A Study of Enzalutamide and LY3023414 in Men With Prostate Cancer

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

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.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer Metastatic
• Intervention / Treatment: Drug: Placebo; Drug: LY3023414; Drug: Enzalutamide

• Study Type: Interventional
• Enrollment (Actual): 142
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Homewood, Alabama, United States, 35209
      • Urology Centers of Alabama, P.C.
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Highlands Oncology Group
  • California
    • Marina Del Rey, California, United States, 90292
      • Prostate Oncology Specialists
    • San Diego, California, United States, 92123
      • Sharp Memorial Hospital
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists
    • Saint Petersburg, Florida, United States, 33705
      • Florida Cancer Specialists North
    • West Palm Beach, Florida, United States, 33401
      • Florida Cancer Specialists East
  • Illinois
    • Harvey, Illinois, United States, 60426
      • Ingalls Memorial Hospital
  • Indiana
    • Fort Wayne, Indiana, United States, 46845
      • Fort Wayne Oncology & Hematology
    • Indianapolis, Indiana, United States, 46202-5286
      • Indiana Cancer Pavilion
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Minnesota Oncology/Hematology PA
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Urology Cancer Center
  • Nevada
    • Las Vegas, Nevada, United States, 89148
      • Comprehensive Cancer Centers of Nevada
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Garden State Urology
    • Voorhees, New Jersey, United States, 08043
      • Delaware Valley Urology
  • New York
    • Syracuse, New York, United States, 13210
      • Associated Medical Professionals of Ny
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Oncology Hematology Care Inc
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
  • Oregon
    • Springfield, Oregon, United States, 97477
      • Oregon Urology Institute
    • Tualatin, Oregon, United States, 97062
      • Northwest Cancer Specialists PC
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17604
      • Urological Associates of Lancaster
    • Pittsburgh, Pennsylvania, United States, 15213
      • Univ of Pittsburgh Cancer Inst. (UPCI)
  • South Carolina
    • Myrtle Beach, South Carolina, United States, 29572
      • Carolina Urologic Research Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology PLLC
    • Nashville, Tennessee, United States, 37209
      • Urology Associates
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute SCRI
  • Texas
    • Dallas, Texas, United States, 75390
      • Southwestern Medical Center - Dallas
    • Fort Worth, Texas, United States, 76104
      • Texas Oncology-Baylor Charles A. Sammons Cancer Center
    • Houston, Texas, United States, 77024
      • Texas Oncology-Memorial City
    • The Woodlands, Texas, United States, 77380
      • US Oncology
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia Health System
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists
    • Norfolk, Virginia, United States, 23502
      • Virginia Oncology Associates
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: 200 mg LY3023414 BID + 160 mg of Enzalutamide QD; 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; Administered orally; Drug: Enzalutamide; Administered orally
Experimental: Part B: 200 mg LY3023414 BID + 160 mg Enzalutamide QD; Participants received 200 mg LY3023414 orally BID in combination with 160 mg enzalutamide orally once daily (QD).	Drug: LY3023414; Administered orally; Drug: Enzalutamide; Administered orally
Active Comparator: Part B: Placebo + 160 mg Enzalutamide QD; Participants received placebo in combination with 160 mg enzalutamide QD.	Drug: Placebo; Administered orally; Drug: Enzalutamide; Administered orally

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Eli Lilly and Company
• Collaborators: Sarah Cannon Development Innovations

Publications and helpful links

General Publications

• Sweeney CJ, Percent IJ, Babu S, Cultrera JL, Mehlhaff BA, Goodman OB, Morris DS, Schnadig ID, Albany C, Shore ND, Sieber PR, Guba SC, Zhang W, Wacheck V, Donoho GP, Szpurka AM, Callies S, Lin BK, Bendell JC. Phase Ib/II Study of Enzalutamide with Samotolisib (LY3023414) or Placebo in Patients with Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res. 2022 Jun 1;28(11):2237-2247. doi: 10.1158/1078-0432.CCR-21-2326.

Study record dates

Study Major Dates

• Study Start (Actual): April 29, 2015
• Primary Completion (Actual): September 26, 2018
• Study Completion (Actual): April 16, 2020

Study Registration Dates

• First Submitted: March 30, 2015
• First Submitted That Met QC Criteria: March 30, 2015
• First Posted (Estimate): April 2, 2015

Study Record Updates

• Last Update Posted (Actual): May 11, 2021
• Last Update Submitted That Met QC Criteria: April 17, 2021
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms
• Other Study ID Numbers: 15798; I6A-MC-CBBD (Other Identifier: Eli Lilly and Company)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• IPD Sharing Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
• IPD Sharing Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)