TY - JOUR
T1 - Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer
AU - Ramanathan, Ramesh K.
AU - Von Hoff, Daniel D.
AU - Eskens, Ferry
AU - Blumenschein, George
AU - Richards, Donald
AU - Genvresse, Isabelle
AU - Reschke, Susanne
AU - Granvil, Camille
AU - Skubala, Adam
AU - Peña, Carol
AU - Mross, Klaus
N1 - Publisher Copyright:
© 2020, Springer Nature Switzerland AG.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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.
AB - 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.
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U2 - 10.1007/s11523-020-00714-0
DO - 10.1007/s11523-020-00714-0
M3 - Article
C2 - 32314268
AN - SCOPUS:85084003854
SN - 1776-2596
VL - 15
SP - 163
EP - 174
JO - Targeted oncology
JF - Targeted oncology
IS - 2
ER -