Weekly Administration of (bi-)Daily Oral Docetaxel in Combination With Ritonavir
The bioavailability of docetaxel is limited due to metabolising cytochrome P450 (CYP)
enzymes, which are abundantly present in the gastrointestinal tract.
Inhibition of CYP3A4 enzymes with ritonavir (an anti-retroviral drug) has in previously
conducted proof-of-concept and phase I trials, proven to enhance the bioavailability of oral
Oral administration of docetaxel has been investigated in five clinical trials, all
initiated by the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI-AVL).
The department of pharmacy of the Slotervaart Hospital and Netherlands Cancer Institute
developed a solid oral dosage form for docetaxel, ModraDoc001 10 mg capsules. This
formulation has now been investigated in more than 40 patients in a first clinical study.
The preliminary results with ModraDoc001 10mg are promising and a linearity between systemic
exposure to docetaxel and the applied dose of ModraDoc001 10mg capsules is seen. In an
attempt to further improve and prolong the systemic exposure we will explore a twice daily
Two other novel dosage forms for docetaxel, ModraDoc003 10 mg tablets and ModraDoc004 10/50
mg tablets, were developed. Both are spray-dried solid dispersions of docetaxel pressed in
tablets. The distinction between both is that ritonavir is included in the co-formulation of
ModraDoc004 10/50 mg tablets (10 mg docetaxel and 50 mg ritonavir). Both dosage forms will
be investigated in arm B to see whether these new formulations have comparable
pharmacokinetic characteristics of docetaxel to the capsule formulation.
Arm A Arm A is a dose escalation study to establish the maximum tolerated dose (MTD)of
weekly bi-daily ModraDoc001 10 mg capsules. This study will be done with a classical dose
escalation design. The starting dose will be 40 mg BID. This dose is based on a safety of
weekly 80 mg single dose in the previously conducted study.
Arm B ModraDoc003 10 mg tablets and ModraDoc004 10/50 mg tablets will be investigated in arm
B to see whether these new formulations have comparable pharmacokinetic characteristics of
docetaxel to the capsule formulation od ModraDoc001 10 mg.
Another part of this study is the screening for 2 different polymorphism, C1236T (for
MDR1)and CYP3A4*1B. Polymorphic variants may influence the absorption and elimination of
docetaxel and ritonavir.
Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment
Number and percentage of Participants with Adverse Events
The maximal tolerated dose (defined as the highest dose resulting in no more that 1/6 probability of causing a dose limiting toxicities defined in the protocol) of bi-daily ModraDoc001 10mg capsules with ritonavir will be assessed in Arm A. Weekly safety assessments for Arm A and Arm B: signs and symptoms/adverse events, physical examination, clinical laboratory tests (hematology, clinical chemistry and urinalysis), 12-lead ECG monitoring (Day 0, End of Th). The incidence of serious AEs (SAEs) and AE related to oral docetaxel and/or to ritonavir will be determined.
AE will be collected during the study treatment and 30 days after discontinuation of the study treatment due to disease progression or unacceptable treatment related toxicity
JHM Schellens, MD, PhD
The Netherlands Cancer Institute
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)