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Oncotarget. 2017 Jul 18;8(45):79750-79760. doi: 10.18632/oncotarget.19336. eCollection 2017 Oct 3.

A phase I clinical trial of binimetinib in combination with FOLFOX in patients with advanced metastatic colorectal cancer who failed prior standard therapy.

Author information

1
Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA.
2
Department of Statistics, City of Hope National Medical Center, Duarte, CA, USA.
3
Department of Cancer Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA.
4
Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte,CA, USA.
5
Department of Surgical Oncology, City of Hope National Medical Center, Duarte, CA, USA.

Abstract

Background:

This was a first in-human, open-label, dose-escalation phase I study conducted to evaluate the maximum tolerated dose (MTD), safety, and efficacy of the combination of oral binimetinib and FOLFOX.

Materials and Methods:

Patients with metastatic colorectal cancer (mCRC) who progressed on prior standard therapies received twice daily binimetinib continuously or intermittently with FOLFOX. Dose-limiting toxicities (DLTs) were assessed in the first 2 cycles of study treatment. Pharmacokinetic (PK) analysis of 5-FU and oxaliplatin was performed at the MTD in an expanded 6 patient cohort.

Results:

Twenty-six patients were enrolled and assessed for safety. In the dose-escalation phase, no DLTs were noted in all binimetinib dosing schedules and the MTD of binimetinib in with FOLFOX was 45 mg orally twice daily. There were no significant differences in the PKs of 5-FU or oxaliplatin with or without binimetinib. Continuous dosing of binimetinib produced SD at 2 months in 9 of 13 evaluable patients and a median PFS of 3.5 months. Nine of 10 patients had PD at 2 months on the intermittent arm.

Conclusions:

Oral binimetinib and FOLFOX has a manageable toxicity profile and showed some evidence of antitumor activity in heavily pretreated mCRC patients.

KEYWORDS:

FOLFOX; MEK inhibitor; binimetinib; metastatic colorectal cancer; refractory disease

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