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

Abstract

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 BRAF(V600E) mutation. Conclusions Cobimetinib is generally well tolerated and durable responses were observed in BRAF(V600E) mutant melanoma patients. Evaluation of cobimetinib in combination with other therapies is ongoing.

• Authors: 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
• Journal: Investigational new drugs (Invest New Drugs) Vol. 34 Issue 5 Pg. 604-13 (10 2016) ISSN: 1573-0646 [Electronic] United States
• PMID: 27424159 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)

Chemical References

• Antineoplastic Agents
• Azetidines
• KRAS protein, human
• Piperidines
• Protein Kinase Inhibitors
• MAP2K2 protein, human
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• Proto-Oncogene Proteins B-raf
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human
• Proto-Oncogene Proteins p21(ras)
• cobimetinib

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Azetidines (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Class I Phosphatidylinositol 3-Kinases (genetics)
• Female
• Genes, ras (genetics)
• Humans
• MAP Kinase Kinase 1 (antagonists & inhibitors)
• MAP Kinase Kinase 2 (antagonists & inhibitors)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Mutation
• Neoplasms (drug therapy, genetics, metabolism)
• Piperidines (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Protein Kinase Inhibitors (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Proto-Oncogene Proteins B-raf (genetics)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Treatment Outcome