Neoadjuvant BKM120 in High-risk Prostate Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by University of California, San Francisco
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Charles Ryan, University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT01695473
First received: September 26, 2012
Last updated: August 15, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
High Risk Prostate Cancer
Drug: BKM120
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pharmacodynamic Study of Pre-prostatectomy BKM120 in Men With High-risk, Localized Prostate Cancer

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • PI3K inhibition in prostate tumor tissue [ Time Frame: 90-120 days ] [ Designated as safety issue: No ]
    Determine the proportion of men with downstream target inhibition of PI3K in prostate tumor tissue as measured by phosphorylated S6 immunohistochemistry (ICH) when treated with 100 mg/day of BKM120 using paired tumor biopsies from before and after drug administration


Secondary Outcome Measures:
  • 4EBP1 protein [ Time Frame: 90-120 days ] [ Designated as safety issue: No ]
    Determine the proportion of men with downstream target inhibition of PI3K in prostate tumor tissue as measured by 4EBP1 protein phosphorylation immunohistochemistry (IHC) using paired tumor biopsies from before and after drug administration

  • BKM120 activity [ Time Frame: 90-120 days ] [ Designated as safety issue: No ]
    Evaluate the activity of short term BKM120 administration in prostate cancer as measured in PSA response immediately prior to surgery

  • AKT protein [ Time Frame: 90-120 days ] [ Designated as safety issue: No ]
    Determine the proportion of men with downstream target inhibition of PI3K in prostate tumor tissue as measured by AKT protein phosphorylation immunohistochemistry (IHC)


Estimated Enrollment: 24
Study Start Date: October 2012
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Neoadjuvant BKM120
Twenty four men will receive 2 weeks of daily BKM120 prior to having radical prostatectomy
Drug: BKM120
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.

Detailed Description:

This is a phase II, prospective, pharmacodynamic study of BKM120 in high-risk, localized prostate cancer. After informed consent and central pathology review of the core prostate biopsy, eligible patients will be enrolled and scheduled to have an ultrasound-guided biopsy of the prostate to confirm high-risk disease and collect tissue for molecular 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 administered after radical prostatectomy.

Up to 24 patients, or 21 evaluable patients, will be enrolled through the Department of Urology or Genitourinary Medical Oncology at the University of California, San Francisco for this pharmacodynamic study. Toxicity will be assessed during BKM120 administration, and will involve a clinic visit on Day 14 ± 2 (i.e. before surgery). Follow-up with safety evaluations will be at 90 ± 7 days post-operatively and involve a toxicity questionnaire, blood tests, and clinic visit. Toxicity will be monitored and reported using NCI Common Toxicity Criteria version 4.0 guidelines.

A patient symptom diary will be distributed to each patient at baseline for symptom self-recording and BKM120 dose self-administration. In addition, a patient identifier card (wallet-sized) will be distributed to each patient after informed consent and registration. This information will contain the patient's age, study name and number, investigator and study coordinator contact information, and expected adverse events that may be present as a result of BKM120 administration.

  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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. ECOG performance status £ 2 6. Ability to take oral medications (capsule must be swallowed with liquid) 7. Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hgb > 9 g/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 ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome) 13. Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min 14. Serum amylase ≤ ULN 15. Serum lipase ≤ ULN 16. Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L) 17. 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):

    1. Female partner with prior placement of an intrauterine device (IUD) or intrauterine system (IUS)
    2. 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 T1/2 (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 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 GnRH agonists, GnRH antagonists or high dose biclutamide 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 ≥ CTCAE grade 3 anxiety
    • 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 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 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 (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
  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 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01695473

Contacts
Contact: Paula Dutton, BS 415-885-7871 walshp@medicine.ucsf.edu
Contact: Charles Ryan, MD 415-353-9279 ryanc@medicine.ucsf.edu

Locations
United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94115
Contact: Paula Dutton, BS    415-885-7871    walshp@medicine.ucsf.edu   
Contact: Charles Ryan, MD    415-353-9279    ryanc@medicine.ucsf.edu   
Sponsors and Collaborators
Charles Ryan
Novartis
Investigators
Study Chair: Charles Ryan, MD University of California, San Francisco
  More Information

No publications provided

Responsible Party: Charles Ryan, UCSF Professor of Medicine and Urology; Leader Prostate Cancer Program, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01695473     History of Changes
Other Study ID Numbers: UCSF CC# 115516
Study First Received: September 26, 2012
Last Updated: August 15, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of California, San Francisco:
Prostate cancer
High-risk prostate cancer
Radical prostatectomy
BKM120

Additional relevant MeSH terms:
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases

ClinicalTrials.gov processed this record on October 02, 2014