A dose-escalation study of bi-daily once weekly oral docetaxel either as ModraDoc001 or ModraDoc006 combined with ritonavir

• Published in: European journal of cancer (1990) Vol. 86; pp. 217 - 225
• Main Authors: de Weger, Vincent A., Stuurman, Frederik E., Hendrikx, Jeroen J.M.A., Moes, Johannes J., Sawicki, Emilia, Huitema, Alwin D.R., Nuijen, Bastiaan, Thijssen, Bas, Rosing, Hilde, Keessen, Marianne, Mergui-Roelvink, Marja, Beijnen, Jos H., Schellens, Jan H.M., Marchetti, Serena
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2017; Elsevier Science Ltd
• Subjects: Administration, Oral; Adult; Aged; Anticancer properties; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antiretroviral drugs; Antiviral drugs; Area Under Curve; Capsules; Diarrhea; Docetaxel; Drug Administration Schedule; Drug Compounding; Drug Dosage Calculations; Drug dosages; Drug therapy; Fatigue; Female; Fever; Half-Life; Humans; Male; Maximum Tolerated Dose; Metabolic Clearance Rate; Metastases; Middle Aged; ModraDoc001; ModraDoc006; Nausea; Neoplasms - drug therapy; Neoplasms - pathology; Netherlands; Neutropenia; Oral administration; Oral docetaxel; Patients; Pharmacokinetics; Pharmacology; Phase I; Prescription drugs; Ritonavir; Ritonavir - administration & dosage; Ritonavir - adverse effects; Safety; Solid tumors; Tablets; Taxoids - administration & dosage; Taxoids - adverse effects; Taxoids - blood; Taxoids - pharmacokinetics; Treatment Outcome; Tumors; Vomiting; ModraDoc001; Phase I; ModraDoc006; Ritonavir; Docetaxel; Oral docetaxel
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2017.09.010

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. 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. 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. 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. •Oral administration of oral docetaxel either as ModraDoc001 or ModraDoc006 combined with ritonavir is feasible and safe.•Toxicity is in line with that observed with intravenous docetaxel, albeit without hypersensitivity reactions and no grade 3 sensory neuropathy.•Docetaxel plasma concentrations (AUC) at the MTD of ModraDoc006 with ritonavir are comparable to intravenous docetaxel in a weekly schedule.•Antitumour activity with ModraDoc/ritonavir is promising.