title: Efficacy of the PARP Inhibitor Veliparib with Carboplatin or as a Single Agent in Patients with GermlineBRCA1- orBRCA2-Associated Metastatic Breast Cancer: California Cancer Consortium Trial NCT01149083.
abstract: Purpose:We aimed to establish the MTD of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germlineBRCA1- andBRCA2- (BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment after progression, and to correlate PAR levels with clinical outcome.Experimental Design:Phase I patients received carboplatin (AUC of 5-6, every 21 days), with escalating doses (50-20 mg) of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID), and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome.Results:Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia [MTD: veliparib 150 mg po BID and carboplatin (AUC of 5)]. Response rate (RR) was 56%; 3 patients remain in complete response (CR) beyond 3 years. Progression-free survival (PFS) and overall survival (OS) were 8.7 and 18.8 months. The PFS and OS were 5.2 and 14.5 months in the 44 patients in the phase II trial, with a 14% RR inBRCA1(n= 22) and 36% inBRCA2(n= 22). One of 30 patients responded to the combination therapy after progression on veliparib. Higher baseline PAR was associated with clinical benefit.Conclusions:Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin inBRCA-associated MBC. Lasting CRs were observed when the combination was administered first in the phase I trial. Further investigation of PAR level association with clinical outcomes is warranted.Clin Cancer Res; 23(15); 4066-76. ©2017 AACR.
authors.affiliation: City of Hope Comprehensive Cancer Center, Duarte, California. jweitzel@coh.org gsomlo@coh.org.
authors.forename: George
authors.initials: G
authors.lastname: Somlo
authors.affiliation: City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Frankel
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Banu K
authors.initials: BK
authors.lastname: Arun
authors.affiliation: Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Cynthia X
authors.initials: CX
authors.lastname: Ma
authors.affiliation: University of Southern California/Norris Cancer Center, Los Angeles, California.
authors.forename: Agustin A
authors.initials: AA
authors.lastname: Garcia
authors.affiliation: Weill Cornell Medicine, New York, New York.
authors.forename: Tessa
authors.initials: T
authors.lastname: Cigler
authors.affiliation: Milton S. Hershey Medical Center, Hershey, Pennsylvania.
authors.forename: Leah V
authors.initials: LV
authors.lastname: Cream
authors.affiliation: Milton S. Hershey Medical Center, Hershey, Pennsylvania.
authors.forename: Harold A
authors.initials: HA
authors.lastname: Harvey
authors.affiliation: Montefiore Medical Center, Moses & Weuker Divisions, Department of Oncology, Bronx, New York.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Sparano
authors.affiliation: The University of Chicago, Chicago, Illinois.
authors.forename: Rita
authors.initials: R
authors.lastname: Nanda
authors.affiliation: University of California, Davis Cancer Center, Sacramento, California.
authors.forename: Helen K
authors.initials: HK
authors.lastname: Chew
authors.affiliation: Mayo Clinic Cancer Center, Rochester, Minnesota.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Moynihan
authors.affiliation: Weill Cornell Medicine, New York, New York.
authors.forename: Linda T
authors.initials: LT
authors.lastname: Vahdat
authors.affiliation: Mayo Clinic Cancer Center, Rochester, Minnesota.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Goetz
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.affiliation: City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Arti
authors.initials: A
authors.lastname: Hurria
authors.affiliation: City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Joanne
authors.initials: J
authors.lastname: Mortimer
authors.affiliation: Investigational Drug Branch, Cancer Therapy Evaluation Program, DCTD, NCI, Bethesda, Maryland.
authors.forename: Richard
authors.initials: R
authors.lastname: Piekarz
authors.affiliation: City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Sharon
authors.initials: S
authors.lastname: Sand
authors.affiliation: City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Josef
authors.initials: J
authors.lastname: Herzog
authors.affiliation: City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Lily R
authors.initials: LR
authors.lastname: Van Tongeren
authors.affiliation: Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratories, Frederick, Maryland.
authors.forename: Katherine V
authors.initials: KV
authors.lastname: Ferry-Galow
authors.affiliation: Investigational Drug Branch, Cancer Therapy Evaluation Program, DCTD, NCI, Bethesda, Maryland.
authors.forename: Alice P
authors.initials: AP
authors.lastname: Chen
authors.affiliation: City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ruel
authors.affiliation: City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Newman
authors.affiliation: University of California, Davis Cancer Center, Sacramento, California.
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
authors.affiliation: City of Hope Comprehensive Cancer Center, Duarte, California. jweitzel@coh.org gsomlo@coh.org.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Weitzel
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002140:California; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D016190:Carboplatin; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1