A Study of Enzalutamide and LY3023414 in Men With Prostate Cancer

• ClinicalTrials.gov Identifier: NCT02407054
• Recruitment Status: Completed
• First Posted: April 2, 2015
• Results First Posted: May 11, 2021
• Last Update Posted: May 11, 2021
• Sponsor: Eli Lilly and Company
• Collaborator: Sarah Cannon Development Innovations
• Information provided by (Responsible Party): Eli Lilly and Company

Tracking Information

• First Submitted Date: March 30, 2015
• First Posted Date: April 2, 2015
• Results First Submitted Date: April 17, 2021
• Results First Posted Date: May 11, 2021
• Last Update Posted Date: May 11, 2021
• Actual Study Start Date: April 29, 2015
• Actual Primary Completion Date: September 26, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 17, 2021)

Part B: Progression Free Survival (PFS) [ Time Frame: Randomization to Measured Progressive Disease or Death from Any Cause (Up To 34 Months) ]

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).

• Original Primary Outcome Measures (submitted: March 30, 2015): Progression Free Survival (PFS) [ Time Frame: Baseline to Measured Progressive Disease or Death from Any Cause (Approximately 6 Months) ]

Current Secondary Outcome Measures (submitted: April 17, 2021)

• Part B: Time to Disease Progression (TTP) [ Time Frame: Randomization to Objective Disease Progression (Up To 34 Months) ]
  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).
• Part B: Percentage of Participants With Prostate Specific Antigen Response [ Time Frame: 12 Weeks ]
  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.
• Part A: Pharmacokinetic (PK): Area Under the Concentration-time Curve Over the Dosing Interval (AUCτ) of LY3023414 [ Time Frame: 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 ]
  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 B: Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR]) [ Time Frame: Randomization to Second Measured Complete Response or Partial Response (Up To 34 Months) ]
  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.

Original Secondary Outcome Measures (submitted: March 30, 2015)

• Time to Disease Progression [ Time Frame: Baseline to Objective Disease Progression (Approximately 6 Months) ]
• Percent Change from Baseline to 12 Weeks in Prostate Specific Antigen (PSA) [ Time Frame: Baseline, 12 Weeks ]
• PK: Area Under the Concentration Curve (AUC) of LY3023414 and Enzalutamide [ Time Frame: Predose Cycle 1 to Cycle 3 Day 1 (Approximately 2 Months) ]
• Proportion of Participants with a Complete or Partial Response (Overall Response Rate) [ Time Frame: Baseline to Second Measured Complete Response or Partial Response (Approximately 4 Months) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Enzalutamide and LY3023414 in Men With Prostate Cancer
• Official 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Prostate Cancer Metastatic

Intervention

• Drug: LY3023414
  Administered orally
• Drug: Enzalutamide
  Administered orally
• Drug: Placebo
  Administered orally

Study Arms

• 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.
  Interventions:

  • Drug: LY3023414
  • Drug: Enzalutamide
• 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).
  Interventions:

  • Drug: LY3023414
  • Drug: Enzalutamide
• Active Comparator: Part B: Placebo + 160 mg Enzalutamide QD
  Participants received placebo in combination with 160 mg enzalutamide QD.
  Interventions:

  • Drug: Enzalutamide
  • Drug: Placebo

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 17, 2021): 142
• Original Estimated Enrollment (submitted: March 30, 2015): 144
• Actual Study Completion Date: April 16, 2020
• Actual Primary Completion Date: September 26, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02407054
• Other Study ID Numbers: 15798; I6A-MC-CBBD ( Other Identifier: Eli Lilly and Company )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• 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.
• Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• URL: https://vivli.org/

• Current Responsible Party: Eli Lilly and Company
• Original Responsible Party: Same as current
• Current Study Sponsor: Eli Lilly and Company
• Original Study Sponsor: Same as current
• Collaborators: Sarah Cannon Development Innovations

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST); Eli Lilly and Company

• PRS Account: Eli Lilly and Company
• Verification Date: June 2020