{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T09:44:33Z","timestamp":1753868673908,"version":"3.41.2"},"reference-count":22,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:00:00Z","timestamp":1615507200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Reports"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>ModraDoc006 is an oral formulation of docetaxel, which is co\u2010administered with the cytochrome P450 3A4 and P\u2010glycoprotein 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\u2010resistant prostate cancer (mCRPC).<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>We assessed safety and pharmacokinetics (PK) of ModraDoc006\/r to establish the recommended phase 2 dose (RP2D) in patients with mCRPC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>mCRPC patients, treatment na\u00efve or following abiraterone or enzalutamide treatment, were included. Dose\u2010escalation of ModraDoc006\/r was based on safety and docetaxel PK. Antitumor activity was assessed by serum prostate\u2010specific antigen (PSA) and radiological evaluation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Cohort 1 (<jats:italic>n<\/jats:italic>\u00a0=\u00a05) received once weekly ModraDoc006 30\u2009mg with ritonavir 100\u2009mg in the morning, and ModraDoc006 20\u2009mg with ritonavir 100\u2009mg in the evening (30\u201020\/100\u2010100). The mean docetaxel area under the plasma concentration\u2010time curve (mAUC0\u2010inf) was 461\u2009ng\/mL\u2009\u00d7\u2009h with 1 dose limiting toxicity (DLT); grade 3 alanine transferase increase. In cohort 2 (<jats:italic>n<\/jats:italic>\u00a0=\u00a06, ModraDoc006\/r 30\u201020\/200\u2010200), the mAUC0\u2010inf was 1687\u2009ng\/mL\u2009\u00d7\u2009h with 2 DLTs; grade 3 diarrhea and mucositis. In cohort 3A (<jats:italic>n<\/jats:italic>\u00a0=\u00a06, ModraDoc006\/r 30\u201020\/200\u2010100), the mAUC0\u2010inf was 1517\u2009ng\/mL\u2009\u00d7\u2009h with 1 DLT; grade 3 diarrhea. In cohort 3B (<jats:italic>n<\/jats:italic>\u00a0=\u00a03, ModraDoc006\/r 20\u201020\/200\u2010100), the mAUC0\u2010inf was 558\u2009ng\/mL\u2009\u00d7\u2009h without DLTs. The mAUC0\u2010inf 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 &gt;50% occurred in 6\/10 evaluable patients throughout the various cohorts. In five radiological evaluable patients, two confirmed partial responses were observed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The RP2D was established at weekly ModraDoc006\/r 30\u201020\/200\u2010100. 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\u2010weekly IV docetaxel in patients with mCRPC.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cnr2.1367","type":"journal-article","created":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T08:10:35Z","timestamp":1615536635000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["<scp>ModraDoc006<\/scp>, an oral docetaxel formulation in combination with ritonavir (<scp>ModraDoc006<\/scp>\/r), in metastatic castration\u2010resistant prostate cancer patients: A phase Ib study"],"prefix":"10.1002","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2674-1291","authenticated-orcid":false,"given":"Marit A. C.","family":"Vermunt","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology The Netherlands Cancer Institute  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2490-9991","authenticated-orcid":false,"given":"Debbie G. J.","family":"Robbrecht","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Erasmus MC Cancer Institute  Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lot A.","family":"Devriese","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology University Medical Center Utrecht  Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie M.","family":"Janssen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmacology The Netherlands Cancer Institute  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bas","family":"Thijssen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmacology The Netherlands Cancer Institute  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianne","family":"Keessen","sequence":"additional","affiliation":[{"name":"Modra Pharmaceuticals B.V.  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7246-4857","authenticated-orcid":false,"given":"Maarten","family":"van Eijk","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmacology The Netherlands Cancer Institute  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rob","family":"Kessels","sequence":"additional","affiliation":[{"name":"Department of Biometrics The Netherlands Cancer Institute  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ferry A. L. M.","family":"Eskens","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Erasmus MC Cancer Institute  Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos H.","family":"Beijnen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmacology The Netherlands Cancer Institute  Amsterdam The Netherlands"},{"name":"Modra Pharmaceuticals B.V.  Amsterdam The Netherlands"},{"name":"Department of Pharmaceutical Sciences Utrecht University  Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niven","family":"Mehra","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andries M.","family":"Bergman","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology and Oncogenomics The Netherlands Cancer Institute  Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,3,12]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa040720"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2005.02.016"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1997.15.1.110"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00520-002-0405-9"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/03007995.2017.1308919"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-2915"},{"issue":"21","key":"e_1_2_12_8_1","first-page":"6158","article-title":"Low systemic exposure of oral docetaxel in mice resulting from extensive first\u2010pass metabolism is boosted by ritonavir","volume":"62","author":"Bardelmeijer HA","year":"2002","journal-title":"Cancer Res"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-2944"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-03-2677"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2016.07.068"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2017.09.010"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.2003"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.64.2702"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-015-0283-1"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2011.08.034"},{"volume-title":"R: A Language and Environment for Statistical Computing","year":"2009","author":"RC Team","key":"e_1_2_12_17_1"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.30.7025"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.12647"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.18.01279"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1998.16.1.187"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2004.09.005"},{"issue":"30","key":"e_1_2_12_23_1","first-page":"4562","article-title":"A population pharmacokinetic model of oral docetaxel coadministered with ritonavir to support early clinical development","volume":"28","author":"Yu H","year":"2019","journal-title":"J Clin Pharmacol"}],"container-title":["Cancer Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cnr2.1367","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cnr2.1367","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cnr2.1367","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T00:57:06Z","timestamp":1693357026000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cnr2.1367"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,12]]},"references-count":22,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,8]]}},"alternative-id":["10.1002\/cnr2.1367"],"URL":"https:\/\/doi.org\/10.1002\/cnr2.1367","archive":["Portico"],"relation":{},"ISSN":["2573-8348","2573-8348"],"issn-type":[{"type":"print","value":"2573-8348"},{"type":"electronic","value":"2573-8348"}],"subject":[],"published":{"date-parts":[[2021,3,12]]},"assertion":[{"value":"2021-01-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-02-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e1367"}}