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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-08-01
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| Series: | Cancer Reports |
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| Online Access: | https://doi.org/10.1002/cnr2.1367 |
| _version_ | 1818677516335841280 |
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| author | Marit A. C. Vermunt Debbie G. J. Robbrecht Lot A. Devriese Julie M. Janssen Bas Thijssen Marianne Keessen Maarten vanEijk Rob Kessels Ferry A. L. M. Eskens Jos H. Beijnen Niven Mehra Andries M. Bergman |
| author_facet | Marit A. C. Vermunt Debbie G. J. Robbrecht Lot A. Devriese Julie M. Janssen Bas Thijssen Marianne Keessen Maarten vanEijk Rob Kessels Ferry A. L. M. Eskens Jos H. Beijnen Niven Mehra Andries M. Bergman |
| author_sort | Marit A. C. Vermunt |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T09:00:37Z |
| format | Article |
| id | doaj.art-ad84cb565b37425dadb093bae9e81fac |
| institution | Directory Open Access Journal |
| issn | 2573-8348 |
| language | English |
| last_indexed | 2024-12-17T09:00:37Z |
| publishDate | 2021-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Reports |
| spelling | doaj.art-ad84cb565b37425dadb093bae9e81fac2022-12-21T21:55:45ZengWileyCancer Reports2573-83482021-08-0144n/an/a10.1002/cnr2.1367ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration‐resistant prostate cancer patients: A phase Ib studyMarit A. C. Vermunt0Debbie G. J. Robbrecht1Lot A. Devriese2Julie M. Janssen3Bas Thijssen4Marianne Keessen5Maarten vanEijk6Rob Kessels7Ferry A. L. M. Eskens8Jos H. Beijnen9Niven Mehra10Andries M. Bergman11Department of Clinical Pharmacology The Netherlands Cancer Institute Amsterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology University Medical Center Utrecht Utrecht The NetherlandsDepartment of Pharmacy and Pharmacology The Netherlands Cancer Institute Amsterdam The NetherlandsDepartment of Pharmacy and Pharmacology The Netherlands Cancer Institute Amsterdam The NetherlandsModra Pharmaceuticals B.V. Amsterdam The NetherlandsDepartment of Pharmacy and Pharmacology The Netherlands Cancer Institute Amsterdam The NetherlandsDepartment of Biometrics The Netherlands Cancer Institute Amsterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Pharmacy and Pharmacology The Netherlands Cancer Institute Amsterdam The NetherlandsDepartment of Medical Oncology Radboud University Medical Center Nijmegen The NetherlandsDepartment of Medical Oncology and Oncogenomics The Netherlands Cancer Institute Amsterdam The NetherlandsAbstract 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.https://doi.org/10.1002/cnr2.1367chemotherapyclinical trialsdrug discovery and deliveryprostate cancer |
| spellingShingle | Marit A. C. Vermunt Debbie G. J. Robbrecht Lot A. Devriese Julie M. Janssen Bas Thijssen Marianne Keessen Maarten vanEijk Rob Kessels Ferry A. L. M. Eskens Jos H. Beijnen Niven Mehra Andries M. Bergman ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration‐resistant prostate cancer patients: A phase Ib study Cancer Reports chemotherapy clinical trials drug discovery and delivery prostate cancer |
| title | ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration‐resistant prostate cancer patients: A phase Ib study |
| title_full | ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration‐resistant prostate cancer patients: A phase Ib study |
| title_fullStr | ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration‐resistant prostate cancer patients: A phase Ib study |
| title_full_unstemmed | ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration‐resistant prostate cancer patients: A phase Ib study |
| title_short | ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration‐resistant prostate cancer patients: A phase Ib study |
| title_sort | modradoc006 an oral docetaxel formulation in combination with ritonavir modradoc006 r in metastatic castration resistant prostate cancer patients a phase ib study |
| topic | chemotherapy clinical trials drug discovery and delivery prostate cancer |
| url | https://doi.org/10.1002/cnr2.1367 |
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