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16.07.2016 | PHASE I STUDIES | Ausgabe 5/2016

Investigational New Drugs 5/2016

A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors

Zeitschrift:
Investigational New Drugs > Ausgabe 5/2016
Autoren:
Lee S. Rosen, Patricia LoRusso, Wen Wee Ma, Jonathan W. Goldman, Amy Weise, A. Dimitrios Colevas, Alex Adjei, Salim Yazji, Angela Shen, Stuart Johnston, Hsin-Ju Hsieh, Iris T. Chan, Branimir I. Sikic
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s10637-016-0374-3) contains supplementary material, which is available to authorized users.

Summary

Objective Cobimetinib, a MEK1/2 inhibitor, was administered to patients with advanced solid tumors to assess safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Methods For dose-escalation, a 3 + 3 design was used. Oral cobimetinib was administered once daily on a 21-day on/7-day off (21/7) or a 14-day on/14-day off (14/14) schedule. Serial plasma samples were collected for pharmacokinetic (PK) analysis on Day 1 and at steady state. In expansion stages, patients with RAS or RAF mutant tumors were treated at the maximum tolerated dose (MTD) of the 21/7 or 14/14 schedule. Results Ninety-seven patients received cobimetinib. In the 21/7 dose escalation, 36 patients enrolled in 8 cohorts (0.05 mg/kg–80 mg). Dose-limiting toxicities (DLTs) were Grade 4 hepatic encephalopathy, Grade 3 diarrhea, and Grade 3 rash. In the 14/14 dose escalation, 20 patients enrolled in 4 cohorts (60–125 mg). DLTs were Grade 3 rash and Grade 3 blurred vision associated with presence of reversible subretinal fluid. The MTD was 60 mg on 21/7 schedule and 100 mg on 14/14 schedule. Cobimetinib PK showed dose-proportional increases in exposure. The most frequent adverse events attributed to cobimetinib were diarrhea, rash, fatigue, edema, nausea, and vomiting. In patients treated at the 60-mg (21/7) or 100-mg (14/14) dose, one unconfirmed complete response and 6 confirmed partial responses were observed. All responses occurred in melanoma patients; 6 harbored the BRAFV600E mutation. Conclusions Cobimetinib is generally well tolerated and durable responses were observed in BRAFV600E mutant melanoma patients. Evaluation of cobimetinib in combination with other therapies is ongoing.

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ESM 1 (PDF 628 kb)
10637_2016_374_MOESM1_ESM.pdf
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