A phase I study of sunitinib combined with modified FOLFOX6 in patients with advanced solid tumors

• Published in: Cancer chemotherapy and pharmacology Vol. 70; no. 1; pp. 65 - 74
• Main Authors: Leong, S., Eckhardt, S. G., Chan, E., Messersmith, W. A., Spratlin, J., Camidge, D. R., Diab, S., Khosravan, R., Lin, X., Chow Maneval, E., Lockhart, A. C.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.07.2012; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Area Under Curve; Biological and medical sciences; Cancer Research; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue - chemically induced; Female; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; Fluorouracil - pharmacokinetics; Humans; Indoles - administration & dosage; Indoles - adverse effects; Indoles - pharmacokinetics; Leucovorin - administration & dosage; Leucovorin - adverse effects; Leucovorin - pharmacokinetics; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Clearance Rate; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neoplasms - pathology; Neutropenia - chemically induced; Oncology; Organoplatinum Compounds; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pyrroles - administration & dosage; Pyrroles - adverse effects; Pyrroles - pharmacokinetics; Thrombocytopenia - chemically induced; Treatment Outcome; Tumors; Sunitinib; Phase I; Solid tumors; FOLFOX; Pharmacokinetics; Tyrosine kinase inhibitor; Antineoplastic agent; Solid tumor; Calcium folinate; Oxaliplatin; Advanced stage; Antiangiogenic agent; Protein-tyrosine kinase; Platinum II Complexes; Fluorouracil; Human; Enzyme; Fluoropyrimidine derivatives; Transferases; Enzyme inhibitor; Patient; Malignant tumor; Thymidylate synthase; Alkylating agent; Treatment; Antimetabolic; Methyltransferases; Phase I trial; Pyrimidine derivatives; Multikinase inhibitor; Therapeutic protocol; Cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-012-1880-4

Purpose This phase I study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor effects of sunitinib combined with modified FOLFOX6 (mFOLFOX6). Methods Patients with advanced solid malignancies received mFOLFOX6 in 2-week cycles with escalating sunitinib doses (25, 37.5, and 50 mg/day) on three schedules: 2 weeks on, 2 weeks off (2/2); 4 weeks on, 2 weeks off (4/2); or continuous daily dosing (CDD). Patients received up to 8 treatment cycles (Schedule 2/2 and CDD schedule) or 6 cycles (Schedule 4/2). An expansion cohort enrolled patients with metastatic colorectal cancer at the Schedule 2/2 MTD. Results Overall, 53 patients were enrolled, with 43 evaluable for dose-limiting toxicity (DLT). On Schedule 2/2 ( n  = 18), DLTs occurred in three patients at 50 mg/day (grade 4 neutropenia [ n  = 1]; grades 3 and 4 thrombocytopenia [ n  = 2]) and two patients achieved partial responses (PRs). On Schedule 4/2 ( n  = 13), 37.5 mg/day exceeded the MTD with two DLTs (febrile neutropenia and grade 4 hypokalemia, respectively). On the CDD schedule ( n  = 12), the MTD was 25 mg/day; one DLT (grade 3 stomatitis) was reported and two patients achieved PRs. The most common adverse events were neutropenia, fatigue, and thrombocytopenia. No clinically significant drug–drug interactions were apparent between sunitinib, its metabolite SU12662, and mFOLFOX6. Conclusions Sunitinib combined with mFOLFOX6 had acceptable tolerability. The MTDs were sunitinib 50 mg/day on Schedule 2/2 and 25 mg/day on the CDD schedule. A MTD for Schedule 4/2 was not established.