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.
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1. 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.
Secondary outcome:
1. 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
2. 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
3. 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
4. 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.
5. 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
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
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.
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
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.
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).
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.
Quelle: ClinicalTrials.gov
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"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."
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