Phase IIb trial of oral ModraDoc006/r as a tolerable and effective option in comparison with intravenous docetaxel in metastatic castration-resistant prostate cancer (mCRPC).

Abstract

Background: ModraDoc006 is a novel, oral tablet formulation of docetaxel To enhance bioavailability, it is co-administered with ritonavir (r), an inhibitor of cytochrome P450 3A4 and Pglycoprotein The oral combination, denoted ModraDoc006/r, has potential advantages in terms of patient convenience, elimination of infusionrelated reactions and avoiding prophylactic steroid administration, as well as safety benefits Safety and preliminary efficacy of ModraDoc006/r in mCRPC were established in a prior phase Ib trial Methods:This is an open label 1:1 randomized phase IIb trial of ModraDoc006/r bidaily once weekly (BIDW) regimen versus IV docetaxel 75 mg/m2 q day 21 Initially, BIDW 30-20 mg ModraDoc006 combined with 200-100 mg ritonavir was administered on days 1, 8 and 15 of a 21-day cycle After 39 patients, the dose of ModraDoc006 was reduced to 20-20 mg BIDW to improve GI tolerability All patients received 5 mg oral prednisone BID Imaging is obtained every 8-9 weeks for the first 24 weeks, every 12 weeks thereafter Initially mCRPC patients with RECIST 1 1 measurable disease were eligible;this was amended to evaluable disease per Prostate Cancer Working Group 3 (PCWG3) to allow for wider recruitment No prior taxane therapy is allowed The primary efficacy endpoint is radiographic progression free survival (rPFS) per PCWG3 criteria Secondary objectives include objective response rate, PSA-PFS, time to skeletal related events, disease control rate, duration of response and safety Patient reported outcomes, QoL and FACT-P questionnaires are assessed It is expected that ModraDoc006/r will be as effective as IV docetaxel A sample size of approximately 50 evaluable patients per arm will provide a point estimate of the primary endpoint of rPFS for this study Results: At the data cut-off of 30 Nov 2020, 90 patients were enrolled in US and EU: 44 patients had been randomized to IV docetaxel and 46 to ModraDoc006/r, with 58 patients currently on treatment Preliminary PSA response rates and rPFS were noted to be comparable in both treatment arms ModraDoc006/r was mainly associated with mild and reversible GI-toxicity, of which grade and incidence were reduced at 20-20 mg compared to the initial dose-level of 30-20 mg ModraDoc006 Myelosuppression and neurotoxicity were low to negligible in the ModraDoc006/r arm, with low accompanying levels of alopecia Conclusions: Adverse events of cytopenias and alopecia were lower with ModraDoc006/r, and preliminary efficacy appears comparable in both arms Oral chemotherapy option has become critically important during the COVID-19 pandemic Preliminary data reveals that ModraDoc006/r is an attractive oral option in mCRPC with favorable toxicity profile and comparable efficacy