Study Assessing the Efficacy and Safety of Treatment With Alpelisib Plus Fulvestrant in Japanese Men and Postmenopausal Women With Advanced Breast Cancer

A Phase II Open-label, 2-Part, Multi-center Study of BYL719 (Alpelisib) in Combination With Fulvestrant for Men and Postmenopausal Women With PIK3CA Mutation Hormone Receptor (HR) Positive, HER2-negative, Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor (AI) Treatment in Japan

The purpose of this study is to assess the safety and efficacy of alpelisib plus fulvestrant in men and postmenopausal women with hormone receptor (HR) positive, human epidermal growth factor 2 (HER2)-negative, advanced breast cancer harboring a PIK3CA mutation in Japan, whose disease has progressed on or after aromatase inhibitor (AI) treatment regardless of prior CDK4/6 inhibitor use.

Study Overview

• Status: Active, not recruiting
• Conditions: Advanced Breast Cancer
• Intervention / Treatment: Drug: Alpelisib; Drug: Fulvestrant

Detailed Description

This is a Phase II open-label, 2-Part, multi-center study in Japan. The study will be conducted in two parts: Part 1 (Cohort 1) includes participants regardless of prior CDK4/6 inhibitor use and is designed to determine the recommended dose (RD), evaluate the tolerability and safety of alpelisib in combination with fulvestrant. Part 2 consists of 2 cohorts (the CDK4/6 inhibitor naive participants are in Cohort 2 and the CDK4/6 inhibitor pre-treated participants are in Cohort 3) which are designed to assess the efficacy and safety of alpelisib in combination with fulvestrant, will start once the RD of alpelisib is established.

Participants will be treated until disease progression, unacceptable toxicity, death or discontinuation from the study treatment for any other reason and will be followed for survival regardless of treatment discontinuation reason (except if consent is withdrawn or participant is lost to follow up).

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Kumamoto, Japan, 860-8556
    • Novartis Investigative Site
  • Niigata, Japan, 951-8566
    • Novartis Investigative Site
  • Aichi-ken
    • Nagoya, Aichi-ken, Japan, 464 8681
      • Novartis Investigative Site
    • Nagoya, Aichi-ken, Japan, 4668560
      • Novartis Investigative Site
    • Nagoya, Aichi-ken, Japan, 4678602
      • Novartis Investigative Site
  • Chiba
    • Kashiwa, Chiba, Japan, 277-8577
      • Novartis Investigative Site
  • Kanagawa
    • Isehara, Kanagawa, Japan, 259-1193
      • Novartis Investigative Site
    • Yokohama, Kanagawa, Japan, 241-8515
      • Novartis Investigative Site
  • Miyagi
    • Sendai, Miyagi, Japan, 9808574
      • Novartis Investigative Site
  • Osaka
    • Osaka, Osaka, Japan, 5418567
      • Novartis Investigative Site
    • Osaka, Osaka, Japan, 5400006
      • Novartis Investigative Site
    • Suita, Osaka, Japan, 565-0871
      • Novartis Investigative Site
  • Tokyo
    • Bunkyo Ku, Tokyo, Japan, 1138677
      • Novartis Investigative Site
    • Koto Ku, Tokyo, Japan, 135-8550
      • Novartis Investigative Site
    • Meguro-ku, Tokyo, Japan, 152-8902
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Japanese man or postmenopausal woman
• Participant has adequate tumor tissue for the analysis of PIK3CA mutational status by a Novartis designated laboratory.
• Participant has identified PIK3CA mutation (as determined by a Novartis designated laboratory)
• Participant has a histologically and/or cytologically confirmed diagnosis of ER+ and/or PgR+ breast cancer by local laboratory
• Participant has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH or SISH) test is required by local laboratory testing
• Participant has measurable disease, i.e., at least one measurable lesion as per RECIST 1.1
• Participant has advanced breast cancer
• Participant has ECOG performance status 0 or 1

Exclusion Criteria:

• Participant with symptomatic visceral disease or any disease burden that makes the participant ineligible for endocrine therapy per the investigator's best judgment
• Participant has received prior treatment;
• with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy), fulvestrant, any PI3K, mTOR or AKT inhibitor for Cohort 1 and 3
• with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy), fulvestrant, any PI3K, mTOR, AKT inhibitor or CDK 4/6 inhibitor for Cohort 2
• Participant has a known hypersensitivity to alpelisib or fulvestrant, or to any of the excipients of alpelisib or fulvestrant
• Participant with inflammatory breast cancer at screening
• Participant is concurrently using other anti-cancer therapy
• Participant has had surgery within 14 days prior to starting study drug or has not recovered from major side effects
• Participant with an established diagnosis at screening of diabetes mellitus type I or not controlled type II (based on FPG and HbA1c)
• Participant has currently documented pneumonitis /interstitial lung disease
• History of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis
• Participant with unresolved osteonecrosis of the jaw
• Participant has a history of severe cutaneous reactions

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1:CDK4/6 inhibitor naive or pre-treated (Part 1); Participants regardless of prior CDK4/6 inhibitor will be treated at escalating doses (200 mg, 250 mg and 300 mg, orally) of BYL719 in combination with Fulvestrant (500 mg, intramuscular).	Drug: Alpelisib; [Part 1] Alpelisib administered at 200 mg (DL 1), 250 mg (DL 2) or 300mg (DL 3) orally once daily on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28 day cycle. If DL 1 is tolerated, the alpelisib doses of 250 mg will be investigated. If DL 2 is tolerated, the alpelisib doses of 300 mg will be investigated. [Part 2] In the Part 2, participants will be enrolled into Cohort 2 (CDK4/6 inhibitor naive) and Cohort 3 (CDK4/6 inhibitor pre-treated) in parallel and alpelisib will be administered at the recommended dose identified in Part 1.; Other Names: BYL719; Drug: Fulvestrant; Fulvestrant is administered at a dose of 500 mg intramuscular on Cycle 1 Day 1, Day 15, and Day 1 of every cycle thereafter (where a cycle is 28 days).; Other Names: Faslodex
Experimental: Cohort 2: CDK4/6 inhibitor naive (Part 2); Participants who are CDK4/6 inhibitor naive will be treated with BYL719 at the recommended dose identified in Part 1 in combination with Fulvestrant (500 mg, intramuscular).	Drug: Alpelisib; [Part 1] Alpelisib administered at 200 mg (DL 1), 250 mg (DL 2) or 300mg (DL 3) orally once daily on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28 day cycle. If DL 1 is tolerated, the alpelisib doses of 250 mg will be investigated. If DL 2 is tolerated, the alpelisib doses of 300 mg will be investigated. [Part 2] In the Part 2, participants will be enrolled into Cohort 2 (CDK4/6 inhibitor naive) and Cohort 3 (CDK4/6 inhibitor pre-treated) in parallel and alpelisib will be administered at the recommended dose identified in Part 1.; Other Names: BYL719; Drug: Fulvestrant; Fulvestrant is administered at a dose of 500 mg intramuscular on Cycle 1 Day 1, Day 15, and Day 1 of every cycle thereafter (where a cycle is 28 days).; Other Names: Faslodex
Experimental: Cohort 3: CDK4/6 inhibitor pre-treated (Part 2); Participants who are CDK4/6 inhibitor pre-treated will be treated with BYL719 at the recommended dose identified in Part 1 in combination with Fulvestrant (500 mg, intramuscular).	Drug: Alpelisib; [Part 1] Alpelisib administered at 200 mg (DL 1), 250 mg (DL 2) or 300mg (DL 3) orally once daily on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28 day cycle. If DL 1 is tolerated, the alpelisib doses of 250 mg will be investigated. If DL 2 is tolerated, the alpelisib doses of 300 mg will be investigated. [Part 2] In the Part 2, participants will be enrolled into Cohort 2 (CDK4/6 inhibitor naive) and Cohort 3 (CDK4/6 inhibitor pre-treated) in parallel and alpelisib will be administered at the recommended dose identified in Part 1.; Other Names: BYL719; Drug: Fulvestrant; Fulvestrant is administered at a dose of 500 mg intramuscular on Cycle 1 Day 1, Day 15, and Day 1 of every cycle thereafter (where a cycle is 28 days).; Other Names: Faslodex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
[Part 1] The incidence of Dose Limiting Toxicities (DLTs) of alpelisib in combination with fulvestrant	A DLT is defined as an AE or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 2 cycles (the first 56 days) of treatment with alpelisib in combination with fulvestrant and meets any of the criteria specified in the protocol .	From Cycle 1 Day 1 to Cycle 2 Day 28 (Cycle = 28 days)
[Part 2] Overall Response Rate (ORR) in CDK4/6 inhibitor naive participants	ORR is defined as the proportion of participants with best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) based on local investigator assessment per RECIST 1.1.	Up to approximately 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
[Part 1] Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)	Safety is determined by incidence, type, and severity of adverse events per CTCAE v4.03 criteria including changes in laboratory values, vital signs, liver assessments, renal and cardiac assessments.	Up to approximately 37 months
[Part 1] Number of participants with dose adjustments	The number of participants with dose adjustments (reductions, interruption, or permanent discontinuation) and the reasons	Up to approximately 37 months
[Part 1] Dose intensity for alpelisib and fulvestrant	The dose intensity (computed as the ratio of actual cumulative dose received and actual duration of exposure) and the relative dose intensity (computed as the ratio of dose intensity and planned dose intensity)	Up to approximately 37 months
[Part 1] Duration of exposure for alpelisib and fulvestrant	The duration of exposure (in months) to alpelisib and fulvestrant	Up to approximately 37 months
[Part 1] Plasma concentrations of alpelisib in combination with fulvestrant	Summary statistics of alpelisib plasma concentrations by time point and dose level	Cycle 1 Day 8 (pre-dose), 15 (pre-dose, post-dose 1 hour, 3 hours) and Day 1 of Cycles 2, 4, 6, 8 (pre-dose) (Cycle = 28 days)
[Part 2] Overall Response Rate (ORR) for CDK4/6 inhibitor pre-treated participants	ORR is defined as the proportion of participants with best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) based on local investigator assessment per RECIST 1.1.	Up to approximately 36 months
[Part 2] Progression Free Survival (PFS)	PFS is defined as the time from the date of first administration of study treatment until the date of the first documented progression or death due to any cause. PFS will be assessed based on local investigator assessment per RECIST 1.1.	Up to approximately 36 months
[Part 2] Overall Survival (OS)	OS is defined as the time from date of first administration of study treatment until date of death due to any cause.	Up to approximately 60 months
[Part 2] Clinical Benefit Rate (CBR)	CBR is defined as the proportion of participants with a best overall response of confirmed CR, or confirmed PR, or an overall response of confirmed stable disease (SD), lasting for a duration of at least 24 weeks. CR, PR, and SD are defined based on local investigator assessment per RECIST 1.1.	Up to approximately 36 months
[Part 2] Duration of Response (DOR)	DOR only applies to participants whose best overall response is CR or PR based on local investigator assessment per RECIST 1.1. The start date is the date of first documented response of CR or PR (i.e. the start date of response, not the date when response was confirmed), and the end date is defined as the date of the first documented progression or death due to underlying cancer.	Up to approximately 36 months
[Part 2] Time to Response (TTR)	TTR is defined as the time from the date of first administration of study treatment until the date of the first documented response of either CR or PR, which must be subsequently confirmed (although date of initial response is used, not date of confirmation).	Up to approximately 36 months
[Part 2] Time to definitive deterioration of Eastern Cooperative Oncology Group (ECOG) performance status	Time to definitive deterioration in ECOG performance status is defined as the time from the date of first administration to the date when ECOG performance status has definitively deteriorated by at least one category compared with baseline. Deterioration is considered definitive if there is no subsequent improvement in ECOG performance status back to the baseline category or above.	Up to approximately 36 months
[Part 2] Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)	Incidence, type, and severity of adverse events per CTCAE v4.03 criteria including changes in laboratory values, vital signs, liver assessments, renal and cardiac assessments	Up to approximately 37 months
[Part 2] Number of participants with dose adjustments	The number and percentage of participants with dose interruptions and dose reductions	Up to approximately 37 months
[Part 2] Dose intensity for alpelisib and fulvestrant	The dose intensity (computed as the ratio of actual cumulative dose received and actual duration of exposure) and the relative dose intensity (computed as the ratio of dose intensity and planned dose intensity)	Up to approximately 37 months
[Part 2] Duration of exposure for alpelisib and fulvestrant	The duration of exposure (in months) to alpelisib and fulvestrant	Up to approximately 37 months
[Part 2] Plasma concentrations of alpelisib in combination with fulvestrant	Summary statistics of alpelisib plasma concentrations by time point and dose level	Cycle 1 Day 8 (pre-dose), 15 (pre-dose, post-dose 1 hour, 3 hours) and Day 1 of Cycles 2, 4, 6, 8 (pre-dose) (Cycle= 28 days)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2021
• Primary Completion (Estimated): February 26, 2027
• Study Completion (Estimated): February 27, 2027

Study Registration Dates

• First Submitted: August 19, 2020
• First Submitted That Met QC Criteria: August 19, 2020
• First Posted (Actual): August 24, 2020

Study Record Updates

• Last Update Posted (Actual): April 8, 2026
• Last Update Submitted That Met QC Criteria: April 7, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: open-label; HR+; Fulvestrant; HER2-negative; Advanced breast cancer; PIK3CA mutation; Alpelisib; Part 1; Part 2; Japanese population
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Estradiol; Estrenes; Estranes; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Fulvestrant; Alpelisib
• Other Study ID Numbers: CBYL719C1201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No