A Study of Enzalutamide and LY3023414 in Men With Prostate Cancer

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the safety and effectiveness of the study drug known as LY3023414 in combination with enzalutamide in men with prostate cancer.

Official Title
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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

Conditions
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Prostate Cancer Metastatic

Intervention / Treatment
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* Drug: LY3023414
* Drug: Enzalutamide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the prostate. Metastatic disease documented by positive bone scan or metastatic lesions on computed tomography (CT) or magnetic resonance imaging (MRI) scan. Prostate cancer progression documented by PSA and/or radiographic progression according to prostate cancer working group 2 (PCWG2). Prior abiraterone treatment completed at least 4 weeks prior to cycle 1 day 1. Participants must have failed prior abiraterone treatment. Surgically or medically castrated, with testosterone levels of < 50 nanograms/deciliter. Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1. Ability to swallow the study drugs whole. Adequate hematologic function. Adequate coagulation parameters, defined as international normalization ratio (INR) ≤ 2. Availability of tumor tissue from any time since diagnosis of prostate cancer disease. If no tumor samples are available the participant might still be eligible following discussion between the investigator and the medical monitor. Exclusion Criteria: Prior cytotoxic chemotherapy, immunotherapy, a PI3K/AKT/mTOR agent (including TORC1 and TORC2 inhibitors), or RA 223 dichloride for the treatment of castration resistant prostate cancer (CRPC). Participants may have received docetaxel in the hormone-sensitive setting. Prior investigational new generation potent anti-androgen therapy (such as ARN 509). Prior treatment with enzalutamide. Pathological finding consistent with small cell carcinoma of the prostate. Prior systemic treatment with an azole drug (fluconazole, itraconazole) within 4 weeks of cycle 1 day 1. Known brain metastasis. 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. Uncontrolled hypertension (systolic blood pressure [BP] ≥ 160 millimeters of mercury [mmHg] or diastolic BP ≥ 95 mmHg). Have serious pre-existing medical conditions (at the discretion of the investigator). Have known acute or chronic leukemia or current hematologic malignancies that, in the judgment of the investigator and sponsor, may affect the interpretation of results. Have insulin-dependent diabetes mellitus. Participants with a type 2 diabetes mellitus are eligible if adequate control of blood glucose level is obtained by oral anti-diabetics as documented by hemoglobin A1c <7%. 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, grade ≥2 diarrhea, and malabsorption syndrome). Have a history of New York Heart Association (NYHA) Class ≥3, QTc interval > 480 milliseconds (ms) on screening electrocardiogram (ECG) per Friderica's formula, unstable angina, or myocardial infarction (MI) in 6 months prior to study drug administration. Clinically significant electrolyte imbalance ≥ grade 2. Currently receiving treatment with therapeutic doses of warfarin sodium. Have initiated treatment with bisphosphonates or approved receptor activator of nuclear factor kappa-B ligand (RANK-L) targeted agents (e.g. denosumab) ≤28 days prior to day 1 of cycle 1. Concurrent serious infections requiring parenteral antibiotic therapy. Have a second primary malignancy that in the judgment of the investigator and medical monitor may affect the interpretation of results. Have an active, known fungal, bacterial, and/or known viral infection.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: 200 mg LY3023414 BID + 160 mg of Enzalutamide QD<br>Participants received 200 milligrams (mg) LY3023414 orally twice daily (BID) during the initial week to assess pharmacokinetics (PK). Thereafter, participants received 200 mg of LY3023414 BID in combination with 160 mg of enzalutamide QD beginning Cycle 1 Day 1. A treatment cycle was defined as 28 days. | Drug: LY3023414<br>* Administered orally<br>Drug: Enzalutamide<br>* Administered orally<br>|
| Experimental: Part B: 200 mg LY3023414 BID + 160 mg Enzalutamide QD<br>Participants received 200 mg LY3023414 orally BID in combination with 160 mg enzalutamide orally once daily (QD). | Drug: LY3023414<br>* Administered orally<br>Drug: Enzalutamide<br>* Administered orally<br>|
| Active Comparator: Part B: Placebo + 160 mg Enzalutamide QD<br>Participants received placebo in combination with 160 mg enzalutamide QD. | Drug: Enzalutamide<br>* Administered orally<br>Drug: Placebo<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B: Progression Free Survival (PFS) | PFS was defined as the time from randomization until the date of clinical (symptomatic or radiographic) and/or prostate specific antigen (PSA) disease progression per Prostate Cancer Clinical Trials Working Group (PCWG2) or death by any cause regardless of whether the participants withdraws from study drug or receives a subsequent anti-cancer therapy (as determined by the investigator). Participants who have not progressed or died at the time of assessment were censored at the time of the last date of assessment (tumor evaluation or PSA level). | Randomization to Measured Progressive Disease or Death from Any Cause (Up To 34 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B: Time to Disease Progression (TTP) | TTP was defined as time from randomization until the date of clinical (symptomatic or radiographic) and/or prostate specific antigen (PSA) disease progression per Prostate Cancer Clinical Trials Working Group (PCWG2). | Randomization to Objective Disease Progression (Up To 34 Months) | 
| Part B: Percentage of Participants With Prostate Specific Antigen Response | PSA response was defined as more than 50% and 90% reduction from baseline to lowest post baseline value. 95% Confidence Intervals are based on Fisher's Exact Method. | 12 Weeks | 
| Part A: Pharmacokinetic (PK): Area Under the Concentration-time Curve Over the Dosing Interval (AUCτ) of LY3023414 | PK: Area under the Concentration-time Curve Over the Dosing Interval (AUCτ) of LY3023414 Time Frame: Part A LY3023414 200 mg: Day-1 pre-dose, 1.5, 3, and 6 hours post LY3023414 dose, Cycle 1 Day 1 pre-dose of LY3023414 and enzalutamide, and Part A Day 15 Pre-dose of LY3023414 and enzalutamide 1.5, 3, and 6 hours post LY3023414 dose; | Part A: 200 mg LY3023414 + 160 mg Enzalutamide: Cycle 1 Day 15 Pre-dose of LY3023414 and enzalutamide 1.5, 3, and 6 hours post LY3023414 dose | 
| Part B: Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR]) | ORR was the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 millimeter (mm), or unequivocal progression of non-target lesions, or 1 or more new lesions. | Randomization to Second Measured Complete Response or Partial Response (Up To 34 Months) |