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01-08-2012 | Original Article

Phase I study of sorafenib in combination with docetaxel and prednisone in chemo-naïve patients with metastatic castration-resistant prostate cancer

Authors: Feby Mardjuadi, Jacques Medioni, Joseph Kerger, Lionel D’Hondt, Jean-Luc Canon, Lionel Duck, Flora Musuamba, Stephane Oudard, Marylene Clausse, Anne Moxhon, Jean-Pascal Machiels

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2012

Abstract

Purpose

We performed a dose-escalation study to investigate the safety of sorafenib in combination with docetaxel and prednisone in chemo-naïve patients with metastatic castration-resistant prostate cancer (mCRPC).

Methods

Six patients were included per dose level. Following docetaxel infusion on day 1 (75 mg/m²/q3 weeks), sorafenib was administered at 200 mg BID on days 2–19 (dose level 1), at 200 mg BID on days 1–21 (dose level 2), at 400 mg BID on days 2–19 (dose level 3), at 400 mg BID on days 1–21 (dose level 4). Maximal tolerated dose (MTD) was exceeded if ≥2 patients experienced dose-limiting toxicities (DLT) during cycle 1. The recommended phase 2 dose for sorafenib was defined as one dose level below MTD. If MTD was not reached, the highest feasible dose would be selected to treat an expanded cohort to confirm safety.

Results

Two DLTs were observed during sorafenib dose-escalation consisting of grade 4 febrile neutropenia (dose level 2) and grade 3 hand-foot syndrome (HFS) (dose level 3). Our pharmacokinetic results showed an increased exposure to docetaxel across all dose levels during sorafenib comedication. The main grade ≥3 toxicities were neutropenia (35 %), HFS (27 %), and febrile neutropenia (19 %). The prostate-specific antigen (PSA) response rate was 74 %. Median overall survival was 25.2 months.

Conclusion

Three-weekly docetaxel and prednisone could be combined with sorafenib at 400 mg BID on days 1–21 without reaching MTD. However, we observed a pharmacokinetic interaction between sorafenib and docetaxel, associated with significant toxicities, raising concerns about the safety of this combination in mCRPC.

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Title: Phase I study of sorafenib in combination with docetaxel and prednisone in chemo-naïve patients with metastatic castration-resistant prostate cancer
Authors: Feby Mardjuadi
Jacques Medioni
Joseph Kerger
Lionel D’Hondt
Jean-Luc Canon
Lionel Duck
Flora Musuamba
Stephane Oudard
Marylene Clausse
Anne Moxhon
Jean-Pascal Machiels
Publication date: 01-08-2012
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2012
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-012-1914-y

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