BKM120 in Metastatic Castration-resistant Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effects of the study drug, BKM120. The study drug, BKM120, is an inhibitor of a protein called phosphatidyl inositol-3-kinase (PI3K). This protein is found in normal cells and in cancer cells, but often in many cancer cells this protein is overactive. Inhibiting the protein may slow the growth of prostate cancer but this has not been tested yet in men with prostate cancer.

Detailed Description
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This is an open label, single arm phase II study of BKM120 in men with metastatic castration resistant prostate cancer (CRPC) who have progressed on or following completion of docetaxel-based chemotherapy. Prior progression on cabazitaxel, provenge, abiraterone, or enzalutamide (MDV3100) is also permitted. Patients must have baseline evaluations performed prior to the first dose of study drug and must meet all inclusion and exclusion criteria. Results of the baseline evaluations, which assure that all inclusion and exclusion criteria have been satisfied, must be reviewed by the Principal Investigator or his/her designee prior to enrollment of that patient. In addition, the patient must be thoroughly informed about all aspects of the study, including the study visit schedule and required evaluations and all regulatory requirements for informed consent. The written informed consent must be obtained from the patient prior to protocol-specific screening tests. The following criteria apply to all patients enrolled onto the study unless otherwise specified.

Official Title
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Phase II Study of BKM120 in Men With Metastatic Castration-Resistant Prostate Cancer

Conditions
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Prostate Cancer, Metastatic (Spread to Other Areas of the Body)

Intervention / Treatment
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* Drug: BKM120


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Karnofsky performance status ≥ 70 Life expectancy of ≥ 12 weeks as determined by treating investigator Adequate laboratory parameters Histologically confirmed diagnosis of adenocarcinoma of the prostate. Histologic variants of prostate cancer, including neuroendocrine features and small cell carcinoma of the prostate are permitted Radiographic evidence of metastatic disease Evidence of disease progression on androgen deprivation therapy (ADT) A minimum of 4 weeks elapsed off of antiandrogen therapy prior to registration (i.e. flutamide, nilutamide) and 6 weeks for bicalutamide, without evidence of an anti-androgen withdrawal response. Patients who did not have a PSA decline with the most recent antiandrogen therapy require only a 2 week washout period prior to registration A minimum of 2 weeks from prior abiraterone acetate, sipuleucel-T, MDV3100, orteronel (TAK700), ketoconazole, or other experimental anti-cancer therapies prior to registration is required. Concomitant treatment with enzalutamide is permitted. At least one prior systemic chemotherapy regimen FDA approved for metastatic prostate cancer A minimum of 4 weeks from any major surgery prior to registration Exclusion Criteria: Have received prior treatment with a PI3K inhibitor Known hypersensitivity to BKM120 or to its excipients Untreated brain metastases Patients with hepatitis B or C, other acute or chronic liver disease, or a recent (within 12 months of administration of first dose of study drug) history of pancreatitis Patients with certain mood disorders as judged by the investigator or a psychiatrist History of treatment in an inpatient psychiatric setting Concurrent severe and/or uncontrolled cardiac conditions which could compromise participation in the study Other concurrent severe and/or uncontrolled concomitant medical conditions that could cause unacceptable safety risks or compromise compliance with the protocol Uncontrolled diabetes mellitus defined as a fasting plasma glucose level of >120. Diarrhea ≥ CTCAE grade 2 Drugs or substances known to be strong inhibitors or inducers of the isoenzyme CYP3A4 should be avoided as systemic therapy in association with BKM120 as these can alter its metabolism. Topical use of creams or other applications not absorbed into the circulation is permitted Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) Have been treated with any granulocyte colony-stimulating growth factors (e.g., G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued Currently receiving treatment with medication that has the potential to significantly prolong the QT interval or induce Torsades de Pointes, and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug Have received immunosuppressive therapy including corticosteroids ≤ 2 weeks prior to starting study drug. Prednisone at a total daily dose of 10 mg orally or its equivalent is permitted, if initiated at least 2 weeks prior to enrollment History of solid organ or stem cell transplantation Have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy prior to administration of first dose of study drug Have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy prior to administration of first dose of study drug Currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant Known diagnosis of human immunodeficiency virus (HIV) infection History of another malignancy within 3 years, except cured basal cell or squamous cell carcinoma of the skin or low grade papillary bladder cancer Other inclusion and exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

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: Study arm<br>BKM120 at 100mg orally daily | Drug: BKM120<br>* BKM120 at the maximum tolerated dose (MTD) of 100mg orally daily<br>* Other names: BKM-120;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) Prostate Cancer Working Group 2 (PCWG2) Criteria or Based on the Onset of a Skeletal Related Event. | Time in months from the start of study treatment to the date of first progression or death due to any cause. Progression was determined either radiographically using a composite of the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and Prostate Cancer Working Group 2 (PCWG2) criteria or clinically as judged from a skeletal-related event, need for change in therapy, or clinical deterioration. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve. Response and progression are evaluated using a combination of Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and guidelines for prostate cancer endpoints developed by the Prostate Cancer Clinical Trials Working Group (PCWG2). Per RECIST, progression is defined 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. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiologic Response | The number of patients achieving a complete response (CR) or partial response (PR) based on RECIST 1.1 criteria. Response and progression is evaluated using a combination of the Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) and the guidelines for prostate cancer endpoints developed by the Prostate Cancer Clinical Trials Working Group (PCWG2). Per RECIST, progression is defined 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. | 2 years | 
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Number of patients experiencing grade 3-5 adverse events as defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 | Up to 28 days post last study drug dose. This is the follow-up safety visit. | 
| Prostate Specific Antigen (PSA) Response | The number of patients with a 30% and 50% decrease in PSA from baseline. | 2 years | 
| Overall Survival of Participants. | Time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up had OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve. | 5 years | 
| Change in Circulating Tumor Cell (CTC) Levels From Baseline | The number of patients with a baseline CTC level of at least 5 who achieved a CTC level of less than 5 during the study. | 2 years | 
| Time to New Metastatic Disease From the Baseline Visit | Time in days from the start of study treatment to time of new metastatic disease. Time to new metastatic disease is, defined from the date of first study agent administration to the onset of a new evaluable site of disease as per PCWG2 and RECIST 1.1 guidelines, excluding the primary site and all sites documented at baseline will be assessed. Only those patients that experienced a new lesion per this definition are included. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BKM120, prostate cancer, metastatic castrate-resistant prostate cancer (mCRPC)