Vincent A de Weger1, Frederik E Stuurman1, Jeroen J M A Hendrikx2, Johannes J Moes2, Emilia Sawicki3, Alwin D R Huitema4, Bastiaan Nuijen2, Bas Thijssen2, Hilde Rosing2, Marianne Keessen5, Marja Mergui-Roelvink1, Jos H Beijnen6, Jan H M Schellens7, Serena Marchetti8. 1. Division of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 2. Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands. 3. Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands; Modra Pharmaceuticals BV, Amsterdam, The Netherlands. 4. Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands; Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands. 5. Division of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Modra Pharmaceuticals BV, Amsterdam, The Netherlands. 6. Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands; Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; Modra Pharmaceuticals BV, Amsterdam, The Netherlands. 7. Division of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; Modra Pharmaceuticals BV, Amsterdam, The Netherlands. 8. Division of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: s.marchetti@nki.nl.
Abstract
INTRODUCTION: Two solid dispersions of docetaxel (denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg)) were co-administered with 100 mg ritonavir (/r) and investigated in a bi-daily once weekly (BIDW) schedule. Safety, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary activity were explored. METHODS: Adult patients with metastatic solid tumours were included in two dose-escalation arms. PK sampling was performed during the first week and the second or third week. Safety was evaluated using US National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Antitumour activity was assessed every 6 weeks according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0. RESULTS: ModraDoc001 capsule/r and ModraDoc006 tablet/r were administered to 17 and 28 patients, respectively. The most common adverse events were nausea, vomiting, diarrhoea and fatigue, mostly of grade 1-2 severity. Grade 3/4 neutropenia/neutropenic fever was observed in 2 patients (4%). The MTD was determined as 20/20 mg ModraDoc001/r and 30/20 mg ModraDoc006/r (morning/afternoon dose) once weekly. The mean area under the plasma concentration-time curve (AUC0-48) ± standard deviation at the MTD for ModraDoc001/r and ModraDoc006/r were 686 ± 388 ng/ml*h and 1126 ± 382 ng/ml*h, respectively. Five partial responses were reported as best response to treatment. CONCLUSION: Oral administration of BIDW ModraDoc001/r or ModraDoc006/r is feasible. The once weekly 30/20 mg ModraDoc006 tablet/r dose-level was selected for future clinical development. Antitumour activity is promising.
INTRODUCTION: Two solid dispersions of docetaxel (denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg)) were co-administered with 100 mg ritonavir (/r) and investigated in a bi-daily once weekly (BIDW) schedule. Safety, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary activity were explored. METHODS: Adult patients with metastatic solid tumours were included in two dose-escalation arms. PK sampling was performed during the first week and the second or third week. Safety was evaluated using US National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Antitumour activity was assessed every 6 weeks according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0. RESULTS: ModraDoc001 capsule/r and ModraDoc006 tablet/r were administered to 17 and 28 patients, respectively. The most common adverse events were nausea, vomiting, diarrhoea and fatigue, mostly of grade 1-2 severity. Grade 3/4 neutropenia/neutropenic fever was observed in 2 patients (4%). The MTD was determined as 20/20 mg ModraDoc001/r and 30/20 mg ModraDoc006/r (morning/afternoon dose) once weekly. The mean area under the plasma concentration-time curve (AUC0-48) ± standard deviation at the MTD for ModraDoc001/r and ModraDoc006/r were 686 ± 388 ng/ml*h and 1126 ± 382 ng/ml*h, respectively. Five partial responses were reported as best response to treatment. CONCLUSION: Oral administration of BIDW ModraDoc001/r or ModraDoc006/r is feasible. The once weekly 30/20 mg ModraDoc006 tablet/r dose-level was selected for future clinical development. Antitumour activity is promising.
Authors: Huixin Yu; Julie M Janssen; Vincent A de Weger; Bastiaan Nuijen; Rik E Stuurman; Serena Marchetti; Jan H M Schellens; Jos H Beijnen; Thomas P C Dorlo; Alwin D R Huitema Journal: Invest New Drugs Date: 2020-04-19 Impact factor: 3.850
Authors: Marit A C Vermunt; Lisa T van der Heijden; Jeroen J M A Hendrikx; Alfred H Schinkel; Vincent A de Weger; Eric van der Putten; Baukelien van Triest; Andries M Bergman; Jos H Beijnen Journal: Cancer Chemother Pharmacol Date: 2021-03-20 Impact factor: 3.333
Authors: Jeroen J M A Hendrikx; Frederik E Stuurman; Ji-Ying Song; Vincent A de Weger; Jurjen S Lagas; Hilde Rosing; Jos H Beijnen; Alfred H Schinkel; Jan H M Schellens; Serena Marchetti Journal: Pharmacol Res Perspect Date: 2020-08
Authors: Maarten van Eijk; René J Boosman; Alfred H Schinkel; Alwin D R Huitema; Jos H Beijnen Journal: Cancer Chemother Pharmacol Date: 2019-07-15 Impact factor: 3.333
Authors: Marit A C Vermunt; Debbie G J Robbrecht; Lot A Devriese; Julie M Janssen; Bas Thijssen; Marianne Keessen; Maarten van Eijk; Rob Kessels; Ferry A L M Eskens; Jos H Beijnen; Niven Mehra; Andries M Bergman Journal: Cancer Rep (Hoboken) Date: 2021-03-12