A Trial of BKM120 (a PI3K Inhibitor) in Patients With Triple Negative Metastatic Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the clinical activity of BKM120 in patients with metastatic triple-negative breast cancer.

Detailed Description
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This is a prospective, non-randomized, open-label, multicenter, single-arm exploratory study of single agent BKM120 in the treatment of metastatic triple negative breast cancer patients. Patients will first undergo screening, tumor measurement and collection of available tumor block from the primary tumor and/or a metastatic site. Available tumor block is required in all patients per inclusion criteria. Analysis of this tumor block will be used for correlation of predictive markers and clinical response in order to define potential subpopulation that benefit from BKM120. Following confirmation of eligibility criteria, subjects will be enrolled. BKM120 will then be administered in a 100mg dose, orally, once daily, in a continuous schedule. A treatment cycle is defined as 28 days for the purposes of scheduling procedures and evaluations. Treatment with BKM120 will continue until disease progression, unacceptable toxicity that precludes any further treatment, and/or discontinuation of the treatment by investigator or patient decision.

Official Title
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A Phase II Trial of BKM120 (a PI3K Inhibitor) in Patients With Triple Negative Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: BKM120


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically and radiologically confirmed metastatic TNBC (Stage IV disease), previously documented by histological analysis, which is ER-negative and PR-negative by IHC and HER2 negative by IHC or FISH/CISH. Subjects must have received maximum two prior chemotherapy regimens for metastatic breast cancer. Availability of a representative tumor specimen (primary or metastasis, archival tissue or fresh biopsy for patients with biopsiable tumor) at baseline. At least one measurable lesion by RECIST 1.1 Age ≥ 18 years at the day of consenting to the study ECOG performance status ≤ 2 Adequate bone marrow and organ function as defined by the following laboratory values: ANC ≥ 1.0 x 109/L, platelets ≥ 100 x 109/L, hemoglobin ≥ 9.0 g/dL, INR ≤ 2; serum potassium between 3.0mmol/L and 5.5 mmol/L; Corrected serum calcium between8.0mg/dL and 11.5mg/dL (OR between 1.0mmol/L and 1.5mmol/L of Ionized calcium); serum magnesium between 1.2mg/dL and 3.0 mg/dL; serum creatinine ≤ 1.5 x ULN, ALT and AST within normal range (or ≤ 3.0 x ULN if liver metastases are present); serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome); fasting plasma glucose (FPG) ≤ 140 mg/dL or ≤ 7.8 mmol/L. Exclusion Criteria: Previous treatment with PI3K inhibitors Symptomatic CNS metastases Patients with controlled and asymptomatic CNS metastases may participate in this trial. As such, the patient must have completed any prior treatment for CNS metastases > 28 days (including radiotherapy and/or surgery) prior to enrollment in this study. Patients with previously treated brain metastases, who are on a stable low dose corticosteroids treatment are eligible Concurrent malignancy or malignancy within 3 years of study enrollment (with the exception of adequately treated basal or squamous cell carcinoma or non-melanomatous skin cancer). An exception to this rule are those patients with documented germline mutations in BRCA1 or 2, who may have previous history of cancer Any of the following mood disorders as judged by the Investigator or a Psychiatrist, or meets the cut-off score of ≥ 10 in the PHQ-9 or a cut-off of ≥ 15 in the GAD-7 mood scale, respectively, or selects a positive response of '1, 2, or 3' to question number 9 regarding potential for suicidal thoughts ideation in the PHQ-9 (independent of the total score of the PHQ-9) Patients with a history or active episodes of major depression, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, history of suicide attempts or suicidal thoughts (eg. Risk of hurting or harming others) or patients with severe personality disorders (as defined by the DSM-IV) are not eligible. Note: For patients who are treated with psychotropic drugs at baseline, the dose and schedule shall not be changed during the 6 weeks prior to initiation of treatment with the study drug. ≥ CTCAE v 4.0 grade 3 anxiety Patients on concurrent use of other approved or investigational antineoplastic and / or chemotherapy or any continuous or intermittent treatment with therapeutic agents of low molecular weight (excluding monoclonal antibodies) in ≤ 21 days prior to enrollment in this study or who have not recovered from the effects such therapy will not be eligible. Radiotherapy ≤ 28 days prior to enrollment in this study or failure to recover from side effects of such therapy at the time of initiation of screening procedures. Major surgery within 28 days prior to starting study drug or has not recovered from major side effects of the surgery Poorly controlled diabetes mellitus (HbA1c > 8%) Active cardiac disease including any of the following: Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)Note: ECHO/MUGA is only required at baseline if patient has a history of abnormal cardiac test results QTc > 480 msec on screening ECG (using the QTcF formula Angina pectoris that requires the use of anti-anginal medication Ventricular arrhythmias except for benign premature ventricular contractions Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication Conduction abnormality requiring a pacemaker Valvular disease with documented compromise in cardiac function Symptomatic pericarditis History of cardiac dysfunction including any of the following; Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function History of documented congestive heart failure (New York Heart Association functional classification III-IV) Documented cardiomyopathy Treatment with QT prolonging medication known to have a risk to induce Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) Chronic treatment with steroids or another immunosuppressive agent. Note: Topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye drops or local injections (e.g., intra-articular) are allowed. Patients with previously treated brain metastases, who are on a stable low dose corticosteroids treatment (e.g., dexamethasone 2 mg/day, prednisone 10 mg/day) for at least 14 days before start of study treatment, are eligible Other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment contraindicate her participation in the clinical study (e.g., chronic pancreatitis, active chronic hepatitis etc.) History of non-compliance to medical regimen Current treatment with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug Known history of HIV (testing not mandatory) infection Pregnant or nursing (lactating) woman Woman of child-bearing potential unwilling to observe total sexual abstinence or to use a double barrier method for birth control throughout the trial. Reliable contraception should be maintained throughout the study and for 6 months after study drug discontinuation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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<br> | Drug: BKM120<br>* BKM120 oral capsules. 100 mg daily in cycles of 28 days, until disease progression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Clinical Benefit | Clinical benefit rate (CBR) was defined as the percentage of participants achieving complete response (CR), partial response (PR), or stable disease (SD) for 4 months or longer based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is the complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria. | Disease was evaluated radiologically at baseline and every 2 cycles on treatment then every 3 months up to 2 years. Participants in this study cohort were followed for response on average approximately 2 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival (PFS) based on the Kaplan-Meier (KM) method is defined as the duration of time from study entry to documented disease progression (PD) or death. Participants alive without PD are censored at the date of last disease assessment. Per RECIST 1.1 criteria: PD is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. | Disease was evaluated radiologically at baseline and every 2 cycles on treatment then every 3 months up to 2 years. Participants in this study cohort were followed for PFS on average approximately 2 months. | 
| Overall Survival | Overall survival was defined as the time from date of study enrollment until death from any cause. | 2 years | 
| Frequency and Severity of Adverse Events | Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per Common Toxicity Criteria for Adverse Events (CTCAE) version 4. | Adverse events (AEs) were assessed every 2 weeks for the first 2 cycles and every cycle thereafter. Participants were followed for AEs on average approximately 2 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, metastatic, triple negative breast cancer, BKM120, SOLTI, PI3K inhibitor