TBCRC 018

Phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases

Carey Anders, Allison M. Deal, Vandana Abramson, Minetta C. Liu, Anna Maria Storniolo, John T. Carpenter, Shannon Puhalla, Rita Nanda, Amal Melhem-Bertrandt, Nancy U. Lin, P. Kelly Marcom, Catherine Van Poznak, Vered Stearns, Michelle Melisko, J. Keith Smith, Olga Karginova, Joel Parker, Jonathan Berg, Eric P. Winer, Amy Peterman & 4 others Aleix Prat, Charles M. Perou, Antonio C. Wolff, Lisa A. Carey

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3 weeks. Time to progression (TTP) was the primary end point; secondary endpoints were response rate (RR), clinical benefit rate (CBR), overall survival (OS), toxicity, and health-related quality of life. Correlative endpoints included molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status. Thirty-seven patients began treatment; 34 were evaluable for efficacy. Five of 24 patients were known to carry a BRCA germline mutation (4 BRCA1, 1 BRCA2). Median TTP was 2.14 months and median OS was 7.8 months. Intracranial RR was 12 %, while intracranial CBR was 27 %. Treatment was well-tolerated; the most common grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 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 TNBC-BM. More importantly, this trial design is feasible and lays the foundation for additional studies for this treatment-refractory disease.

Original languageEnglish (US)
Pages (from-to)557-566
Number of pages10
JournalBreast Cancer Research and Treatment
Volume146
Issue number3
DOIs
StatePublished - 2014

Fingerprint

irinotecan
Triple Negative Breast Neoplasms
Brain Neoplasms
Neoplasm Metastasis
Topoisomerase I Inhibitors
Neoplasms
Germ-Line Mutation
Therapeutics
Neutropenia
Blood-Brain Barrier
Fatigue
Diarrhea
Reactive Oxygen Species
Survival Rate
Quality of Life
iniparib
Safety
Gene Expression

Keywords

  • Brain metastases
  • Breast cancer
  • Iniparib
  • Irinotecan
  • Phase II
  • Triple negative

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Medicine(all)

Cite this

TBCRC 018 : Phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases. / Anders, Carey; Deal, Allison M.; Abramson, Vandana; Liu, Minetta C.; Storniolo, Anna Maria; Carpenter, John T.; Puhalla, Shannon; Nanda, Rita; Melhem-Bertrandt, Amal; Lin, Nancy U.; Kelly Marcom, P.; Van Poznak, Catherine; Stearns, Vered; Melisko, Michelle; Smith, J. Keith; Karginova, Olga; Parker, Joel; Berg, Jonathan; Winer, Eric P.; Peterman, Amy; Prat, Aleix; Perou, Charles M.; Wolff, Antonio C.; Carey, Lisa A.

In: Breast Cancer Research and Treatment, Vol. 146, No. 3, 2014, p. 557-566.

Research output: Contribution to journalArticle

Anders, C, Deal, AM, Abramson, V, Liu, MC, Storniolo, AM, Carpenter, JT, Puhalla, S, Nanda, R, Melhem-Bertrandt, A, Lin, NU, Kelly Marcom, P, Van Poznak, C, Stearns, V, Melisko, M, Smith, JK, Karginova, O, Parker, J, Berg, J, Winer, EP, Peterman, A, Prat, A, Perou, CM, Wolff, AC & Carey, LA 2014, 'TBCRC 018: Phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases', Breast Cancer Research and Treatment, vol. 146, no. 3, pp. 557-566. https://doi.org/10.1007/s10549-014-3039-y
Anders, Carey ; Deal, Allison M. ; Abramson, Vandana ; Liu, Minetta C. ; Storniolo, Anna Maria ; Carpenter, John T. ; Puhalla, Shannon ; Nanda, Rita ; Melhem-Bertrandt, Amal ; Lin, Nancy U. ; Kelly Marcom, P. ; Van Poznak, Catherine ; Stearns, Vered ; Melisko, Michelle ; Smith, J. Keith ; Karginova, Olga ; Parker, Joel ; Berg, Jonathan ; Winer, Eric P. ; Peterman, Amy ; Prat, Aleix ; Perou, Charles M. ; Wolff, Antonio C. ; Carey, Lisa A. / TBCRC 018 : Phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases. In: Breast Cancer Research and Treatment. 2014 ; Vol. 146, No. 3. pp. 557-566.
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T2 - Phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases

AU - Anders, Carey

AU - Deal, Allison M.

AU - Abramson, Vandana

AU - Liu, Minetta C.

AU - Storniolo, Anna Maria

AU - Carpenter, John T.

AU - Puhalla, Shannon

AU - Nanda, Rita

AU - Melhem-Bertrandt, Amal

AU - Lin, Nancy U.

AU - Kelly Marcom, P.

AU - Van Poznak, Catherine

AU - Stearns, Vered

AU - Melisko, Michelle

AU - Smith, J. Keith

AU - Karginova, Olga

AU - Parker, Joel

AU - Berg, Jonathan

AU - Winer, Eric P.

AU - Peterman, Amy

AU - Prat, Aleix

AU - Perou, Charles M.

AU - Wolff, Antonio C.

AU - Carey, Lisa A.

PY - 2014

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N2 - Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3 weeks. Time to progression (TTP) was the primary end point; secondary endpoints were response rate (RR), clinical benefit rate (CBR), overall survival (OS), toxicity, and health-related quality of life. Correlative endpoints included molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status. Thirty-seven patients began treatment; 34 were evaluable for efficacy. Five of 24 patients were known to carry a BRCA germline mutation (4 BRCA1, 1 BRCA2). Median TTP was 2.14 months and median OS was 7.8 months. Intracranial RR was 12 %, while intracranial CBR was 27 %. Treatment was well-tolerated; the most common grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 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 TNBC-BM. More importantly, this trial design is feasible and lays the foundation for additional studies for this treatment-refractory disease.

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