Abstract CT037: Clinical phase Ib trial of L-NMMA plus docetaxel in the treatment of refractory locally advanced or metastatic triple negative breast cancer patients
Authors: Chang Jenny , Rodriguez Angel , Ensor Joe 
Published: July 2017

Abstract
Chemoresistance and metastasis are the main causes of death in triple negative breast cancer (TNBC) patients and have been linked to a subpopulation of cancer stem cells (CSCs) with self-renewal and tumor-initiating properties. We have previously demonstrated that nitric oxide synthase (NOS) promotes tumor relapse and metastasis through modulation of CSC self-renewal properties. Importantly, NOS inhibition with the pan-NOS inhibitor NG-monmethyl-L-arginine (L-NMMA) reduced tumor growth and CSC renewal and tumor-initiating capacity and improved chemosensitivity to docetaxel in mouse models of TNBC. Based on these findings, we are conducting an ongoing Phase Ib trial of proprietary L-NMMA plus docetaxel in refractory locally advanced or metastatic TNBC (NCT02834403). The primary endpoint will be the maximum tolerated dose (MTD) of the L-NMMA and docetaxel combination. The study will be conducted in two stages. Stage 1 will determine the MTD of L-NMMA when combined with 75 mg/m2 docetaxel, and stage 2 will determine the MTD of L-NMMA when combined with 60 mg/m2 docetaxel. Five dose levels of L-NMMA (5, 7.5, 10, 12.5, and 15 mg/kg) will be investigated in stage 1, with 7.5 mg/kg as the starting dose. In stage 2, the starting dose of L-NMMA will be one dose level above the MTD determined in stage 1. As patients are accrued in both stages, a standard Bayesian model averaging continual reassessment method approach will be used to determine L-NMMA escalation/de-escalation. L-NMMA (Days 1−5 of each cycle) and docetaxel (Day 1 of each cycle) will be administered for six 21-day cycles. The major inclusion criteria will be female patients with pathologically advanced (progressive disease or refractory to 3 cycles of standard chemotherapy) or metastatic (any line) TNBC, Eastern Cooperative Oncology Group performance status of ≤2, life expectancy ≥6 months, and adequate organ function. Major exclusion criteria include any cardiac history and pregnancy/breastfeeding. Correlative studies will include evaluation of the pharmacokinetics and pharmacodynamics of the L-NMMA and docetaxel combination and tissue and blood-based markers of treatment response. Notably, analysis of RPL39 and MLF2 in plasma cell-free DNA samples will be performed. We have previously identified these genes as part of a chemotherapy resistance signature derived from breast cancer patient biopsies and have found that they promote breast CSC self-renewal, treatment resistance, and lung metastasis through NOS upregulation. Study enrollment began in August 2016. Two patients have been enrolled; both patients received 7.5 mg/kg L-NMMA and 75 mg/m2 docetaxel and no dose-limiting toxicities have been observed to date.
L-NMMA Plus Docetaxel for refractory TNBC
Citation Format: Jenny Chang, Angel Rodriguez, Joe Ensor. Clinical phase Ib trial of L-NMMA plus docetaxel in the treatment of refractory locally advanced or metastatic triple negative breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT037. doi:10.1158/1538-7445.AM2017-CT037