Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer.

ABSTRACT: BACKGROUND:Dual inhibition of PI3K and MAPK signaling is conceptually a promising anticancer therapy. OBJECTIVE:This phase 1b trial investigated the safety, maximum tolerated dose (MTD), recommended phase II dose, pharmacokinetics, tumor response, fluorodeoxyglucose positron emission tomography (FDG-PET) pharmacodynamics, and biomarker explorations for the combination of pan-PI3K inhibitor copanlisib and allosteric MEK inhibitor refametinib in patients with advanced solid tumors. PATIENTS AND METHODS:This was an adaptive trial with eight dose cohorts combining dose escalation and varying schedules in repeated 28-day cycles. Patients received copanlisib (0.2-0.8 mg/kg intravenously) intermittently (days 1, 8, 15) or weekly (days 1, 8, 15, 22) each cycle, and refametinib (30-50 mg twice daily orally) continuously or 4 days on/3 days off. Patients with KRAS, NRAS, BRAF, or PI3KCA mutations were eligible for the expansion cohort. RESULTS:In the dose-escalation (n?=?49) and expansion (n?=?15) cohorts, the most common treatment-emergent adverse events included diarrhea (59.4%), nausea, acneiform rash, and fatigue (51.6% each). Dose-limiting toxicities included oral mucositis (n?=?4), increased alanine aminotransferase/aspartate aminotransferase (n?=?3), rash acneiform, hypertension (n?=?2 each), and diarrhea (n?=?1). MTD was copanlisib 0.4 mg/kg weekly and refametinib 30 mg twice daily. No pharmacokinetic interactions were identified. Decreased tumor FDG uptake and MEK-ERK signaling inhibition were demonstrated during treatment. Best response was stable disease (n?=?21); median treatment duration was 6 weeks. CONCLUSIONS:Despite sound rationale and demonstrable pharmacodynamic tumor activity in relevant tumor populations, a dose and schedule could not be identified for this drug combination that was both tolerable and offered clear efficacy in the population assessed. CLINICALTRIALS. GOV IDENTIFIER:NCT01392521.

SUBMITTER: Ramanathan RK 

PROVIDER: S-EPMC7591420 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature