Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant or Letrozole, Based on Prior Endocrine Therapy, in Patients With PIK3CA Mutant, HR+, HER2- Advanced Breast Cancer Who Have Progressed on or After Prior Treatments

NCT03056755 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: CBYL719X24022023-509167-24-00
• Study Type: interventional
• Target: 383
• Locations: 19 countries
• Sites: 94

Brief Summary

This was a Phase II, multicenter, open-label, three-cohort, non-comparative study of alpelisib plus endocrine therapy (either fulvestrant or letrozole) in subjects (pre- and post-menopausal women and men) with HR-positive, HER2-negative aBC harboring PIK3CA mutation(s) in the tumor, whose disease had progressed on or after prior treatments.

Conditions

Breast Cancer

Keywords

advanced breast cancer; PIK3CA; CDK 4/6 inhibitor; fulvestrant; letrozole; HR+; HER2-negative; post menopausal; pre-menopausal; aromatase inhibitor; endocrine treatment; AI; ET

Outcome Measures

Primary Outcomes (1)

• Core Phase: Percentage of Participants Who Were Alive Without Disease Progression at 6 Months

  Percentage of participants who were alive without disease progression at 6-month follow-up based on local investigator assessment per RECIST v1.1 in Cohort A, Cohort B and Cohort C. Participants who progressed, died, or discontinued study before 6 months were counted as a failure.

  At 6 months

Secondary Outcomes (7)

• Core Phase: Progression Free Survival (PFS)

  From date of first dose to date of first documented progression or death, up to 46 months

• Core Phase: Progression Free Survival on Next Line Treatment (PFS2)

  From date of first dose to date of first documented progression on next-line therapy or death, up to approximately 55 months

• Core Phase: Overall Response Rate (ORR)

  Up to 46 months

• Core Phase: Clinical Benefit Rate (CBR)

  Up to 46 months

• Core Phase: Duration of Response (DOR)

  From date of first documented response to first documented progression or death, up to 33.3 months

Study Arms (3)

Cohort A: Pre-treated with CDK 4/6i + AI

EXPERIMENTAL

Participants who received any Cyclin-Dependent Kinases 4 and 6 inhibitor (CDK 4/6i) plus aromatase inhibitor (AI) as immediate prior treatment will receive alpelisib + fulvestrant

Drug: Alpelisib; Drug: Fulvestrant; Drug: Goserelin; Drug: Leuprolide

Cohort B: Pre-treated with CDK 4/6i + fulvestrant

EXPERIMENTAL

Patients who received any CDK 4/6i plus fulvestrant as immediate prior treatment will receive alpelisib + letrozole

Drug: Alpelisib; Drug: Letrozole; Drug: Goserelin; Drug: Leuprolide

Cohort C: Pre-treated with systemic chemotherapy or ET

EXPERIMENTAL

Participants who received systemic chemotherapy or endocrine therapy (ET) (as monotherapy or in combination with targeted treatment except CDK 4/6i + AI) as immediate prior treatment will receive alpelisib + fulvestrant.

Drug: Alpelisib; Drug: Fulvestrant; Drug: Goserelin; Drug: Leuprolide

Interventions

Alpelisib DRUG

300 mg of alpelisib film-coated tablets administered orally once daily

Also known as: BYL719

Cohort A: Pre-treated with CDK 4/6i + AI; Cohort B: Pre-treated with CDK 4/6i + fulvestrant; Cohort C: Pre-treated with systemic chemotherapy or ET

Fulvestrant DRUG

500 mg of fulvestrant via intramuscular injection administered on Days 1, 15 on Cycle 1 and Day 1 at each cycle thereafter. Cycle=28 days

Cohort A: Pre-treated with CDK 4/6i + AI; Cohort C: Pre-treated with systemic chemotherapy or ET

Letrozole DRUG

2.5 mg of letrozole film-coated tablets administered orally once daily

Cohort B: Pre-treated with CDK 4/6i + fulvestrant

Goserelin DRUG

3.6 mg of goserelin via injectable subcutaneous implant administered every 28 days. Only for men in Cohort B and premenopausal women.

Cohort A: Pre-treated with CDK 4/6i + AI; Cohort B: Pre-treated with CDK 4/6i + fulvestrant; Cohort C: Pre-treated with systemic chemotherapy or ET

Leuprolide DRUG

7.5 mg of leuprolide via injectable intramuscular depot administered every 28 days. Only for men in cohort B and premenopausal women.

Cohort A: Pre-treated with CDK 4/6i + AI; Cohort B: Pre-treated with CDK 4/6i + fulvestrant; Cohort C: Pre-treated with systemic chemotherapy or ET

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject was an adult male or female ≥ 18 years of age.
• Subjects with histologically and/or cytologically confirmed diagnosis of estrogen receptor (ER)-positive and/or progesterone receptor (PgR)-positive breast cancer by local laboratory.
• Subjects with a confirmed human epidermal growth factor receptor-2 (HER2)-negative aBC.
• Subjects with gene encoding the p110alpha catalytic subunit of PI3K (phosphatidylinositol-3-kinase) (PIK3CA) mutation.
• In case of women, both premenopausal and postmenopausal subjects were allowed to be included in this study.
• Subjects with documented evidence of tumor progression on or after:
• i. Cyclin-Dependent Kinase 4 and 6 inhibitor (CDK4/6i) treatment as last treatment regimen in Cohorts A and B.
• ii. aromatase inhibitor (AI) treatment (either in adjuvant or metastatic setting) and received systemic chemotherapy or ET (monotherapy or combination except CDK4/6i + AI) as last treatment regimen in Cohort C. Upon completion of enrollment of Cohort B, subjects who received CDK4/6i + fulvestrant as immediate prior therapy were eligible for Cohort C.
• iii. No more than 2 prior anticancer therapies for aBC. iv. Received no more than 1 prior regimen of chemotherapy for the treatment of advanced/metastatic disease was permitted.
• v. Recovered to grade 1 or better from any adverse events (AEs) related to previous anticancer therapy prior to study entry (except alopecia or other toxicities not considered a safety risk for the subject at the investigator's discretion).
• Subjects with:
• i. Measurable disease, i.e., at least 1 measurable lesion as per RECIST v1.1 criteria; or ii. If no measurable disease was present, at least 1 predominantly lytic bone lesion had to be present.
• Subjects with adequate bone marrow and coagulation function, liver function and renal function as shown by laboratory values.
• Subjects with Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2.

You may not qualify if:

• Subjects with a known hypersensitivity to alpelisib, fulvestrant, letrozole, goserelin, or leuprolide or to any of their excipients.
• Subjects with prior treatment with any PI3K inhibitor (PI3Ki).
• Subjects with central nervous system (CNS) involvement unless they met all of the following criteria:
• i. At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment, ii. Clinically stable CNS tumor at the time of screening untreated or without evidence of progressions for at least 4 weeks after treatment as determined by clinical examination and brain imaging (magnetic resonance imaging (MRI) or computed tomography (CT) during screening period and stable low dose of steroids for 2 weeks prior to initiating study treatment.
• Subjects with an established diagnosis of diabetes mellitus type I or uncontrolled type II.
• Any concurrent severe and/or uncontrolled medical conditions that would, in the investigator's judgment, contraindicate subject participation in the study (e.g., chronic active hepatitis, severe hepatic impairment, etc.).
• Subjects with a history of noncompliance to medical regimens.
• Subjects with impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of the study drugs based on investigator discretion.
• Subjects with documented pneumonitis/interstitial lung disease which was active and requiring treatment.
• Subjects concurrently using other anticancer therapy. All anticancer therapy had to be discontinued prior to Day 1 of study treatment.
• Subjects who had major surgery within 14 days prior to starting treatment with alpelisib, or did not recover from major side effects.
• Subjects with significant cardiac abnormalities.
• History of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis.
• Subjects who did not use highly effective contraception while on alpelisib and through the duration after the final dose of alpelisib (not applicable to postmenopausal women).
• Subjects with unresolved osteonecrosis of the jaw.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (94)

Banner MD Anderson Cancer Center

Gilbert, Arizona, 85234, United States

Location

Mayo Clinic Arizona

Phoenix, Arizona, 85054, United States

Location

Kaiser Permanente Medical Group

Anaheim, California, 92807, United States

Location

Beverly Hills Cancer Center

Beverly Hills, California, 90211, United States

Location

University of Calif Irvine Med Cntr

Irvine, California, 92660, United States

Location

Kaiser Permanent Southern Californi

San Diego, California, 92120, United States

Location

UCSF

San Francisco, California, 94115, United States

Location

Yale University Yale Cancer Center

New Haven, Connecticut, 06511, United States

Location

Advent Health Cancer Institute

Orlando, Florida, 32804, United States

Location

University of Kansas Cancer Center

Kansas City, Kansas, 66205, United States

Location

University of Louisville James Graham Brown Cancer Center

Louisville, Kentucky, 40202, United States

Location

Mercy Medical Center

Baltimore, Maryland, 21202, United States

Location

Greater Baltimore Med Center Cancer Center

Baltimore, Maryland, 21204, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Lahey Clinic

Burlington, Massachusetts, 01805, United States

Location

Josephine Ford Cancer Center

Detroit, Michigan, 48202, United States

Location

St Vincent Frontier Cancer Center

Billings, Montana, 59102, United States

Location

New Mexico Cancer Care Alliance

Albuquerque, New Mexico, 87106, United States

Location

Memorial Sloane Ketterin Cancer Ctr

New York, New York, 10065, United States

Location

Uni Hosp of Cleveland Cancer Center

Cleveland, Ohio, 44106, United States

Location

Texas Oncology

Dallas, Texas, 75246, United States

Location

Cancer Care Centers of South Texas HOAST

San Antonio, Texas, 78229, United States

Location

UT Health San Antonio

San Antonio, Texas, 78229, United States

Location

Virginia Oncology Associates

Norfolk, Virginia, 23502, United States

Location

Northwest Medical Specialists

Tacoma, Washington, 98405, United States

Location

Novartis Investigative Site

CABA, Buenos Aires, C1118AAT, Argentina

Location

Novartis Investigative Site

CABA, Buenos Aires, C1125ABD, Argentina

Location

Novartis Investigative Site

CABA, Buenos Aires, C1426ANZ, Argentina

Location

Novartis Investigative Site

Rosario, Santa Fe Province, S2000DSV, Argentina

Location

Novartis Investigative Site

Rosario, Sante Fe, S200KZE, Argentina

Location

Novartis Investigative Site

La Rioja, 5300, Argentina

Location

Novartis Investigative Site

Leuven, 3000, Belgium

Location

Novartis Investigative Site

Liège, 4000, Belgium

Location

Novartis Investigative Site

Vancouver, British Columbia, V5Z 4E6, Canada

Location

Novartis Investigative Site

Halifax, Nova Scotia, B3H 2Y9, Canada

Location

Novartis Investigative Site

Kitchener, Ontario, N2G 1G3, Canada

Location

Novartis Investigative Site

Toronto, Ontario, M5B 1N9, Canada

Location

Novartis Investigative Site

Temuco, Región de la Araucanía, 4810469, Chile

Location

Novartis Investigative Site

Santiago, 7500921, Chile

Location

Novartis Investigative Site

Santiago, 8420383, Chile

Location

Novartis Investigative Site

Odense C, 5000, Denmark

Location

Novartis Investigative Site

Vejle, DK-7100, Denmark

Location

Novartis Investigative Site

Nice, Alpes Maritimes, 06189, France

Location

Novartis Investigative Site

Saint-Cloud, Hauts De Seine, 92210, France

Location

Novartis Investigative Site

Bordeaux, 33076, France

Location

Novartis Investigative Site

Caen, 14021, France

Location

Novartis Investigative Site

Lille, 59020, France

Location

Novartis Investigative Site

Lyon, 69373, France

Location

Novartis Investigative Site

Montpellier, 34298, France

Location

Novartis Investigative Site

Saint-Herblain, 44805, France

Location

Novartis Investigative Site

Strasbourg, 67000, France

Location

Novartis Investigative Site

Toulouse, 31059, France

Location

Novartis Investigative Site

Dresden, Saxony, 01307, Germany

Location

Novartis Investigative Site

Augsburg, 86150, Germany

Location

Novartis Investigative Site

Berlin, 14169, Germany

Location

Novartis Investigative Site

Erlangen, 91054, Germany

Location

Novartis Investigative Site

Essen, 45136, Germany

Location

Novartis Investigative Site

Heidelberg, 69120, Germany

Location

Novartis Investigative Site

Ulm, 89081, Germany

Location

Novartis Investigative Site

Delhi, 110085, India

Location

Novartis Investigative Site

Petah Tikva, 4941492, Israel

Location

Novartis Investigative Site

Ramat Gan, 5265601, Israel

Location

Novartis Investigative Site

Rehovot, 7661041, Israel

Location

Novartis Investigative Site

Tel Aviv, 6423906, Israel

Location

Novartis Investigative Site

Ancona, AN, 60126, Italy

Location

Novartis Investigative Site

Bergamo, BG, 24127, Italy

Location

Novartis Investigative Site

Bologna, BO, 40138, Italy

Location

Novartis Investigative Site

Genova, GE, 16132, Italy

Location

Novartis Investigative Site

Milan, MI, 20133, Italy

Location

Novartis Investigative Site

Milan, MI, 20141, Italy

Location

Novartis Investigative Site

Roma, RM, 00168, Italy

Location

Novartis Investigative Site

Naples, 80131, Italy

Location

Novartis Investigative Site

Osaka, Osaka, 540-0006, Japan

Location

Novartis Investigative Site

Jalisco, 45640, Mexico

Location

Novartis Investigative Site

Maastricht, Limburg, 6229 HX, Netherlands

Location

Novartis Investigative Site

Singapore, 168583, Singapore

Location

Novartis Investigative Site

Singapore, 217562, Singapore

Location

Novartis Investigative Site

Seoul, Korea, 03080, South Korea

Location

Novartis Investigative Site

Seoul, 06351, South Korea

Location

Novartis Investigative Site

L'Hospitalet de Llobregat, Barcelona, 08907, Spain

Location

Novartis Investigative Site

Salamanca, Castille and León, 37007, Spain

Location

Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

Location

Novartis Investigative Site

Barcelona, 08036, Spain

Location

Novartis Investigative Site

Castellon, 12002, Spain

Location

Novartis Investigative Site

Madrid, 28041, Spain

Location

Novartis Investigative Site

Seville, 41013, Spain

Location

Novartis Investigative Site

Tainan, 70403, Taiwan

Location

Novartis Investigative Site

Taipei, 10002, Taiwan

Location

Novartis Investigative Site

Taipei, 103616, Taiwan

Location

Novartis Investigative Site

Edinburgh, Scotland, EH4 2XU, United Kingdom

Location

Novartis Investigative Site

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Novartis Investigative Site

Leicester, LE2 7LG, United Kingdom

Location

Novartis Investigative Site

London, SW3 6JJ, United Kingdom

Location

Novartis Investigative Site

Nottingham, NG5 1PB, United Kingdom

Location

Related Publications (4)

• Rugo HS, Lerebours F, Ciruelos E, Drullinsky P, Ruiz-Borrego M, Neven P, Park YH, Prat A, Bachelot T, Juric D, Turner N, Sophos N, Zarate JP, Arce C, Shen YM, Turner S, Kanakamedala H, Hsu WC, Chia S. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2024 Dec;25(12):e629-e638. doi: 10.1016/S1470-2045(24)00673-9.

  PMID: 39637900 DERIVED

• Borrego MR, Lu YS, Reyes-Cosmelli F, Park YH, Yamashita T, Chiu J, Airoldi M, Turner N, Fein L, Ghaznawi F, Singh J, Pantoja K, Schnell C, Akdere M, Chia S. SGLT2 inhibition improves PI3Kalpha inhibitor-induced hyperglycemia: findings from preclinical animal models and from patients in the BYLieve and SOLAR-1 trials. Breast Cancer Res Treat. 2024 Nov;208(1):111-121. doi: 10.1007/s10549-024-07405-8. Epub 2024 Aug 23.

  PMID: 39177931 DERIVED

• Rodon J, Demanse D, Rugo HS, Burris HA, Simo R, Farooki A, Wellons MF, Andre F, Hu H, Vuina D, Quadt C, Juric D. A risk analysis of alpelisib-induced hyperglycemia in patients with advanced solid tumors and breast cancer. Breast Cancer Res. 2024 Mar 4;26(1):36. doi: 10.1186/s13058-024-01773-1.

  PMID: 38439079 DERIVED

• Rugo HS, Lerebours F, Ciruelos E, Drullinsky P, Ruiz-Borrego M, Neven P, Park YH, Prat A, Bachelot T, Juric D, Turner N, Sophos N, Zarate JP, Arce C, Shen YM, Turner S, Kanakamedala H, Hsu WC, Chia S. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021 Apr;22(4):489-498. doi: 10.1016/S1470-2045(21)00034-6.

  PMID: 33794206 DERIVED

Related Links

• A Plain Language Trial Summary is available on www.novctrd.com

MeSH Terms

Conditions

Breast Neoplasms; Hereditary Sensory and Autonomic Neuropathies

Interventions

Alpelisib; Fulvestrant; Letrozole; Goserelin; Leuprolide

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins

Results Point of Contact

• Title: Study director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 15, 2017
• First Posted: February 17, 2017
• Study Start: August 29, 2017
• Primary Completion: June 14, 2021
• Study Completion: November 12, 2024
• Last Updated: January 13, 2026
• Results First Posted: March 27, 2024

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share

Locations

NL (1); US (25); CA (4); KR (2); IL (4); GB (5); ME (1); DE (7); FR (10); IN (1); CL (3); SG (2); DK (2); ES (7); TW (3); BE (2); AR (6); JP (1); IT (8)