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Iniparib administered weekly or twice-weekly in combination with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: a phase II randomized open-label study with pharmacokinetics

  • Véronique DiérasEmail author
  • Hervé Bonnefoi
  • Emilio Alba
  • Ahmad Awada
  • Bruno Coudert
  • Xavier Pivot
  • Joseph Gligorov
  • Agnes Jager
  • Stefania Zambelli
  • Geoffrey J. Lindeman
  • Eric Charpentier
  • Gary T. Emmons
  • Ignacio Garcia-Ribas
  • Robert Paridaens
  • Jaap Verweij
Clinical trial
  • 39 Downloads

Abstract

Purpose

Metastatic triple-negative breast cancer (TNBC) is a phenotypic breast cancer subgroup with a very poor prognosis, despite standard treatments. Combined twice-weekly iniparib and gemcitabine/carboplatin (GC+tw-iniparib) showed benefit over gemcitabine/carboplatin in a randomized phase II trial, and a phase III was initiated comparing these regimens. The present phase II study was initiated to compare GC+tw-iniparib with a more practical once-weekly schedule (GC+w-iniparib) in TNBC.

Methods

Metastatic TNBC patients were randomized to receive iniparib weekly (11.2 mg/kg on days 1 and 8) or twice-weekly (5.6 mg/kg on days 1, 4, 8, and 11) with gemcitabine (1000 mg/m2) and carboplatin (area under the curve 2 on days 1 and 8), every 3 weeks. The primary endpoint was the overall response rate (ORR). Pharmacokinetics of iniparib and its two metabolites were analyzed.

Results

A total of 163 patients were randomized, 82 GC+w-iniparib and 81 GC+tw-iniparib. Demographic and baseline characteristics were well balanced. ORR was 34.1% (95% CI 23.9–44.4%) vs. 29.6% (95% CI 19.7–39.6%) and median progression-free survival was 5.5 months (95% CI 4.2–5.7) vs. 4.3 months (95% CI 3.0–5.8) for GC+w-iniparib and GC+tw-iniparib, respectively. Safety was similar across treatment arms in terms of event severity and type. Iniparib plasma concentrations and exposure were two-fold higher with w-iniparib compared to tw-iniparib. Iniparib and its metabolites were cleared rapidly with a terminal half-life of < 1 h, without accumulation.

Conclusions

Despite a doubled maximum concentration with weekly iniparib, no detectable differences in safety or efficacy were observed between the weekly and twice-weekly administration schedules in this population.

Trial registration

ClinicalTrial.gov Identifier NCT01045304.

Keywords

Iniparib Metastatic triple-negative breast cancer Pharmacokinetics Administration schedule 

Abbreviations

AE

Adverse events

AUC2

Carboplatin area under the curve

CBR

Clinical benefit rate

ER

Estrogen receptor

GC+w-iniparib

Gemcitabine-carboplatin plus weekly iniparib

GC+tw-iniparib

Gemcitabine-carboplatin plus twice-weekly iniparib

HER2

Human epidermal growth factor receptor 2

IABA

4-Iodo-3-amino-benzoic acid

IABM

4-Iodo-aminobenzamide

IHC

Immunohistochemistry

ITT

Intent-to-treat

ORR

Overall response rate

OS

Overall survival

PARP

Poly(ADP-ribose)polymerase

PFS

Progression-free survival

PR

Progesterone receptor

RECIST

Response Evaluation Criteria in Solid Tumors

TNBC

Triple-negative breast cancers

ULN

Upper limit of normal

Notes

Acknowledgements

We thank the patients, their families, and the investigators who participated in this study. We thank Nathalie Debbas and Sarah MacKenzie (MediAxe, France, funded by Sanofi) for assistance drafting the manuscript, and Wenjuan Zhang (Sanofi) for programming support.

Funding

This study was funded by Sanofi.

Compliance with ethical standards

Conflicts of interest

EC, GTE and IGR are current or former employees and have stock options of Sanofi. JG and JV have received remuneration and/or had an advisory/consultancy role for Sanofi. VD, EA, AA, JG, and JV have/had a consultancy/advisory role with and/or received remuneration from pharmaceutical companies other than Sanofi. All other authors declare no potential conflicts of interest (HB, BC, XP, AJ, SZ, GL, RP).

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Medical OncologyInstitut CurieParisFrance
  2. 2.Centre Eugène MarquisRennes CedexFrance
  3. 3.Institut Bergonié, Univ. Bordeaux, INSERM U1218, INSERM CIC1401BordeauxFrance
  4. 4.Department of Clinical OncologyHospital Clínico Universitario Virgen de la VictoriaMálagaSpain
  5. 5.Oncology Medicine DepartmentInstitut Jules Bordet, Université Libre de BruxellesBrusselsBelgium
  6. 6.Medical Oncology DepartmentCentre Georges François LeclercDijonFrance
  7. 7.Department of Medical OncologyCentre Paul StraussStrasbourgFrance
  8. 8.Medical Oncology Dept Tenon Hospital, Inserm U938Institut Universitaire de Cancérologie APHP-Sorbonne UniversitéParisFrance
  9. 9.Department of Medical OncologyErasmus MC Cancer InstituteRotterdamThe Netherlands
  10. 10.Department of Medical OncologyIRCCS OSR, San RaffaeleMilanItaly
  11. 11.Department of Medical Oncology, Peter MacCallum Cancer Centre and Royal Melbourne HospitalThe Walter and Eliza Hall Institute of Medical ResearchMelbourneAustralia
  12. 12.Statistics DepartmentSanofiCambridgeUSA
  13. 13.Translational Medicine and Early DevelopmentSanofiBridgewaterUSA
  14. 14.Early Oncology DevelopmentSanofiMadridSpain
  15. 15.Department of Medical OncologyUniversity Hospital Gasthuisberg, Catholic University of LeuvenLeuvenBelgium

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