ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration‐resistant prostate cancer patients: A phase Ib study

Abstract

Abstract Background ModraDoc006 is an oral formulation of docetaxel, which is co‐administered with the cytochrome P450 3A4 and P‐glycoprotein inhibitor ritonavir (r): ModraDoc006/r. Weekly treatment with ModraDoc006/r had been evaluated in phase I trials in patients with different types of advanced solid tumors, but up to this point in time not in patients with metastatic castration‐resistant prostate cancer (mCRPC). Aim We assessed safety and pharmacokinetics (PK) of ModraDoc006/r to establish the recommended phase 2 dose (RP2D) in patients with mCRPC. Methods mCRPC patients, treatment naïve or following abiraterone or enzalutamide treatment, were included. Dose‐escalation of ModraDoc006/r was based on safety and docetaxel PK. Antitumor activity was assessed by serum prostate‐specific antigen (PSA) and radiological evaluation. Results Cohort 1 (n = 5) received once weekly ModraDoc006 30 mg with ritonavir 100 mg in the morning, and ModraDoc006 20 mg with ritonavir 100 mg in the evening (30‐20/100‐100). The mean docetaxel area under the plasma concentration‐time curve (mAUC0‐inf) was 461 ng/mL × h with 1 dose limiting toxicity (DLT); grade 3 alanine transferase increase. In cohort 2 (n = 6, ModraDoc006/r 30‐20/200‐200), the mAUC0‐inf was 1687 ng/mL × h with 2 DLTs; grade 3 diarrhea and mucositis. In cohort 3A (n = 6, ModraDoc006/r 30‐20/200‐100), the mAUC0‐inf was 1517 ng/mL × h with 1 DLT; grade 3 diarrhea. In cohort 3B (n = 3, ModraDoc006/r 20‐20/200‐100), the mAUC0‐inf was 558 ng/mL × h without DLTs. The mAUC0‐inf exceeded estimated exposures of intravenous docetaxel in cohort 2 and 3A, was lower in cohort 1 and was in range in cohort 3B. PSA decreases of >50% occurred in 6/10 evaluable patients throughout the various cohorts. In five radiological evaluable patients, two confirmed partial responses were observed. Conclusion The RP2D was established at weekly ModraDoc006/r 30‐20/200‐100. Observed PSA and radiological responses suggest promising clinical activity. These results have led to an ongoing randomized Phase 2b study, comparing weekly ModraDoc006/r with 3‐weekly IV docetaxel in patients with mCRPC.

Keywords

• chemotherapy
• clinical trials
• drug discovery and delivery
• prostate cancer