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

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.

• Authors: Marit A C Vermunt, Debbie G J Robbrecht, Lot A Devriese, Julie M Janssen, Bas Thijssen, Marianne Keessen, Maarten van Eijk, Rob Kessels, Ferry A L M Eskens, Jos H Beijnen, Niven Mehra, Andries M Bergman
• Journal: Cancer reports (Hoboken, N.J.) (Cancer Rep (Hoboken)) Vol. 4 Issue 4 Pg. e1367 (08 2021) ISSN: 2573-8348 [Electronic] United States
• PMID: 33709626 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.

Chemical References

• Docetaxel
• KLK3 protein, human
• Kallikreins
• Prostate-Specific Antigen
• Ritonavir

Topics

• Administration, Oral
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Docetaxel (administration & dosage, adverse effects)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Humans
• Kallikreins (blood)
• Male
• Middle Aged
• Neoplasm Grading
• Prostate-Specific Antigen (blood)
• Prostatic Neoplasms, Castration-Resistant (blood, diagnosis, drug therapy)
• Ritonavir (administration & dosage, adverse effects)
• Treatment Outcome