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

Feby Mardjuadi; Jacques Medioni; Joseph Kerger; Lionel D'Hondt; Jean Luc Canon; Lionel Duck; Flora Musuamba Tshinanu; Stephane Oudard; Marylene Clausse; Anne Moxhon; Jean Pascal Machiels

doi:10.1007/s00280-012-1914-y

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

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

Research output: Contribution to journal › Article › peer-review

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/m ²/q ³ 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 doselimiting 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 doseescalation 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.

Original language	English
Pages (from-to)	293-303
Number of pages	11
Journal	Cancer Chemotherapy and Pharmacology
Volume	70
Issue number	2
DOIs	https://doi.org/10.1007/s00280-012-1914-y
Publication status	Published - Aug 2012
Externally published	Yes

Keywords

Docetaxel
Metastatic
Pharmacokinetic
Phase 1
Prostate
Sorafenib

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s00280-012-1914-y

Cite this

Mardjuadi, F., Medioni, J., Kerger, J., D'Hondt, L., Canon, J. L., Duck, L., Musuamba Tshinanu, F., Oudard, S., Clausse, M., Moxhon, A., & Machiels, J. P. (2012). Phase I study of sorafenib in combination with docetaxel and prednisone in chemo-naïve patients with metastatic castration-resistant prostate cancer. Cancer Chemotherapy and Pharmacology, 70(2), 293-303. https://doi.org/10.1007/s00280-012-1914-y

@article{b8b739bb896045e8b7d7df0440a2b8bb,

title = "Phase I study of sorafenib in combination with docetaxel and prednisone in chemo-na{\"i}ve patients with metastatic castration-resistant prostate cancer",

abstract = "Purpose We performed a dose-escalation study to investigate the safety of sorafenib in combination with docetaxel and prednisone in chemo-na{\"i}ve patients with metastatic castration-resistant prostate cancer (mCRPC). Methods Six patients were included per dose level. Following docetaxel infusion on day 1 (75 mg/m 2/q 3 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 doselimiting 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 doseescalation 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.",

keywords = "Docetaxel, Metastatic, Pharmacokinetic, Phase 1, Prostate, Sorafenib",

author = "Feby Mardjuadi and Jacques Medioni and Joseph Kerger and Lionel D'Hondt and Canon, {Jean Luc} and Lionel Duck and {Musuamba Tshinanu}, Flora and Stephane Oudard and Marylene Clausse and Anne Moxhon and Machiels, {Jean Pascal}",

note = "Funding Information: Acknowledgments We are grateful to the patients and their families who participated in this study. We also thank the study coordinators, Roger Verbeeck, PhD (Louvain Drug Research Institute, Belgium) for the pharmacokinetic analyses, Fatima Hammouch, MsC for statistical assistance, Marie-Alix Bonny for administrative support, and Aileen Eiszele, BA(Hons) Dip.Ed. for editing the manuscript. This work was supported by St-Luc University Hospital, Belgium and by an educational grant from Bayer, Belgium. Funding Information: Conflict of interest J. Medioni has received compensations from Sanofi Aventis for consultant/advisory board and as honoraria. However, none is related to the present trial. S. Oudard has received compensations from Novartis for consultant/advisory board and honoraria from Pfizer, Roche, and Sanofi Aventis. However, none is related to the present trial. J-P. Machiels has received compensations from Genmab and Boehringer Ingelheim for consultant/advisory board and an educational research grant from Bayer, Belgium, to support the present trial. All remaining authors have declared no conflicts of interest.",

year = "2012",

month = aug,

doi = "10.1007/s00280-012-1914-y",

language = "English",

volume = "70",

pages = "293--303",

journal = "Cancer Chemotherapy and Pharmacology",

issn = "0344-5704",

publisher = "Springer Verlag",

number = "2",

}

Mardjuadi, F, Medioni, J, Kerger, J, D'Hondt, L, Canon, JL, Duck, L, Musuamba Tshinanu, F, Oudard, S, Clausse, M, Moxhon, A & Machiels, JP 2012, 'Phase I study of sorafenib in combination with docetaxel and prednisone in chemo-naïve patients with metastatic castration-resistant prostate cancer', Cancer Chemotherapy and Pharmacology, vol. 70, no. 2, pp. 293-303. https://doi.org/10.1007/s00280-012-1914-y

TY - JOUR

T1 - Phase I study of sorafenib in combination with docetaxel and prednisone in chemo-naïve patients with metastatic castration-resistant prostate cancer

AU - Mardjuadi, Feby

AU - Medioni, Jacques

AU - Kerger, Joseph

AU - D'Hondt, Lionel

AU - Canon, Jean Luc

AU - Duck, Lionel

AU - Musuamba Tshinanu, Flora

AU - Oudard, Stephane

AU - Clausse, Marylene

AU - Moxhon, Anne

AU - Machiels, Jean Pascal

N1 - Funding Information: Acknowledgments We are grateful to the patients and their families who participated in this study. We also thank the study coordinators, Roger Verbeeck, PhD (Louvain Drug Research Institute, Belgium) for the pharmacokinetic analyses, Fatima Hammouch, MsC for statistical assistance, Marie-Alix Bonny for administrative support, and Aileen Eiszele, BA(Hons) Dip.Ed. for editing the manuscript. This work was supported by St-Luc University Hospital, Belgium and by an educational grant from Bayer, Belgium. Funding Information: Conflict of interest J. Medioni has received compensations from Sanofi Aventis for consultant/advisory board and as honoraria. However, none is related to the present trial. S. Oudard has received compensations from Novartis for consultant/advisory board and honoraria from Pfizer, Roche, and Sanofi Aventis. However, none is related to the present trial. J-P. Machiels has received compensations from Genmab and Boehringer Ingelheim for consultant/advisory board and an educational research grant from Bayer, Belgium, to support the present trial. All remaining authors have declared no conflicts of interest.

PY - 2012/8

Y1 - 2012/8

N2 - 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/m 2/q 3 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 doselimiting 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 doseescalation 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.

AB - 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/m 2/q 3 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 doselimiting 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 doseescalation 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.

KW - Docetaxel

KW - Metastatic

KW - Pharmacokinetic

KW - Phase 1

KW - Prostate

KW - Sorafenib

UR - http://www.scopus.com/inward/record.url?scp=84866545393&partnerID=8YFLogxK

U2 - 10.1007/s00280-012-1914-y

DO - 10.1007/s00280-012-1914-y

M3 - Article

C2 - 22752248

AN - SCOPUS:84866545393

SN - 0344-5704

VL - 70

SP - 293

EP - 303

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

IS - 2

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this