Clinical trial NCT03056755: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: advanced breast cancer
PIK3CA
CDK 4/6 inhibitor
fulvestrant
letrozole
HR+
HER2-negative
post menopausal
pre-menopausal
aromatase inhibitor
endocrine treatment
AI
ET
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2017-02-17
Enrollment: 379
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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

Primary outcomes:
measure: Core Phase: Percentage of Participants Who Were Alive Without Disease Progression at 6 Months
timeFrame: At 6 months
Secondary outcomes:
measure: Core Phase: Progression Free Survival (PFS)
timeFrame: From date of first dose to date of first documented progression or death, up to 46 months
measure: Core Phase: Progression Free Survival on Next Line Treatment (PFS2)
timeFrame: From date of first dose to date of first documented progression on next-line therapy or death, up to approximately 55 months
measure: Core Phase: Overall Response Rate (ORR)
timeFrame: Up to 46 months
measure: Core Phase: Clinical Benefit Rate (CBR)
timeFrame: Up to 46 months
measure: Core Phase: Duration of Response (DOR)
timeFrame: From date of first documented response to first documented progression or death, up to 33.3 months
measure: Core Phase: Overall Survival (OS)
timeFrame: From date of first dose and up to approximately 55 months
measure: Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase
timeFrame: From end of core phase up to 12 months
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Anaheim
country: United States
facility: Kaiser Permanente Medical Group
state: California
city: Beverly Hills
country: United States
facility: Beverly Hills Cancer Center
state: California
city: Irvine
country: United States
facility: University of Calif Irvine Med Cntr
state: California
city: San Diego
country: United States
facility: Kaiser Permanent Southern Californi
state: California
city: San Francisco
country: United States
facility: UCSF
state: California
city: New Haven
country: United States
facility: Yale University Yale Cancer Center
state: Connecticut
city: Orlando
country: United States
facility: Advent Health Cancer Institute
state: Florida
city: Kansas City
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Louisville
country: United States
facility: University of Louisville James Graham Brown Cancer Center
state: Kentucky
city: Baltimore
country: United States
facility: Mercy Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Greater Baltimore Med Center Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Clinic
state: Massachusetts
city: Detroit
country: United States
facility: Josephine Ford Cancer Center
state: Michigan
city: Billings
country: United States
facility: St Vincent Frontier Cancer Center
state: Montana
city: Albuquerque
country: United States
facility: New Mexico Cancer Care Alliance
state: New Mexico
city: New York
country: United States
facility: Memorial Sloane Ketterin Cancer Ctr
state: New York
city: Cleveland
country: United States
facility: Uni Hosp of Cleveland Cancer Center
state: Ohio
city: Dallas
country: United States
facility: Texas Oncology
state: Texas
city: San Antonio
country: United States
facility: Cancer Care Centers of South Texas HOAST
state: Texas
city: San Antonio
country: United States
facility: UT Health San Antonio
state: Texas
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
city: Tacoma
country: United States
facility: Northwest Medical Specialists
state: Washington
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Santa Fe
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Sante Fe
city: La Rioja
country: Argentina
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Liege
country: Belgium
facility: Novartis Investigative Site
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Halifax
country: Canada
facility: Novartis Investigative Site
state: Nova Scotia
city: Kitchener
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Temuco
country: Chile
facility: Novartis Investigative Site
state: Araucania
city: Santiago
country: Chile
facility: Novartis Investigative Site
city: Santiago
country: Chile
facility: Novartis Investigative Site
city: Odense C
country: Denmark
facility: Novartis Investigative Site
city: Vejle
country: Denmark
facility: Novartis Investigative Site
city: Nice
country: France
facility: Novartis Investigative Site
state: Alpes Maritimes
city: Saint-Cloud
country: France
facility: Novartis Investigative Site
state: Hauts De Seine
city: Bordeaux
country: France
facility: Novartis Investigative Site
city: Caen
country: France
facility: Novartis Investigative Site
city: Lille Cedex
country: France
facility: Novartis Investigative Site
city: Lyon
country: France
facility: Novartis Investigative Site
city: Montpellier
country: France
facility: Novartis Investigative Site
city: Saint Herblain
country: France
facility: Novartis Investigative Site
city: Strasbourg
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Augsburg
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Erlangen
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Delhi
country: India
facility: Novartis Investigative Site
city: Petach Tikva
country: Israel
facility: Novartis Investigative Site
city: Ramat Gan
country: Israel
facility: Novartis Investigative Site
city: Rehovot
country: Israel
facility: Novartis Investigative Site
city: Tel Aviv
country: Israel
facility: Novartis Investigative Site
city: Ancona
country: Italy
facility: Novartis Investigative Site
state: AN
city: Bergamo
country: Italy
facility: Novartis Investigative Site
state: BG
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Osaka-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Jalisco
country: Mexico
facility: Novartis Investigative Site
city: Maastricht
country: Netherlands
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Salamanca
country: Spain
facility: Novartis Investigative Site
state: Castilla Y Leon
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Castellon
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Tainan
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Edinburgh
country: United Kingdom
facility: Novartis Investigative Site
state: Scotland
city: Sutton
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
city: Leicester
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Nottingham
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.