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HER2-negative Breast CancerPhase 2NCT05660083

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

A Phase 2 study testing L-NMMA in people with HER2-negative Breast Cancer and Metastatic Breast Cancer, run by The Methodist Hospital Research Institute at 3 sites in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
L-NMMA
Could I receive a placebo?
No, everyone receives an active treatment
How many people
36 participants
Where
3 sitesUnited States
Study dates
12 Jan 2023to 2 Dec 2028
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
Show all 19Show fewer
  • 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.

Who cannot join

  • 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.
Show all 31Show fewer
  • 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.

Trial locations and contacts

3 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Alexys Brock contact

346-238-4814

abrock@houstonmethodist.org

Titilayo Olubajo contact

713-363-9803

tolubajo@houstonmethodist.org

United States3 sites, 3 recruiting

  • National Institute of Health Clinical Center

    Bethesda, Maryland, 20892

    Stanley Lipkowitz, Principal Investigator, MD, 240-541-4547, lipkowis@navmed.nci.nih.gov

    Recruiting

  • Houston Methodist Neal Cancer Center

    Houston, Texas, 77030

    Polly Niravath, MD

    Recruiting

  • The University of Texas MD Anderson Cancer Center

    Houston, Texas, 77030

    Clinton Yam, Principal Investigator, MD, MS, 713-792-2817, TNBC-NOW@mdanderson.org

    Recruiting

Other trials in United States

About this study

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

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.

Read the detailed description

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.

Being tested
L-NMMA
Medical subject headings
Breast Neoplasms, Triple Negative Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • L-NMMADrug

    Also called iNOS inhibitor

    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.

Study groups in NCT05660083
Study groupRoleWhat they receive
iNOS inhibitor and nab-paclitaxel in combination with alpelisib.ExperimentaliNOS inhibitor and nab-paclitaxel in combination with alpelisib in patients with HER2 negative, metastatic or locally advanced MpBC.
Receives: Drug: L-NMMA

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: 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)

  2. 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.

    Measured: 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 (4)

  1. 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.

    Measured: Study treatment will continue until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws from the study. An average of 6 cycles q3week.

  2. 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.

    Measured: Study treatment will continue until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws from the study. An average of 6 cycles q3week.

  3. 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.

    Measured: Study treatment will continue until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws from the study. An average of 6 cycles q3week.

  4. 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.

    Measured: Core biopsy will be collected at Baseline and after Cycle 2. Each cycle is 21 days (q3week).

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Dec 2022
  2. Study start12 Jan 2023
  3. Primary completion1 Dec 2026 (estimated)
  4. Study completion2 Dec 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
36 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05660083
Sponsor's protocol ID
PRO00037649 (HMCC-BR22-001)
Status last verified
Jun 2026
First submitted
13 Oct 2022
Last updated
4 Jun 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Moreno AC, Lin YH, Bedrosian I, Shen Y, Babiera GV, Shaitelman SF. Outcomes after Treatment of Metaplastic Versus Other Breast Cancer Subtypes. J Cancer. 2020 Jan 1;11(6):1341-1350. doi: 10.7150/jca.40817. eCollection 2020.

    PubMed 32047541

  • Granados-Principal S, Liu Y, Guevara ML, Blanco E, Choi DS, Qian W, Patel T, Rodriguez AA, Cusimano J, Weiss HL, Zhao H, Landis MD, Dave B, Gross SS, Chang JC. Inhibition of iNOS as a novel effective targeted therapy against triple-negative breast cancer. Breast Cancer Res. 2015 Feb 22;17(1):25. doi: 10.1186/s13058-015-0527-x.

    PubMed 25849745

  • Dave B, Gonzalez DD, Liu ZB, Li X, Wong H, Granados S, Ezzedine NE, Sieglaff DH, Ensor JE, Miller KD, Radovich M, KarinaEtrovic A, Gross SS, Elemento O, Mills GB, Gilcrease MZ, Chang JC. Role of RPL39 in Metaplastic Breast Cancer. J Natl Cancer Inst. 2016 Dec 31;109(6):djw292. doi: 10.1093/jnci/djw292. Print 2017 Jun.

    PubMed 28040796

  • Davila-Gonzalez D, Choi DS, Rosato RR, Granados-Principal SM, Kuhn JG, Li WF, Qian W, Chen W, Kozielski AJ, Wong H, Dave B, Chang JC. Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer. Clin Cancer Res. 2018 Mar 1;24(5):1152-1162. doi: 10.1158/1078-0432.CCR-17-1437. Epub 2018 Jan 4.

    PubMed 29301832

  • Garrido P, Shalaby A, Walsh EM, Keane N, Webber M, Keane MM, Sullivan FJ, Kerin MJ, Callagy G, Ryan AE, Glynn SA. Impact of inducible nitric oxide synthase (iNOS) expression on triple negative breast cancer outcome and activation of EGFR and ERK signaling pathways. Oncotarget. 2017 Jul 26;8(46):80568-80588. doi: 10.18632/oncotarget.19631. eCollection 2017 Oct 6.

    PubMed 29113326

  • Switzer CH, Glynn SA, Cheng RY, Ridnour LA, Green JE, Ambs S, Wink DA. S-nitrosylation of EGFR and Src activates an oncogenic signaling network in human basal-like breast cancer. Mol Cancer Res. 2012 Sep;10(9):1203-15. doi: 10.1158/1541-7786.MCR-12-0124. Epub 2012 Aug 9.

    PubMed 22878588

  • Ridnour LA, Barasch KM, Windhausen AN, Dorsey TH, Lizardo MM, Yfantis HG, Lee DH, Switzer CH, Cheng RY, Heinecke JL, Brueggemann E, Hines HB, Khanna C, Glynn SA, Ambs S, Wink DA. Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation. PLoS One. 2012;7(9):e44081. doi: 10.1371/journal.pone.0044081. Epub 2012 Sep 5.

    PubMed 22957045

  • Thomas DD, Ridnour LA, Isenberg JS, Flores-Santana W, Switzer CH, Donzelli S, Hussain P, Vecoli C, Paolocci N, Ambs S, Colton CA, Harris CC, Roberts DD, Wink DA. The chemical biology of nitric oxide: implications in cellular signaling. Free Radic Biol Med. 2008 Jul 1;45(1):18-31. doi: 10.1016/j.freeradbiomed.2008.03.020. Epub 2008 Apr 4.

    PubMed 18439435

  • Prueitt RL, Boersma BJ, Howe TM, Goodman JE, Thomas DD, Ying L, Pfiester CM, Yfantis HG, Cottrell JR, Lee DH, Remaley AT, Hofseth LJ, Wink DA, Ambs S. Inflammation and IGF-I activate the Akt pathway in breast cancer. Int J Cancer. 2007 Feb 15;120(4):796-805. doi: 10.1002/ijc.22336.

    PubMed 17096325

  • Yu HG, Ai YW, Yu LL, Zhou XD, Liu J, Li JH, Xu XM, Liu S, Chen J, Liu F, Qi YL, Deng Q, Cao J, Liu SQ, Luo HS, Yu JP. Phosphoinositide 3-kinase/Akt pathway plays an important role in chemoresistance of gastric cancer cells against etoposide and doxorubicin induced cell death. Int J Cancer. 2008 Jan 15;122(2):433-43. doi: 10.1002/ijc.23049.

    PubMed 17935137

  • Huang WC, Hung MC. Induction of Akt activity by chemotherapy confers acquired resistance. J Formos Med Assoc. 2009 Mar;108(3):180-94. doi: 10.1016/S0929-6646(09)60051-6.

    PubMed 19293033

  • Cai Y, Tan X, Liu J, Shen Y, Wu D, Ren M, Huang P, Yu D. Inhibition of PI3K/Akt/mTOR signaling pathway enhances the sensitivity of the SKOV3/DDP ovarian cancer cell line to cisplatin in vitro. Chin J Cancer Res. 2014 Oct;26(5):564-72. doi: 10.3978/j.issn.1000-9604.2014.08.20.

    PubMed 25400422

  • Li B, Li J, Xu WW, Guan XY, Qin YR, Zhang LY, Law S, Tsao SW, Cheung AL. Suppression of esophageal tumor growth and chemoresistance by directly targeting the PI3K/AKT pathway. Oncotarget. 2014 Nov 30;5(22):11576-87. doi: 10.18632/oncotarget.2596.

    PubMed 25344912

  • Wang Q, Shi YL, Zhou K, Wang LL, Yan ZX, Liu YL, Xu LL, Zhao SW, Chu HL, Shi TT, Ma QH, Bi J. PIK3CA mutations confer resistance to first-line chemotherapy in colorectal cancer. Cell Death Dis. 2018 Jul 3;9(7):739. doi: 10.1038/s41419-018-0776-6.

    PubMed 29970892

  • Takala S, Heikkila P, Nevanlinna H, Blomqvist C, Mattson J. Metaplastic carcinoma of the breast: Prognosis and response to systemic treatment in metastatic disease. Breast J. 2019 May;25(3):418-424. doi: 10.1111/tbj.13234. Epub 2019 Mar 29.

    PubMed 30925636

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing L-NMMA in people with HER2-negative Breast Cancer and Metastatic Breast Cancer, run by The Methodist Hospital Research Institute at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 4 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Alexys Brock (346-238-4814, abrock@houstonmethodist.org), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Define recommended phase II dose (RP2D) (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)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05660083, which also lists 31 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Jun 2026.

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