Phase III Study of BKM120/Placebo With Fulvestrant in Postmenopausal Patients With Hormone Receptor Positive HER2-negative Locally Advanced or Metastatic Breast Cancer Refractory to Aromatase Inhibitor

Study Overview
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Brief Summary
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This study was a multi-center, randomized, double-blind, placebo controlled Phase III study to determine the efficacy and safety of treatment with buparlisib plus fulvestrant versus fulvestrant plus placebo in postmenopausal women with hormone Receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative), locally advanced or metastatic breast cancer (MBC) whose disease has progressed on or after aromatase inhibitor (AI) treatment.

Detailed Description
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Patients were randomized (1:1) to receive buparlisib (100 mg/day) or placebo with fulvestrant (500 mg); randomization was stratified by PI3K pathway activation status (activated, non-activated, unknown determined in archival tumor tissue) and visceral disease status (present or absent). Tumor evaluation was performed 6 weeks after the randomization date and then every 8 weeks until radiological progression (based on Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1). Novartis made the decision not to pursue further development of buparlisib and to terminate the ongoing studies in the program. Accordingly, on 19-Dec-2016, Novartis notified all the Investigators about the decision not to pursue further development of buparlisib in Breast Cancer. As a result, the CBKM120F2302 study was terminated on 19-Apr-2019 (last subject last visit).

Official Title
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A Phase III Randomized, Double Blind Placebo Controlled Study of BKM120 With Fulvestrant, in Postmenopausal Women With Hormone Receptor-positive HER2-negative Locally Advanced or Metastatic Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Fulvestrant
* Drug: BKM120
* Drug: BKM120 matching placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Locally advanced or metastatic breast cancer HER2-negative and hormone receptor-positive status (common breast cancer classification tests) Postmenopausal woman A tumor sample must be shipped to a Novartis designated laboratory for identification of biomarkers (PI3K activation status) Progression or recurrence of breast cancer while on or after aromatase inhibitor treatment Measurable disease or non measurable disease bone lesions in the absence of measurable disease as per RECIST 1.1 Adequate bone marrow and organ function defined by laboratory values Key Exclusion Criteria: Previous treatment with PI3K inhibitors, AKT inhibitors, mTOR inhibitor or fulvestrant More than one prior chemotherapy line for metastatic disease Symptomatic brain metastases Increasing or chronic treatment (> 5 days) with corticosteroids or another immunosuppressive agent Active heart (cardiac) disease as defined in the protocol Certain scores on an anxiety and depression mood questionnaires

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BKM120 100mg + Fulvestrant<br>BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol. | Drug: Fulvestrant<br>* Intramuscular fulvestrant 500 mg (Day 1 and Day 15 of Cycle 1 and Day 1 of every cycle thereafter)<br>Drug: BKM120<br>* BKM120 100 mg once daily<br>|
| Placebo Comparator: Placebo + Fulvestrant<br>BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol. | Drug: Fulvestrant<br>* Intramuscular fulvestrant 500 mg (Day 1 and Day 15 of Cycle 1 and Day 1 of every cycle thereafter)<br>Drug: BKM120 matching placebo<br>* BKM120 matching placebo, once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) Based on Local Investigator Assessment - Full Analysis Set (FAS) in Full Population, Main Study Cohort and PI3K Unknown Cohort | Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 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 and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm. | Date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to approximately 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) - Full Analysis Set (FAS) in Full Population, Main Study Cohort and PI3K Unknown Cohort | Overall Survival (OS) is 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 by the date of analysis cut-off, OS was censored at the date of last known date patient alive. Patients were followed up for the duration of the study and for an expected average of every 3 months after end of treatment. | Every 3 months following end of treatment visit, assessed for approximately 5 years | 
| Overall Response Rate (ORR) - Full Analysis Set (FAS) in Full Population, Main Study Cohort and PI3K Unknown Cohort | Overall Response Rate (ORR) is defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST 1.1. ORR was analyzed in the full population. Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for target/non target lesions: Complete Response (CR), disappearance of all target/non target lesions (all lymph nodes assigned as non-target lesions must be non-pathological in size (< 10 mm short axis)); Partial response (PR), >=30% decrease in the sum of the longest diameter of target lesions ; Overall Response (OR)= CR+PR. Only descriptive analysis performed. | From the date of randomization until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 5 years | 
| Clinical Benefit Rate (CBR) - Full Analysis Set (FAS) in Full Population, Main Study Cohort and PI3K Unknown Cohort | Clinical Benefit Rate (CBR) is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) or Non-CR/non-PD lasting more than 24 weeks based on local investigator's assessment according to RECIST 1.1. CBR was analyzed in the full population. Only descriptive analysis performed. | From the date of randomization until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 5 years | 
| Number of Participants With On-Treatments Adverse Events, Serious Adverse Events and Deaths | Analysis of frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths. Only descriptive analysis performed. | From first dose of study treatment to 30 days after last dose of study treatment, assessed for approximately 5 years | 
| Plasma Concentration-time Profiles of BKM120 in Combination With Fulvestrant at Cycle 2 Day 1 | Plasma samples were collected from the first 200 BKM120-treated patients on Cycle 2 Day 1 (at pre-dose, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h and 24h [before Cycle 2 Day 2 dose] post-dose). Each cycle is 28 days. Only descriptive analysis performed. | Cycle2 Day1 (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours post-dose). Each cycle is 28 days. | 
| Predose Trough Concentration-time Profile of BKM120 in Combination With Fulvestrant Over Time - Pharmacokinetic Analysis Set (PAS) | Pre-dose samples were collected for trough concentrations at Cycle 2 Day 1, Cycle 2 Day 15 and Cycle 3 Day 1. Each cycle is 28 days. Only descriptive analysis performed. | Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1. Each cycle is 28 days. | 
| Median Time to Definitive Deterioration of the ECOG Performance Status - Full Analysis Set (FAS) | Time to definitive deterioration of the ECOG PS was defined as the time between the date of randomization and the date of the assessment at which definitive deterioration was seen. Only descriptive analysis performed. | Up to approx 27 months | 
| Health-related Quality of Life (HRQoL):Time to 10% Definitive Deterioration in the Global Health Status/Quality of Life Per EORTC-QLQ-C30 | The global health status/QoL scale score of the QLQ-C30 is identified as the primary PRO variable of interest. Physical Functioning (PF), Emotional Functioning (EF) and Social Functioning (SF) scale scores of the QLQ-C30. The time to definitive 10% deterioration is defined as the time from the randomization date to the date of an event, which is defined as a worsening (decrease) in score by at least 10% compared to baseline, with no later increase above this threshold observed during the course of the study or death due to any cause. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high /healthy level of functioning, a high score for the global health status / QoL represents a high QoL. Patients were assessed up to approx. 8.3 months. Only descriptive analysis performed. | Cycle 1 day 1, cycle 1 day 15, 6 weeks after randomisation and then every 8 weeks until end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast cancer, Hormone receptor positive, HER2-negative, Metastatic, Locally advanced, PI3K, Fulvestrant, Refractory, Aromatase inhibitor