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|Ref Type||Journal Article|
|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.|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Refametinib||BAY 869766|BAY 8697661|BAY-869766|BAY-8697661|BAY86-9766|RDEA-119||MEK inhibitor (Pan) 22 MEK1 Inhibitor 20 MEK2 Inhibitor 18||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|
|Unknown unknown||Advanced Solid Tumor||no benefit||Copanlisib + Refametinib||Phase I||Actionable||In a Phase I trial, Aliqopa (copanlisib) and Refametinib (BAY86-9766) combination treatment resulted in stable disease as best response in 33% (21/64) of patients with advanced solid tumors, however, the study failed to establish a tolerable and efficacious dose and schedule of this combination (PMID: 32314268; NCT01392521).||32314268|