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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase II Trial of Alpelisib With iNOS Inhibitor and Nab-paclitaxel in Patients With HER2 Negative Metastatic or Locally Advanced Metaplastic Breast Cancer (MpBC)

Conditions
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HER2-negative Breast Cancer, Metastatic Breast Cancer, Metaplastic Breast Carcinoma, TNBC - Triple-Negative Breast Cancer

Intervention / Treatment
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* Drug: L-NMMA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Locally advanced inoperable or metastatic MpBC with measurable disease by RECIST 1.1 Both first- and second-line patients will be eligible for this trial. Patients may have received prior immunotherapy, per standard of care. Eastern Cooperative Oncology Group performance status of 0 or 1. Adequate organ and marrow function as defined below: Hemoglobin ≥9.0 g/dl (without blood transfusion within 2 weeks of laboratory test used to determine eligibility) Absolute neutrophil count ≥1000/μL (without granulocyte colony stimulating factor support within 2 weeks of laboratory test used to determine eligibility) Platelet count ≥100,000/μL (without transfusion within 2 weeks of laboratory test used to determine eligibility) Serum total bilirubin (TB) ≤1.5 x institutional upper limit of normal (ULN; In the case of known Gilbert's syndrome, a higher serum TB [>1.5 x ULN] is allowed), Aspartate transaminase/alanine transaminase ≤5 x institutional ULN Creatinine ≤1.5X the ULN or measured creatinine clearance ≥ 60 mL/min/1. Fasting blood glucose of ≤140 mg/dl and HgbA1c ≤7.0. Ability to swallow oral medication. Ability to take aspirin. Women of childbearing potential must agree to use contraception for the duration of the study through 90 days after the last dose of study treatment. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm during the study and up to the time period as specified in labels of study drugs. If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting the study treatment. Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations. Exclusion Criteria: 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. Known history of Steven Johnson's syndrome or toxic epidermal necrolysis. Since HAART agents are metabolized by CYP3A4, HIV positive patients will be excluded from this trial. Poorly controlled hypertension at baseline (defined as systolic blood pressure >150 mm Hg). Isolated, unconfirmed systolic BP elevations will NOT exclude participation. Patients with medication-controlled hypertension are allowed provided they have been on their current medications for at least 4 weeks prior to Cycle 1, Day 1. Has any of the following cardiac abnormalities: Symptomatic congestive heart failure History of documented congestive heart failure (New York Heart Association functional classification III-IV) Documented cardiomyopathy Left ventricular ejection fraction <50% as determined by multigated acquisition scan or echocardiogram Myocardial infarction  6 months prior to enrollment Unstable angina pectoris Serious uncontrolled cardiac arrhythmia Symptomatic pericarditis History of congenital QT prolongation Absolute corrected QT interval of >480 msec in the presence of potassium >4.0 mEq/L and magnesium >1.8 mg/dl. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 3 weeks prior to study treatment administration. NOTE: Patients who have entered the follow-up phase of an investigational study may participate as long as it has been 3 weeks after the last dose of the previous investigational agent. Known or suspected hypersensitivity to any component or excipient of the proposed regimen (nab-paclitaxel, alpelisib, iNOS inhibitor, aspirin). Known additional malignancy that requires active treatment. Pneumonitis/ interstitial lung disease on baseline CT scan of the chest or moderate to severe chronic lung disease Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study. Manifestations of malabsorption due to prior gastrointestinal surgery, gastrointestinal surgery disease, or an unknown reason. Symptomatic/untreated metastatic central nervous system disease. Type I diabetes mellitus irrespective of Hgb A1c OR uncontrolled type II diabetes mellitus defined as hemoglobin A1c >7%. Uncontrolled gastric ulcer ≥ Grade 2 sensory neuropathy Osteonecrosis of jaw Pancreatitis Pregnant, breastfeeding or expecting to conceive children within the projected duration of the study, starting with the prescreening or screening visit through 30 days after the last dose of study treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: iNOS inhibitor and nab-paclitaxel in combination with alpelisib.<br>iNOS inhibitor and nab-paclitaxel in combination with alpelisib in patients with HER2 negative, metastatic or locally advanced MpBC. | Drug: L-NMMA<br>* 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.<br>* Other names: iNOS inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Study treatment will continue until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws from the study. An average of 6 cycles q3week. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | Core biopsy will be collected at Baseline and after Cycle 2. Each cycle is 21 days (q3week). |