Patients with tumor progression on the nab-PAC arm were allowed to rollover to the TIG/nab-PAC arm

Patients with tumor progression on the nab-PAC arm were allowed to rollover to the TIG/nab-PAC arm. 8 partial remissions (PRs; 1 almost CR), 11 stable diseases (SDs) and 17 progressive diseases (PDs) in the TIG/nab-PAC arm (ORR=28%), and no CRs, 8 PRs, 4 SDs and 9 PDs in nab-PAC arm (ORR=38%). There was a numerical increase in CRs and several patients had prolonged PFS (1025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29% respectively with no grade 4C5. 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-DR-5 agents. ROCK pathway activation merits further evaluation. and activity against basal-like breast cancer cells that is enhanced by chemotherapy agents like paclitaxel and albumin-bound paclitaxel (nab-PAC).22C25 A phase 1, dose-escalation Coelenterazine H study of TIG in patients with relapsed or refractory carcinomas was conducted to determine the maximal tolerated dose (MTD), pharmacokinetics, immunogenicity, and safety.26 Seventeen patients were enrolled in 4 cohorts (1, 2, 4 and 8 mg/kg). TIG was well tolerated with no infusion reactions or grade 3C4-5 toxicity; the MTD was not reached. Plasma half-life was 6C10 days, and no anti-TIG responses were detected. Seven patients had stable disease (SD), with the duration of response ranging from 81 to 798 days. Phase 2 studies in other solid tumors using TIG in combination with chemotherapy demonstrated the safety of the combination.27 Thus, based on the preclinical data and the safety of TIG as single agent and in Coelenterazine H combination with chemotherapy, we conducted a randomized, phase II clinical trial, of nab-PAC with or without TIG in patients with TNBC. Materials and Methods Patients Patients older than 18 years of age with histologically confirmed metastatic TNBC were enrolled. A tumor was considered triple negative if HER-2-neu was negative (0 or 1+ staining by IHC or gene amplification ratio 2.0 by FISH), and the ER and PR were negative ( 1% of the tumor cells by IHC). There was no restriction as to the number of prior chemotherapy Coelenterazine H regimens for metastatic disease but patients had to have prior exposure to anthracyclines and taxanes in the neoadjuvant or adjuvant settings. Patients with no prior Coelenterazine H chemotherapy for metastatic disease and patients who have received prior therapy with taxanes for metastatic disease (paclitaxel or docetaxel) were eligible. All patients had to have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1), an ECOG to 2, and adequate organ and bone marrow function (Supplemental Material). Patients previously treated with nab-PAC or with active central nervous involvement were excluded. Study Design and Treatment Schedule This study was a randomized (2:1) phase 2 multicenter trial of nab-PAC with or without TIG in patients with metastatic TNBC. The trial was conducted through the Translational Breast Cancer Research Consortium (TBCRC); 13 sites activated the study. A treatment cycle was defined as 4 weeks. Patients received intravenous nab-PAC on days 1, 8, and 15 (100 mg/m2) at 28-days interval with or without TIG intravenously on days 1 and 15 of every cycle (10 mg/kg loading dose followed by 5 mg/kg every other week). Response to therapy was assessed every two cycles (every 8 weeks). Treatment continued without interruption in hCIT529I10 patients with a complete response (CR) or partial response (PR) or SD until progressive disease (PD) or unacceptable toxicity. Patients with tumor progression on the nab-PAC arm were allowed to rollover to the TIG/nab-PAC arm. All patients gave informed consent to participate in the study, which was approved by local Institutional Review Boards and conducted in accordance with the ethical principles of the Declaration of.