Alpelisib/iNOS Inhibitor/Nab-paclitaxel in Patients With HER2 Negative Metaplastic Breast Cancer (MpBC)

This is a Phase II trial with a dose escalation/de-escalation lead-in that will investigate the efficacy and safety of an iNOS inhibitor and nab-paclitaxel in combination with alpelisib in patients with HER2 negative, metastatic or locally advanced MpBC. The prognosis for metastatic or locally advanced metaplastic breast cancer (MpBC), a rare and highly chemotherapy-resistant subtype of TNBC, is even worse than for non-metaplastic TNBC, with a median overall survival ranging from 3 to 8 months.1 Standard systemic chemotherapy remains the only available treatment option for patients with metastatic or locally advanced MpBC, even though this disease is largely refractory to cytotoxic drugs. Therefore, combination strategies to understand and overcome mechanisms of resistance to improve marginal chemotherapeutic efficacy are needed to improve the prognosis of these patients. We have found that inducible nitric oxide synthase (iNOS) is a critical target for overcoming chemotherapy resistance in TNBC.2,3 iNOS expression is increased and associated with poor prognosis in invasive TNBC and MpBC.2-5 It has been shown that nitric oxide (NO) through iNOS induces many of the major oncogenic pathways such as RAS/ERK, HIF1α, NF- κB, and others making this a unique oncogenic driver. One of the major oncogenic pathways activated by iNOS/NO is the phosphatidylinositol 3-kinase (PI3K)/Akt pathway.6-9 Alterations in the Pl3K/Akt pathway have also been linked with chemotherapy resistance, especially in MpBC.10-14 We hypothesize that addition of the PI3K inhibitor, alpelisib, to a pan-NOS inhibitor (L-NMMA) and nab-paclitaxel will increase objective response rate (ORR) in patients with HER2 negative metastatic or locally advanced MpBC. Both first- and second-line patients will be eligible for this trial. Patients may have received prior immunotherapy, per standard of care.