NCT01173913

Weekly Administration of (bi-)Daily Oral Docetaxel in Combination With Ritonavir

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 57 (actual)
• Sponsor: The Netherlands Cancer Institute · Academic / Other
• Sex: All
• Age: —
• Healthy volunteers: Not accepted

Summary

Oral administration has many advantages above intravenously administrated drugs for patients. Up to now, oral administration of docetaxel as single agent has not been feasible due to low and variable bioavailability. This low systematic exposure to docetaxel can effectively be increased after co-administration of ritonavir. The department of pharmacy of the Slotervaart Hospital and Netherlands Cancer Institute developed a solid oral dosage form for docetaxel, ModraDoc001 10 mg capsules. Two other novel dosage forms of docetaxel with improved pharmaceutical characteristics, have been developed: ModraDoc003 10 mg tablets and ModraDoc004 10/50 mg tablets. The systemic exposure after administration of those forms is now being investigated.

Detailed description

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 docetaxel. 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 dosing schedule. 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. Arm D is a dose escalation study to establish the maximum tolerated dose (MTD)of weekly bi-daily ModraDoc006 10 mg tablets. This study will be done with a classical dose escalation design. The starting dose will be 20 mg BID. This dose is based on a safety of BID weekly ModraDoc001 mg in the previously conducted arm A.

Conditions

• Cancer

Interventions

Type	Name	Description
DRUG	ModraDoc001 10mg capsules	Bi-daily administration. One cycle will last 7 days
DRUG	ModraDoc003 10mg tablets and ModraDoc004 10/50 mg	The patients will receive 40 mg docetaxel and 200 mg ritonavir once daily as different dosage forms (ModraDoc001 10 mg capsules, ModraDoc003 10 mg tablets and ModraDoc004 10/50 mg tablets). Patients continue in Week 4 with 80 mg docetaxel (as ModraDoc001 10 mg capsules) in combination with 100 mg ritonavir once daily in a weekly schedule until progressive disease or adverse events, which require dose modifications or discontinuation of therapy, are observed.
DRUG	ModraDoc006 10 mg tablet	Bi-daily administration. One cycle will last 7 days

Timeline

• Start date: 2010-09-01
• Primary completion: 2016-10-04
• Completion: 2017-01-26
• First posted: 2010-08-02
• Last updated: 2019-01-10

Locations

1 site across 1 country: Netherlands