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Phase 1 Dose-Escalation Study of Oral Tyrosine Kinase Inhibitor Masitinib in Advanced And/Or Metastatic Solid Cancers

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Phase 1 Dose-Escalation Study of Oral Tyrosine Kinase Inhibitor Masitinib in Advanced And/Or Metastatic Solid Cancers ARTICLE IN PRESS EUROPEAN JOURNAL OF CANCER xxx (2009) xxx– xxx available at www.sciencedirect.com journal homepage: www.ejconline.com Phase 1 dose-escalation study of oral tyrosine kinase inhibitor masitinib in advanced and/or metastatic solid cancers J.C. Soriaa,*, C. Massarda, N. Magne´a, Th. Baderb, C.D. Mansfieldb, J.Y. Blayc, B.N. Buid, A. Moussyb, O. Herminee,*, J.P. Armanda aUniversite´ Paris XI, SITEP (Service des Innovations The´rapeutiques Pre´coces), De´partement de Me´decine, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif, France bAB Science, S.A., Paris, France cUnite´ Cytokines et Cancers, Centre Le´on Be´rard, Lyon, France dInstitut Bergonie´, Bordeaux, France eService d’He´matologie, Centre de Re´fe´rence des Mastocytoses, CNRS UMR 8147, Universite´ Paris V Rene´ Descartes, Assistance Publique Hoˆpitaux de Paris, Hoˆpital Necker, Paris, France ARTICLE INFO ABSTRACT Article history: Background: Masitinib is a tyrosine kinase inhibitor with a pre-clinical profile suggesting Received 29 April 2009 greater affinity and selectivity in vitro for the wild-type c-Kit receptor and its juxtamem- Accepted 7 May 2009 brane mutation than imatinib. Methods: This dose-escalation study was conducted in patients with advanced and/or met- astatic cancer to determine the maximum tolerated dose (MTD) for orally administered Keywords: masitinib over a 12-week period. Secondary objectives were a clinical assessment of masit- Masitinib inib’s activity in cancer patients and establishment of a pharmacokinetic profile. c-Kit Results: Forty patients with various solid tumours (predominantly GIST, 19 patients) were Imatinib treated with masitinib at doses ranging between 0.7 and 17.2 mg/kg/day. Although the GIST MTD was not formally reached, an acceptable dose for chronic use was identified at Tyrosine kinase inhibitor 12 mg/kg/day. Treatment-related AEs were frequent (38/40 patients), however, the majority Phase 1 study were grade 1 or 2 and demonstrated dose dependency at higher concentrations. Pharmaco- kinetic results showed a linear, dose-dependent increase of Cmax and AUC. One of two GIST patients with imatinib intolerance had a partial response at 11.1 mg/kg/day. About 29% of the imatinib-resistant GIST population and 38% of the overall population had stable dis- ease. Conclusions: The safety profile of masitinib at 12 mg/kg/day b.i.d. for the treatment of solid cancers appears favourable and compatible with a long-term regimen. Tumour control rate in imatinib-resistant patients was encouraging, hence, the activity of masitinib in c-Kit expressing tumours, such as GIST, warrants further exploration as first-line anticancer therapy as well as for imatinib-resistant patients. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction been involved in cancer and other proliferative disorders.1 TKs may be cell surface receptors or cytoplasmic proteins.2 Tyrosine kinases (TKs) play a fundamental role in signal Specific TK-inhibitors are of interest as potential therapies transduction, with the deregulated activity of these enzymes for solid tumours or as part of synergistic combination * Corresponding authors: Tel.: +33 1 42 11 43 85; fax: +33 1 42 11 61 70 (J.C. Soria). E-mail addresses: [email protected] (J.C. Soria), [email protected] (O. Hermine). 0959-8049/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2009.05.010 Please cite this article in press as: Soria JC et al., Phase 1 dose-escalation study of oral tyrosine kinase inhibitor masitinib in advanced and/or metastatic solid cancers, Eur J Cancer (2009), doi:10.1016/j.ejca.2009.05.010 ARTICLE IN PRESS 2 EUROPEANJOURNALOFCANCERxxx (2009) xxx– xxx regimens. Molecular targeted therapies have been developed In the present report we describe the results of a phase 1 to limit tumour growth and metastatic diffusion in various study in patients with solid tumours. The primary objective ways and at different stages of cancer development.3 was to identify the maximum tolerated dose (MTD) of orally Deregulation of c-Kit, the stem cell factor receptor upon administered masitinib as a single agent. Secondary objec- which some types of tumour cells depend for proliferation, tives were to assess the safety, efficacy and the pharmacoki- has been implicated in a number of human cancers including netic (PK) profile of masitinib in patients suffering from gastro-intestinal stromal tumour (GIST), acute myelogenous advanced cancer, as well as the antitumoural activity of leukaemia, small cell lung carcinomas, seminoma, ovarian masitinib to explore its potential in first-line or combination cancer, breast carcinoma, colorectal carcinoma, neuroblasto- therapy in imatinib-resistant or -intolerant GIST patients, mas and mastocytosis.3,4 Of these, GIST is exemplary of the and in patients with c-Kit positive solid tumours naı¨ve to strong relation between the SCF/c-Kit pathway and pathogen- imatinib. esis of cancer, with 90% of all GISTs showing overexpression of c-Kit, and 70–80% showing mutations, respectively.5,6 The 2. Patients and methods majority of these mutations are in-frame deletions and mis- sense mutations clustered at the 5’-end of the juxtamem- 2.1. Study design brane domain (exon 11). A rare mutation, an Ala502-Tyr503 duplication in exon 9, is specific for intestinal GISTs.7,8 This was a multicentre, non-randomised, open-label, sequen- Imatinib (GleevecÒ, STI571; Novartis) is the forerunner of tial cohort, dose-escalation phase1 study in adults with ad- such therapeutic agents and an example of a TK inhibitor that vanced and/or metastatic cancer (Fig. 1). Masitinib was not only competes with ATP and inhibits the activity of the administered per os for up to 12 weeks, or until unacceptable Breakpoint Cluster Region-Abelson kinase (BCR-ABL), but also toxicity or documentation of disease progression (as defined c-Kit or PDGF receptors (Table 1). Masitinib, the investiga- in Response Evaluation Criteria in Solid Tumours [RECIST]).9 tional drug of this study, is a novel TK inhibitor that potently Upon conclusion of the dose-escalation cohorts, GIST pa- inhibits wild-type (WT) c-Kit and its activated form, mutated tients resistant or intolerant to imatinib and patients with in the juxtamembrane region (JM), PDGFRa, PDGFRb, Lyn, and c-Kit positive solid tumours, who received chemotherapy to a lesser extent FGFR3 and the FAK pathway. In cell prolifer- other than imatinib, were also evaluated for safety and anti- ation assays, masitinib inhibits with an IC50 at 3 nM c-Kit JM, tumour activity of masitinib. 150 nM c-Kit WT, 250 nM PDGFRa, PDGFRb and 2.5 lMr FGFR3. In kinase assays, Lyn activity was inhibited with an IC50 of 2.2. Patient selection 400 nM and masitinib (1 lM) reduced FAK phosphorylation by 21% (Table 1). Due to its specificity masitinib may exhibit Patients with histologically proven advanced solid malignan- a better safety profile than other TK inhibitors and could cies for which no standard alternative curative therapy could therefore be effective in imatinib-intolerant patients. In vivo be proposed were eligible. All patients were required to have masitinib showed significant antitumour activity after intra- at least one measurable target site. Other eligibility criteria venous (i.v.) or oral administration at well-tolerated doses in included the following: age P18 years, an Eastern Coopera- a BALB/c nude mouse model with a subcutaneous graft of a tive Oncology Group (ECOG) performance status between 0 transgenic murine hematopoietic cell line, transfected with and 2 and the absence of serious concomitant medical disor- a gene encoding c-Kit JMD27. Masitinib given at either 100 ders. Additionally, patients had to exhibit adequate renal or 200 mg/kg resulted in a complete dissolution of the tumour function (serum creatinine <1.5 times the upper limit of nor- following a 10-day treatment (Dubreuil et al., submitted). mal (ULN) or a calculated creatinine clearance >40 ml/min, adequate bone marrow function (WBC count >3500/mm,3 absolute neutrophil count [ANC] >2000 mm3, platelet count Table 1 – Inhibition of protein kinases: comparison of >105/mm3 and haemoglobin >11 g/dl), and adequate liver masitinib to imatinib. function (total bilirubin value <1.5 times ULN, ALAT level Enzyme IC50 (lM) <2.5 times ULN and ASAT <2.5 times ULN). An effective con- traceptive method was requested for women of childbearing Masitinib Imatiniba age and a negative pregnancy test was required prior to treat- b c c-Kit (exon 11 mutant) 0.003 0.027 ment administration. Patients were excluded if they were c-Kit WT 0.15 0.41 pregnant or nursing, had a known history of brain metasta- PDGFRa, b 0.25, 0.02 0.4, 0,44 ses, myocardial infarction or coronary disease, or had a his- Lyn 0.4 2 FAK 5–10 n/a tory of gastro-intestinal (GI) disorder that could interfere ABL 1.5 0.2 with drug absorption. Patients with a history of any other FGFR3 2.5 5.7 (R1) malignancy, apart from in situ carcinoma of the cervix or ba- VEGFR1 >10 19.5 sal cell carcinoma of the skin within five years prior to entry SRC 2 3 to the study, were also excluded. Patients could not have Concentrations causing a 50% reduction in kinase activity (IC50) are undergone surgery within the last six weeks and should not given. have been treated within the preceding four weeks to enrol- 10 a From Deininger et al. ment with any investigational drug, chemotherapy, radio- b Determined in transfected cells. therapy, immunotherapy or hormonal therapy. The c From Weisberg et al.19 exclusion period was extended to six weeks for previous Please cite this article in press as: Soria JC et al., Phase 1 dose-escalation study of oral tyrosine kinase inhibitor masitinib in advanced and/or metastatic solid cancers, Eur J Cancer (2009), doi:10.1016/j.ejca.2009.05.010 ARTICLE IN PRESS EUROPEAN JOURNAL OF CANCER xxx (2009) xxx– xxx 3 Fig.
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