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BKM120 in Metastatic Castration-resistant Prostate Cancer

Complete title: A Phase II Study of BKM120 in Men with Metastatic Castration-Resistant Prostate Cancer BKM120 Investigator-Initiated Protocol

Research Study Number       7553
Principal Investigator       Evan Yu, MD
Phase       II

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Research Study Description

The purpose of this Phase II study is to look at how BKM120, an inhibitor of a protein called phosphatidyl inositol-3-kinase (PI3K), works in treating men with prostate cancer. The protein is found in normal cells as well as cancer cells, but in many cancer cells this protein can be overactive. In particular, very strong preclinical data from the laboratory shows that treatment with enzalutamide, an exciting new FDA approved therapy, leads to this pathway activation. Therefore, adding BKM120 at the time of resistance to enzalutamide could induce responses again. This study will see if stopping this protein will slow the growth of prostate cancer and focus will be placed on patients currently starting to have progression on enzalutamide. We will also investigate how cancer changes in response to BKM120 by studying DNA, RNA, and/or protein changes in circulating tumor cells. This is the first time this drug is being tested in men with prostate cancer and is being conducted at UW Washington Medical Center, Seattle Cancer Care Alliance, Duke University Medical Center, and several other study centers associated with the Prostate Cancer Clinical Trials Consortium.

Eligibility Criteria (must meet the following to participate in this study)

Ages Eligible for Study: 18 Years and older

Genders Eligible for Study: Male

- 1. Karnofsky performance status =/> 70

- 2. Life expectancy of = 12 weeks as determined by treating investigator

- 3. Adequate bone marrow function as shown by: ANC =/> 1.5 x 10^9/L, Platelets =/> 100 x 10^9/L, Hb > 9 g/dL, AST/SGOT and ALT/SGPT =/< 2.5 x Institutional Upper Limit of Normal (ULN) or =/< 5.0 x ULN if liver metastases present, Serum bilirubin =/< 1.5 x Institutional ULN, Serum creatinine =/> 1.5 x Institutional ULN or 24-hour clearance =/> 50 mL/min, Fasting plasma glucose =/< 120 mg/dL (6.7 mmol/L), and PT, PTT <1.4 x Institutional ULN

- 4. 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.

- 5. Radiographic evidence of metastatic disease.

- 6. Ongoing ADT using an LHRH agonist (e.g. leuprolide, goserelin) or antagonist (e.g. degarelix) must continue on therapy unless prior bilateral orchiectomy has been performed. Screening serum testosterone must be <50 ng/dl.

- 7. Evidence of disease progression on most recent therapy as evidenced by one of the following: 2 consecutive rising PSA levels separated at least 1 week apart above nadir PSA on last systemic therapy. If no nadir, then 2 rising PSA values greater than baseline pretreatment value is required from the most immediate prior therapy OR CT or MRI based evidence of disease progression (soft tissue, nodal or visceral disease progression) according to PCWG2 criteria or RECIST 1.1 criteria, or at least 1 new bone scan lesion as compared to the most immediate prior radiologic studies.

- 8. 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 antiandrogen 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.

- 9. A minimum of 2 weeks from prior abiraterone acetate, sipuleucel-T, TAK700, ketoconazole, or other experimental anti-cancer therapies prior to registration is required. Enzalutamide is permitted as a concomitant medication and no washout is

required. Enzalutamide must not be started within 28 days of screening and patients who are taking concomitant enzalutamide must meet the above progression criteria while taking enzalutamide to enroll.

- 10. At least one prior systemic chemotherapy regimen FDA approved for metastatic prostate cancer. If a patient has not received cabazitaxel chemotherapy, the patient must be informed of this treatment choice as an alternative unless he is not a candidate for this therapy. If the patient is not a candidate for docetaxel or cabazitaxel chemotherapy or refuses one of both of these therapies, this rationale must be documented and the patient is then eligible by this criteria. Patient must be offered and

made aware of all FDA-approved treatment options, including abiraterone.

- 11. A minimum of 4 weeks from any major surgery prior to registration.

- 12. Ability to swallow, retain, and absorb oral medication.

- 13. Ability to un understand and the willingness to sign a written informed consent document.

Other eligibility criteria may apply.

Exclusions (conditions that would prevent participation in this study)

- 1. Patients who have received prior treatment with a PI3K inhibitor.

- 2. Patients with a known hypersensitivity to BKM120 or to its excipients.

- 3. Patients with untreated brain metastases. Treated brain metastasis or focal leptomeningeal disease is allowed if the patient is > 4 weeks from therapy completion (radiation and/or surgery), is clinically stable at the time of study entry, and is not receiving corticosteroid therapy greater than prednisone 10mg daily or equivalent.

- 4. Patients with hepatitis B or C, other acute or chronic liver disease, or a recent (within 12 months of registration) history of pancreatitis.

- 5. Patients with certain mood disorders as judged by the investigator or a psychiatrist.

- 6. Patients with concurrent severe and/or uncontrolled cardiac conditions which could compromise participation in the study.

- 7. Patients with 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.

- 8. Patients with uncontrolled diabetes mellitus defined as a fasting plasma glucose level of >120. Patients with evidence of end-organ damage (neuropathy, nephropathy, vision loss) due to uncontrolled diabetes will also be excluded.

- 9. Patients with diarrhea =/> CTCAE grade 2.

- 10. 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.

- 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).

- 12. Patients who 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.

- 13. Patients who are 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.

- 14. Patients who 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.

- 15. Patients with a history of solid organ or stem cell transplantation.

- 16. Patients who 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 registration.

- 17. Patients who have undergone major surgery =/< 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy prior to registration.

- 18. Patients currently taking therapeutic doses of warfarin sodium or any other Coumadin derivative anticoagulant.

- 19. Known diagnosis of human immunodeficiency virus (HIV) infection.

- 20. History of another malignancy within 3 years, except cured basal cell or squamous cell carcinoma of the skin or low grade papillary bladder cancer.

- 21. Fertile males unwilling to wear a condom during treatment and up to 3 months after stopping treatment.

- 22. History of or current presence of pneumonitis of any grade.

Other exclusion criteria may apply.

Research Study Number       7553
Contact       Seattle Cancer Care Alliance Intake Office
Telephone       800-804-8824 / 206-288-1024

Prostate Cancer; Solid Tumors

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Please remember:

  • Talk to your health care providers first before making decisions about your health care.
  • Whether you are eligible for a research study depends on many things. There are specific requirements to be in research studies. These requirements are different for each study.

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