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Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant or Letrozole, Based on Prior Endocrine Therapy, in Patients With PIK3CA Mutation With Advanced Breast Cancer Who Have Progressed on or After Prior Treatments (BYLieve)

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ClinicalTrials.gov Identifier: NCT03056755
Recruitment Status : Recruiting
First Posted : February 17, 2017
Last Update Posted : August 5, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE February 15, 2017
First Posted Date  ICMJE February 17, 2017
Last Update Posted Date August 5, 2019
Actual Study Start Date  ICMJE August 14, 2017
Estimated Primary Completion Date November 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 29, 2019)
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, cohort B and cohort C
Original Primary Outcome Measures  ICMJE
 (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
Change History Complete list of historical versions of study NCT03056755 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 29, 2019)
  • 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 based on local investigator's assessment according to RECIST v1.1 in each cohort
  • Percentage of participants with clinical benefit rate (CBR) for each cohort [ Time Frame: Date of first dose and up to approximately 25 months ]
    Clinical Benefit Rate (CBR) based on local investigator's assessment according to RECIST v1.1 in each cohort
  • 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
  • Percentable of overall suvivial (OS) for each cohort [ Time Frame: Date of first dose and up to approximately 25 months ]
    Overall Survival is defined as the time of start of treatment to date of death or lost to follow-up.
Original Secondary Outcome Measures  ICMJE
 (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  ICMJE Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant or Letrozole, Based on Prior Endocrine Therapy, in Patients With PIK3CA Mutation With Advanced Breast Cancer Who Have Progressed on or After Prior Treatments
Official Title  ICMJE 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 PIK3CA mutation with advanced breast cancer who have progressed on or after prior treatments
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Intervention Model 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-negative aBC harboring PIK3CA mutation(s) in the tumor whose disease has progressed on or after prior treatments
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • Drug: alpelisib
    300 mg; oral; once daily
    Other Name: BYL719
  • Drug: fulvestrant
    500 mg; intramuscular injection on Days 1, 15 on Cycle 1 and Day 1 at each cycle thereafter
  • Drug: letrozole
    2.5 mg; oral; once daily
  • Drug: Goserelin
    Every 28 days (only for men in cohort B and premenopausal women). Administered as injectable subcutaneous implant (3.6 mg)
  • Drug: Leuprolide
    Every 28 days (only for men in cohort B and premenopausal women). Administered as injectable intramuscular depot (7.5 mg)
Study Arms  ICMJE
  • Experimental: Prior CDK 4/6 + aromatase
    Patients who received any CDK 4/6 inhibitor plus aromatase inhibitor as treatment (immediately prior) will receive alpelisib 500 mg oral.+ fulvestrant 500 mg intramuscular (i.m)
    Interventions:
    • Drug: alpelisib
    • Drug: fulvestrant
  • Experimental: Prior CDK 4/6 + fulvestrant
    Patients who received any CDK 4/6 inhibitor plus fulvestrant as treatment (immediately prior) will receive alpelisib 300 mg oral + letrozole 2.5 mg oral
    Interventions:
    • Drug: alpelisib
    • Drug: letrozole
    • Drug: Goserelin
    • Drug: Leuprolide
  • Experimental: Prior systemic chemo or ET
    Patients who received systemic chemotherapy or endrocrine therapy (ET) as immediate prior treatment will receive alpelisib 300 mg oral + fulvestrant 500 mg i.m.
    Interventions:
    • Drug: alpelisib
    • Drug: fulvestrant
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 7, 2019)
340
Original Estimated Enrollment  ICMJE
 (submitted: February 15, 2017)
160
Estimated Study Completion Date  ICMJE November 30, 2021
Estimated Primary Completion Date November 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patient is male or female 18 years or older
  • Males or females with advanced (locoregionally recurrent or metatstatic) breast cancer not amenable to curative therapy
  • In case of women, both premenopausal and postmenopausal patients are allowed to be included in study; menopausal status is relevant for the requirement of LHRH agonist (examples for use in this study include but not limited to goserelin, leuprolide or locally available treatment) to be used concomitantly with alpelisib and letrozole/fulvestrant

    1. Patient is postmenopausal woman defined as either:

      • Prior bilateral oophorectomy or
      • Age ≥60 or
      • Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and FSH and/or estradiol in the postmenopausal range per local normal range.

      If patient is taking tamoxifen or toremifene and age <60, then FSH and plasma estradiol levels should be in post-menopausal range per local normal range.

      Note: For women using therapy-induced amenorrhea other than ovarian radiation, goserelin or leuprolide, etc., serial measurements of FSH and/or estradiol are needed to ensure menopausal status

    2. Patient is premenopausal defined as either:

      • Patient had last menstrual period within the last 12 months or
      • If on tamoxifen or toremifene with in the past 14 days, plasma estradiol and FSH must be in the premenopausal range per local normal range, or
      • In case of therapy induced amenorrhea, plasma estradiol and/or FSH must be in the premenopausal range per local normal range
  • Patient has histological and/or cytological confirmed ER+ and/or PgR+ aBC
  • Patient has confirmed HER2-negative advanced breast cancer (aBC)
  • Patient has a PIK3CA mutation confirmed by Novartis designated central lab or patient has a pathology report confirming PIK3CA mutant status by certified laboratory (using validated PI3KCA mutation assay) either from tissue or blood and must (mandatory) send tumor tissue to Novartis designated central lab for confirmation of mutational status
  • Patient must have:

    • Documented evidence of tumor progression on or after CDK 4/ 6 inhibitor combination treatment; CDK 4/6 inhibitor must be the last treatment regimen prior to study entry,
    • AI treatment (either in adjuvant or metastatic setting) and received systemic chemotherapy or ET as last treatment regimen in cohort C
    • Maintenance therapies, where applicable, must be regarded as part of the main treatment.
    • No more than two (2) prior anti-cancer therapies for aBC
    • Received no more than one prior regimen of chemotherapy in the metastatic setting
  • Patient has either measurable disease per RECIST v1.1 or at least one predominantly lytic bone lesion must be present
  • ECOG performance status ≤ 2
  • Patient has fasting plasma glucose (FPG) ≤140 mg/dL (7.7 mmol/L) and glycosylated hemoglobin (HbA1c) ≤ 6.4% (both criteria have to be met)
  • Patient has adequate bone marrow, coagulation, liver and renal function

Exclusion Criteria:

  • patient has known hypersensitivity to alpelisib, fulvestrant or letrozole
  • Patient has received prior treatment with any PI3K inhibitors
  • Patient 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, non-melanoma 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
  • History of acute pancreatitis within 1 year of screening or past medical history of pancreatitis
  • Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria:

    • At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment
    • 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 (MRI or CT) during screening period and stable low dose of steroids for 2 weeks prior to initiating study treatment
  • Patient with severe liver impairment (Child Pugh score B/C)
  • Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs
  • Patient has documented pneumonitis which is active and requiring treatment
  • Patient has a history of Stevens-Johnson-Syndrome (SJS) or Toxic Epidermal Necroloysis (TEN)
  • Patient is concurrently using other anti-cancer therapy. All anti-cancer therapy must be discontinued prior to day one of study treatment.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Novartis Pharmaceuticals 1-888-669-6682 Novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111
Listed Location Countries  ICMJE Mexico,   Argentina,   Belgium,   Canada,   Chile,   Denmark,   France,   Germany,   India,   Israel,   Italy,   Japan,   Korea, Republic of,   Netherlands,   Singapore,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03056755
Other Study ID Numbers  ICMJE CBYL719X2402
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  ICMJE
Plan to Share IPD: Undecided
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Novartis
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP