A Phase 3, Multi-Center Study of Gemcitabine/Carboplatin, With or Without BSI-201, in Patients With ER-, PR-, and Her2-Negative Metastatic Breast Cancer

• ClinicalTrials.gov Identifier: NCT00938652
• Recruitment Status: Completed
• First Posted: July 14, 2009
• Last Update Posted: September 19, 2013
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

Tracking Information

• First Submitted Date: July 10, 2009
• First Posted Date: July 14, 2009
• Last Update Posted Date: September 19, 2013
• Study Start Date: July 2009
• Actual Primary Completion Date: January 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 21, 2012)

• progression free survival [ Time Frame: until cut-off date established from deaths rate ]
  Progression free survival was defined as the time interval from the date of randomization to the date of first disease progression (as assessed by Independent Radiologic Review (IRR) based on Response Evaluation Criteria in Solid Tumor (RECIST) criteria), or the date of death due to any cause, whichever occurred first. In the absence disease progression or death, the participant was censored at the date of the last valid tumor assessment performed before the cut-off date.
• Overall survival [ Time Frame: until cut-off date established from deaths rate ]
  Overall survival was defined as the time interval from the date of randomization to the date of death due to any cause. In the absence of confirmation of death, participant was censored at the last date he/she was known to be alive, or at the cut-off date, whichever was earlier.

Original Primary Outcome Measures (submitted: July 13, 2009)

• progression free survival [ Time Frame: 12 months ]
• overall survival [ Time Frame: 18 months ]

Current Secondary Outcome Measures (submitted: December 21, 2012)

• Best overall response [ Time Frame: until treatment discontinuation (assessment at the end of cycle 2 then every other cycle) ]
  Best overall response was defined as the best evaluation observed through the entire treatment period as assessed by Independent Radiologic Review [IRR] based on Response Evaluation Criteria in Solid Tumor (RECIST) criteria.
• Objective response rate [ Time Frame: until treatment discontinuation (assessment at the end of cycle 2 then every other cycle) ]
  Objective response rate was defined as the percentage of patients with IRR confirmed partial response or complete response prior to disease progression or treatment discontinuation.

• Original Secondary Outcome Measures (submitted: July 13, 2009): response rate [ Time Frame: 8 months ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 3, Multi-Center Study of Gemcitabine/Carboplatin, With or Without BSI-201, in Patients With ER-, PR-, and Her2-Negative Metastatic Breast Cancer
• Official Title: A Phase 3, Multi-Center, Open-Label, Randomized Study of Gemcitabine/Carboplatin, With or Without BSI-201, in Patients With ER-, PR-, and Her2-Negative Metastatic Breast Cancer

Brief Summary

The goal of this study was to determine the effect on overall survival and progression free survival by adding iniparib (BSI-201/SAR240550) to the combination of gemcitabine/carboplatin in adult patients with triple negative breast cancer (estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and human epidermal growth factor receptor 2 (HER2)-negative).

Based on data generated by BiPar/Sanofi, it is concluded that iniparib does not possess characteristics typical of the poly (ADP-ribose) polymerase (PARP) inhibitor class. The exact mechanism has not yet been fully elucidated, however based on experiments on tumor cells performed in the laboratory, iniparib is a novel investigational anti-cancer agent that induces gamma-H2AX (a marker of DNA damage) in tumor cell lines, induces cell cycle arrest in the G2/M phase in tumor cell lines, and potentiates the cell cycle effects of DNA damaging modalities in tumor cell lines. Investigations into potential targets of iniparib and its metabolites are ongoing.

• Detailed Description: Participants were treated for 21-day cycles until disease progression, unacceptable toxicity, or consent withdrawal. After treatment discontinuation, participants were followed until end of study or death or receipt of new anticancer therapy, whichever was first.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: gemcitabine/carboplatin

  Gemcitabine 1000 mg/m2 intravenous infusion (30 ± 10 minutes)

  Carboplatin AUC 2 intravenous infusion (30 ± 10 minutes or 60 ± 10 minutes)

• Drug: Iniparib

  Body weight adjusted dose

  intravenous infusion (60 ± 10 minutes)

  Other Names:

  • BSI-201
  • SAR240550

Study Arms

• Active Comparator: Arm G/C
  gemcitabine/carboplatin on Days 1 and 8 of 21-day cycle(s)
  Intervention: Drug: gemcitabine/carboplatin
• Experimental: Arm G/C/I
  gemcitabine/carboplatin on Days 1 and 8, plus iniparib on Days 1, 4, 8, and 11 of 21-day cycle(s)
  Interventions:

  • Drug: gemcitabine/carboplatin
  • Drug: Iniparib

• Publications *: O'Shaughnessy J, Schwartzberg L, Danso MA, Miller KD, Rugo HS, Neubauer M, Robert N, Hellerstedt B, Saleh M, Richards P, Specht JM, Yardley DA, Carlson RW, Finn RS, Charpentier E, Garcia-Ribas I, Winer EP. Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol. 2014 Dec 1;32(34):3840-7. doi: 10.1200/JCO.2014.55.2984. Epub 2014 Oct 27.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 26, 2011): 519
• Original Estimated Enrollment (submitted: July 13, 2009): 420
• Actual Study Completion Date: February 2012
• Actual Primary Completion Date: January 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

- Histologically documented breast cancer (either primary or metastatic site) that is ER-negative, PR-negative, and HER2 non-overexpressing by immunohistochemistry (0, 1) or fluorescence in situ hybridization (FISH).

Triple-negative tumors were defined by the following criteria:

• HER2-non-overexpressing: FISH-negative (defined by ratio <2.2) or, immunohistochemical (IHC) 0, IHC 1+ or, IHC 2+ or IHC 3+ and FISH-negative.

• ER- and PR-negative: <10% tumor staining by immunohistochemistry (IHC).

  • Never having received chemotherapy for metastatic disease or, having received 1 or 2 prior chemotherapy regimens in the metastatic setting (Prior adjuvant/neoadjuvant therapy was allowed);
  • Metastatic breast cancer (Stage IV) with measurable disease by RECIST 1.1 criteria;
  • Female, ≥18 years of age;
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;
  • Organ and marrow function as follows: absolute neutrophil count (ANC) ≥1500/mm3, platelets ≥100,000/dL, hemoglobin ≥9 g/dL, bilirubin ≤1.5 mg/dL, serum creatinine ≤1.5 mg/dL or creatinine clearance ≥60 mL/min, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times the upper limit of normal if no liver involvement or ≤5 times the upper limit of normal with liver involvement;
  • Radiation therapy completed at least 14 days before study dosing on day 1; radiated lesions may not have served as measurable disease;
  • Central nervous system metastases allowed if subject did not require steroids, whole brain radiation therapy (XRT), gamma/cyber knife, and brain metastases were clinically stable without symptomatic progression;
  • For women of child bearing potential, documented negative pregnancy test within two weeks of study entry and agreement to acceptable birth control during the duration of the study therapy;
  • Tissue block (primary or metastatic) or readily available fresh frozen tumor tissue for PARP expression and other pharmacogenomic studies recommended (although its absence will not exclude subjects from participating);
  • No other diagnosis of malignancy (with exception of non melanoma skin cancer or a malignancy diagnosed ≥5 years ago);
  • Obtained informed consent;
  • Capability to understand and comply with the protocol and signed informed consent document.

Exclusion Criteria:

• Systemic anticancer therapy within 14 days of the first dose of study drug;
• Prior treatment with gemcitabine, carboplatin, cisplatin or iniparib
• Had not recovered to grade ≤1 from adverse events (AEs) per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v3.0 or to within 10% of baseline values due to investigational drugs or other medications administered more than 30 days prior to study enrollment;
• Major medical conditions that might have affected study participation (e.g. uncontrolled pulmonary, renal, or hepatic dysfunction, uncontrolled infection, cardiac disease);
• Concurrent radiation therapy intended to treat primary tumor not permitted throughout the course of the study; palliative radiation was acceptable;
• Leptomeningeal disease or brain metastases requiring steroids or other therapeutic intervention;
• Pregnancy or breastfeeding;
• Inability or unwillingness to abide by the study protocol or cooperate fully with the investigator or designee.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00938652
• Other Study ID Numbers: EFC11486; 20090301 ( Other Identifier: BiPar ); U1111-1119-8208 ( Other Identifier: WHO )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Sanofi
• Original Responsible Party: VP Clinical Development, bipar sciences
• Current Study Sponsor: Sanofi
• Original Study Sponsor: BiPar Sciences
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

• PRS Account: Sanofi
• Verification Date: September 2013