A Study of the Experimental Drug BKM120 With Paclitaxel in Patients With HER2 Negative, Locally Advanced or Metastatic Breast Cancer, With or Without PI3K Activation

Study Overview
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Brief Summary
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This study evaluated whether the addition of daily BKM120 to weekly paclitaxel was effective and safe in treating patients with HER2- locally advanced or metastatic breast cancer.

Detailed Description
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Based on the efficacy results at the time of the interim analyses, the DMC recommended stopping the study at Phase II during the interim as it met the protocol pre-specified futility criteria. Consequently, the Phase III portion of the study was not conducted.

Official Title
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A Randomized, Double-blind, Placebo Controlled, Phase II/III Study of BKM120 Plus Paclitaxel in Patients With HER2 Negative Inoperable Locally Advanced or Metastatic Breast Cancer, With or Without PI3K Pathway Activation.

Conditions
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Breast Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Breast cancer that is locally advanced or metastatic HER2 negative disease, and a known hormone receptor status - ER/PgR (common breast cancer classification tests) A tumor sample must be shipped to a central lab for identification of biomarkers (PI3K activation status) before randomization Adequate bone marrow and organ function Measurable or non-measurable disease Exclusion Criteria: Prior chemotherapy for locally advanced or metastatic disease Previous treatment with PI3K or AKT inhibitors Patient has symptomatic CNS metastases Concurrent malignancy or malignancy within 3 years of study enrollment Hematopoietic colony-stimulating growth factors or radiation within 2-4 weeks prior to starting study drug Increasing or chronic treatment (> 5 days) with corticosteroids or another immunosuppressive agent Active heart (cardiac) disease as defined in the protocol Known hypersensitivity or contraindications to use paclitaxel Pregnant or nursing (lactating) woman Certain scores on an anxiety and depression mood questionaire given at screening Other protocol defined criteria may apply

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 and paclitaxel<br>Adult females with histologically confirmed, inoperable, locally advanced or metastatic HER2- BC who received study drug plus paclitaxel. | Drug: Paclitaxel<br>* intravenous paclitaxel 80 mg/m2 per week given until progression<br>* Other names: Taxol;Drug: BKM120<br>* Buparlisib (BKM120) were supplied as 100 mg and 50 mg hard gelatin capsules. Buparlisib was dosed on a flat scale of mg/day and was not adjusted to body weight or body surface area.<br>* Other names: Buparlisib;|
| Active Comparator: Placebo and paclitaxel<br>Adult females with histologically confirmed, inoperable, locally advanced or metastatic HER2- BC who received placebo plus paclitaxel. | Drug: Paclitaxel<br>* intravenous paclitaxel 80 mg/m2 per week given until progression<br>* Other names: Taxol;Drug: BKM120 matching placebo<br>* Buparlisib maching plaxcebo were supplied as 100 mg and 50 mg hard gelatin capsules. Buparlisib placebo was dosed on a flat scale of mg/day and was not adjusted to body weight or body surface area.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS)Assessed by Local Investigator's Assessment (Phase ll) | PFS was defined as the time from the date of randomization to the date of the event, defined as the first radiologically documented disease progression or death due to any cause. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Every 8 weeks from randomization until disease progression up to 10 months after futility was analyzed | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival by Kaplan-Meier Estimate (Phase ll) | Overall survival (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 by the date of analysis cut-off, OS was censored at the date of last contact. | every 3 months until death, lost to follow-up, or withdrawal of consent to survival follow-up, up to 10 months after futility was analyzed | 
| Overall Response Rate (Phase ll) | Percentage of patients with best overall response of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST v1.1. According to this criteria, CR = at least two determinations of CR at least 4 weeks apart before progression; PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | every 8 weeks after randomization Up to 3 months after end of Treatment | 
| Duration of Response (Phase Lll) | time from the date of the first documented response (CR or PR, which had to be confirmed subsequently) to the date of the first radiologically documented disease progression or death due to disease | every 8 weeks after randomization Up to 3 months after end of Treatment | 
| Time to Response (Phase Lll) | time from date of randomization until first documented response (CR or PR, which has to be confirmed subsequently). | every 8 weeks after randomization Up to 3 months after end of Treatment | 
| Clinical Benefit Rate (CBR) (Phase ll) | CBR was defined as the percentage of patients with an overall response of CR or PR or SD or non-CR/non-PD lasting more than 24 weeks based on local Investigator's assessment according to RECIST v1.1. | every 8 weeks after randomization Up to 3 months after end of Treatment | 
| Plasma Concentration-time Profiles of BKM120 - Pharmacokinetics (PK) (Phase Lll) | Summary statistics for PK: plasma concentration-time profiles of BKM120 and appropriate individual PK parameters based on population PK model , if deemed appropriate; each cycle = 28 days | Cycle 1 day 1, 15, 16, 22 and Cycle 2 day 1. | 
| Time to Definitive Deterioration of ECOG Performance Status (Phase Lll) | Time to definitive deterioration of the ECOG performance status from baseline | every 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BKM120, paclitaxel, breast cancer, metastatic, locally advanced, PI3K, PIK3CA, PTEN