title: TBCRC 019: A Phase II Trial of Nanoparticle Albumin-Bound Paclitaxel with or without the Anti-Death Receptor 5 Monoclonal Antibody Tigatuzumab in Patients with Triple-Negative Breast Cancer.
abstract: OBJECTIVE
  Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5(+) human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC).
  
  
  METHODS
  Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required.
  
  
  RESULTS
  Among 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4-5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm.
  
  
  CONCLUSIONS
  ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation.
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama. aforero@uab.edu.
authors.forename: Andres
authors.initials: A
authors.lastname: Forero-Torres
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Varley
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Vandana G
authors.initials: VG
authors.lastname: Abramson
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Li
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Christos
authors.initials: C
authors.lastname: Vaklavas
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Nancy U
authors.initials: NU
authors.lastname: Lin
authors.affiliation: Georgetown University Hospital, Washington, District of Columbia.
authors.forename: Minetta C
authors.initials: MC
authors.lastname: Liu
authors.affiliation: University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California.
authors.forename: Hope S
authors.initials: HS
authors.lastname: Rugo
authors.affiliation: The University of Chicago, Chicago, Illinois.
authors.forename: Rita
authors.initials: R
authors.lastname: Nanda
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Storniolo
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Traina
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Sujata
authors.initials: S
authors.lastname: Patil
authors.affiliation: University of Michigan, Ann Arbor, Michigan.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Van Poznak
authors.affiliation: Baylor College of Medicine, Houston, Texas.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Nangia
authors.affiliation: University of North Carolina, Chapel Hill, North Carolina.
authors.forename: William J
authors.initials: WJ
authors.lastname: Irvin
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Helen
authors.initials: H
authors.lastname: Krontiras
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: De Los Santos
authors.affiliation: Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: William
authors.initials: W
authors.lastname: Grizzle
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.affiliation: Johns Hopkins Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Wolff
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001706:Biopsy; D005260:Female; D006801:Humans; D008875:Middle Aged; D053758:Nanoparticles / Q000008:administration & dosage / Q000627:therapeutic use*; D017239:Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors; D019233:Retreatment; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C552861:tigatuzumab; D017239:Paclitaxel