Trial of BKM120/Tamoxifen-combination in Patients With HR-pos, HER2-neg Breast Cancer

Study Overview
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Brief Summary
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This is a clinical trial with a molecularly stratified parallel cohort, single arm design to explore the efficacy and safety of BKM120 in combination with tamoxifen in patients with ER/PR-positive, HER2-negative breast cancer with prior exposure to antihormonal therapy, and different biomarker profiles, two of them potentially indicative of constitutive PI3K pathway activation.

Detailed Description
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This is a clinical trial with a molecularly stratified parallel cohort, single arm design to explore the efficacy and safety of BKM120 in combination with tamoxifen in patients with ER/PR-positive, HER2-negative breast cancer with prior exposure to antihormonal therapy, and different biomarker profiles, two of them potentially indicative of constitutive PI3K pathway activation: PIK3CA mutation/preserved PTEN expression PIK3CA wildtype or mutation/ loss of PTEN expression PIK3CA wildtype/preserved PTEN expression. This trial will explore, if the combination of BKM120 and tamoxifen can overcome resistance to antihormonal therapies. BKM120 is selective for class I PI3K enzymes with no mTOR inhibitory activity that has entered Phase II and III clinical trials. The tumor suppressor PTEN is the most important negative regulator of the PI3K signaling pathway. Therefore, in addition the trial will prospectively evaluate PIK3CA mutations and/or loss of PTEN expression as predictive biomarkers for clinical benefit from combined treatment with BKM120 and tamoxifen.

Official Title
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Molecularly Stratified Parallel Cohort, Single Arm Phase II Trial of the Phosphoinositide 3-kinase (PI3K) Inhibitor Buparlisib (BKM120) in Combination With Tamoxifen in Patients With Hormone Receptor-positive, HER2-negative Inoperable (Locally Advanced or Metastatic) Breast Cancer With Prior Exposure to Antihormonal Therapy

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: BKM120
* Drug: Tamoxifen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has histologically and/or cytologically confirmed diagnosis of breast cancer Patient has radiologic or objective evidence of inoperable locally advanced, or metastatic breast cancer Patient has a known hormone receptor status HR-positive (ER and/or PR positive) and HER2-negative status Patient has a representative archival formalin-fixed tumor biopsy (metastasis or primary tumor) Patient has prior exposure to antihormonal therapy Patient has received ≤ 2 prior antihormonal treatments in the metastatic setting Prior treatment with tamoxifen in the (neo-)adjuvant setting is allowed but has to be discontinued for at least 1 year. Patient may have received up to one prior chemotherapy in the metastatic setting Measurable or non-measurable lesions according to RECIST v1.1 criteria Patient has an Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2 Exclusion Criteria: Patient has received previous treatment with a PI3K- or AKT-inhibitor or mTOR-inhibitors Prior treatment with Tamoxifen in the metastatic setting. Treatment with tamoxifen in the (neo-)adjuvant setting is allowed, but has to be discontinued for at least 1 year Patient has symptomatic CNS metastases Patient has a medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others), or patients with active severe personality disorders (defined according to DSM-IV). Patient has a known history of HIV infection (testing not mandatory) infection

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BKM120 + Tamoxifen<br>BKM120 (Buparlisib): 100 mg/day, orally, on a continuous dosing schedule without interruption starting on day 1 in 28 day cycle Tamoxifen: 20 mg/day, orally, on a continuous dosing schedule without interruption starting on day 1 in 28 day cycle | Drug: BKM120<br>* daily oral<br>* Other names: Buparlisib;Drug: Tamoxifen<br>* daily oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS)-rate in the full population, after 6 months | PFS is defined as time from date of start of treatment to the date of the event, defined as the first documented disease progression or death due to any cause per local investigator assessment | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS)- rate in the subpopulations after 6 months of combination therapy | PFS is defined as time from date of start of treatment to the date of the event, defined as the first documented disease progression or death due to any cause per local investigator assessment | 6 months | 
| Progression-free survival (PFS) | PFS in subpopulations and full population. PFS is defined as time from date of start of treatment to the date of the event, defined as the first documented disease progression or death due to any cause per local investigator assessment | 6 months | 
| 1 year overall survival (OS) rate | OS is defined as time from date of start of treatment to the date of death from any cause. | 1 year | 
| 2 years overall survival (OS) rate | OS is defined as time from date of start of treatment to the date of death from any cause. | 2 years | 
| Overall response rate (ORR) | ORR is defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR) (RECIST v1.1). | 6 months | 
| Disease control rate (DCR) | DCR is defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR) or stable disease (SD) lasting more than 12 weeks (RECIST v1.1). | 6 months | 
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability | Type, frequency and severity of adverse events per CTCAE v4.03 | From date of informed consent to +30 days from last application of study medication | 
| Incidence and severity of depressive episodes during the course of treatment | Change in depressive episodes assessed by PHQ-9 questionnaire | From date of informed consent to +30 days from last application of study medication | 
| Incidence and severity of depressive episodes during the course of treatment | Change in depressive episodes assessed by GAD-7 questionnaire | From date of informed consent to +30 days from last application of study medication |