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.
Name: ModraDoc001 10mg capsules
Description: Bi-daily administration. One cycle will last 7 daysType: DrugModraDoc001 10 mg capsules
Name: ModraDoc003 10mg tablets and ModraDoc004 10/50 mg
Description: 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.Type: DrugModraDoc003 10mg tablets and ModraDoc004 10/50 mg
Name: ModraDoc006 10 mg tablet
Description: Bi-daily administration. One cycle will last 7 daysType: DrugModraDoc006 10 mg tablet
Description: 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.
Measure: Number and percentage of Participants with Adverse Events Time: 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 toxicityDescription: The PK of bi-daily ModraDoc001 10mg, ModraDoc003 10mg tablets both in combination with ritonavir capsules and ModraDoc004 10/50mg tablets will be determed using non-compartmental methods and compartmental methods using NONMEM. Correlation between PK data and toxicity are subsequently analyzed for their significance.
Measure: Pharmacokinetics assessments Time: Day 1 of week: 1, 2 and 3Description: Weekly safety assessments for Arm B (administration of ModraDoc003 10mg capsules and ritonavir and ModraDoc004 10/50 mg tablets) are: 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.
Measure: Number and percentage of Participants with Adverse Events Time: during the study treatment and 30 days after the study discontinuationDescription: Tumor measurement according to RECIST
Measure: Radiological antitumor activity Time: at least every six weeksDescription: To establish the effect of functional genetic polymorphisms, C1236T (for MDR1) and CYP3A4*1B, on pharmacokinetics of orally administered docetaxel.
Measure: Pharmacogenetic sampling Time: Day 1 - predoseAllocation: Randomized
Crossover Assignment
There is one SNP
To establish the effect of functional genetic polymorphisms, C1236T (for MDR1) and CYP3A4*1B, on pharmacokinetics of orally administered docetaxel.. Inclusion Criteria: 1. Histological or cytological proof of cancer 2. Patients for whom no standard therapy of proven benefit exist 3. Patients who might benefit from treatment with docetaxel, e.g. --- C1236T ---
Another part of this study is the screening for 2 different polymorphism, C1236T (for MDR1)and CYP3A4*1B. --- C1236T ---