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

• ClinicalTrials.gov Identifier: NCT04524000
• Recruitment Status: Recruiting
• First Posted: August 24, 2020
• Last Update Posted: December 19, 2020
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: August 19, 2020
• First Posted Date: August 24, 2020
• Last Update Posted Date: December 19, 2020
• Actual Study Start Date: November 20, 2020
• Estimated Primary Completion Date: June 30, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 19, 2020)

• [Part 1] The incidence of Dose Limiting Toxicities (DLTs) of alpelisib in combination with fulvestrant [ Time Frame: From Cycle 1 Day 1 to Cycle 2 Day 28 (Cycle = 28 days) ]
  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 [ Time Frame: Up to approximately 36 months ]
  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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 19, 2020)

• [Part 1] Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to approximately 37 months ]
  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 [ Time Frame: Up to approximately 37 months ]
  The number of participants with dose adjustments (reductions, interruption, or permanent discontinuation) and the reasons
• [Part 1] Dose intensity for alpelisib and fulvestrant [ Time Frame: Up to approximately 37 months ]
  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 [ Time Frame: Up to approximately 37 months ]
  The duration of exposure (in months) to alpelisib and fulvestrant
• [Part 1] Plasma concentrations of alpelisib in combination with fulvestrant [ 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) ]
  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 [ Time Frame: Up to approximately 36 months ]
  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) [ Time Frame: Up to approximately 36 months ]
  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) [ Time Frame: Up to approximately 60 months ]
  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) [ Time Frame: Up to approximately 36 months ]
  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) [ Time Frame: Up to approximately 36 months ]
  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) [ Time Frame: Up to approximately 36 months ]
  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 Frame: Up to approximately 36 months ]
  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) [ Time Frame: Up to approximately 37 months ]
  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 [ Time Frame: Up to approximately 37 months ]
  The number and percentage of participants with dose interruptions and dose reductions
• [Part 2] Dose intensity for alpelisib and fulvestrant [ Time Frame: Up to approximately 37 months ]
  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 [ Time Frame: Up to approximately 37 months ]
  The duration of exposure (in months) to alpelisib and fulvestrant
• [Part 2] Plasma concentrations of alpelisib in combination with fulvestrant [ 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) ]
  Summary statistics of alpelisib plasma concentrations by time point and dose level

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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).

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Part 1 of the study has a "Single group" design and the Part 2 has a "Parallel" design.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Advanced Breast Cancer

Intervention

• 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 Name: 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 Name: Faslodex

Study Arms

• 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).
  Interventions:

  • Drug: Alpelisib
  • Drug: Fulvestrant
• 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).
  Interventions:

  • Drug: Alpelisib
  • Drug: Fulvestrant
• 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).
  Interventions:

  • Drug: Alpelisib
  • Drug: Fulvestrant

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 19, 2020): 50
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 1, 2027
• Estimated Primary Completion Date: June 30, 2023 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Novartis Pharmaceuticals; +81337978748; novartis.email@novartis.com

Contact: Novartis Pharmaceuticals

• Listed Location Countries: Japan

Administrative Information

• NCT Number: NCT04524000
• Other Study ID Numbers: CBYL719C1201
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Yes

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

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Study Sponsor: Novartis Pharmaceuticals
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: December 2020