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Phase 1 dose-escalation study of oral tyrosine kinase inhibitor masitinib in advanced and/or metastatic solid cancers

      Abstract

      Background

      Masitinib is a tyrosine kinase inhibitor with a pre-clinical profile suggesting greater affinity and selectivity in vitro for the wild-type c-Kit receptor and its juxtamembrane mutation than imatinib.

      Methods

      This dose-escalation study was conducted in patients with advanced and/or metastatic cancer to determine the maximum tolerated dose (MTD) for orally administered masitinib over a 12-week period. Secondary objectives were a clinical assessment of masitinib’s activity in cancer patients and establishment of a pharmacokinetic profile.

      Results

      Forty patients with various solid tumours (predominantly GIST, 19 patients) were treated with masitinib at doses ranging between 0.7 and 17.2 mg/kg/day. Although the MTD was not formally reached, an acceptable dose for chronic use was identified at 12 mg/kg/day. Treatment-related AEs were frequent (38/40 patients), however, the majority were grade 1 or 2 and demonstrated dose dependency at higher concentrations. Pharmacokinetic 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 disease.

      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.

      Keywords

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      References

        • Hanahan D.
        • Weinberg R.A.
        The hallmarks of cancer.
        Cell. 2000; 100: 57-70
        • Heinrich M.C.
        • Griffith D.J.
        • Druker B.J.
        • Wait C.L.
        • Ott K.A.
        • Zigler A.J.
        Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor.
        Blood. 2000; 96: 925-932
        • Heinrich M.C.
        • Blanke C.D.
        • Druker B.J.
        • Corless C.L.
        Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies.
        J Clin Oncol. 2002; 20: 1692-1703
        • Lennartsson J.
        • Jelacic T.
        • Linnekin D.
        • Shivakrupa R.
        Normal and oncogenic forms of the receptor tyrosine kinase kit.
        Stem Cells. 2005; 23: 16-43
        • Hirota S.
        • Isozaki K.
        • Moriyama Y.
        • Hashimoto K.
        • Nishida T.
        • Ishiguro S.
        • et al.
        Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.
        Science. 1998; 279: 577-580
        • Miettinen M.
        • Lasota J.
        Gastrointestinal stromal tumors (GISTs): definition, occurrence, pathology, differential diagnosis and molecular genetics.
        Pol J Pathol. 2003; 54: 3-24
        • Miettinen M.
        • Lasota J.
        Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis.
        Arch Pathol Lab Med. 2006; 130: 1466-1478
        • Sleijfer S.
        • Wiemer E.
        • Verweij J.
        Drug Insight: gastrointestinal stromal tumors (GIST) – the solid tumor model for cancer-specific treatment.
        Nat Clin Pract Oncol. 2008; 5: 102-111
        • Therasse P.
        • Arbuck S.G.
        • Eisenhauer E.A.
        • Wanders J.
        • Kaplan R.S.
        • Rubinstein L.
        • et al.
        New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.
        J Natl Cancer Inst. 2000; 92: 205-216
        • Deininger M.
        • Buchdunger E.
        • Druker B.J.
        The development of imatinib as a therapeutic agent for chronic myeloid leukemia.
        Blood. 2005; 105: 2640-2653
        • Provenzano P.P.
        • Inman D.R.
        • Eliceiri K.W.
        • Beggs H.E.
        • Keely P.J.
        Mammary epithelial-specific disruption of focal adhesion kinase retards tumor formation and metastasis in a transgenic mouse model of human breast cancer.
        Am J Pathol. 2008; 173: 1551-1565
        • Hernandez-Hansen V.
        • Mackay G.A.
        • Lowell C.A.
        • Wilson B.S.
        • Oliver J.M.
        The Src kinase Lyn is a negative regulator of mast cell proliferation.
        J Leukoc Biol. 2004; 75: 143-151
        • Linnekin D.
        • DeBerry C.S.
        • Mou S.
        Lyn associates with the juxtamembrane region of c-Kit and is activated by stem cell factor in hematopoietic cell lines and normal progenitor cells.
        J Biol Chem. 1997; 272: 27450-27455
        • Kerkela R.
        • Grazette L.
        • Yacobi R.
        • Iliescu C.
        • Patten R.
        • Beahm C.
        • et al.
        Cardiotoxicity of the cancer therapeutic agent imatinib mesylate.
        Nat Med. 2006; 12: 908-916
        • Judson I.
        • Demetri G.
        Advances in the treatment of gastrointestinal stromal tumours.
        Ann Oncol. 2007; 18: 20-24
        • Goodman V.L.
        • Rock E.P.
        • Dagher R.
        • Ramchandani R.P.
        • Abraham S.
        • Gobburu J.V.
        • et al.
        Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma.
        Clin Cancer Res. 2007; 13: 1367-1373
        • Chu T.F.
        • Rupnick M.A.
        • Kerkela R.
        • Dallabrida S.M.
        • Zurakowski D.
        • Nguyen L.
        • et al.
        Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib.
        Lancet. 2007; 370: 2011-2019
        • Deininger M.W.
        Nilotinib.
        Clin Cancer Res. 2008; 14: 4027-4031
        • Weisberg E.
        • Manley P.W.
        • Breitenstein W.
        • Bruggen J.
        • Cowan-Jacob S.W.
        • Ray A.
        • et al.
        Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl.
        Cancer Cell. 2005; 7: 129-141