1. A phase I study of sunitinib combined with modified FOLFOX6 in patients with advanced solid tumors.
- Author
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Leong S, Eckhardt SG, Chan E, Messersmith WA, Spratlin J, Camidge DR, Diab S, Khosravan R, Lin X, Chow Maneval E, and Lockhart AC
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Area Under Curve, 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, Metabolic Clearance Rate, Middle Aged, Neoplasms pathology, Neutropenia chemically induced, Organoplatinum Compounds, Oxaliplatin, Pyrroles administration & dosage, Pyrroles adverse effects, Pyrroles pharmacokinetics, Sunitinib, Thrombocytopenia chemically induced, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Neoplasms drug therapy
- Abstract
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.
- Published
- 2012
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