A phase I dose escalation study of once weekly oral administration of docetaxel as ModraDoc001 capsule or ModraDoc006 tablet in combination with ritonavir.

Purpose: Oral bioavailability of docetaxel is poor. Absorption could be improved by development of pharmaceutical formulations based on docetaxel solid dispersions, denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg) and co-administration of ritonavir, an inhibitor of CYP3A4 and P-glycoprotein. In this study the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), pharmacokinetics and preliminary antitumor activity of oral docetaxel combined with ritonavir in a once weekly (QW) continuous schedule was investigated. Experimental design: Patients with metastatic solid tumors were included. Dose-escalation was performed using a classical 3+3 design. Pharmacokinetic sampling was performed for up to 48 hours after drug administration. Safety was evaluated using CTCAE v3.0. Anti-tumor activity was assessed according to RECIST v1.0. Results: Sixty-seven patients were treated at weekly docetaxel dosages ranging from 30-80 mg in combination with 100 or 200 mg ritonavir. Most common toxicities were nausea, vomiting, diarrhea and fatigue, mostly of grade 1-2 severity. No hypersensitivity reactions were observed. The area under the plasma concentration-time curve (AUC0-48) of docetaxel at the RP2D of QW 60 mg ModraDoc001 capsule with 100 mg ritonavir was 1000 ± 687 ng/ml*h and for QW 60 mg ModraDoc006 tablet with 100 mg ritonavir the AUC0-48 was 1790 ± 819 ng/ml*h. Nine partial responses were reported as best response to treatment. Conclusions: Oral administration of once weekly docetaxel as ModraDoc001 capsule or ModraDoc006 tablet in combination with ritonavir is feasible. The RP2D for both formulations is 60 mg ModraDoc with 100 mg ritonavir. Anti-tumor activity is considered promising.