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

Plain English Summary

Alpelisib/iNOS Inhibitor/Nab-paclitaxel in Patients With HER2 Negative Metaplastic Breast Cancer (MpBC) is a Phase 2 clinical trial sponsored by The Methodist Hospital Research Institute studying HER2-negative Breast Cancer, Metastatic Breast Cancer, Metaplastic Breast Carcinoma, TNBC - Triple-Negative Breast Cancer. This trial is testing a combination of drugs: alpelisib, an iNOS inhibitor (L-NMMA), and nab-paclitaxel chemotherapy. It is for patients with HER2-negative metaplastic breast cancer (MpBC) that has spread or cannot be removed by surgery, and has not responded to previous treatments. Participants will receive the study drugs intravenously and orally, along with standard chemotherapy, every 3 weeks. Alternative treatments may include other chemotherapy regimens, targeted therapies, or immunotherapy, depending on the patient's specific situation and prior treatments. The trial aims to enroll 36 participants.

Official Summary

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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Patients must be at least 18 years old and have a confirmed diagnosis of HER2-negative metaplastic or triple-negative breast cancer with specific cell types. The cancer must be locally advanced and inoperable or metastatic, with measurable disease. Patients should have good general health, with adequate organ and blood cell counts, and controlled blood sugar and blood pressure. Individuals with certain heart conditions, a history of severe skin reactions to drugs, or those currently taking specific interacting medications will not be eligible. This trial is studying HER2-negative Breast Cancer, Metastatic Breast Cancer, Metaplastic Breast Carcinoma, TNBC - Triple-Negative Breast Cancer, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcome measures will determine the recommended dose for future studies and how often the cancer shrinks or stops growing in response to the new drug combination. The specific primary outcome measures are: Define recommended phase II dose (RP2D) (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) (Study treatment will continue until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws from the study. An average of 6 cycles q3week.). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 2, which tests whether the treatment actually works against the target condition. Phase 2 trials involve 100-300 patients and continue to monitor safety while evaluating effectiveness. This phase often tests different dosages to find the optimal amount. About 33% of Phase 2 drugs advance to Phase 3. If successful, the treatment will move to large-scale Phase 3 trials needed for FDA approval.

Why This Trial Matters

This trial addresses a critical need for new treatments for metaplastic breast cancer, a rare and aggressive subtype of breast cancer that often has limited treatment options. Phase 2 success would typically lead to larger Phase 3 trials needed for regulatory approval. This research targets HER2-negative Breast Cancer, Metastatic Breast Cancer, Metaplastic Breast Carcinoma, TNBC - Triple-Negative Breast Cancer, where improved treatment options are needed.

Investor Insight

This trial targets a rare but aggressive cancer, indicating a focus on unmet needs. Success could lead to a new treatment option for a difficult-to-treat patient population, potentially opening a new Phase 2 trials have approximately a 15-20% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about how this combination therapy might work for your specific type of breast cancer and if it's a suitable option compared to other available treatments. Be prepared for regular clinic visits for infusions, oral medication, and monitoring of side effects and disease progression. You will need to take daily aspirin and amlodipine for prevention, and potentially metformin to manage blood sugar. This trial is currently recruiting participants. The trial is being conducted at 3 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NA
• Model: SINGLE_GROUP
• Masking: NONE
• Enrollment: 36 participants

Interventions

• 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 dos

Primary Outcomes

• Define recommended phase II dose (RP2D) (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) (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 Outcomes

• PFS of 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.)
• OS of 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.)
• Analysis of responses to 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.)
• PIK3CA mutation (Core biopsy will be collected at Baseline and after Cycle 2. Each cycle is 21 days (q3week).)

Full Eligibility Criteria

Inclusion Criteria:

1. The patient (or legally acceptable representative if applicable) provides written informed consent for the study.
2. At least 18 years of age on the day of informed consent signing.
3. Histologically confirmed HER2 negative MpBC and/or Triple Negative Breast Cancer (TNBC) with squamous and/or sarcomatoid elements, including osseous, chondroid, and spindle morphology.
4. HER2 negative status as defined by the current American Society of Clinical Oncology and College of American Pathologists guidelines at time of study entry.
5. 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.
6. Eastern Cooperative Oncology Group performance status of 0 or 1.
7. 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.
8. Fasting blood glucose of ≤140 mg/dl and HgbA1c ≤7.0.
9. Ability to swallow oral medication.
10. Ability to take aspirin.
11. 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.
12. 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.
13. Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.

Exclusion Criteria:

1. 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).
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.
3. Concurrent use of medications that interact with nitrate/nitrite levels (Examples included in Appendix 3).
4. Received previous treatment with nab-paclitaxel, Pl3K inhibitor, AKT inhibitor, or mTOR inhibitor.
5. Known history of Steven Johnson's syndrome or toxic epidermal necrolysis.
6. Since HAART agents are metabolized by CYP3A4, HIV positive patients will be excluded from this trial.
7. 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.
8. 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.
9. 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.
10. Known or suspected hypersensitivity to any component or excipient of the proposed regimen (nab-paclitaxel, alpelisib, iNOS inhibitor, aspirin).
11. Known additional malig

Trial Locations

• National Institute of Health Clinical Center, Bethesda, Maryland, United States
• Houston Methodist Neal Cancer Center, Houston, Texas, United States
• The University of Texas MD Anderson Cancer Center, Houston, Texas, United States

Frequently Asked Questions

Related Conditions

• Breast Cancer
• Metastatic Breast Cancer
• Triple-Negative Breast Cancer
• HER2-Negative Breast Cancer
• Metaplastic Breast Cancer
• Oncology
• Cancer Therapy
• Targeted Therapy
• Chemotherapy
• Rare Cancers

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