Reference Detail

Ref Type

Journal Article

PMID

(32314268)

Authors

Ramanathan RK, Von Hoff DD, Eskens F, Blumenschein G, Richards D, Genvresse I, Reschke S, Granvil C, Skubala A, Peña C, Mross K

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Targeted oncology	15	2	2020 04	163-174	Target Oncol

URL

Abstract Text

Dual inhibition of PI3K and MAPK signaling is conceptually a promising anticancer therapy.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.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.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.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.NCT01392521.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Refametinib	Refametinib	4	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Refametinib		BAY 869766\|BAY 8697661\|BAY-869766\|BAY-8697661\|BAY86-9766\|RDEA-119\|RDEA119	MEK inhibitor (Pan) 24 MEK1 Inhibitor 26 MEK2 Inhibitor 24	Refametinib (BAY86-9766) is an inhibitor of MEK1 and MEK2, which prevents growth-factor mediated cell proliferation (PMID: 24204195, PMID: 32314268).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References