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Method of Optimizing the Treatment of Philadelphia-positive Leukemia with lmatinib Mesylate

The present invention relates to a method of treating Philadelphia-positive leukemia (Ph 1 H+π leukemia) in a human patient population. In a particular aspect, the present invention relates to a method of treating chronic myeloid leukemia (CML) in a human patient population.

In May 2001 the mesylate salt of N-{5-[4-(4-methyl~piperazino-methyl)-benzoylamido]-2- methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine (lmatinib mesylate, STI571B, Glivec®) was approved by the FDA for the treatment of CML in patients who had failed to benefit from IFN- alpha therapy. Glivec became very soon the standard of care for the treatment of CML.

In the International Randomized Study of Interferon and STI571 (IRIS) the therapeutic benefit for CML patients treated with lmatinib mesylate was monitored over several years. In WO2008/036792 a method of optimizing the treatment of Ph+ leukemia is described, which is based on the results of the results of the IRIS and a study conducted at the University of Bordeaux. WO2008/036792 teaches that the treatment of Ph+ leukemia using a Bcr-Abl inhibitor, especially lmatinib mesylate, can be optimized by adjusting the dose of the Bcr-Abl inhibitor applied to an individual patient in a manner that a specific minimum plasma trough level (Cmin) is achieved in that individual patient.

The OCT-1 protein is a member of the largest superfamily of transporters, the solute carrier family (Koepsell H, Endou H. Pflugers Arch. 2004;447:666-676) which transport in an elec- trogenic fashion a variety of organic cations, including drugs, toxins and other xenobiotics. The transporter is predicted to have 12 transmembrane domains, and binding pockets with partially overlapping interaction domains for different substrates and inhibitors (Koepsell H, Schmitt BM ₁ Gorboulev V. Rev Physiol Biochem Pharmacol. 2003; 150:36-90). Post transcriptional regulation of OCT-1 by phosphorylation status (Ciarimboli G, Schlatter E. Pflugers Arch. 2005;449:423-441 ) and such compounds as PKA ₁ Src-like p56 and CaM have also been demonstrated.

In a further development of the invention described in WO2008/036792 and on the basis of a further evaluation of the data of clinical studies in CML. including the IRIS study, the present invention provides an improved method for treating Ph+ leukemias in human patients being 53142A

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treated with lmatinib or a pharmaceutically acceptable salt thereof. It was now surprisingly found that CML patients having a low OCT-1 Activity experience a substantially higher therapeutic benefit from the methods described in WO2008/036792 than those having a relatively high OCT-1 Activity. Actually, it was found that the chance of CML patients having an lmatinib Cmin value below the threshold of at least 800 ng/mL blood and at the same time a low OCT-1 Activity have no chance to obtain an MMR at 12 months, which is a critical landmark for successful treatment of Ph+ leukemia with a Bcr-Abl inhibitor such as lmatinib mesylate, whereas an lmatinib Cmin value below the threshold mentioned above has no impact on the treatment outcome for those patients having a high OCT-1 Activity.

CML belongs to the group of Ph+ leukemia. The results obtained with the CML patient population described herein can be transferred directly to the whole group of Ph+ leukemias. The reason for that is that the characterizing feature of Ph+ leukemias is the existence of the Philadelphia chromosome causing the Bcr-Abl fusion protein. The latter protein is the target of all Bcr-Abl inhibitors.

The abbreviation "Ph+ ALL" as used herein denotes Philadelphia chromosome positive acute lymphoblastic leukemia.

The term "major molecular response (MMR)" as used herein means a 3 logarithm reduction in BCR-ABL transcripts, quantified from peripheral blood using real-time quantitative re- verse-transcriptase polymerase chain reaction, after, e.g. 12 months lmatinib mesylate therapy.

The term "complete cytogenic response (CCR)" as used herein means 0 % Philadelphia- chromosome positive metaphases among at least 20 or 25 cells in metaphase in the bone marrow aspirate (Colombat M, Fort MP, Chollet C ₁ et al. Molecular remission in chronic myeloid leukemia patients with sustained complete cytogenetic remission after imatinib mesylate treatment. Haematologica 2006;91 :162-8.).

The term "method of treatment" as used herein relates also to a method of prevention of the diseases mentioned herein, i.e. the prophylactic administration of a pharmaceutical composition comprising Imatinib mesylate to healthy patients to prevent the development of the diseases mentioned herein. 53142A

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The terms "adjusting the dose" and "the dose of ... is adjusted" as used herein preferably denote that the dose referred to is increased or decreased.

OCT-1 Activity as referred to herein is measured in pre-therapy blood from CML patients by calculating the difference in intracellular uptake and retention (IUR) of [ ¹⁴ C]-lmatinib with and without OCT-1 inhibition. For instance, OCT-1 Activity can be calculated as the difference in IUR in the absence (total IUR) and presence of prazosin, to provide a measure of the actual activity of the OCT-1 protein in the transport of imatinib. For example: [Total IUR 32ng/200,000 cells)] - [prazosin IUR 23ng/200,000 cells] gives an OCT-1 Activity of 9ng/200,000 cells. However, the present invention also embraces corresponding methods employing alternative assays or processes for determining the OCT-1 Activity. Methods for the determination of the OCT-Activity are, for instance, described in Blood, 2007 Dec 1 ; 110(12):4064-72.

Hence, the present invention relates to a method of treating Ph+ leukemia, such as CML or Ph+ ALL, in a human patient suffering from Ph+ leukemia comprising the steps of

(a) administering a predetermined fixed amount of Imatinib as a free base or in the form of a pharmaceutically acceptable salt thereof, e.g. an oral daily dose of 400 mg or 800 mg of the mono-mesylate salt of Imatinib, to the human patient,

(b) collecting at least one blood sample from the patient, e.g. within the first 12 months of treatment, especially the first 3 months, preferably within the first 30 days,

(c) determining the plasma trough level (Cmin) of Imatinib,

(d) determining the OCT-1 Activity in the blood sample, and

(e) adjusting the dose of Imatinib applied to the individual patient in a manner that an Imatinib Cmin value is achieved in the patient of at least 800 ng/mL, if in step (c) an Imatinib Cmin value of less than 800 ng/mL is found and in step (d) an OCT-1 Activity is found below 6.0 to 10.0 ng/200,000 cells, especially 8.0 to 8.5 ng/200,000 cells.

Furthermore, the present invention relates to the use of Imatinib as a free base or in the form of a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a Ph+ leukemia, wherein

(a) administering a predetermined fixed amount of Imatinib as a free base or in the form of a pharmaceutically acceptable salt thereof to the human patient, 53142A

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(b) collecting at least one blood sample from the patient,

(c) determining the plasma trough level (Cmin) of Imatinib,

(d) determining the OCT-1 Activity in the blood sample, the dose of Imatinib applied to the individual patient is adjusted in a manner that an Imatinib Cmin value is achieved in the patient of at least 800 ng/mL, if in step (c) an Imatinib Cmin value of less than 800 ng/mL is found after administration of the predetermined fixed amount of Imatinib and in step (d) an OCT-1 Activity is found below 6.0 to 10.0 ng/200,000 cells.

Preferably, the Imatinib Cmin level is adjusted to a value between 800 and 3500 ng/mL, more preferably a Cmin between 1000 and 3000 ng/mL. At a Cmin value above 3000 ng/mL and even more above 3500 ng/mL the risk of adverse events is outweighing the therapeutic benefit of high Imatinib blood levels.

Preferably, the Ph+ leukemia is Philadelphia chromosome Ph+ ALL or, preferably, CML.

In one embodiment of the present invention, the predetermined fixed amount referred to herein under step (a) represents a therapeutically effective amount.

Throughout the present invention, preferably the mono-mesylate salt of Imatinib is used in step (a), e.g. in an oral daily dose of between 200 and 800 mg, preferably in a daily dose of 400 mg.

The methods described herein are particularly beneficial for CML patients having an Intermediate Sokal score (ISS). Methods to determine the ISS are known to the person skilled in the art.

Imatinib is specifically disclosed in the patent applications US 5,521 ,184, the subject-matter of which is hereby incorporated into the present application by reference. Imatinib can also be prepared in accordance with the processes disclosed in WO03/066613.

For the purpose of the present invention, Imatinib is preferably applied in the form of its mono-mesylate salt. Imatinib mono-mesylate can also be prepared in accordance with the processes disclosed in US 6,894,051 the subject-matter of which is hereby incorporated into 53142 A

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the present application by reference. Comprised are likewise the corresponding polymorphs, e.g. crystal modifications, which are disclosed therein.

In step (a) of the method described above, in particular a daily dose of between 200 and 800 mg, e.g. 400 mg, of the mono-mesylate salt of lmatinib is administered orally, lmatinib mono- mesylate can be administered in dosage forms as described in US 5,521 ,184, US 6,894,051, US 2005-0267125 or WO2006/121941.

The collection of a blood sample from CML patients required under step (b) of the methods described herein can be accomplished by standard procedures being state of the art. A suitable procedure for the determination of the plasma trough level Cmin of lmatinib and N-{5- [4-(piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-py ridyl)-2-pyrimidine-amine is described by R. Bakhtiar R et al. in J Chromatogr B Analyt Technol Biomed Life Sci. 2002 Mar 5;768(2):325-40.