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 (BYLieve)

• ClinicalTrials.gov Identifier: NCT03056755
• Recruitment Status: Active, not recruiting
• First Posted: February 17, 2017
• Results First Posted: March 27, 2024
• Last Update Posted: March 27, 2024
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: February 15, 2017
• First Posted Date: February 17, 2017
• Results First Submitted Date: February 29, 2024
• Results First Posted Date: March 27, 2024
• Last Update Posted Date: March 27, 2024
• Actual Study Start Date: August 14, 2017
• Actual Primary Completion Date: June 14, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 29, 2024)

Core Phase: Percentage of Participants Who Were Alive Without Disease Progression at 6 Months [ Time Frame: 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.

Original Primary Outcome Measures (submitted: February 15, 2017)

The percentage of patients who are alive without disease progression [ Time Frame: Date of first dose to approximately 6 months ]

Assess the percentage of patients without disease progression based on local investigator assessment per RECIST in cohort A and cohort B

Current Secondary Outcome Measures (submitted: February 29, 2024)

• Core Phase: Progression Free Survival (PFS) [ Time Frame: From date of first dose to date of first documented progression or death, up to 46 months ]
  PFS is defined as the time from the date of first dose of study medication to the date of the first documented progression or death due to any cause occurring in the study. PFS was assessed based on local investigator's assessment according to RECIST v1.1. PFS was censored if no PFS event was observed before the cut-off date. The censoring date was the date of last adequate tumor assessment before the cut-off date. If a PFS event was observed after two or more missing or non-adequate tumor assessments, then PFS was censored at the last adequate tumor assessment. PFS was estimated using the Kaplan-Meier method.
• Core Phase: Progression Free Survival on Next Line Treatment (PFS2) [ Time Frame: From date of first dose to date of first documented progression on next-line therapy or death, up to approximately 55 months ]
  PFS2 is defined as time from the date of first dose of study medication to the date of first documented progression on next-line therapy or death from any cause. The first documented progression on next-line treatment is based on investigator assessment of progressive disease. PFS2 was estimated using the Kaplan-Meier method.
• Core Phase: Overall Response Rate (ORR) [ Time Frame: Up to 46 months ]
  ORR is defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST v1.1 in each cohort. CR: Disappearance of all non-nodal target lesions and all non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm and all lymph nodes assigned as non-target lesions must be non-pathological in size (<10 mm short axis) PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
• Core Phase: Clinical Benefit Rate (CBR) [ Time Frame: Up to 46 months ]
  CBR is defined as the percentage of participants with a BOR of CR or PR or an overall lesion response of stable disease (SD) or Non-CR/ Non-PD lasting ≥ 24 weeks based on local investigator's assessment according to RECIST v1.1. CR: Disappearance of all non-nodal target lesions and all non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm and all lymph nodes assigned as non-target lesions must be non-pathological in size (<10 mm short axis) PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
• Core Phase: Duration of Response (DOR) [ Time Frame: From date of first documented response to first documented progression or death, up to 33.3 months ]
  DOR is the time from the date of first documented response (confirmed CR or PR based on local investigator's assessment according to RECIST v1.1) to the date of first documented progression or death due to underlying cancer. Subjects continuing without progression or death due to underlying cancer were censored at the date of their last adequate tumor assessment. DOR was estimated using the Kaplan-Meier method.
• Core Phase: Overall Survival (OS) [ Time Frame: From date of first dose and up to approximately 55 months ]
  OS is defined as the time of start of treatment to date of death or lost to follow-up. If a subject was not known to have died, then the OS data was censored at the date of the last known alive status for the patient.
• Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase [ Time Frame: From end of core phase up to 12 months ]
  Percentage of participants with clinical benefit as assessed by the Investigator at scheduled visits during the extension phase

Original Secondary Outcome Measures (submitted: February 15, 2017)

• Progression free survival (PFS) for each cohort [ Time Frame: date of first dose to up to approximately 25 months ]
  PFS is defined as the time from the date of first dose of study medication to the date of the first documented progression or death due to any cause occurring in the study. PFS will be assessed based on local investigator's assessment according to RECIST v1.1
• Progression free survival (PFS) on next line treatment PFS2) for each cohort [ Time Frame: Date of first dose to date of first documented progression up to approximately 25 months ]
  Progression free survival (PFS) on next line treatment (PFS2) is defined as time from the date of first dose of study medication to the date of first documented progression on next-line therapy or death from any cause
• Percentage of participants Overall response rate (ORR) for each cohort [ Time Frame: Date of first dose and up to approximately 25 months ]
  ORR is defined as the percentage of participants with best overall response (BOR) of CR or partial response (PR), as per local investigator's assessment and according to RECIST v1.1.
• Percentage of participants with clinical benefit rate (CBR) for each cohort [ Time Frame: Date of first dose and up to approximately 25 months ]
  CBR is defined as the percentage of participants with a best ORR of complete response (CR) or partial response (PR) or an overall lesion response of stable disease (SD) or Non-CR/ Non-PD lasting ≥ 24 weeks based on local investigator's assessment according to RECIST v1.1
• Duration of response (DOR) [ Time Frame: Date of first documented response to first documented progression or death up to approximately 25 months ]
  Duration of Response is the time from the date of first documented response (confirmed CR or PR) to the date of first documented progression or death due to underlying cancer

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: BYLieve: A Phase II, Multicenter, Open-label, Three-cohort, Non- Comparative Study to Assess the Efficacy and Safety of Alpelisib Plus Fulvestrant or Letrozole in Patients With PIK3CA Mutant, Hormone Receptor (HR) Positive, HER2-negative Advanced Breast Cancer (aBC), Who Have Progressed on or After Prior Treatments
• Brief Summary: Study assessing the efficacy and safety of alpelisib plus fulvestrant or letrozole, based on prior endocrine therapy, in patients with hormone receptor (HR) positive, HER2-negative advanced breast cancer (aBC), harboring PIK3CA mutations, who have progressed on or after prior treatments.

Detailed Description

This is a phase II, multicenter, open-label, three-cohort, non-comparative study of alpelisib plus endocrine therapy (either fulvestrant or letrozole) in patients with HR+, HER2- aBC harboring PIK3CA mutation(s) in the tumor whose disease has progressed on or after prior treatments.

The study includes two phases:

• Core Phase: includes treatment phase for all patients from First Patient First Treatment (FPFT) until 18 months post Last Patient First Treatment (LPFT) + 1 month Safety follow-up (total 19 months post LPFT)
• Extension Phase: includes treatment phase starting at the end of the treatment Core Phase up to 36 months. The extension treatment phase is only for patients who are continuing to benefit from treatment at the end of the Core Phase and are not eligible for PSDS (Post-Study Drug Supply) in their country based on local regulations. Patients will continue on their existing treatment assigned in the Core Phase. If PSDS becomes available for a patient, the patient should be discontinued from the study and access treatment via PSDS. During the Extension Phase there will be no per protocol efficacy assessments other than physician's determination as per standard of care of whether or not the patient is continuing to derive clinical benefit from the study treatment.

Patients who are benefiting from treatment and are eligible for PSDS will exit the trial at the end of the Core Phase.

After discontinuation of study treatment, all patients will be followed for safety for at least 30 days except in case of death, loss to follow-up or withdrawal of consent.

During the Core Phase only: If a patient discontinues study treatment for reasons other than documented disease progression, death, lost to follow-up, or withdrawal of consent for efficacy follow-up, tumor assessments should continue to be performed until documented disease progression, death, lost to follow-up, or withdrawn consent to efficacy follow-up or end of study (Post-treatment efficacy follow-up). Moreover, all participants will be followed for survival status (after progression) regardless of treatment discontinuation reason (except if consent is withdrawn, death or patient is lost to follow-up) until death, lost to follow-up, or withdrawal of consent for survival follow-up or end of the Core Phase

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: Alpelisib
  300 mg of alpelisib film-coated tablets administered orally once daily
  Other Name: BYL719
• Drug: 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
• Drug: Letrozole
  2.5 mg of letrozole film-coated tablets administered orally once daily
• Drug: Goserelin
  3.6 mg of goserelin via injectable subcutaneous implant administered every 28 days. Only for men in Cohort B and premenopausal women.
• Drug: Leuprolide
  7.5 mg of leuprolide via injectable intramuscular depot administered every 28 days. Only for men in cohort B and premenopausal women.

Study Arms

• Experimental: 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
  Interventions:

  • Drug: Alpelisib
  • Drug: Fulvestrant
  • Drug: Goserelin
  • Drug: Leuprolide
• Experimental: 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
  Interventions:

  • Drug: Alpelisib
  • Drug: Letrozole
  • Drug: Goserelin
  • Drug: Leuprolide
• Experimental: 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.
  Interventions:

  • Drug: Alpelisib
  • Drug: Fulvestrant
  • Drug: Goserelin
  • Drug: Leuprolide

• Publications *: 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 29, 2024): 379
• Original Estimated Enrollment (submitted: February 15, 2017): 160
• Estimated Study Completion Date: July 17, 2025
• Actual Primary Completion Date: June 14, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

• Patient has adequate tumor tissue for the analysis of PIK3CA mutational status by a Novartis designated laboratory. It is recommended to provide a tumor sample collected after the most recent progression or recurrence.
• Advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy
• Patient has been confirmed as PIK3CA mutant as determined by a certified designated laboratory
• Patient has histologically and/or cytologically confirmed ER+ and/ or PgR+ BC
• Patient has confirmed, HER2-negative aBC. HER2-negative defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0, 1+ or 2+.
• Patients must be diagnosed with aBC, with documented evidence of tumor progression on or after prior treatments. No more than one prior regimen of chemotherapy for the treatment of metastatic disease is permitted. The maximum number of prior therapies for aBC or mBC is limited to two (maintenance therapies, where applicable, must be regarded as part of the main therapy). Patients must have recovered to grade 1 or better from any adverse events (except alopecia) related to previous therapy prior to study entry.
• Patient has either measurable disease, i.e. at least one measurable lesion as per RECIST v1.1 criteria or if no measurable disease is present than at least one predominantly lytic bone lesion must be present
• Patient has ECOG performance status of ≤ 2
• Patient has adequate bone marrow function

Key Exclusion Criteria:

• Patient has received prior treatment with any PI3K inhibitors
• Patients with an established diagnosis of diabetes mellitus type I or uncontrolled type II
• Patient has a concurrent malignancy or malignancy within 3 years of study screening period, with the exception of adequately treated basal or squamous cell carcinoma, nonmelanoma skin cancer or curatively resected cervical cancer
• Patient has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to enrollment, and who has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia)
• Patients receiving systemic corticosteroids ≤ 2 weeks prior to treatment with alpelisib
• History of acute pancreatitis within 1 year of screening or past medical history of pancreatitis
• Patient has impaired GI function or GI disease that may affect the absorption of study drugs
• Patient has documented pneumonitis
• Patients being concurrently treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme Cytochrome P (CYP)3A within the last 5 days prior to study entry

Other inclusion/exclusion criteria may apply

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Belgium, Canada, Chile, Denmark, France, Germany, India, Israel, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Singapore, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT03056755
• Other Study ID Numbers: CBYL719X2402; 2016-004586-67 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: February 2024