TBCRC 018: A Phase II Study of the PARP Inhibitor, BSI-201, in Combination with Chemotherapy to Treat Triple Negative Breast Cancer Brain Metastasis

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Purpose of the Study: 

Nearly half of patients with advanced Triple Negative Breast cancer (TNBC) develop brain metastases (BM). Triple Negative Breast Cancer (TNBC) lacks the three types of receptors known to fuel breast cancer growth-estrogen (ER), progesterone (PR), and HER2/neu. The purpose of this study is to determine how well the treatment with Irinotecan(chemotherapy) plus Iniparib(PARP Inhibitor) works and how safe it is for TNBC that has spread to the brain.


BiPAR Sciences and Sanofi-Aventis

Participating Sites: 
  • Dana-Farber/ Harvard Cancer Center
  • Duke University Medical Cancer Center
  • Georgetown University Lombard Cancer Center
  • Indiana University Simon Cancer Center
  • Johns Hopkins University
  • MD Anderson Cancer Center
  • University of Alabama, Birmingham
  • University of California, San Francisco
  • University of Chicago Medical Center
  • University of Michigan Comprehensive Cancer Center
  • University of North Carolina, Chapel Hill
  • University of Pittsburgh Cancer Institute
  • Vanderbilt University
Start Date & Stop Date: 

Date First Site Activated: July, 201

Date Trial Closed to Accrual: August, 2012

Key Eligibility Requirements: 
  • Triple Negative Breast Cancer with brain metastasis measuring greater than 5 mm on Magnetic Resonance Imaging (MRI).
  • No limit to number of prior systemic therapies (use drugs that spread throughout the body to treat cancer cells wherever they may be).
  • Stable or decreasing dose of steroids for greater than or equal to 7 days.
  • Must be at least 21 years old
  • ECOG performance status less than 2 (ambulatory and capable of all self care but unable to carry out any work activities; up and about more than 50% of waking hours)
  • Life expectancy of greater than or equal to 12 weeks.
  • Have adequate organ function, no serious infection or other chronic or acute diseases.
  • Must not be pregnant or breast-feeding.
  • Must not have had a previous allergic reaction to Iniparib or Irinotecan
  • Patients with intracranial hemorrhage, impending herniation or diffuse leptomeningeal disease were excluded.
  • Use of a class of drugs, CYP3A4 inhibitors (except systemic glucocorticoids) was prohibited.
Study Design: 
  • Eligible patients had TNBC with new or progressive brain metastasis and received Irinotecan and Iniparib every 3 weeks.
  • Primary Endpoint – Time to progression.
  • Secondary Endpoints - response rate, clinical benefit rate, overall survival, toxicity, and health-related quality of life
  • Correlative Endpoints - molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status.
  • Thirty-seven patients began treatment with iniparib and irinotecan;
    • Thirty-four were able to be evaluated for effectiveness.
    • Five of thirty-four patients were known to carry a BRCA germline mutation (four with BRCA1, one withBRCA2).
    • Mean age was 48 years
  • Median time to progression was 2.14 months.
  • Median overall survival was 7.8 months.
  • Intracranial response rate was 12% (four of thirty-four patients) while intracranial clinical benefit rate was 27% (nine of thirty four patients).
  • Treatment was well tolerated.
    • The most common moderate to severe- adverse events were neutropenia (14%) and fatigue (5%).
    • Diarrhea was common (54%), but moderate to severe - diarrhea was rare (3%).
  • Intrinsic subtyping revealed 19 of 21 tumors (79%) were basal-like, and intracranial response was associated with high expression of proliferation-related genes.

This study suggests a modest benefit of Irinotecan plus Iniparib in progressive triple negative breast cancer brain metastases.

Next Steps: 
  • In addition to illustrating modest efficacy and general tolerability of combination of Irinotecan and Iniparib in the setting of progressive triple negative breast cancer (TNBC) brain metastases, this study illustrated feasibility of enrolling patients into clinical trials with this aggressive disease.
  • The completion of TBCRC 018 laid the foundation for future studies evaluating novel agents for this treatment-resistant disease.
    • As an example, investigators from both Alliance and SWOG are working together to initiate a randomized clinical trial of cisplatin/placebo vs. cisplatin/ABT-888 (veliparib) in patients with advanced TNBC (SWOG1416); this study includes a brain metastases cohort. Many of the TBCRC investigators will be taking part in this study through their affiliations with SWOG and Alliance, and will have experience enrolling patients with TNBC brain metastases as a result of their participation in TBCRC 018.
Scientific Publications Available for this Clinical Trial: 

Anders, C.K., Nanda, R.,  Liu, M.C.,  Blackwell, K.L.,  Van Poznak, C.H.,  Abramson, V.G., Storniolo, A.M.,  Lin, N.U.,  Stearns, V.,  Melhem, A.,  Puhalla, S.,  Carpenter, J.T.,  Melisko, M.E.,  Deal, A.M.,  Hudis, C.,  Winer, E.P., Perou, C.M.,  Bradley, C.R.,  Wolff, A.C.,  Carey, L.A. TBCRC 018: Phase II study of iniparib plus chemotherapy to treat triple-negative breast cancer (TNBC) brain metastases (BM). 2011 ASCO, Trials in Progress Poster TPS127

Anders, C., Deal, A.,  Abramson, V.,  Liu, M.,  Storniolo, A.M.,  Carpenter, J.T., Puhalla, S.,  Nanda, R.,  Melhem-Bertrandt, A.,  Lin , N.U.,  Marcom, P.K., Van Poznak, C.,  Stearns, V., Melisko, M.,  Smith, J.K., Karginova, O.,  Winer, E.P., Perou, C.M.,  Wolff, A.C.,  Carey, L.A. TBCRC 018: Phase II study of iniparib plus chemotherapy to treat triple negative breast cancer (TNBC) central nervous system (CNS) metastases (mets). 2013 ASCO, Poster Discussion Session, Abstract #515.

Anders, C., Deal, A.M., Abramson, V., Liu, M.C., Storniolo, A.M., Carpenter, J.T., Puhalla, S., Nanda, R., Melhem-Bertrandt, A., Lin, N.U., Marcom, P.K., Van Poznak, C., Stearns, V., Melisko, M., Smith, J.K.,  Karginova, O., Parker, J., Berg, J., Winer, E.P., Peterman, A., Pratt, A., Perou, C.M.,  Wolff, A.C., Carey, L.A. TBCRC 018:  Phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases. Breast Cancer Res Treat 146 (3): 2014.

 *This summary was reviewed by: Carey K. Anders, M.D.  This summary was also reviewed and approved by the members of the TBCRC Patient Advocate Working Group.