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)
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| ClinicalTrials.gov Identifier: NCT03056755 |
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Recruitment Status :
Active, not recruiting
First Posted : February 17, 2017
Results First Posted : March 27, 2024
Last Update Posted : March 27, 2024
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Breast Cancer | Drug: Alpelisib Drug: Fulvestrant Drug: Letrozole Drug: Goserelin Drug: Leuprolide | Phase 2 |
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 (Clinical Trial) |
| Actual Enrollment : | 379 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| 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 |
| Actual Study Start Date : | August 14, 2017 |
| Actual Primary Completion Date : | June 14, 2021 |
| Estimated Study Completion Date : | July 17, 2025 |
| Arm | Intervention/treatment |
|---|---|
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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
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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: 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. |
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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
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Drug: Alpelisib
300 mg of alpelisib film-coated tablets administered orally once daily
Other Name: BYL719 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. |
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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.
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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: 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. |
- 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.
- 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
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03056755
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| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
Documents provided by Novartis ( Novartis Pharmaceuticals ):
| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT03056755 |
| Other Study ID Numbers: |
CBYL719X2402 2016-004586-67 ( EudraCT Number ) |
| First Posted: | February 17, 2017 Key Record Dates |
| Results First Posted: | March 27, 2024 |
| Last Update Posted: | March 27, 2024 |
| Last Verified: | February 2024 |
| Individual Participant Data (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 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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advanced breast cancer PIK3CA CDK 4/6 inhibitor fulvestrant letrozole HR+ HER2-negative |
post menopausal pre-menopausal aromatase inhibitor endocrine treatment AI ET |
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Breast Neoplasms Neoplasms by Site Neoplasms Breast Diseases Skin Diseases Letrozole Fulvestrant Leuprolide Goserelin Antineoplastic Agents Aromatase Inhibitors Steroid Synthesis Inhibitors |
Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Estrogen Antagonists Hormone Antagonists Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs Antineoplastic Agents, Hormonal Estrogen Receptor Antagonists Fertility Agents, Female Fertility Agents Reproductive Control Agents |