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

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?Cdrug 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.