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

Autor: Vermunt MAC; Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Robbrecht DGJ; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands., Devriese LA; Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands., Janssen JM; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Thijssen B; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Keessen M; Modra Pharmaceuticals B.V., Amsterdam, The Netherlands., van Eijk M; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Kessels R; Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Eskens FALM; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands., Beijnen JH; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; Modra Pharmaceuticals B.V., Amsterdam, The Netherlands.; Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands., Mehra N; Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands., Bergman AM; Department of Medical Oncology and Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Jazyk: angličtina
Zdroj: Cancer reports (Hoboken, N.J.) [Cancer Rep (Hoboken)] 2021 Aug; Vol. 4 (4), pp. e1367. Date of Electronic Publication: 2021 Mar 12.
DOI: 10.1002/cnr2.1367
Abstrakt: 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.
(© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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