A phase I trial of imatinib in combination with mFOLFOX6–bevacizumab in patients with advanced colorectal cancer

• Published in: Cancer chemotherapy and pharmacology 2013-02, Vol.71 (2), p.321-330
• Main Authors: Michael, M., Zalcberg, J., Gibbs, P., Lipton, L., Gouillou, M., Jefford, M., McArthur, G., Copeman, M., Lynch, K., Tebbutt, N. C.
• Format: Article
• Language: English
• Subjects: Aged; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Arterial hypertension. Arterial hypotension; Benzamides; Bevacizumab; Biological and medical sciences; Blood and lymphatic vessels; Cancer Research; Cardiology. Vascular system; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Female; Fluorouracil - administration & dosage; Fluorouracil - pharmacokinetics; Fluorouracil - therapeutic use; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Imatinib Mesylate; Leucovorin - administration & dosage; Leucovorin - pharmacokinetics; Leucovorin - therapeutic use; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncology; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - pharmacokinetics; Organoplatinum Compounds - therapeutic use; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Piperazines - administration & dosage; Piperazines - pharmacokinetics; Piperazines - therapeutic use; Pyrimidines - administration & dosage; Pyrimidines - pharmacokinetics; Pyrimidines - therapeutic use; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-012-2009-5

Purpose Platelet-derived growth factor receptor (PDGFR) inhibition by reducing tumoral interstitial fluid pressure might increase the efficacy of chemotherapy. Imatinib inhibits PDGFR kinase activity at therapeutically relevant doses. This phase I study aimed to assess the maximal tolerated dose (MTD) of imatinib in combination with mFOLFOX6–bevacizumab in patients with advanced colorectal cancer and to identify pharmacokinetic (PK) interactions and toxicities. Methods Eligible patients had measurable disease and adequate organ function. On day-14, patients commenced imatinib daily plus bevacizumab (5 mg/kg/2 weekly). Two weeks later (day 1), patients were also treated with full dose mFOLFOX6–bevacizumab for 12 cycles. Blood samples were taken for PK. DLTs defined in the first 6 weeks. Standard dose escalation of imatinib, with 3 patient cohorts: planned dose levels (DL): DL1; 400 mg, DL2; 600 mg, DL3; 800 mg daily. Results Ten patients enrolled. DL1 3 patients, DL2 7 patients. DLTs observed in 3 of 6 patients in DL2: febrile neutropenia (2); Grade 3 infection and Grade 4 neutropenia (1). Neutropenia was most frequent AEs: Grade 3/4 in >60 % of patients overall. In DL2 pts, imatinib clearance was reduced post-chemotherapy ( P