Clinical Research Papers:
A phase I clinical trial of binimetinib in combination with FOLFOX in patients with advanced metastatic colorectal cancer who failed prior standard therapy
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May Cho1,*, Jun Gong1,*, Paul Frankel2, Timothy W. Synold3, Dean Lim1, Vincent Chung1, Joseph Chao1, Daneng Li1, Yuan Chen4, Stephen Sentovich5, Kurt Melstrom5, Gagandeep Singh5, Eloise Luevanos1 and Marwan Fakih1
1Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
2Department of Statistics, City of Hope National Medical Center, Duarte, CA, USA
3Department of Cancer Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA
4Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA, USA
5Department of Surgical Oncology, City of Hope National Medical Center, Duarte, CA, USA
*These authors contributed equally to this work
Marwan Fakih, email: [email protected]
Keywords: binimetinib, MEK inhibitor, FOLFOX, metastatic colorectal cancer, refractory disease
Received: May 12, 2017 Accepted: June 30, 2017 Published: July 18, 2017
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.
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