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

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.

Conflict of interest statement

Conflict of interest RK, XL, ECM are/were employees of Pfizer. SGE and DRC have acted as consultants or in an advisory role for Pfizer, while EC has done so for Pfizer, Sanofi-Aventis, Genentech, Amgen, Imclone, Bristol-Myers Squibb, and Celegene. RK, XL, and ECM all own Pfizer stock. SL, SGE, EC, WAM, and ACL have all received research funding from Pfizer. EC has also received research funding from Genentech, Amgen, Idera, Merck, Bristol-Myers Squibb, Lilly, Imclone, and MethylGene, while ACL has received additional funding from Allos, Amgen, Bayer, Cephalon, Imclone/Lilly, Merck, Millennium, Novartis, Sanofi-Aventis, and Zenyaku. JS has received research funding from Roche Canada and Sanofi-Aventis Canada. SL has received travel support from Pfizer to attend meetings. SD has no conflicts of interest to disclose.

Figures

Fig. 1

Mean (±SD) plasma concentration–time profiles for a sunitinib and SU12662 following administration of sunitinib (50 mg/day on Schedule 2/2) with or without mFOLFOX6, b free platinum following administration of mFOLFOX6 with or without sunitinib, c 5-FU following administration of mFOLFOX6 with or without sunitinib