Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant in Men and Postmenopausal Women With Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment.

Novartis Pharmaceuticals572 enrolled

Overview

To determine whether treatment with alpelisib plus fulvestrant prolonged progression-free survival (PFS) compared to fulvestrant and placebo in men and postmenopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor-2 (HER2)-negative advanced breast cancer, who received prior treatment with an aromatase Inhibitor (AI) either as (neo)adjuvant or for advanced disease.

This was a randomized, double-blind, placebo-controlled, international multicenter Phase III study that evaluated the efficacy and safety of treatment with alpelisib plus fulvestrant versus placebo plus fulvestrant in men and postmenopausal women with HR-positive, HER2-negative advanced breast cancer which had progressed on or after AI treatment. Subjects were allocated to either the PIK3CA mutant or PIK3CA non-mutant cohort, based on central testing of hotspot-mutations in tumor tissue. Subjects with unknown results were not eligible. Within each cohort, subjects were randomized in a 1:1 ratio to receive either alpelisib 300 mg orally once daily (q.d.), in combination with fulvestrant 500 mg intramuscular (i.m.) on Days 1 and 15 of Cycle 1 and Day 1 of a 28-day cycle thereafter, or placebo daily in combination with fulvestrant 500 mg following the same treatment regimen. Subjects were treated until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason. All subjects who discontinued study treatment were followed for safety, until 30 days after last study treatment administration, except in the case of death, loss to follow-up, or withdrawal of consent. Subjects who discontinued study treatment for reasons other than disease progression or withdrawal of consent, were followed until disease progression, death, withdrawal of consent, loss to follow-up, or subject/guardian decision (post-treatment efficacy follow-up). Finally, all subjects were followed for survival after discontinuation of study treatment and tumor evaluations until the subject's death, loss to follow-up, or withdrawal of consent for survival follow-up (post-treatment survival follow-up)

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Eligibility

Sex: ALLMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

Inclusion Criteria: * If female, the patient was postmenopausal. * The patient had identified PIK3CA status. * Patients could be: * Relapsed with documented evidence of progression while on (neo)adjuvant endocrine therapy or within 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for metastatic disease. * Relapsed with documented evidence of progression more than 12 months from completion of (neo)adjuvant endocrine therapy and then subsequently progressed with documented evidence of progression while on or after only one line of endocrine therapy for metastatic disease. * Newly diagnosed with advanced breast cancer, then relapsed with documented evidence of progression while on or after only one line of endocrine therapy. * The patient had recurrence or progression of the disease during or after AI therapy (i.e., letrozole, anastrozole, exemestane). * The patient had a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive breast cancer by a local laboratory and had HER2 negative breast cancer. * The patient had either measurable disease per RECIST 1.1 criteria or at least one predominantly lytic bone lesion present. * The patient had adequate bone marrow function. Exclusion Criteria: * The patient had symptomatic visceral disease or any disease burden that made the patient ineligible for endocrine therapy per the investigator's best judgment. * The patient had received prior treatment with chemotherapy (except for neoadjuvant/adjuvant chemotherapy), fulvestrant, any PI3K, mTOR, or AKT inhibitor (pre-treatment with CDK4/6 inhibitors was allowed). * The patient had inflammatory breast cancer at screening. * Patients had Child pugh score B or C. * Patients had an established diagnosis of diabetes mellitus type I or uncontrolled type II. * The patient had Eastern Cooperative Oncology Group (ECOG) performance status 2 or more. * The patient had CNS involvement unless he/she was at least 4 weeks from prior therapy completion to starting the study treatment and had a stable CNS tumor at the time of screening and was not receiving steroids and/or enzyme-inducing antiepileptic medications for brain metastases. * The patient had participated in a prior investigational study within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever was longer. * The patient had a history of acute pancreatitis within 1 year of screening or a past medical history of chronic pancreatitis. * The patient relapsed with documented evidence of progression more than 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for metastatic disease.

Locations (197)

Ironwood Cancer and Research Centers

Chandler, Arizona, United States

Mayo Clinic Arizona

Scottsdale, Arizona, United States

Highlands Oncology Group

Fayetteville, Arkansas, United States

Beverly Hills Cancer Center

Beverly Hills, California, United States

City of Hope National Medical Center

Duarte, California, United States

Outcomes

Primary Outcomes

Progression-free Survival (PFS) Per Investigator Assessment in the PIK3CA Mutant Cohort

PFS was defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS was assessed via a local radiology assessment according to RECIST 1.1. If a patient did not have an event, PFS was censored at the date of last adequate tumor assessment. The PFS distribution was estimated using Kaplan-Meier methodology. Progression was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Time frame: Once approximately 243 PFS events in the PIK3CA mutant cohort had been observed, up to 33.3 months

Secondary Outcomes

Overall Survival (OS) in the PIK3CA Mutant Cohort

OS was defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last known date patient alive. The OS distribution was estimated using Kaplan-Meier methodology.

Time frame: Once approximately 178 deaths in the PIK3CA mutant cohort had been observed, up to 55.7 months

PFS Per Investigator Assessment in the PIK3CA Non-mutant Cohort

Time frame: Up to 56.4 months

OS in the PIK3CA Non-mutant Cohort

Time frame: Up to 56.4 months

Overall Response Rate (ORR) Per Investigator Assessment

ORR was defined as the percentage of patients with best overall response of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, any pathological lymph nodes assigned as target and non-target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

Time frame: Up to 56.4 months

Clinical Benefit Rate (CBR) Per Investigator Assessment

Clinical benefit rate was defined as the percentage of patients with a best overall response of CR or PR or stable disease (SD) or Non-CR/Non-PD lasting more than 24 weeks based on local investigator assessment according to RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, any pathological lymph nodes assigned as target and non-target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.

Time frame: Up to 56.4 months

Time to Definitive Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Score From Baseline

ECOG PS categorized patients based on their ability to perform daily activities and self-care, with scores ranging from 0 to 5. A score of 0 indicated no restrictions in activity, while higher scores indicated increasing limitations. Time to definitive deterioration of ECOG PS by one score was defined as the time from the date of randomization to the date of the event, defined as experiencing at least one score lower than the baseline. A deterioration was considered definitive if no improvements in the ECOG PS were observed at a subsequent time. The Kaplan-Meier method was used to estimate the distribution. Patients receiving any further therapy prior to definitive worsening were censored at their date of last assessment prior to start of therapy. Patients that had not worsened at the data cutoff point were censored at the date of last assessment.

Time frame: From baseline up to 56.4 months

Time to 10% Deterioration in the Global Health Status (GHS) /Quality of Life (QOL) Scale Score of the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30)

The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, 1 GHS/QoL scale, and 6 single items. GHS/QoL scale score ranges between 0 and 100. A high score for GHS/QoL represents better functioning or QoL.The time to definitive 10% deterioration was defined as the time from the date of randomization to the date of event, which was defined as at least 10% relative to baseline worsening of the GHS/QoL score (without further improvement above the threshold) or death due to any cause. The Kaplan-Meier method was used to estimate the distribution. If a patient had not had an event, time to deterioration was censored at the date of the last adequate QoL evaluation.

Time frame: From baseline up to 55.7 months

Change From Baseline in the GHS/QOL Scale Score of the EORTC QLQ-C30

The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, 1 GHS/QoL scale, and 6 single items. GHS/QoL scale score ranges between 0 and 100. A high score for GHS/QoL represents better functioning or QoL.The change from baseline in the GHS/QoL score was assessed. A positive change from baseline indicated improvement. For each cohort, this analysis only included assessments up to the time point where there were at least 10 patients on each of the 2 treatment groups.

Time frame: Baseline, every 8 weeks after randomization during the first 18 months and thereafter every 12 weeks, up to 120 weeks.

Trough Plasma Concentration of Alpelisib

Pre-dose plasma concentrations of alpelisib were assessed. Only participants randomized to the alpelisib + fulvestrant arm were included in this analysis.

Time frame: Day 8 and Day 15 of Cycle 1, then Day 1 of Cycles 2, 4, 6 and 8. Cycle = 28 days

Trough Plasma Concentration of Fulvestrant

Pre-dose plasma concentrations of fulvestrant were assessed.

Time frame: Day 15 of Cycle 1, then Day 1 of Cycles 2, 4, 6 and 8. Cycle = 28 days

PFS Per Investigator Criteria in Subjects With PIK3CA Mutation Status Measured in ctDNA at Baseline

PFS was defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS was assessed via a local radiology assessment according to RECIST 1.1. If a patient did not have an event, PFS was censored at the date of last adequate tumor assessment. The PFS distribution was estimated using Kaplan-Meier methodology. Subjects were analyzed according to the PIK3CA mutation status (mutant or non-mutant) as identified using plasma ctDNA. Progression was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Time frame: From baseline up to 56.4 months

Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant in Men and Postmenopausal Women With Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment.

Overview

Conditions

Interventions

Eligibility

Locations (197)

Outcomes

Primary Outcomes

Secondary Outcomes