780); N-[3,4- Difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl]-1 -[(2R)-2,3-dihydroxypropyl]- cyclopropanesulfonamide (also known as RDEA1 19 or BAY869766 and described in PCT Publication No. W0200701401 1 ); (3S,4R,5Z,8S,9S,1 1 E)-14-(Ethylamino)-8,9, 16-trihydroxy- 3,4-dimethyl-3,4,9, 19-tetrahydro-1 H-2-benzoxacyclotetradecine-1 ,7(8H)-dione] (also known as E6201 and described in PCT Publication No. W02003076424); 2’-Amino-3’- methoxyflavone (also known as PD98059 available from Biaffin GmbH & Co., KG, Germany); Vemurafenib (PLX-4032, CAS 918504-65-1 ); (R)-3-(2,3-Dihydroxypropyl)-6- fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]p yrimidine-4,7(3H,8H)-dione (TAK-733, CAS 1035555-63-5); Pimasertib (AS-703026, CAS 1204531-26-9); Trametinib dimethyl sulfoxide (GSK-1 120212, CAS 1204531-25-80); 2-(2-Fluoro-4-iodophenylamino)- N-(2-hydroxyethoxy)-1 ,5-dimethyl-6-oxo-1 ,6-dihydropyridine-3-carboxamide (AZD 8330); and 3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyet hoxy)-5-[(3-oxo-[1 ,2] oxazinan-2-yl)methyl]benzamide (CH 4987655 or Ro 4987655).

Alkylating agents: Oxaliplatin (Eloxatin®); Temozolomide (Temodar® and Temodal®); Dactinomycin (also known as actinomycin-D, Cosmegen®); Melphalan (also known as L- PAM, L-sarcolysin, and phenylalanine mustard, Alkeran®); Altretamine (also known as hexamethylmelamine (HMM), Hexalen®); Carmustine (BiCNU®); Bendamustine (Treanda®); Busulfan (Busulfex® and Myleran®); Carboplatin (Paraplatin®); Lomustine (also known as CCNU, CeeNU®); Cisplatin (also known as CDDP, Platinol® and Platinol®- AQ); Chlorambucil (Leukeran®); Cyclophosphamide (Cytoxan® and Neosar®); Dacarbazine (also known as DTIC, DIC and imidazole carboxamide, DTIC-Dome®); Altretamine (also known as hexamethylmelamine (HMM), Hexalen®); Ifosfamide (Ifex®); Prednumustine; Procarbazine (Matulane®); Mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, Mustargen®); Streptozocin (Zanosar®); Thiotepa (also known as thiophosphoamide, TESPA and TSPA, Thioplex®); Cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®); and Bendamustine HCI (Treanda®).

Aromatase inhibitors: Exemestane (Aromasin®); Letrozole (Femara®); and Anastrozole (Arimidex®).

Topoisomerase I inhibitors: Irinotecan (Camptosar®); Topotecan hydrochloride (Hycamtin®); and 7-Ethyl-10-hydroxycampothecin (SN38). Topoisomerase II inhibitors: Etoposide (VP-16 and Etoposide phosphate, Toposar®, VePesid® and Etopophos®); Teniposide (VM-26, Vumon®); and Tafluposide .

DNA Synthesis inhibitors: Capecitabine (Xeloda®); Gemcitabine hydrochloride (Gemzar®); Nelarabine ((2R,3S,4R,5R)-2-(2-am/no-6-methoxy-purin-9-yl)-5-

(hydroxymethyl)oxolane-3,4-diol, Arranon® and Atriance®); and Sapacitabine (1 -(2-cyano-2- deoxy-3-D-arabinofuranosyl)-4-(palmitoylamino)pyrimidin-2(1 /-/)-one).

Folate Antagonists or Antifolates: Trimetrexate glucuronate (Neutrexin®); Piritrexim isethionate (BW201 U); Pemetrexed (LY231514); Raltitrexed (Tomudex®); and Methotrexate (Rheumatrex®, Trexal®).

Immunomodulators: Afutuzumab (available from Roche®); Pegfilgrastim (Neulasta®); Lenalidomide (CC-5013, Revlimid®); Thalidomide (Thalomid®), Actimid (CC4047); and IRX-2 (mixture of human cytokines including interleukin 1 , interleukin 2, and interferon y, CAS 951209-71 -5, available from IRX Therapeutics).

G-Protein-coupled Somatostain receptors Inhibitors: Octreotide (also known as octreotide acetate, Sandostatin® and Sandostatin LAR®); Lanreotide acetate (CAS 127984-74-1 ); Seglitide (MK678); Vapreotide acetate (Sanvar®); and Cyclo(D-Trp-Lys- Abu-Phe-MeAla-Tyr)( BIM23027).

Interleukin-11 and Synthetic Interleukin-11 (IL-11): Oprelvekin (Neumega®).

Erythropoietin and Synthetic erythropoietin: Erythropoietin (Epogen® and Procrit®); Darbepoetin alfa (Aranesp®); Peginesatide (Hematide®); and EPO covalently linked to polyethylene glycol (Micera®).

Histone deacetylase (HDAC) inhibitors: Voninostat (Zolinza®); Romidepsin (Istodax®); Treichostatin A (TSA); Oxamflatin; Vorinostat (Zolinza®, Suberoylanilide hydroxamic acid); Pyroxamide (syberoyl-3-aminopyridineamide hydroxamic acid); Trapoxin A (RF-1023A); Trapoxin B (RF-10238); Cyclo[(aS,2S)-a-amino-r|-oxo-2-oxiraneoctanoyl-0-methyl-D- tyrosyl-L-isoleucyl-L-prolyl] (Cyl-1 ); Cyclo[(aS,2S)-a-amino-r|-oxo-2-oxiraneoctanoyl-0- methyl-D-tyrosyl-L-isoleucyl-(2S)-2-piperidinecarbonyl] (Cyl-2); Cyclic[L-alanyl-D-alanyl-(2S)- h-oxo-L-a-aminooxiraneoctanoyl-D-prolyl] (FIC-toxin); Cyclo[(aS,2S)-a-amino-r|-oxo-2- oxiraneoctanoyl-D-phenylalanyl-L-leucyl-(2S)-2-piperidinecar bonyl] (WF-3161 );

Chlamydocin ((S)-Cyclic(2-methylalanyl-L-phenylalanyl-D-prolyl-r|-oxo-L- a- aminooxiraneoctanoyl); Apicidin (Cyclo(8-oxo-L-2-aminodecanoyl-1-methoxy-L-tryptophyl-L- isoleucyl-D-2-piperidinecarbonyl); Romidepsin (Istodax®, FR-901228); 4-Phenylbutyrate; Spiruchostatin A; Mylproin (Valproic acid); Entinostat (MS-275, N-(2-Aminophenyl)-4-[N- (pyridine-3-yl-methoxycarbonyl)-amino-methyl]-benzamide); and Depudecin (4, 5:8, 9- dianhydro-1 ,2,6,7, 1 1-pentadeoxy- D-f/7reo-D-/cfo-Undeca-1 ,6-dienitol).

Biologic response modifiers: Include therapeutics such as interferons, interleukins, colony-stimulating factors, monoclonal antibodies, vaccines (therapeutic and prophylactic), gene therapy, and nonspecific immunomodulating agents. Interferon alpha (Intron®, Roferson®-A); Interferon beta; Interferon gamma; lnterleukin-2 (IL-2 or aldesleukin, Proleukin®); Filgrastim (Neupogen®); Sargramostim (Leukine®); Erythropoietin (epoetin); Interleukin-1 1 (oprelvekin); Imiquimod (Aldara®); Lenalidomide (Revlimid®); Rituximab (Rituxan®); Trastuzumab (Flerceptin®); Bacillus calmette-guerin (theraCys® and TICE® BCG); Levamisole (Ergamisol®); and Denileukin diftitox (Ontak®).

Plant Alkaloids: Paclitaxel (Taxol and Onxal™); Paclitaxel protein-bound (Abraxane®); Vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, Alkaban-AQ® and Velban®); Vincristine (also known as vincristine sulfate, LCR, and VCR, Oncovin® and Vincasar Pfs®); and Vinorelbine (Navelbine®).

Taxane anti-neoplastic agents: Paclitaxel (Taxol®); Docetaxel (Taxotere®); Cabazitaxel (Jevtana®, 1 -hydroxy-73, 103-dimethoxy-9-oxo-53, 20-epoxytax- 1 1 -ene-2a,4, 13a-triyl-4- acetate-2-benzoate-13-[(2R,3S)-3-{[(tert-butoxy)carbonyl]ami no}-2-hydroxy-3- phenylpropanoate); and Larotaxel ((2a^,4a,53,7a,103,13a)-4, 10-bis(acetyloxy)-13- ({(2R,3S)-3- [(ferf-butoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1- hydroxy-9- oxo-5,20-epoxy-7, 19-cyclotax-1 1 -en-2-yl benzoate).

Heat Shock Protein (HSP) inhibitors: Tanespimycin (17-allylamino-17- demethoxygeldanamycin, also known as KOS-953 and 17-AAG, available from SIGMA, and described in US Patent No. 4,261 ,989); Retaspimycin (IPI504), Ganetespib (STA-9090); [6- Chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin -2-yl]amine (BIIB021 or CNF2024, CAS 848695-25-0); frans-4-[[2-(Aminocarbonyl)-5-[4,5,6,7-tetrahydro-6,6- dimethyl-4-oxo-3-(trifluoromethyl)-1 /-/-indazol-1-yl]phenyl]amino]cyclohexyl glycine ester (SNX5422 or PF049291 13, CAS 9081 15-27-5); and 17-Dimethylaminoethylamino-17- demethoxygeldanamycin (17-DMAG).

Thrombopoietin (TpoR) agonists: Eltrombopag (SB4971 15, Promacta® and Revolade®); and Romiplostim (Nplate®).

Demethylating agents: 5-Azacitidine (Vidaza®); and Decitabine (Dacogen®).

Cytokines: lnterleukin-2 (also known as aldesleukin and IL-2, Proleukin®); Interleukin-1 1 (also known as oprevelkin, Neumega®); and Alpha interferon alfa (also known as IFN- alpha, Intron® A, and Roferon-A®).

17 a-hydroxyiase/C17,20 lyase (CYP17A1) inhibitors: Abiraterone acetate (Zyitga®).

Miscellaneous cytotoxic agents: Arsenic trioxide (Trisenox®); Asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, Elspar® and Kidrolase®); and Asparaginase Erwinia Chrysanthemi (Erwinaze®).

C-C Chemokine receptor 4 (CCR4) Antibody: Mogamulizumab (Potelligent®)

CD20 antibodies: Rituximab (Riuxan® and MabThera®); and Tositumomab (Bexxar®); and Ofatumumab (Arzerra®).

CD20 Antibody Drug Conjugates: Ibritumomab tiuxetan (Zevalin®); and Tositumomab,

CD22 Antibody Drug Conjugates: Inotuzumab ozogamicin (also referred to as CMC-544 and WAY-207294, available from Flangzhou Sage Chemical Co., Ltd.)

CD30 mAb-cytotoxin Conjugates: Brentuximab vedotin (Adcetrix®);

CD33 Antibody Drug Conjugates: Gemtuzumab ozogamicin (Mylotarg®),

CD40 antibodies: Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc),

CD52 antibodies: Alemtuzumab (Campath®),

Anti-CS1 antibodies: Elotuzumab (FluLuc63, CAS No. 915296-00-3) CTLA-4 inhibitor antibodies: Tremelimumab (lgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675,206); and Ipilimumab (CTLA-4 antibody, also known as MDX-010, CAS No. 477202-00-9).

TPH inhibitors: telotristat

PARP (poly ADP ribose polymerase) inhibitors: olaparib (Lynparza), rucaparib (Rubraca), Niraparib (Zeluja), Talazoparib, Veliparib.

PD-1 Inhibitors : Spartalizumab (PDR001 , Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck & Co), Pidilizumab (CureTech), MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB-A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune).

PD-L1 inhibitors: Durvalumab, Atezolizumab, Avelumab

In particular, the present disclosure provides the combination or combination therapy of the complex formed by the radionuclide ¹⁷⁷ Lu (Lutetium-177), and a somatostatin receptor binding peptide linked to the chelating agent as defined herein, or the combination or combination therapy of the pharmaceutical aqueous solution as defined herein, together with one of more therapeutic agents selected from the group consisting of octreotide, lanreotide, vaproreotide, pasireotide, satoreotide, everolimus, temozolomide, telotristat, sunitinib, sulfatinib, ribociclib, entinostat, and pazopanib. In particular embodiments, those combinations are for use in the treatment of NET tumors, e.g. GEP-NET, pulmonary NET, pNET, lung NET, Carcinoid syndrome, SCLC. In particular embodiments, the disclosure provides a method of treating a patient with NET tumors, e.g. GEP-NET, pulmonary NET, pNET, lung NET, Carcinoid syndrome, SCLC, by administering a therapeutically effective amount of the components of those combinations.

In particular embodiments, the present disclosure provides the combination or combination therapy of the complex formed by the radionuclide ¹⁷⁷ Lu (Lutetium-177), and a somatostatin receptor binding peptide linked to the chelating agent as defined herein, or the combination or combination therapy of the pharmaceutical aqueous solution as defined herein, together with one of more immuno-oncology therapeutic agents selected from the group consisting of PD-1 , PD-L1 and CTLA-4 inhibitors, in particular the l-O therapeutic agents selected from Spartalizumab, Nivolumab, Pembrolizumab, Pidilizumab, Durvalumab, Atezolizumab, Avelumab, Ipilimumab, and Tremelimumab. In particular embodiments, those combinations are for use in the treatment of NET tumors, e.g. GEP-NET, pulmonary NET, pNET, lung NET, Carcinoid syndrome, SCLC. In particular embodiments, the invention provides a method of treating a patient with NET tumors, e.g. GEP-NET, pulmonary NET, pNET, lung NET, Carcinoid syndrome, SCLC, by administering a therapeutically effective amount of the components of those combinations.

EXAMPLES

Hereinafter, the present invention is described in more details and specifically with reference to the examples, which however are not intended to limit the present invention.

Materials:

The ¹⁷⁷ LUCI ₃ may be obtained from commercial sources, e.g. I.D.B. Holland BV. The DOTA°- Tyr ³ -Octreotate may be obtained from commercial sources, e.g. by piCHEM Forschungs- und Entwicklungs GmbH, Austria. All other components of the drug product are commercially available from various sources.

Example 1 : Composition of drug product

The Drug Product ( ¹⁷⁷ Lu-DOTA°-Tyr ³ -Octreotate 370 MBq/mL solution for infusion) is designed as a sterile ready-to-use solution for infusion containing ¹⁷⁷ Lu-DOTA°-Tyr ³ - Octreotate as Drug Substance with a volumetric activity of 370 MBq/mL at reference date and time (calibration time (to)). Calibration time (to) corresponds to the End of Production (EOP = tO) which is the time of measurement of the activity of the first QC vial. The shelf-life of Drug Product is defined as 72 hours after calibration time. Drug Product is a single dose vial, containing suitable amount of solution that allows delivery of 7.4 GBq of radioactivity at injection time.

Manufacturing site prepares single doses calibrated within the range of 7.4 GBq ± 10 % (200 mCi) after the end of production. Certificates of analysis reports both the exact activity provided and the time when this activity is reached. This value is declared as“Injection time: {DD MM YYYY} {hh:mm} UTC”. Considering the variable injection time and constant decay of the radionuclide, the filling volume needed for an activity of 7.4 GBq at injection time is calculated and can range from 20.5 and 25.0 mL.

Composition of drug product per mL

EOP: End of Production=t ₀ =activity measurement of the first vial=calibration time t _c

RSE: Radiation Stability Enhancer

Example 2: Manufacturing of drug product

For a 74 GBq batch size (2 Ci batch size) a ¹⁷⁷ LuCI ₃ solution, about 74 GBq in HCI, is mixed together with a DOTA-Tyr ³ -Octreotate (about 2 mg) solution, and a Reaction Buffer solution, containing an antioxidant agent (and stabilizator against radiolytic regradation) (i.e. Gentisic acid, about 157 mg) and a buffer system (i.e. Acetate buffer system), resulting in a total of about 5.5 mL solution, which is used for radiolabelling that occurs at a temperature of about 90 to about 98°C within less than 15 minutes.

The synthesis is carried out using a single use disposable kit cassette installed on the front of the synthesis module which contains the fluid pathway (tubing), reactor vial and sealed reagent vials.

The obtained mother solution is diluted with a solution containing a chelating agent (i.e. DTPA), an antioxidant agent (i.e. Ascorbic acid) sodium hydroxide, and sodium chloride and, then sterile filtered through 0.2 pm to give the ready-to-use solution as described in Example 1 with a pH of 4.5-6.0, in particular 5.2-5.3. Finally, the solution is dispensed in volumes of from 20.5 to 25.0 mL into sterile vials. The stoppered vials are enclosed within lead containers for protective shielding.

Manufacturing Process can also be implemented for batch sizes higher than 74GBq. In this case the amount of the raw materials (Lutetium, peptide and Reaction Buffer) are multiplied to guarantee the same raw materials ratio.

Example 3: Combination therapies using CA20948 tumor model

We have xenografted BALB-c immunocompromised mice with neuroendocrine tumor cells. To increase the window of opportunity, we have started PARP inhibitor administration two days prior to PRRT injection for in total 14 days.

Outcome

Animals from both PRRT and PRRT+olaparib groups showed a tumor shrinkage starting at 3 days after injection. The average tumor size from the PRRT+olaparib group decreased faster and to a smaller size. Time until tumor regrowth in the PRRT+olaparib is significantly increased compared to PRRT. The speed of tumor regrowth is the same in both groups. Median survival of the PRRT+olaparib is significantly increased compared to PRRT and 1 animal (10%) showed a clinical complete response in the PRRT+olaparib group. No effect on tumor growth and survival was observed by olaparib compared to vehicle (see Figure 1 ).

No signs of acute toxicity were observed in any of the groups. Concluding remarks

The in vivo experiments show activity in which this regimen of Olaparib can be used as radiosensitizer for PRRT in GEP-NETs.