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)

• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

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

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Drug: alpelisib; Drug: fulvestrant; Drug: letrozole; Drug: Goserelin; Drug: Leuprolide	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 340 participants
• 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
• 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
• Estimated Primary Completion Date: November 30, 2020
• Estimated Study Completion Date: November 30, 2021

Arms and Interventions

Arm	Intervention/treatment
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)	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
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	Drug: alpelisib; 300 mg; oral; once daily; Other Name: BYL719; 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)
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.	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

Outcome Measures

Primary Outcome Measures :

1. 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

Secondary Outcome Measures :

1. 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
2. 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
3. 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
4. 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
5. 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
6. 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Novartis Pharmaceuticals; 1-888-669-6682; Novartis.email@novartis.com

Contact: Novartis Pharmaceuticals; +41613241111

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Sponsors and Collaborators

Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03056755 History of Changes
• Other Study ID Numbers: CBYL719X2402
• First Posted: February 17, 2017
• Last Update Posted: August 5, 2019
• Last Verified: August 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

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

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

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

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Letrozole; Fulvestrant; Leuprolide; Goserelin; Aromatase Inhibitors; Antineoplastic Agents; 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