Study to Assess the Efficacy and Safety of Alpelisib Plus Fulvestrant in Participants With HR-postitive (HR+), HER2-negative, Advanced Breast Cancer After Treatment With a CDK4/6 Inhibitor and an Aromatase Inhibitor. (EPIK-B5)

• ClinicalTrials.gov Identifier: NCT05038735
• Recruitment Status: Recruiting
• First Posted: September 9, 2021
• Last Update Posted: May 7, 2024
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: September 1, 2021
• First Posted Date: September 9, 2021
• Last Update Posted Date: May 7, 2024
• Actual Study Start Date: November 29, 2021
• Estimated Primary Completion Date: August 22, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 1, 2021)

Progression-free survival (PFS) based on BIRC assessments and using RECIST v1.1 criteria [ Time Frame: From randomization to date of the first documented progression or death due to any cause, assessed up to a maximum duration of 60 months. ]

To determine whether treatment with alpelisib plus fulvestrant prolongs progression-free survival (PFS) compared to treatment with placebo plus fulvestrant. PFS is the defined as the time from randomization to date of randomization to the date of the first documented progression as per BIRC criteria using RECIST v1.1 or death due to any cause, whichever comes first.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 1, 2021)

• Overall survival (OS) [ Time Frame: From the date of randomization to the date of death up to a maximum duration of 60 months ]
  To determine whether treatment with alpelisib plus fulvestrant prolongs overall survival (OS) compared to treatment with placebo plus fulvestrant. OS is defined as the time from randomization to the date of death due to any cause
• Overall response rate (ORR) with confirmed response based on BIRC assessments and using RECIST v1.1 criteria [ Time Frame: From the date of randomization up to a maximum duration of 60 months ]
  To evaluate alpelisib plus fulvestrant compared to placebo plus fulvestrant, with regards to objective response by RECIST 1.1 criteria. Overall response rate (ORR) with confirmed response is defined as the proportion of participants with best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR), as per BIRC and according to RECIST 1.1
• Clinical benefit rate (CBR) with confirmed response based on BIRC assessments and using RECIST v1.1 criteria [ Time Frame: From the date of randomization up to a maximum duration of 60 months ]
  To evaluate alpelisib plus fulvestrant compared to placebo plus fulvestrant, with regards to objective response by RECIST 1.1 criteria. CBR with confirmed response is defined as the proportion of participants with a best overall response of confirmed CR or PR, or SD lasting for a duration of at least 24 weeks. CR, PR and SD are defined as per BIRC review according to RECIST 1.1
• Duration of response (DOR) with confirmed response based on BIRC assessments and using RECIST v1.1 criteria [ Time Frame: From first documented response to the date of first progression or deaths, up to a maximum duration of 60 months ]
  To evaluate alpelisib plus fulvestrant compared to placebo plus fulvestrant, with regards to objective response by RECIST 1.1 criteria. Duration of response (DOR) with confirmed response only applies to participants whose best overall response is confirmed complete response (CR) or confirmed partial response (PR) according to RECIST 1.1 based on tumor response data per BIRC review. The start date is the date of first documented response of CR or PR and the end date is defined as the date of the first documented progression or death due to underlying cancer.
• Time to response (TTR) based on BIRC assessments and using RECIST v1.1 criteria [ Time Frame: From the date of randomization to the first documented response up to a maximum duration of 60 months ]
  To evaluate alpelisib plus fulvestrant compared to placebo plus fulvestrant, with regards to objective response by RECIST 1.1 criteria. Time to response (TTR) is defined as the time from the date of randomization to the first documented response of either complete response (CR) or partial response (PR), which must be subsequently confirmed. CR and PR are based on tumor response data as per BIRC review and according to RECIST 1.1
• PFS based on BIRC assessment and using RECIST v1.1 criteria for participants by PIK3CA mutation status [ Time Frame: From the date of randomization up to a maximum duration of 60 months ]
  To evaluate the association between PIK3CA mutation status with PFS upon treatment with alpelisib. PFS is the defined as the time from randomization to date of randomization to the date of the first documented progression as per BIRC criteria using RECIST v1.1 or death due to any cause, whichever comes first. Results will be presented by PIK3CA mutation status measured in circulating tumor deoxyribonucleic acid (ctDNA) collected at baseline.
• Time to definitive deterioration of Eastern Cooperative Oncology Group (ECOG) performance status (PS) from baseline [ Time Frame: From the date of randomization up to maximum duration of 60 months ]
  To evaluate treatment with alpelisib plus fulvestrant compared to placebo plus fulvestrant, with respect to time to deterioration of ECOG performance status. Time to definitive deterioration in ECOG PS is defined as the time from the date of randomization to the date when ECOG PS has definitively deteriorated by at least one category compared with baseline. Deterioration is considered definitive if there is no subsequent improvement in ECOG PS back to the baseline category or above.
• Time to definitive (10%) deterioration in the global health status/Quality of Life (QoL) and symptom scale scores of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30-item Core Module (EORTC QLQ-C30) [ Time Frame: From the date of randomization up to maximum duration of 60 months ]
  To evaluate patient-reported outcomes of alpelisib plus fulvestrant compared to placebo and fulvestrant. Time from date of randomization to date of event, defined as at least a 10% worsening from baseline with no later improvement above this threshold observed during the course of the treatment or until death due to any cause, in the global health status/QOL and symptom scale scores of EORTC QLQ-C30, a questionnaire to assess the quality of life of cancer patients. The questionnaire contains 30 items and is composed of both multi-item scales and single-item measures based on the patient's experience over the past week. This includes 5 functional scales, 3 symptom scales, 6 single items and a global health status/QoL scale. The scales and single-item measures range in score from 0 - 100. A high scale score represents a higher response level.
• Change from baseline in global health status/QoL and symptom scale scores of the EORTC QLQ-C30 [ Time Frame: From the date of randomization up to maximum duration of 60 months ]
  To evaluate patient-reported outcomes of alpelisib plus fulvestrant compared to placebo and fulvestrant. Change from baseline in the domain scores, health states, overall health status, and index values at the time of each assessment. EORTC QLQ-C30 is a questionnaire to assess the quality of life of cancer patients. The questionnaire contains 30 items and is composed of both multi-item scales and single-item measures based on the patient's experience over the past week. This includes 5 functional scales, 3 symptom scales, 6 single items and a global health status/QoL scale. The scales and single-item measures range in score from 0 - 100. A high scale score represents a higher response level.
• Time from randomization to objective tumour progression on next line treatment or death from any cause (PFS2) [ Time Frame: From the date of randomization up to maximum duration of 60 months ]
  To explore the long-term benefit intermediate to PFS and OS. PFS2 is defined as time from date of randomization to the first documented progression on nextline therapy or death from any cause, whichever occurs first. Disease progression will be determined based on investigator assessment of progression on next-line therapy.

• 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 to Assess the Efficacy and Safety of Alpelisib Plus Fulvestrant in Participants With HR-postitive (HR+), HER2-negative, Advanced Breast Cancer After Treatment With a CDK4/6 Inhibitor and an Aromatase Inhibitor.
• Official Title: EPIK-B5: A Phase III, Randomized, Double-blind, Placebo-controlled Study of Alpelisib in Combination With Fulvestrant for Men and Postmenopausal Women With HR-positive, HER2-negative Advanced Breast Cancer With a PIK3CA Mutation, Who Progressed on or After Aromatase Inhibitor and a CDK4/6 Inhibitor
• Brief Summary: The purpose of this study is to complement Study CBYL719C2301 (SOLAR-1) and obtain more comprehensive data on the efficacy and safety of alpelisib (BYL719) in combination with fulvestrant compared with placebo plus fulvestrant in men or postmenopausal women with HR-positive, HER2-negative advanced breast cancer with a PIK3CA mutation who progressed or relapsed on or after treatment with an AI plus a CDK4/6 inhibitor.

Detailed Description

This is a Phase III, randomized, double-blind, placebo-controlled, international, multi-center trial. Approximately 234 men and postmenopausal women will be randomized to either alpelisib plus fulvestrant or alpelisib-matching placebo plus fulvestrant. Randomization will follow a 1:1 randomization ratio and be stratified by presence of lung and/or liver metastases (yes vs. no) and setting at last prior CDK4/6 inhibitor therapy (adjuvant vs metastatic).

Study treatment with alpelisib plus fulvestrant or alpelisib-matching placebo plus fulvestrant will be initiated on Cycle 1 Day 1, and will continue until disease progression per RECIST v1.1 as per BIRC assessment, start of new antineoplastic therapy, death, lost to follow-up, or withdrawal of consent. A cycle is defined as 28 days.

Participants randomized to the alpelisib-matching placebo plus fulvestrant arm who have disease progression per RECIST v1.1 as assessed by BIRC will have the option to crossover to be treated with alpelisib plus fulvestrant.

Unblinding a single participant at a site will be permitted after disease progression confirmed by BIRC after discussion with the Novartis team to determine eligibility for cross-over to treatment with alpelisib plus fulvestrant.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: Alpelisib
  Alpelisib (tablets) administered at 300mg orally once daily on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28 day cycle.
• Drug: Fulvestrant
  Fulvestrant (prefilled syringe) 500mg administered intramuscularly at Cycle 1 Day 1 and 15 and then at Day 1 of each subsequent cycle (each cycle is 28 days).
• Drug: Alpelisib-matching placebo
  Alpelisib-matching placebo (tablets) administered orally once daily on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28 day cycle.

Study Arms

• Experimental: Alpelisib plus fulvestrant
  Alpelisib 300 mg orally once daily on a continuous dosing schedule, in a 28-day cycle + fulvestrant 500 mg as intramuscular injection on Cycle 1 Day 1 and 15, and on Day 1 on every Cycle thereafter, in a 28 days cycle.
  Interventions:

  • Drug: Alpelisib
  • Drug: Fulvestrant
• Placebo Comparator: Alpelisib-matching placebo plus fulvestrant
  Alpelisib-matching placebo orally once daily on a continuous dosing schedule, in a 28-day cycle + fulvestrant 500 mg as intramuscular injection on Cycle 1 Day 1 and 15 and on Day 1 on every Cycle thereafter, in a 28 days cycle. Participants who have disease progression per RECIST v1.1 as assessed by BIRC will have the option to crossover to be treated with alpelisib plus fulvestrant
  Interventions:

  • Drug: Fulvestrant
  • Drug: Alpelisib-matching placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 1, 2021): 234
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 23, 2027
• Estimated Primary Completion Date: August 22, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Participant is an adult ≥ 18 years old at the time of informed consent and has signed informed consent before any trial related activities and according to local guidelines.
• If female, then the participant must be in postmenopausal status. Postmenopausal status is defined either by: prior bilateral oophorectomy, age ≥60 or age <60 and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range per local normal range.
• 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 (Fluorescent in situ hybridization (FISH), Chromogenic in situ hybridization (CISH), or Silver-enhanced in situ hybridization (SISH)) test is required by local laboratory testing.
• Participant has at least one measurable lesion as per RECIST v1.1 criteria as assessed by Investigator (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation).
• Participant has recurrence or progression of disease during or after combined AI (i.e. letrozole, anastrozole, exemestane) and CDK4/6 inhibitor therapy. The combined AI and CDK4/6 inhibitor therapy does not need to be the latest treatment regimen (including adjuvant setting).
• Participant has received ≤2 prior lines of systemic therapies overall in the metastatic setting, of which a maximum of 1 line of prior treatment with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy).
• Participant must show the presence of a PIK3CA mutation(s) determined in tumor tissue prior ro enrollment either by a Novartis designated laboratory or in tumor tissue or plasma ctDNA by a local laboratory using a Food and Drug Administration (FDA)-approved PIK3CA Companion Diagnostics (CDx) test for alpelisib or the CE-IVD QIAGEN Therascreen® PIK3CA RGQ PCR test.

Exclusion Criteria:

• Participant with symptomatic visceral disease that makes the participant ineligible for endocrine therapy (ET) per the investigator's best judgment.
• Participant who relapsed with documented evidence of progression more than 12 months from completion of (neo)adjuvant endocrine/endocrine-based therapy with no treatment for metastatic disease
• Participant has received prior treatment with fulvestrant, any oral selective estrogen receptor degrader (SERDs), any Phosphatidylinositol-3-Kinase (PI3K), mammalian Target of Rapamycin (mTOR) or Protein Kinase B (AKT) inhibitor

Other Inclusion and Exclusion Criteria do apply

Sex/Gender

• Sexes Eligible for Study: All

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

Contacts

Contact: Novartis Pharmaceuticals; +41613241111; novartis.email@novartis.com

Contact: Novartis Pharmaceuticals

• Listed Location Countries: Belgium, Bulgaria, Canada, Czechia, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Poland, Portugal, Romania, Slovakia, Spain

Administrative Information

• NCT Number: NCT05038735
• Other Study ID Numbers: CBYL719C2303; 2021-001966-39 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

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

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: May 2024