Abstract OT3-08-01: A phase Ib/II clinical trial investigating the efficacy of nitric oxide deprivation and docetaxel in triple negative breast cancer

Triple negative breast cancer (TNBC) is an aggressive disease that currently lacks an efficacious form of therapy. Although chemotherapy is the current standard of care for metastatic TNBC, the 5-year prognosis remains grim with a high rate of disease recurrence. Cancer relapse is thought to be initiated by chemotherapy-resistant breast cancer stem cells (BCSCs). These BCSCs give rise to a diverse clonal population that results in a heterogeneous cancer, which complicates targeted therapeutic strategies. Our previous studies revealed that BCSCs utilize inducible nitric oxide synthase (iNOS)-derived nitric oxide to promote their proliferation, migration, and self-renewal capacity. In an effort to target the BCSC population, we found that iNOS inhibition with NG-monomethyl-L-arginine (L-NMMA) sensitized BCSCs to docetaxel in vivo in TNBC xenograft models, leading to decreased BCSC viability and tumor burden. These findings suggest that BCSC resist conventional therapy in a nitric oxide-dependent manner and that combination of L-NMMA with docetaxel will effectively target BCSCs to prevent further relapse. A phase Ib/II clinical trial was conducted to determine the maximum tolerated dose, recommended phase 2 dose (R2PD), dose-limiting toxicities (DLTs), and efficacy of the L-NMMA and docetaxel combination in TNBC patients with chemotherapy-refractory locally advanced or metastatic disease. For the phase Ib portion of the study, a standard Bayesian continual reassessment method is being used to investigate 7 dose levels of L-NMMA (5, 7.5, 10, 12.5, 15, 17.5, and 20 mg/kg) and two dose levels of docetaxel (75 and 100 mg/m 2 ). Sixteen patients have been recruited to date, and based on current pharmacokinetics, pharmacodynamics, and safety data, the RP2D is expected to be docetaxel 100 mg/m 2 (Day 1) and L-NMMA 20 mg/kg (Days 1-5) every 3 weeks. Two and three patients received 15 mg/kg L-NMMA + 75 mg/m 2 docetaxel and 17.5 mg/kg L-NMMA + 100 mg/m 2 docetaxel, respectively. Of these 5 patients, one partial responder completed 8 cycles before discontinuing treatment due to taxane-associated neuropathy. Among the five patients treated at the RP2D, only one taxane-associated DLT occurred. The overall response rate for patients treated at the higher doses was 22.2%. Early results of the phase Ib/II trial indicate the safety, tolerability, and promising activity of the first-in-class pan-NOS inhibitor L-NMMA in combination with chemotherapy in the treatment of chemotherapy-refractory TNBC. Citation Format: Chung AW, Ensor JE, Darcourt J, Belcheva A, Patel T, Chang JC, Niravath PA. A phase Ib/II clinical trial investigating the efficacy of nitric oxide deprivation and docetaxel in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-08-01.