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

JRCT ID: jRCT2080225342

Registered date:25/08/2020

Basic Information

• Recruitment status: completed
• Health condition(s) or Problem(s) studied: Advanced Breast Cancer
• Date of first enrollment: 26/01/2021
• Target sample size: 50
• Countries of recruitment: Japan
• Study type: Interventional

Intervention(s)

Drug: Alpelisib (BYL719)
[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.

Drug: Fulvestrant (Faslodex)
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).

Outcome(s)

Primary Outcome

[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 .
[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.

Secondary Outcome

1.[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.

2.[Part 1] Number of participants with dose adjustments
The number of participants with dose adjustments (reductions, interruption, or permanent discontinuation) and the reasons

3.[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)

4.[Part 1] Duration of exposure for alpelisib and fulvestrant
The duration of exposure (in months) to alpelisib and fulvestrant

5.[Part 1] Plasma concentrations of alpelisib in combination with fulvestrant
Summary statistics of alpelisib plasma concentrations by time point and dose level

6.[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.

7.[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.

8.[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.

9.[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.

10.[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.

11.[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).

12.[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.

13.[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

14.[Part 2] Number of participants with dose adjustments
The number and percentage of participants with dose interruptions and dose reductions

15.[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)

16.[Part 2] Duration of exposure for alpelisib and fulvestrant
The duration of exposure (in months) to alpelisib and fulvestrant

17.[Part 2] Plasma concentrations of alpelisib in combination with fulvestrant
Summary statistics of alpelisib plasma concentrations by time point and dose level

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include 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

Exclude 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

Related Information

• Primary Sponsor: Novartis Pharma. K.K.
• Secondary ID(s): NCT04524000,JapicCTI-205438