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

PURPOSE:

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).

EXPERIMENTAL DESIGN:

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: Andres Forero-Torres, Katherine E Varley, Vandana G Abramson, Yufeng Li, Christos Vaklavas, Nancy U Lin, Minetta C Liu, Hope S Rugo, Rita Nanda, Anna M Storniolo, Tiffany A Traina, Sujata Patil, Catherine H Van Poznak, Julie R Nangia, William J Irvin Jr, Helen Krontiras, Jennifer F De Los Santos, Paul Haluska, William Grizzle, Richard M Myers, Antonio C Wolff, Translational Breast Cancer Research Consortium (TBCRC)
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 12 Pg. 2722-9 (Jun 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25779953 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal, Humanized
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• tigatuzumab
• Paclitaxel

Topics

• Adult
• Aged
• Antibodies, Monoclonal, Humanized (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Biopsy
• Female
• Humans
• Middle Aged
• Nanoparticles (administration & dosage, therapeutic use)
• Paclitaxel (administration & dosage, therapeutic use)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (antagonists & inhibitors)
• Retreatment
• Treatment Outcome
• Triple Negative Breast Neoplasms (drug therapy, mortality, pathology)