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

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