Neoadjuvant BKM120 in High-risk Prostate Cancer
Condition: High Risk Prostate Cancer
MeSH terms: Prostatic Neoplasms
Intervention: BKM120
Intervention description: Two weeks after confirmatory biopsy, patients will begin taking 100 mg/day of BKM120. BKM120 will be given at this dose level orally once daily for 14 days prior to radical prostatectomy. Radical prostatectomy will be performed on the day of the last dose of BKM120 at day 14. No further drug will be administered after radical prostatectomy. For unforeseen delays in OR scheduling, up to 7 additional days of BKM120 may be administered prior to surgery.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 11.0
Sex: Male
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: Prostate cancer; High-risk prostate cancer; Radical prostatectomy; BKM120

Summary:

      This is a phase II, study of BKM120 in patients with high-risk, localized prostate cancer.
      Eligible patients will be enrolled and scheduled to have an ultrasound-guided biopsy of the
      prostate to confirm high-risk disease and collect prostate tissue for analysis. Two weeks
      after the biopsy, patients will begin taking 100 mg/day of BKM120. BKM120 will be given at
      this dose level orally once daily for 14 days prior to radical prostatectomy at University of
      California, San Francisco. Radical prostatectomy will be performed on the day of the last
      dose of BKM120 at day 14. No further drug will be tken after the radical prostatectomy.
    

Eligibility criteria:

        INCLUSION CRITERIA

          1. Histologically confirmed adenocarcinoma of the prostate

          2. Candidate for radical prostatectomy

          3. Prostate cancer with the following pathological characteristics:

               1. Gleason sum > 8 AND at least 2 discrete core biopsies containing a minimum of 20%
                  cancer or,

               2. Gleason pattern 4 + 3 = 7 and greater than 50% of biopsies positive for prostate
                  cancer

          4. Age >= 18 years

          5. Eastern Cooperative Oncology Group (ECOG) performance status > 2

          6. Ability to take oral medications (capsule must be swallowed with liquid)

          7. Adequate bone marrow function as shown by: Absolute Neutrophil Count (ANC) >= 1.5 x
             109/liter, Platelets ≥ 100 x 109/L, Hemoglobin > 9 grams(g) /decilitre(dL)

          8. Total calcium (corrected for serum albumin) within normal limits (biphosphonate use
             for malignant hypercalcemia control is not allowed)

          9. Magnesium >= the lower limit of normal

         10. Potassium within normal limits for the institution

         11. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal
             range

         12. Serum bilirubin within normal range (or total bilirubin <= 3.0 x upper limit of normal
             (ULN) with direct bilirubin within normal range in patients with well documented
             Gilbert Syndrome)

         13. Serum creatinine <= 1.5 x upper limit of normal (ULN) or 24-hour clearance >= 50
             milliliter per min (mL/min)

         14. Serum amylase <= ULN

         15. Serum lipase <= ULN

         16. Fasting plasma glucose <= 120 mg/dL (6.7 mmol/L)

         17. International Normalized Ratio (INR) <= 2

         18. Men of reproductive potential and their female partners must use highly effective
             contraception during treatment, for 5 half-lives (8 days) after stopping treatment and
             for additional 12 weeks (3 months in total after study drug discontinuation) and
             should not father a child in this period The highly effective contraception is defined
             as either:

               1. True abstinence: When this is in line with the preferred and usual lifestyle of
                  the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
                  post-ovulation methods) and withdrawal are not acceptable methods of
                  contraception.

               2. Sterilization: Female partners have had surgical bilateral oophorectomy (with or
                  without hysterectomy) or tubal ligation at least six weeks ago. In case of
                  oophorectomy alone, only when the reproductive status of the woman has been
                  confirmed by follow up hormone level assessment.

               3. Male participant sterilization (with the appropriate post-vasectomy documentation
                  of the absence of sperm in the ejaculate).

               4. Use of a combination of any two of the following (a+b):

               5. Female partner with prior placement of an intrauterine device (IUD) or
                  intrauterine system (IUS)

               6. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
                  cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository •
                  Oral contraception use by female partners, injected or implanted hormonal methods
                  are not allowed as BKM120 potentially decreases the effectiveness of hormonal
                  contraceptives.

                    -  Fertile males, defined as all males physiologically capable of conceiving
                       offspring must use condom during treatment, for 5 half-lives (8 days) after
                       stopping treatment and for additional 12 weeks (3 months in total after
                       study drug discontinuation) and should not father a child in this period.

         19. Ability to understand and the willingness to sign a written informed consent document

        EXCLUSION CRITERIA

          1. Prior treatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor

          2. Known hypersensitivity to BKM120 or to its excipients

          3. History of another malignancy within 3 years, except cured basal cell carcinoma of the
             skin

          4. Hormonal therapy with Gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists
             or high dose bicalutamide within 1 month of enrollment unless serum testosterone is
             within normal limits.

          5. Following mood disorders as judged by the investigator and/or symptom management
             service co-investigator, or as a result of patient's mood assessment questionnaire:

             • 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 (immediate risk of doing harm to others)

             • Current >= NCI Common Terminology Criteria for Adverse Events (CTCAE) grade 3
             anxiety

             • Meets the cut-off score of >= 10 in the Patient Health Questionnaire (PHQ-9) or a
             cut-off of >= 15 in the Generalized Anxiety Disorder (GAD-7) mood scale, respectively,
             or selects a positive response of "1, 2, or 3" to question number 9 regarding
             potential for suicidal thoughts in the PHQ-9 (independent of the total score of the
             PHQ-9) will be excluded from the study

          6. Current diarrhea >= CTCAE grade 2

          7. Active cardiac disease including any of the following:

             • History of left ventricular ejection fraction (LVEF) < 50% as determined by Multiple
             Grated acquisition (MUGA) scan or echocardiogram (ECHO)

             • QTc > 450 msec on screening electrocardiogram (ECG (using the QTcF formula)

               -  Angina pectoris that requires the use of anti-anginal medication

               -  History of 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

          8. 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

          9. Poorly controlled diabetes mellitus or active, steroid-induced diabetes mellitus

         10. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.,
             active or uncontrolled infection) that could cause unacceptable safety risks or
             compromise compliance with the protocol

         11. 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). Patients with
             unresolved diarrhea will be excluded as previously indicated

         12. Treatment with any hematopoietic colony-stimulating growth factors (G-CSF or 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

         13. Current treatment with medication with a known risk to prolong the QT interval or
             inducing Torsades de Pointes and the treatment cannot either be discontinued or
             switched to a different medication prior to starting study drug. Please refer to
             section 10.2 for a list of prohibited QT prolonging drugs with risk of Torsades de
             Pointes.

         14. Current, 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. intr-articular) are allowed. If a
             patient stops corticosteroids prior to study participation, a 2-week washout is
             required.

         15. Taking herbal medications and certain fruits and juices within 7 days prior to
             starting study drug. Herbal medications include, but are not limited to St. John's
             wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe,
             saw palmetto, and ginseng. Fruits and juice include the Cytochrome P450 3A (CYP3A)
             inhibitors: Seville oranges, grapefruit, and pomelos.

         16. 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. Please refer to Section 10.2 for a list of
             prohibited inhibitors and inducers of CYP3A (Please note that co-treatment with weak
             inhibitors of CYP3A is allowed)

         17. Chemotherapy or targeted anticancer therapy ≤ 4 weeks (6 weeks for nitrosourea,
             antibodies or mitomycin-C) prior to starting study drug

         18. Any continuous or intermittent small molecule therapeutics (excluding monoclonal
             antibodies) <= 5 effective half lives prior to starting study drug or patients who
             have not recovered from side effects of such therapy 19 Major surgery <= 2 weeks prior
             to starting study drug or who have not recovered from side effects of such therapy

        20. Current treatment with warfarin sodium or any other coumadin-derivative anticoagulant
        21. Known diagnosis of human immunodeficiency virus (HIV) infection. Testing is not
        required for participation.

        22. Unable or unwilling to abide by the study protocol or cooperate fully with the
        investigator