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 - Funding Information:
R. K. Ramanathan is employed by Merck and received research funding from Bayer for the conduct of the study. D.D. Von Hoff is employed as a consultant at McKesson; reports stock and ownership at Anthem, Inc., CerRx, Medtronic, Stromatis Pharma, SynDevRx, Systems Oncology, and UnitedHealthcare; has participated in a consulting or advisory role for Aadi, Actinium Pharmaceuticals, Adicet Bio, Aeglea BioTherapeutics, Agenus, AiMed Bio, Alpha Cancer Technologies, Amunix, APEIRON, Aptose Biosciences, Arvinas, Athenex, Bellicum Pharmaceuticals, BioLineRx, BioSpecifics Technologies, BioXCel Therapeutics, Boston Scientific, Bryologyx, CanBas, Celgene, Codiak Biosciences, Corcept Therapeutics, CORRONA, CV6 Therapeutics, CytomX Therapeutics, Decoy Biosystems, DNAtrix, EMD Serono, Erimos Pharmaceuticals, Esperance Pharmaceuticals, Evelo Biosciences, Fate Therapeutics, FibroGen, Five Prime Therapeutics, Fujifilm, Geistlich Pharma, Genzada Pharmaceuticals, Gimbal, GiraFpharma, Globe Life Sciences, Helix BioPharma, Hills Pharma, Histogen, Horizon Discovery, HUYA Bioscience International, Imaging Endpoints, Immodulon Therapeutics, Immunophotonics, Innokeys, Intezyne Technologies, Ipsen, Jounce Therapeutics, Kalos Therapeutics, Kelun-Klus Pharma, Kura, L.E.A.F. Pharmaceuticals, Lixte Biotechnology, Medical Prognosis Institute, Novita Pharmaceuticals, Novocure, NuCana BioMed, Oncology Venture, Oncolyze, Pfizer, Phosplatin Therapeutics, Radimmune, RefleXion Medical, RenovoRx, Riptide Bioscience, Samumed, Samus Therapeutics, Senhwa Biosciences, Sirnaomics, Sobi, SOTIO, Strategia Therapeutics, Sun Biopharma, Synergene, TD2, Tolero Pharmaceuticals, TP Therapeutics, TransMed, Trovagene, Verily, Vicus Therapeutics, and 2X Oncology; and has received research funding from AbbVie, Aduro Biotech, Agios, ArQule, Baxalta, Celgene, Cleave Biosciences, CytRx Corporation, Daiichi Sankyo, Deciphera, Endocyte, ESSA, Exelixis, Five Prime Therapeutics, Genentech, Gilead Sciences, Halozyme, Incyte, Lilly, Merck, Merrimack, Minneamrita Therapeutics, Mirna Therapeutics, Pfizer, Pharmacyclics, Phoenix Biotech, Plexxikon, Proderm IQ, Samumed, Strategia, Trovagene, Verastem, and 3-V Biosciences. G. Blumenschein Jr has received grants from Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Exelixis, Genentech, GlaxoSmithKline, Immatics, Immunocore, Incyte, Kite Pharma, MacroGenics, MedImmune, Merck, Novartis, Roche, Tmunity, Torque, and Xcovery; and has received personal fees from AbbVie, Adicet, Amgen, ARIAD, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Clovis, Genentech, Johnson & Johnson, Maverick Therapeutics, MedImmune, Merck, Novartis, Roche, Virogin Biotech and Xcovery. I. Genvresse is employed by Bayer AG. C. Granvil is employed by Bayer HealthCare Pharmaceuticals, Inc. A. Skubala is employed by Chrestos Concept GmbH & Co. KG and acts as a consultant to Bayer. C. Peña is employed by and owns stock at Bayer HealthCare Pharmaceuticals, Inc., and is a co-inventor on Bayer patents related to one of the investigational drugs used in the present study. K. Mross has received grants and support for travel from Bayer AG. F. Eskens, D. Richards, and S. Reschke report no conflicts of interest.
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
VL - 15
SP - 163
EP - 174
JO - Targeted Oncology
JF - Targeted Oncology
SN - 1776-2596
IS - 2
ER -