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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

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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.

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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

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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.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Institut Curie, Paris, France

    Véronique Diéras

  2. Centre Eugène Marquis, Avenue de la bataille Flandres-Dunkerque, CS 44229, 35042, Rennes Cedex, France

    Véronique Diéras

  3. Institut Bergonié, Univ. Bordeaux, INSERM U1218, INSERM CIC1401, Bordeaux, France

    Hervé Bonnefoi

  4. Department of Clinical Oncology, Hospital Clínico Universitario Virgen de la Victoria, Málaga, Spain

    Emilio Alba

  5. Oncology Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium

    Ahmad Awada

  6. Medical Oncology Department, Centre Georges François Leclerc, Dijon, France

    Bruno Coudert

  7. Department of Medical Oncology, Centre Paul Strauss, Strasbourg, France

    Xavier Pivot

  8. Medical Oncology Dept Tenon Hospital, Inserm U938, Institut Universitaire de Cancérologie APHP-Sorbonne Université, Paris, France

    Joseph Gligorov

  9. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    Agnes Jager & Jaap Verweij

  10. Department of Medical Oncology, IRCCS OSR, San Raffaele, Milan, Italy

    Stefania Zambelli

  11. Department of Medical Oncology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia

    Geoffrey J. Lindeman

  12. Statistics Department, Sanofi, 640 Memorial Drive, Cambridge, MA, 02139, USA

    Eric Charpentier

  13. Translational Medicine and Early Development, Sanofi, Bridgewater, NJ, USA

    Gary T. Emmons

  14. Early Oncology Development, Sanofi, Madrid, Spain

    Ignacio Garcia-Ribas

  15. Department of Medical Oncology, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium

    Robert Paridaens

Authors
  1. Véronique Diéras
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  2. Hervé Bonnefoi
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  3. Emilio Alba
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  4. Ahmad Awada
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  15. Jaap Verweij
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Corresponding author

Correspondence to Véronique Diéras.

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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.

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

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Diéras, V., Bonnefoi, H., Alba, E. et al. 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. Breast Cancer Res Treat 177, 383–393 (2019). https://doi.org/10.1007/s10549-019-05305-w

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  • DOI: https://doi.org/10.1007/s10549-019-05305-w

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