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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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.
ClinicalTrial.gov Identifier NCT01045304.
KeywordsIniparib Metastatic triple-negative breast cancer Pharmacokinetics Administration schedule
Carboplatin area under the curve
Clinical benefit rate
Gemcitabine-carboplatin plus weekly iniparib
Gemcitabine-carboplatin plus twice-weekly iniparib
Human epidermal growth factor receptor 2
Overall response rate
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).
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 was obtained from all individual participants included in the study.
- 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. https://doi.org/10.1200/JCO.2014.55.2984 CrossRefGoogle Scholar
- 16.Simon R, Wittes RE, Ellenberg SS (1985) Randomized phase II clinical trials. Cancer Treat Rep 69:1375–1381Google Scholar