A Phase 2 interventional study of L-NMMA in HER2-negative Breast Cancer, Metastatic Breast Cancer and Metaplastic Breast Carcinoma, sponsored by The Methodist Hospital Research Institute. Recruiting at 3 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-06-04.
Sponsored by The Methodist Hospital Research Institute · Phase 2, Interventional, and Treatment
This is a research study to test the safety and effectiveness of using the drug alpelisib together with chemotherapy (nab-paclitaxel) and a drug called L-NMMA in patients with HER2 negative metastatic or locally advanced metaplastic breast cancer, who have not responded to previous treatments.
Participants in this study in addition to the standard care chemotherapy will also receive the drug alpelisib and L-NMMA. The therapies will be administered every 3 weeks (1 cycle) until disease progression, toxicity or until the participant withdraws from the study. The nab-paclitaxel chemotherapy will be administered intravenously on Day 1 of the 3 week cycles. Participants will take the drug alpelisib by mouth once daily at a dose determined by a safety study and the drug L-NMMA will be given intravenously on days 1 to 5 of the 3 week cycles.
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.
12,544 studies on the registry are indexed under Breast Neoplasms; 2,892 are open to participants now.
This study's planned enrollment of 36 is below the median of 72 across 9,303 interventional studies indexed under Breast Neoplasms.
Browse Breast Neoplasms studies →The Methodist Hospital Research Institute is the lead sponsor of 157 studies on the registry; 60 are open to participants now.
Of its 25 completed or terminated interventional studies of FDA-regulated products, 15 (60%) have results posted.
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Adequate organ and marrow function as defined below:
Exclusion Criteria:
Has any of the following cardiac abnormalities:
iNOS inhibitor and nab-paclitaxel in combination with alpelisib in patients with HER2 negative, metastatic or locally advanced MpBC.
Drug: L-NMMA
Patients with HER2 negative metastatic or locally advanced MpBC, will receive a combination of an iNOS inhibitor, nab-paclitaxel and alpelisib . As prophylaxis against deep venous thrombosis and hypertension, patients will receive aspirin (81 mg po daily) and amlodipine (10 mg po Days 0-5 each cycle). Metformin will be initiated at 500 mg once daily starting one week prior to treatment to reduce risk of severe hyperglycemia. Based on tolerability and serial blood sugar assessments, metformin dose will be increased to 500 mg twice daily, followed by 500 mg with breakfast and 1000 mg with dinner, followed by further increase to 1000 mg twice daily if needed. Insulin sensitizers and/or SGLT2i will be used as second anti-diabetic agents, if necessary. For prophylaxis of alpelisib rash, patients will be treated with an anti-histamine (cetirizine 10 mg daily) along with alpelisib.
Also known as: iNOS inhibitor
Define recommended phase II dose (RP2D)
Define recommended phase II dose (RP2D) of Alpelisib in combination with standard dose of q3wk nab-paclitaxel and L-NMMA
Time frame: The RP2D will be defined as the highest dose administered at which 6 patients complete treatment with experiencing <2 DLTs (Study completion is an average of 6 cycles, determined by diseases progression, unacceptable toxicity, physician's discretion)
Objective response rate (ORR)
Objective response rate (ORR) of an iNOS inhibitor and nab-paclitaxel in combination with alpelisib in patients with HER2 negative metastatic or locally advanced MpBC.
Time frame: Study treatment will continue until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws from the study. An average of 6 cycles q3week.
PFS of patients with HER2 negative metastatic or locally advanced MpBC
Progression-free survival (PFS) of patients with HER2 negative metastatic or locally advanced MpBC treated with an iNOS inhibitor and nab-paclitaxel in combination with alpelisib.
Time frame: Study treatment will continue until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws from the study. An average of 6 cycles q3week.
OS of patients with HER2 negative metastatic or locally advanced MpBC
Overall survival (OS) of patients with HER2 negative metastatic or locally advanced MpBC treated with an iNOS inhibitor and nab-paclitaxel in combination with alpelisib.
Time frame: Study treatment will continue until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws from the study. An average of 6 cycles q3week.
Analysis of responses to an iNOS inhibitor and nab-paclitaxel in combination with alpelisib.
Analysis of tissue and-blood-based correlates of responses to an iNOS inhibitor and nab-paclitaxel in combination with alpelisib in available specimens.
Time frame: Study treatment will continue until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws from the study. An average of 6 cycles q3week.
PIK3CA mutation
Tissue will be collected to detect the presence of a PIK3CA mutation (e.g. E545K, E542K, H1047R/Y/L), and efficacy according to PIK3CA mutation status assessed retrospectively.
Time frame: Core biopsy will be collected at Baseline and after Cycle 2. Each cycle is 21 days (q3week).
Plan to share: No
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