Highlights
- •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.
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.
Keywords
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Article info
Publication history
Published online: October 12, 2017
Accepted:
September 14,
2017
Received:
August 31,
2017
Identification
Copyright
© 2017 Elsevier Ltd. All rights reserved.
