A Phase 2 Trial of Standard Chemotherapy, With or Without BSI-201, in Patients With Triple Negative Metastatic Breast Cancer

A Phase 2, Multi-center, Open-Label, Randomized Trial of Gemcitabine/ Carboplatin, With or Without BSI-201, in Patients With ER, PR and HER2-negative Metastatic Breast Cancer

The purpose of this clinical trial was to determine whether combining iniparib (BSI-201) with standard chemotherapy in estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer patients improve clinical benefit compared to treatment with standard chemotherapy alone.

Based on data generated by BiPar/Sanofi, it was 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.

Patients were treated until disease progression, unacceptable toxicity, Investigator's decision to discontinue, or withdrawal of consent. After treatment discontinuation, all patients were evaluated every 90 days after last dose of gemcitabine/carboplatin with or without iniparib, for up to 3 years or death or end of study, which ever occurred first.

Inclusion Criteria:

• At least 18 years of age;
• Metastatic breast cancer (Stage IV) with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria;
• 0-2 prior chemotherapy regimens in the metastatic setting;
• Histologically documented (either primary or metastatic site) breast cancer that was ER-negative, PR-negative, and HER-2 nonoverexpressing by immunohistochemistry (0,1) or non-gene amplification by fluorescence in situ hybridization (FISH);
• Completion of prior chemotherapy at least 2 weeks prior to trial entry and recovery from toxicity of prior chemotherapy;
• Radiation therapy must have been completed at least 2 weeks prior to trial entry, and radiated lesions may not have served as measurable disease;
• Patient may have had central nervous system (CNS) metastases if he/she did not require steroids, whole brain radiation therapy (XRT), gamma/cyber knife, and brain metastases were clinically stable without symptomatic progression;
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1;
• Adequate organ function defined as: absolute neutrophil count (ANC)≥1,500/mm3, platelets ≥100,000/mm3, creatinine clearance >50mL/min, ALT and AST <2.5 x upper limit of normal (ULN) (or <5 x ULN in case of liver metastases); total bilirubin <1.5 mg/dL.
• Tissue block (primary or metastatic) available for PARP and PG studies was recommended, although its absence did not exclude subjects from participating;
• Woman of child bearing potential must have had documented negative pregnancy test within two weeks of trial entry and agreed to acceptable birth control during the duration of the trial therapy;
• Signed, IRB approved written informed consent.

Exclusion Criteria:

• Lesions identifiable only by positron emission tomography (PET);
• Prior treatment with gemcitabine, carboplatin, cisplatin or iniparib;
• Major medical conditions that might have affected trial participation (uncontrolled pulmonary, renal, or hepatic dysfunction, uncontrolled infection);
• Significant history of uncontrolled cardiac disease; i.e. uncontrolled hypertension, unstable angina, recent myocardial infarction (within prior 6 months), uncontrolled congestive heart failure, and cardiomyopathy that was either symptomatic or asymptomatic but with decreased ejection fraction <45%;
• Other significant comorbid condition which the investigator felt might compromise effective and safe participation in the trial;
• Patient enrolled in another investigational device or drug trial, or was receiving other investigational agents;
• Concurrent or prior (within 7 days of trial day 1) anticoagulation therapy (low dose for port maintenance allowed);
• Concurrent radiation therapy was not permitted throughout the course of the trial;
• Inability to comply with the requirements of the trial;
• Pregnant or lactating woman;
• Leptomeningeal disease or brain metastases requiring steroids or other therapeutic intervention.