Details

Details

Title A Double-Blinded, Placebo-Controlled, Randomized Phase II Study of Enzalutamide With or Without the PI3 Kinase/mTOR Inhibitor LY3023414 in Men with Metastatic Castration Resistant Prostate Cancer

IRB LILY1816

CC 16-787

Hospital Main Campus

Stage Advanced/Metastatic

Phase Phase 2

Disease Prostate

Drug Enzalutamide, LY3023414

Description

Description

Primary Objective
  • To compare progression-free survival (PFS) - PSA, radiographic, or Prostate Cancer Clinical Trials Working Group (PCWG2) symptomatic progression - in men with mCRPC who are receiving enzalutamide plus LY3023414 versus enzalutamide plus placebo using Prostate Cancer Clinical Trials Working Group (PCWG2) criteria.
Secondary Objectives
  • To compare the clinical response rates (RRs) in men with mCRPC who are receiving enzalutamide plus LY3023414 versus enzalutamide plus placebo who have measurable disease at baseline using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1(Eisenhauer et al. 2009).
  • To compare time to clinical (symptomatic or radiographic) and/or PSA progression (TTP) in men with mCRPC who are receiving enzalutamide plus LY3023414 versus enzalutamide plus placebo using PCWG2 criteria.
  • To compare the maximum decline in PSA that occurs following treatment in men with mCRPC who are receiving enzalutamide plus LY3023414 versus enzalutamide plus placebo.
  • To demonstrate the safety and tolerability of 200 mg twice daily (BID) oral LY3023414given in combination with 160 mg once daily (QD) oral dose of enzalutamide.
  • To evaluate potential pharmacokinetic (PK) drug interactions (i.e. impact of enzalutamide on LY3023414 exposure) and to further characterize LY3023414 PK properties.
  • To characterize the safety profile of enzalutamide plus LY3023414 as compared to enzalutamide plus placebo in this patient population.
Exploratory Objective
  • To collect blood and archival tissue for exploratory studies to identify potential biomarkers predictive of clinical efficacy of study treatment and disease progression in this patient population.
Inclusion Criteria

Inclusion Criteria

  1. Histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate.
  2. Metastatic disease documented by positive bone scan or metastatic lesions on CT, MRI. If lymph node metastasis is the only evidence of metastasis, it must be ≥ 2 cm in diameter.
  3. Prostate cancer progression documented by PSA and/or radiographic progression according to PCWG2 criteria (Appendix F).
  4. Prior abiraterone treatment completed at least 2 weeks prior to Cycle 1 Day 1.
  5. If patient has previously been treated with RA-223 dichloride, treatment must be completed at least 4 weeks prior to Cycle 1 Day 1 (minimum 4 week wash out period).
  6. If a patient was treated with abiraterone, but their last treatment prior to enrolment was an anti-androgen as last treatment prior to enrolment, PSA or symptomatic progression will need to be documented. The minimum washout period for these agents is as follows:
    • 6 weeks for long acting agents (nilutamide, bicalutamide)
    • 4 weeks for short acting agents (flutamide).

    Patients whose PSA did not decline for 3 or more months in response to an anti-androgen given as a second line or later intervention will require only a 2-week washout prior to Cycle 1 Day 1.

  7. Surgically or medically castrated, with testosterone levels of < 50 ng/dL. If the patient is being treated with LHRH agonists (patients who have not undergone orchiectomy), this therapy must be continued throughout the study.
  8. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 (Appendix A).
  9. Able to swallow the study drugs whole.
  10. Adequate hematologic function defined as:
    • Absolute neutrophil count (ANC) ≥1500/μL
    • Platelets ≥100,000/μL
    • Hemoglobin ≥8 g/dL
  11. Adequate liver function defined as:
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x the upper limit of normal (ULN). If the liver has tumor involvement, AST and ALT equaling ≤5 times ULN are acceptable.
    • Total bilirubin ≤1.5 x ULN (unless the patient has Grade 1 bilirubin elevation due to Gilbert's disease or a similar syndrome involving slow conjugation of bilirubin)
  12. Adequate renal function defined as serum creatinine < 1.5 x ULN OR creatinine clearance > 45 mL/min by Cockcroft-Gault formula for patients with serum creatinine > 1.5x ULN.
  13. Adequate coagulation parameters, defined as International Normalization Ratio (INR) ≤ 2. Patients with history of blood clot may receive anticoagulation with low molecular weight heparin, central line prophylaxis-dose warfarin, or anti-factor Xa agents.
  14. Patients who have partners of childbearing potential must be willing to use a method of birth control with adequate barrier protection as determined to be acceptable by the principal investigator and sponsor during the study and for 3 months after last study drug administration.
  15. Male, Age ≥ 18 years.
  16. Willingness and ability to comply with study and follow -up procedures.
  17. Ability to understand the nature of this study and give written informed consent.
  18. Availability of tumor tissue (formalin-fixed paraffin-embedded [FFPE] blocks) or unstained slides from any time since diagnosis of prostate cancer disease (i.e., archival tumor samples). If no tumor samples are available the patient might still be eligible following discussion between the investigator and the Medical Monitor.
Exclusion Criteria

Exclusion Criteria

  1. Patients that have received the following prior treatments for CRPC
    • Prior cytotoxic chemotherapy Note: Patients may have received docetaxel in the hormone-sensitive setting.
    • PI3K/AKT /mTOR agent (including TORC1 and TORC2 inhibitors) for the treatment of CRPC.
    • Immune checkpoint inhibitors (e.g. inhibitors of CTLA4, PD1, PDL1)
    • Prior investigational new generation potent anti-androgen therapy (such as ARN 509).
    • Prior treatment with enzalutamide.
  2. Pathological finding consistent with small cell carcinoma of the prostate.
  3. Concurrent use of another investigational agent(s).
  4. Prior systemic treatment with an azole drug (fluconazole, itraconazole) within 4 weeks of Cycle 1 Day 1.
  5. Known brain metastasis.
  6. History of (a) seizure or any condition that may predispose to seizure (prior cortical stroke or significant brain trauma); (b) loss of consciousness or transient ischemic attack within 12 months prior to Day 1 of Cycle 1.
  7. Uncontrolled hypertension (systolic blood pressure [BP] ≥ 160 mmHg or diastolic BP ≥ 95 mmHg). Patients with a history of hypertension are allowed, provided blood pressure is controlled by anti-hypertensive treatment.
  8. Have serious pre-existing medical conditions (at the discretion of the investigator).
  9. Have known acute or chronic leukemia or current hematologic malignancies that, in the judgment of the investigator and Medical Monitor, may affect the interpretation of results.
  10. Have insulin-dependent diabetes mellitus. Patients with a type 2 diabetes mellitus are eligible if adequate control of blood glucose level is obtained by oral anti-diabetics as documented by HbA1c <7%.
  11. Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea Grade ≥2, and malabsorption syndrome).
  12. Have a history of New York Heart Association (NYHA) Class ≥3, QTc interval > 450 ms on screening electrocardiogram (ECG) per Friderica's formula at several consecutive days of assessment, unstable angina, or myocardial infarction (MI) in 6 months prior to study drug administration.
  13. Clinically significant electrolyte imbalance ≥ Grade 2.
  14. Currently receiving treatment with therapeutic doses of warfarin sodium. Low molecular weight heparin and oral Xa inhibitors are allowed.
  15. Have initiated treatment with bisphosphonates or approved RANK ligand (RANK-L) targeted agents (e.g. denosumab) ≤28 days prior to Day 1 of Cycle 1.
  16. Concurrent serious infections requiring parenteral antibiotic therapy.
  17. Have a second primary malignancy that in the judgment of the investigator and sponsor may affect the interpretation of results.
  18. Have an active, known fungal, bacterial, and/or known viral infection including:
    • human immunodeficiency virus (HIV) (screening not required)
    • hepatitis A (screening not required)
    • hepatitis B or C (screening not required).
  19. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.