title: TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases.
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.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, 450 West Drive, Campus Box 7295, Chapel Hill, NC, 27599, USA, carey_anders@med.unc.edu.
authors.forename: Carey
authors.initials: C
authors.lastname: Anders
authors.forename: Allison M
authors.initials: AM
authors.lastname: Deal
authors.forename: Vandana
authors.initials: V
authors.lastname: Abramson
authors.forename: Minetta C
authors.initials: MC
authors.lastname: Liu
authors.forename: Anna M
authors.initials: AM
authors.lastname: Storniolo
authors.forename: John T
authors.initials: JT
authors.lastname: Carpenter
authors.forename: Shannon
authors.initials: S
authors.lastname: Puhalla
authors.forename: Rita
authors.initials: R
authors.lastname: Nanda
authors.forename: Amal
authors.initials: A
authors.lastname: Melhem-Bertrandt
authors.forename: Nancy U
authors.initials: NU
authors.lastname: Lin
authors.forename: P
authors.initials: P
authors.lastname: Kelly Marcom
authors.forename: Catherine
authors.initials: C
authors.lastname: Van Poznak
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
authors.forename: Michelle
authors.initials: M
authors.lastname: Melisko
authors.forename: J Keith
authors.initials: JK
authors.lastname: Smith
authors.forename: Olga
authors.initials: O
authors.lastname: Karginova
authors.forename: Joel
authors.initials: J
authors.lastname: Parker
authors.forename: Jonathan
authors.initials: J
authors.lastname: Berg
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
authors.forename: Amy
authors.initials: A
authors.lastname: Peterman
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Wolff
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Carey
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008875:Middle Aged; D009367:Neoplasm Staging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D016019:Survival Analysis; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D001549:Benzamides; D002166:Camptothecin; D000077146:Irinotecan; D018719:Erb-b2 Receptor Tyrosine Kinases; D042461:Vascular Endothelial Growth Factor A; C467484:VEGFA protein, human; C090712:iniparib; C508053:ERBB2 protein, human