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

Primary Purpose

Advanced Breast Cancer

Status
Active
Phase
Phase 2
Locations
Japan
Study Type
Interventional
Intervention
Alpelisib
Fulvestrant
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Advanced Breast Cancer focused on measuring HR+, HER2-negative, PIK3CA mutation, Advanced breast cancer, Alpelisib, Fulvestrant, open-label, Part 1, Part 2, Japanese population

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Cohort 1:CDK4/6 inhibitor naive or pre-treated (Part 1)

Cohort 2: CDK4/6 inhibitor naive (Part 2)

Cohort 3: CDK4/6 inhibitor pre-treated (Part 2)

Arm Description

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).

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).

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).

Outcomes

Primary Outcome Measures

[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 Measures

[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.
[Part 1] Number of participants with dose adjustments
The number of participants with dose adjustments (reductions, interruption, or permanent discontinuation) and the reasons
[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)
[Part 1] Duration of exposure for alpelisib and fulvestrant
The duration of exposure (in months) to alpelisib and fulvestrant
[Part 1] Plasma concentrations of alpelisib in combination with fulvestrant
Summary statistics of alpelisib plasma concentrations by time point and dose level
[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.
[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.
[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.
[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.
[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.
[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).
[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.
[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
[Part 2] Number of participants with dose adjustments
The number and percentage of participants with dose interruptions and dose reductions
[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)
[Part 2] Duration of exposure for alpelisib and fulvestrant
The duration of exposure (in months) to alpelisib and fulvestrant
[Part 2] Plasma concentrations of alpelisib in combination with fulvestrant
Summary statistics of alpelisib plasma concentrations by time point and dose level

Full Information

First Posted
August 19, 2020
Last Updated
September 5, 2023
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT04524000
Brief Title
Study Assessing the Efficacy and Safety of Treatment With Alpelisib Plus Fulvestrant in Japanese Men and Postmenopausal Women With Advanced Breast Cancer
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
November 20, 2020 (Actual)
Primary Completion Date
January 31, 2025 (Anticipated)
Study Completion Date
January 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced Breast Cancer
Keywords
HR+, HER2-negative, PIK3CA mutation, Advanced breast cancer, Alpelisib, Fulvestrant, open-label, Part 1, Part 2, Japanese population

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Part 1 of the study has a "Single group" design and the Part 2 has a "Parallel" design.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1:CDK4/6 inhibitor naive or pre-treated (Part 1)
Arm Type
Experimental
Arm Description
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).
Arm Title
Cohort 2: CDK4/6 inhibitor naive (Part 2)
Arm Type
Experimental
Arm Description
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).
Arm Title
Cohort 3: CDK4/6 inhibitor pre-treated (Part 2)
Arm Type
Experimental
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Alpelisib
Other Intervention Name(s)
BYL719
Intervention Description
[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.
Intervention Type
Drug
Intervention Name(s)
Fulvestrant
Other Intervention Name(s)
Faslodex
Intervention Description
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).
Primary Outcome Measure Information:
Title
[Part 1] The incidence of Dose Limiting Toxicities (DLTs) of alpelisib in combination with fulvestrant
Description
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 .
Time Frame
From Cycle 1 Day 1 to Cycle 2 Day 28 (Cycle = 28 days)
Title
[Part 2] Overall Response Rate (ORR) in CDK4/6 inhibitor naive participants
Description
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.
Time Frame
Up to approximately 36 months
Secondary Outcome Measure Information:
Title
[Part 1] Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
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.
Time Frame
Up to approximately 37 months
Title
[Part 1] Number of participants with dose adjustments
Description
The number of participants with dose adjustments (reductions, interruption, or permanent discontinuation) and the reasons
Time Frame
Up to approximately 37 months
Title
[Part 1] Dose intensity for alpelisib and fulvestrant
Description
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)
Time Frame
Up to approximately 37 months
Title
[Part 1] Duration of exposure for alpelisib and fulvestrant
Description
The duration of exposure (in months) to alpelisib and fulvestrant
Time Frame
Up to approximately 37 months
Title
[Part 1] Plasma concentrations of alpelisib in combination with fulvestrant
Description
Summary statistics of alpelisib plasma concentrations by time point and dose level
Time Frame
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)
Title
[Part 2] Overall Response Rate (ORR) for CDK4/6 inhibitor pre-treated participants
Description
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.
Time Frame
Up to approximately 36 months
Title
[Part 2] Progression Free Survival (PFS)
Description
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.
Time Frame
Up to approximately 36 months
Title
[Part 2] Overall Survival (OS)
Description
OS is defined as the time from date of first administration of study treatment until date of death due to any cause.
Time Frame
Up to approximately 60 months
Title
[Part 2] Clinical Benefit Rate (CBR)
Description
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.
Time Frame
Up to approximately 36 months
Title
[Part 2] Duration of Response (DOR)
Description
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.
Time Frame
Up to approximately 36 months
Title
[Part 2] Time to Response (TTR)
Description
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).
Time Frame
Up to approximately 36 months
Title
[Part 2] Time to definitive deterioration of Eastern Cooperative Oncology Group (ECOG) performance status
Description
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.
Time Frame
Up to approximately 36 months
Title
[Part 2] Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
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
Time Frame
Up to approximately 37 months
Title
[Part 2] Number of participants with dose adjustments
Description
The number and percentage of participants with dose interruptions and dose reductions
Time Frame
Up to approximately 37 months
Title
[Part 2] Dose intensity for alpelisib and fulvestrant
Description
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)
Time Frame
Up to approximately 37 months
Title
[Part 2] Duration of exposure for alpelisib and fulvestrant
Description
The duration of exposure (in months) to alpelisib and fulvestrant
Time Frame
Up to approximately 37 months
Title
[Part 2] Plasma concentrations of alpelisib in combination with fulvestrant
Description
Summary statistics of alpelisib plasma concentrations by time point and dose level
Time Frame
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)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Nagoya-city
State/Province
Aichi
ZIP/Postal Code
467-8602
Country
Japan
Facility Name
Novartis Investigative Site
City
Nagoya
State/Province
Aichi
ZIP/Postal Code
464 8681
Country
Japan
Facility Name
Novartis Investigative Site
City
Nagoya
State/Province
Aichi
ZIP/Postal Code
466 8560
Country
Japan
Facility Name
Novartis Investigative Site
City
Kashiwa
State/Province
Chiba
ZIP/Postal Code
277 8577
Country
Japan
Facility Name
Novartis Investigative Site
City
Maebashi city
State/Province
Gunma
ZIP/Postal Code
371 8511
Country
Japan
Facility Name
Novartis Investigative Site
City
Isehara
State/Province
Kanagawa
ZIP/Postal Code
259-1193
Country
Japan
Facility Name
Novartis Investigative Site
City
Yokohama-city
State/Province
Kanagawa
ZIP/Postal Code
241-8515
Country
Japan
Facility Name
Novartis Investigative Site
City
Kumamoto City
State/Province
Kumamoto
ZIP/Postal Code
860-8556
Country
Japan
Facility Name
Novartis Investigative Site
City
Sendai city
State/Province
Miyagi
ZIP/Postal Code
980 8574
Country
Japan
Facility Name
Novartis Investigative Site
City
Osaka-city
State/Province
Osaka
ZIP/Postal Code
540-0006
Country
Japan
Facility Name
Novartis Investigative Site
City
Osaka-city
State/Province
Osaka
ZIP/Postal Code
541-8567
Country
Japan
Facility Name
Novartis Investigative Site
City
Suita
State/Province
Osaka
ZIP/Postal Code
565 0871
Country
Japan
Facility Name
Novartis Investigative Site
City
Bunkyo ku
State/Province
Tokyo
ZIP/Postal Code
113-8677
Country
Japan
Facility Name
Novartis Investigative Site
City
Koto ku
State/Province
Tokyo
ZIP/Postal Code
135 8550
Country
Japan
Facility Name
Novartis Investigative Site
City
Meguro-ku
State/Province
Tokyo
ZIP/Postal Code
152-8902
Country
Japan
Facility Name
Novartis Investigative Site
City
Niigata
ZIP/Postal Code
951-8566
Country
Japan

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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

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

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