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
NCT ID: NCT03056755
Last Updated: 2026-01-13
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2
383 participants
INTERVENTIONAL
2017-08-29
2024-11-12
Brief Summary
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Detailed Description
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1. Core Phase: included a treatment phase for all subjects from first subject first treatment (FSFT) until disease progression, unacceptable toxicity, or death until 18 months post last subject first treatment (LSFT) + 1 month safety follow-up (total 19 months post LSFT), discontinuation from the study treatment for any other reason, or sponsor terminates the study. At the start of the Core Phase, subjects were assigned to Cohort A, Cohort B, or Cohort C based on previous therapy as follows:
* Cohort A: alpelisib (300 mg oral QD) + fulvestrant (500 mg intramuscular (IM)) to subjects whose last prior treatment was a CDK4/6i plus any AI;
* Cohort B: alpelisib (300 mg oral QD) + letrozole (2.5 mg oral QD) to subjects whose last prior treatment was a CDK4/6i plus fulvestrant;
* Cohort C: alpelisib (300 mg oral QD)+ fulvestrant (500 mg IM) to subjects who failed prior AI based therapy and whose last prior treatment was systemic chemotherapy or endocrine therapy (as monotherapy or in combination with targeted treatment except CDK 4/6i + AI). Endocrine therapy included letrozole, fulvestrant and CDK 4/6 inhibitor plus fulvestrant.
2. Extension Phase: included a treatment phase starting at the end of the treatment Core Phase until last subject last visit(LSLV) (up to 36 months). Following the end of the Core Phase, subjects continuing to derive benefit from study treatment who were not eligible for Post-Study Drug Supply (PSDS) in their country based on local regulations were re-consented and transitioned to the Extension Phase. Subjects continued on their existing study treatment assigned in the Core Phase until disease progression/lack of clinical benefit or any other reason for which the subject may have been discontinued from study treatment. If PSDS became available for a subject, the subject was to be discontinued from the study and to access treatment via PSDS. When subjects discontinued treatment for any reason, the end of treatment visit was performed after discontinuation of the medication , followed by safety follow-up 30 days after last dose.
A total of 340 subjects were planned to be enrolled, with approximately 112 subjects in each cohort. In the Core Phase, 379 subjects were analyzed, with 127 subjects in Cohort A, 126 subjects in Cohort B, and 126 subjects in Cohort C. In the Extension Phase, 11 subjects were analyzed, with 1 subject in Cohort A and 10 subjects in Cohort C.
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Cohort A: Pre-treated with CDK 4/6i + AI
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
Alpelisib
300 mg of alpelisib film-coated tablets administered orally once daily
Fulvestrant
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
Goserelin
3.6 mg of goserelin via injectable subcutaneous implant administered every 28 days. Only for men in Cohort B and premenopausal women.
Leuprolide
7.5 mg of leuprolide via injectable intramuscular depot administered every 28 days. Only for men in cohort B and premenopausal women.
Cohort B: Pre-treated with CDK 4/6i + fulvestrant
Patients who received any CDK 4/6i plus fulvestrant as immediate prior treatment will receive alpelisib + letrozole
Alpelisib
300 mg of alpelisib film-coated tablets administered orally once daily
Letrozole
2.5 mg of letrozole film-coated tablets administered orally once daily
Goserelin
3.6 mg of goserelin via injectable subcutaneous implant administered every 28 days. Only for men in Cohort B and premenopausal women.
Leuprolide
7.5 mg of leuprolide via injectable intramuscular depot administered every 28 days. Only for men in cohort B and premenopausal women.
Cohort C: Pre-treated with systemic chemotherapy or ET
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.
Alpelisib
300 mg of alpelisib film-coated tablets administered orally once daily
Fulvestrant
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
Goserelin
3.6 mg of goserelin via injectable subcutaneous implant administered every 28 days. Only for men in Cohort B and premenopausal women.
Leuprolide
7.5 mg of leuprolide via injectable intramuscular depot administered every 28 days. Only for men in cohort B and premenopausal women.
Interventions
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Alpelisib
300 mg of alpelisib film-coated tablets administered orally once daily
Fulvestrant
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
Letrozole
2.5 mg of letrozole film-coated tablets administered orally once daily
Goserelin
3.6 mg of goserelin via injectable subcutaneous implant administered every 28 days. Only for men in Cohort B and premenopausal women.
Leuprolide
7.5 mg of leuprolide via injectable intramuscular depot administered every 28 days. Only for men in cohort B and premenopausal women.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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.
Exclusion Criteria
* 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.
18 Years
99 Years
ALL
No
Sponsors
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Novartis Pharmaceuticals
INDUSTRY
Responsible Party
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Principal Investigators
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Novartis Pharmaceuticals
Role: STUDY_DIRECTOR
Novartis Pharmaceuticals
Locations
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Banner MD Anderson Cancer Center
Gilbert, Arizona, United States
Mayo Clinic Arizona
Phoenix, Arizona, United States
Kaiser Permanente Medical Group
Anaheim, California, United States
Beverly Hills Cancer Center
Beverly Hills, California, United States
University of Calif Irvine Med Cntr
Irvine, California, United States
Kaiser Permanent Southern Californi
San Diego, California, United States
UCSF
San Francisco, California, United States
Yale University Yale Cancer Center
New Haven, Connecticut, United States
Advent Health Cancer Institute
Orlando, Florida, United States
University of Kansas Cancer Center
Kansas City, Kansas, United States
University of Louisville James Graham Brown Cancer Center
Louisville, Kentucky, United States
Mercy Medical Center
Baltimore, Maryland, United States
Greater Baltimore Med Center Cancer Center
Baltimore, Maryland, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Lahey Clinic
Burlington, Massachusetts, United States
Josephine Ford Cancer Center
Detroit, Michigan, United States
St Vincent Frontier Cancer Center
Billings, Montana, United States
New Mexico Cancer Care Alliance
Albuquerque, New Mexico, United States
Memorial Sloane Ketterin Cancer Ctr
New York, New York, United States
Uni Hosp of Cleveland Cancer Center
Cleveland, Ohio, United States
Texas Oncology
Dallas, Texas, United States
Cancer Care Centers of South Texas HOAST
San Antonio, Texas, United States
UT Health San Antonio
San Antonio, Texas, United States
Virginia Oncology Associates
Norfolk, Virginia, United States
Northwest Medical Specialists
Tacoma, Washington, United States
Novartis Investigative Site
CABA, Buenos Aires, Argentina
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CABA, Buenos Aires, Argentina
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CABA, Buenos Aires, Argentina
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Rosario, Santa Fe Province, Argentina
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Rosario, Sante Fe, Argentina
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La Rioja, , Argentina
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Leuven, , Belgium
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Liège, , Belgium
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Vancouver, British Columbia, Canada
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Halifax, Nova Scotia, Canada
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Kitchener, Ontario, Canada
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Toronto, Ontario, Canada
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Temuco, Región de la Araucanía, Chile
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Santiago, , Chile
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Santiago, , Chile
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Odense C, , Denmark
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Vejle, , Denmark
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Nice, Alpes Maritimes, France
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Saint-Cloud, Hauts De Seine, France
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Bordeaux, , France
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Caen, , France
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Lille, , France
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Lyon, , France
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Montpellier, , France
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Saint-Herblain, , France
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Strasbourg, , France
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Toulouse, , France
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Dresden, Saxony, Germany
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Augsburg, , Germany
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Berlin, , Germany
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Erlangen, , Germany
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Essen, , Germany
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Heidelberg, , Germany
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Ulm, , Germany
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Delhi, , India
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Petah Tikva, , Israel
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Ramat Gan, , Israel
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Rehovot, , Israel
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Tel Aviv, , Israel
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Ancona, AN, Italy
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Bergamo, BG, Italy
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Bologna, BO, Italy
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Genova, GE, Italy
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Milan, MI, Italy
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Milan, MI, Italy
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Roma, RM, Italy
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Napoli, , Italy
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Osaka, Osaka, Japan
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Jalisco, , Mexico
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Maastricht, Limburg, Netherlands
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Singapore, , Singapore
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Singapore, , Singapore
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Seoul, Korea, South Korea
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Seoul, , South Korea
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L'Hospitalet de Llobregat, Barcelona, Spain
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Salamanca, Castille and León, Spain
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Barcelona, Catalonia, Spain
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Barcelona, , Spain
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Castellon, , Spain
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Madrid, , Spain
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Seville, , Spain
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Tainan, , Taiwan
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Taipei, , Taiwan
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Taipei, , Taiwan
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Edinburgh, Scotland, United Kingdom
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Sutton, Surrey, United Kingdom
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Leicester, , United Kingdom
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London, , United Kingdom
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Nottingham, , United Kingdom
Countries
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References
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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.
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.
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.
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. Erratum In: Lancet Oncol. 2021 May;22(5):e184. doi: 10.1016/S1470-2045(21)00194-7.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Related Links
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A Plain Language Trial Summary is available on www.novctrd.com
Other Identifiers
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2023-509167-24-00
Identifier Type: REGISTRY
Identifier Source: secondary_id
CBYL719X2402
Identifier Type: -
Identifier Source: org_study_id
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