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.
The patient (or legally acceptable representative if applicable) provides written informed consent for the study.
At least 18 years of age on the day of informed consent signing.
Histologically confirmed HER2 negative MpBC and/or Triple Negative Breast Cancer (TNBC) with squamous and/or sarcomatoid elements, including osseous, chondroid, and spindle morphology.
HER2 negative status as defined by the current American Society of Clinical Oncology and College of American Pathologists guidelines at time of study entry.
Concomitant use of strong inhibitors or strong inducers of cytochrome P450 (CYP)3A4. The patient must have discontinued strong CYP3A4 inhibitors or strong CYP3A4 inducers for at least 1 week prior to study treatment initiation (Examples included in Appendix 2).
Currently receiving warfarin or other coumarin-derived anticoagulant for treatment, prophylaxis, or otherwise. Therapy with DOACs, heparin, low molecular weight heparin, direct oral anticoagulants or fondaparinux is allowed.
Concurrent use of medications that interact with nitrate/nitrite levels (Examples included in Appendix 3).
Received previous treatment with nab-paclitaxel, Pl3K inhibitor, AKT inhibitor, or mTOR inhibitor.
Single group
L-NMMA
DrugPatients 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.
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
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.
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.
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.
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.
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.
Click on the lead sponsor to view all of their trials.
The Methodist Hospital Research Institute
Lead sponsor
Novartis Pharmaceuticals
Collaborator
