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



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.


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.


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.


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 Identifier NCT01045304.


Iniparib Metastatic triple-negative breast cancer Pharmacokinetics Administration schedule 



Adverse events


Carboplatin area under the curve


Clinical benefit rate


Estrogen receptor


Gemcitabine-carboplatin plus weekly iniparib


Gemcitabine-carboplatin plus twice-weekly iniparib


Human epidermal growth factor receptor 2


4-Iodo-3-amino-benzoic acid








Overall response rate


Overall survival




Progression-free survival


Progesterone receptor


Response Evaluation Criteria in Solid Tumors


Triple-negative breast cancers


Upper limit of normal



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.


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.


  1. 1.
    Howlader N, Altekruse SF, Li CI et al (2014) US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. Google Scholar
  2. 2.
    Carey LA, Perou CM, Livasy CA et al (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295:2492–2502. CrossRefGoogle Scholar
  3. 3.
    Dent R, Trudeau M, Pritchard KI et al (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13:4429–4434. CrossRefGoogle Scholar
  4. 4.
    Dent R, Hanna WM, Trudeau M et al (2009) Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res Treat 115:423–428. CrossRefGoogle Scholar
  5. 5.
    Lin NU, Vanderplas A, Hughes ME et al (2012) Clinicopathologic features, patterns of recurrence, and survival among women with triple-negative breast cancer in the National Comprehensive Cancer Network. Cancer 118:5463–5472. CrossRefGoogle Scholar
  6. 6.
    Kennecke H, Yerushalmi R, Woods R et al (2010) Metastatic behavior of breast cancer subtypes. J Clin Oncol 28:3271–3277. CrossRefGoogle Scholar
  7. 7.
    Kassam F, Enright K, Dent R et al (2009) Survival outcomes for patients with metastatic triple-negative breast cancer: implications for clinical practice and trial design. Clin Breast Cancer 9:29–33. CrossRefGoogle Scholar
  8. 8.
    Tutt A, Tovey H, Cheang MCU et al (2018) Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. Nat Med 24:628–637. CrossRefGoogle Scholar
  9. 9.
    Schmid P, Adams S, Rugo HS et al (2018) Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. Google Scholar
  10. 10.
    Robson M, Im S-A, Senkus E et al (2017) Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377:523–533. CrossRefGoogle Scholar
  11. 11.
    Litton JK, Rugo HS, Ettl J et al (2018) Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 379:753–763. CrossRefGoogle Scholar
  12. 12.
    Liu X, Shi Y, Maag DX et al (2012) Iniparib nonselectively modifies cysteine-containing proteins in tumor cells and is not a bona fide PARP inhibitor. Clin Cancer Res 18:510–523. CrossRefGoogle Scholar
  13. 13.
    Patel AG, De Lorenzo SB, Flatten KS et al (2012) Failure of iniparib to inhibit poly(ADP-ribose) polymerase in vitro. Clin Cancer Res 18:1655–1662. CrossRefGoogle Scholar
  14. 14.
    O’Shaughnessy J, Osborne C, Pippen JE et al (2011) Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 364:205–214. CrossRefGoogle Scholar
  15. 15.
    O’Shaughnessy J, Schwartzberg L, Danso MA et al (2014) Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol 32:3840–3847. CrossRefGoogle Scholar
  16. 16.
    Simon R, Wittes RE, Ellenberg SS (1985) Randomized phase II clinical trials. Cancer Treat Rep 69:1375–1381Google Scholar
  17. 17.
    Mendeleyev J, Kirsten E, Hakam A et al (1995) Potential chemotherapeutic activity of 4-iodo-3-nitrobenzamide. Metabolic reduction to the 3-nitroso derivative and induction of cell death in tumor cells in culture. Biochem Pharmacol 50:705–714CrossRefGoogle Scholar
  18. 18.
    Lee JJ, Feng L (2005) Randomized phase II designs in cancer clinical trials: current status and future directions. J Clin Oncol 23:4450–4457. CrossRefGoogle Scholar
  19. 19.
    Verweij J, Diéras V, Rockich K et al (2011) A134 Pharmacokinetics and metabolism of iniparib for the treatment of metastatic triple-negative breast cancer (TNBC). Mol Cancer Ther. Google Scholar

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

Personalised recommendations