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

NCT05660083 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: HMCC-BR22-001
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Metaplastic Breast Carcinoma; TNBC - Triple-Negative Breast Cancer; HER2-negative Breast Cancer; Metastatic Breast Cancer

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (4)

• 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).

Study Arms (1)

iNOS inhibitor and nab-paclitaxel in combination with alpelisib.

EXPERIMENTAL

iNOS inhibitor and nab-paclitaxel in combination with alpelisib in patients with HER2 negative, metastatic or locally advanced MpBC.

Drug: L-NMMA

Interventions

L-NMMA DRUG

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

iNOS inhibitor and nab-paclitaxel in combination with alpelisib.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• The Methodist Hospital Research Institute: lead
• Novartis Pharmaceuticals: collaborator

Study Sites (3)

National Institute of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Houston Methodist Neal Cancer Center

Houston, Texas, 77030, United States

RECRUITING

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

RECRUITING

Related Publications (31)

• 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.

  PMID: 32047541 BACKGROUND

• 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.

  PMID: 25849745 BACKGROUND

• 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.

  PMID: 28040796 BACKGROUND

• 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.

  PMID: 29301832 BACKGROUND

• 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.

  PMID: 29113326 BACKGROUND

• 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.

  PMID: 22878588 BACKGROUND

• 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.

  PMID: 22957045 BACKGROUND

• 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.

  PMID: 18439435 BACKGROUND

• 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.

  PMID: 17096325 BACKGROUND

• 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.

  PMID: 17935137 BACKGROUND

• 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.

  PMID: 19293033 BACKGROUND

• 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.

  PMID: 25400422 BACKGROUND

• 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.

  PMID: 25344912 BACKGROUND

• 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.

  PMID: 29970892 BACKGROUND

• 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.

  PMID: 30925636 BACKGROUND

• Reddy TP, Rosato RR, Li X, Moulder S, Piwnica-Worms H, Chang JC. A comprehensive overview of metaplastic breast cancer: clinical features and molecular aberrations. Breast Cancer Res. 2020 Nov 4;22(1):121. doi: 10.1186/s13058-020-01353-z.

  PMID: 33148288 BACKGROUND

• Somasundaram V, Basudhar D, Bharadwaj G, No JH, Ridnour LA, Cheng RYS, Fujita M, Thomas DD, Anderson SK, McVicar DW, Wink DA. Molecular Mechanisms of Nitric Oxide in Cancer Progression, Signal Transduction, and Metabolism. Antioxid Redox Signal. 2019 Mar 10;30(8):1124-1143. doi: 10.1089/ars.2018.7527. Epub 2018 May 2.

  PMID: 29634348 BACKGROUND

• Basudhar D, Bharadwaj G, Somasundaram V, Cheng RYS, Ridnour LA, Fujita M, Lockett SJ, Anderson SK, McVicar DW, Wink DA. Understanding the tumour micro-environment communication network from an NOS2/COX2 perspective. Br J Pharmacol. 2019 Jan;176(2):155-176. doi: 10.1111/bph.14488. Epub 2018 Nov 6.

  PMID: 30152521 BACKGROUND

• Janku F, Yap TA, Meric-Bernstam F. Targeting the PI3K pathway in cancer: are we making headway? Nat Rev Clin Oncol. 2018 May;15(5):273-291. doi: 10.1038/nrclinonc.2018.28. Epub 2018 Mar 6.

  PMID: 29508857 BACKGROUND

• Cossu-Rocca P, Orru S, Muroni MR, Sanges F, Sotgiu G, Ena S, Pira G, Murgia L, Manca A, Uras MG, Sarobba MG, Urru S, De Miglio MR. Analysis of PIK3CA Mutations and Activation Pathways in Triple Negative Breast Cancer. PLoS One. 2015 Nov 5;10(11):e0141763. doi: 10.1371/journal.pone.0141763. eCollection 2015.

  PMID: 26540293 BACKGROUND

• Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012 Oct 4;490(7418):61-70. doi: 10.1038/nature11412. Epub 2012 Sep 23.

  PMID: 23000897 BACKGROUND

• Kriegsmann M, Endris V, Wolf T, Pfarr N, Stenzinger A, Loibl S, Denkert C, Schneeweiss A, Budczies J, Sinn P, Weichert W. Mutational profiles in triple-negative breast cancer defined by ultradeep multigene sequencing show high rates of PI3K pathway alterations and clinically relevant entity subgroup specific differences. Oncotarget. 2014 Oct 30;5(20):9952-65. doi: 10.18632/oncotarget.2481.

  PMID: 25296970 BACKGROUND

• Zhai J, Giannini G, Ewalt MD, Zhang EY, Invernizzi M, Niland J, Lai LL. Molecular characterization of metaplastic breast carcinoma via next-generation sequencing. Hum Pathol. 2019 Apr;86:85-92. doi: 10.1016/j.humpath.2018.11.023. Epub 2018 Dec 8.

  PMID: 30537493 BACKGROUND

• Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, Gilcrease MZ, Krishnamurthy S, Lee JS, Fridlyand J, Sahin A, Agarwal R, Joy C, Liu W, Stivers D, Baggerly K, Carey M, Lluch A, Monteagudo C, He X, Weigman V, Fan C, Palazzo J, Hortobagyi GN, Nolden LK, Wang NJ, Valero V, Gray JW, Perou CM, Mills GB. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 2009 May 15;69(10):4116-24. doi: 10.1158/0008-5472.CAN-08-3441. Epub 2009 May 12.

  PMID: 19435916 BACKGROUND

• Afkhami M, Schmolze D, Yost SE, Frankel PH, Dagis A, Amanam IU, Telatar M, Nguyen K, Yu KW, Luu T, Pillai R, Aoun PA, Mortimer J, Yuan Y. Mutation and immune profiling of metaplastic breast cancer: Correlation with survival. PLoS One. 2019 Nov 6;14(11):e0224726. doi: 10.1371/journal.pone.0224726. eCollection 2019.

  PMID: 31693690 BACKGROUND

• Chan JJ, Tan TJY, Dent RA. Novel therapeutic avenues in triple-negative breast cancer: PI3K/AKT inhibition, androgen receptor blockade, and beyond. Ther Adv Med Oncol. 2019 Oct 9;11:1758835919880429. doi: 10.1177/1758835919880429. eCollection 2019.

  PMID: 31636720 BACKGROUND

• Andre F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P, Mayer IA, Kaufman B, Yamashita T, Lu YS, Inoue K, Takahashi M, Papai Z, Longin AS, Mills D, Wilke C, Hirawat S, Juric D; SOLAR-1 Study Group. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019 May 16;380(20):1929-1940. doi: 10.1056/NEJMoa1813904.

  PMID: 31091374 BACKGROUND

• Reddy T, et al. Combination PI3K and NOS targeted therapy for metaplastic breast cancer (abstract). In: European Journal of Cancer, Molecular Targeted Agents. 2020; 138:S49-S50.

  BACKGROUND

• Nelson RA, Guye ML, Luu T, Lai LL. Survival outcomes of metaplastic breast cancer patients: results from a US population-based analysis. Ann Surg Oncol. 2015 Jan;22(1):24-31. doi: 10.1245/s10434-014-3890-4. Epub 2014 Jul 11.

  PMID: 25012264 BACKGROUND

• Rayson D, Adjei AA, Suman VJ, Wold LE, Ingle JN. Metaplastic breast cancer: prognosis and response to systemic therapy. Ann Oncol. 1999 Apr;10(4):413-9. doi: 10.1023/a:1008329910362.

  PMID: 10370783 BACKGROUND

• Moulder S, Helgason T, Janku F, Wheler J, Moroney J, Booser D, Albarracin C, Morrow PK, Atkins J, Koenig K, Gilcrease M, Kurzrock R. Inhibition of the phosphoinositide 3-kinase pathway for the treatment of patients with metastatic metaplastic breast cancer. Ann Oncol. 2015 Jul;26(7):1346-52. doi: 10.1093/annonc/mdv163. Epub 2015 Apr 15.

  PMID: 25878190 BACKGROUND

MeSH Terms

Conditions

Breast Neoplasms; Triple Negative Breast Neoplasms

Interventions

omega-N-Methylarginine; N(6)-(1-iminoethyl)lysine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Arginine; Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino; Amino Acids, Essential

Study Officials

• Polly A Niravath, MD

  Houston Methodist Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Alexys Brock

CONTACT

346-238-4814; abrock@houstonmethodist.org

Titilayo Olubajo

CONTACT

713-363-9803; tolubajo@houstonmethodist.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 13, 2022
• First Posted: December 21, 2022
• Study Start: January 12, 2023
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 2, 2028
• Last Updated: February 18, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)