A Phase 2 Study With Enzastaurin Plus Chemotherapy or Placebo Plus Chemotherapy for Prostate Cancer Patients

Study Overview
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Brief Summary
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The purpose of the study is to compare the response rates for prostate cancer patients taking chemotherapy plus enzastaurin versus chemotherapy plus placebo.

Official Title
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A Randomized, Double-Blinded, Placebo-Controlled, Phase 2 Study With and Without Enzastaurin in Combination With Docetaxel and Prednisone, Followed By Enzastaurin Maintenance as First-Line Treatment in Hormone Refractory Metastatic Prostate Cancer Patients

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: enzastaurin
* Drug: placebo
* Drug: docetaxel
* Drug: prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: You are at least 18 years old. You live close enough to the doctor's office to attend all of your required visits. You have not been treated with chemotherapy for your prostate cancer. Your organs must be functioning properly. Exclusion Criteria: You are unable to swallow pills. You have another serious illness besides your prostate cancer. You have taken another experimental drug within the last 30 days. You have a serious heart condition. You are receiving another anti-cancer therapy.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: docetaxel + prednisone + enzastaurin<br>Regimen A: docetaxel 75 milligrams per square meter (mg/m^2), intravenous (IV) is administered on Day 1 every 3 weeks for 6 cycles (maximum up to 10 cycles) and prednisone 5 milligrams (mg) oral (po), twice daily (BID) every day. In Cycle 1, enzastaurin is given as a loading dose of 1125 mg on the day prior to docetaxel and prednisone therapy, followed by enzastaurin 500 mg po, daily (QD) for the remaining Period 2 (chemotherapy) and Period 3 (maintenance). | Drug: enzastaurin<br>* 1125 mg loading dose, then 500 mg po QD until disease progression, toxicity, or maximum 3 years<br>* Other names: LY317615;Drug: docetaxel<br>* 75 mg/m^2 IV, every 21 days, six 21-day cycles, maximum 10 cycles<br>Drug: prednisone<br>* 5 mg po BID, six 21-day cycles<br>|
| Placebo Comparator: docetaxel + prednisone + placebo<br>Regimen B: docetaxel 75 mg/m^2, IV is administered on Day 1 every 3 weeks for 6 cycles (maximum up to 10 cycles) and prednisone 5 mg po, BID every day. In Cycle 1, placebo is given as a loading dose on the day prior to docetaxel and prednisone therapy, followed by po, QD placebo for the remaining Period 2 (chemotherapy) and Period 3 (maintenance), until unblinding. | Drug: placebo<br>* Loading dose, then po QD until unblinding<br>|
| Experimental: docetaxel + prednisone + enzastaurin (modified Regimen A)<br>Modified Regimen A, including pharmacokinetic (PK) characterization: Participants were treated with a modified investigational regimen with no dose escalation: docetaxel 75 mg/m2, IV was administered on Day 1 every 3 weeks for 6 cycles (maximum up to 10 cycles) and prednisone 5 mg po, BID every day. In Cycle 1, enzastaurin was given as a loading dose of 1125 mg starting on Day 4, followed by enzastaurin 500 mg po, QD for the remaining Period 2 (chemotherapy) and Period 3 (maintenance). | Drug: enzastaurin<br>* 1125 mg loading dose, then 500 mg po QD until disease progression, toxicity, or maximum 3 years<br>* Other names: LY317615;Drug: docetaxel<br>* 75 mg/m^2 IV, every 21 days, six 21-day cycles, maximum 10 cycles<br>Drug: prednisone<br>* 5 mg po BID, six 21-day cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Percentage of Participants With Objective Tumor Response (Response Rate) | Response using Response Evaluation Criteria In Solid Tumors (RECIST). Complete Response (CR)=disappearance of all target lesions; Partial Response (PR)=30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD)=20% increase in sum of longest diameter of target lesions; Stable Disease (SD)=small changes that do not meet above criteria. Objective response rate (%)=number of objective responders divided by the number of participants qualified for efficacy analysis *100, where objective responders are those participants who have met criteria either for CR or PR. | Baseline up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Exhibiting a Decline in Prostate-Specific Androgen (PSA) From Baseline ≥30% Within First 3 Months of Treatment | PSA is a protein produced by the cells of the prostate gland. PSA is present in small quantities in the serum of men with healthy prostates, but is often elevated in the presence of prostate cancer and in other prostate disorders. A blood test to measure PSA is considered the most effective test currently available for the early detection of prostate cancer. Decline in PSA of ≥30% from baseline within the first 3 months of treatment was calculated. | Baseline up to 3 months | 
| Prostate-Specific Androgen (PSA) Velocity at 2 Months | PSA is a protein produced by the cells of the prostate gland. PSA is present in small quantities in the serum of men with healthy prostates, but is often elevated in the presence of prostate cancer and in other prostate disorders. A blood test to measure PSA is considered the most effective test currently available for the early detection of prostate cancer. PSA velocity is computed for each participant by means of linear regression on the logarithm of PSA. The linear regression fits a line through the logarithm of the PSA value on the y-axis, and the time from baseline on the x-axis with the baseline PSA value at time zero. The resulting slope is PSA velocity. | Baseline up to 2 months | 
| Prostate-Specific Androgen (PSA) Velocity at 3 Months | PSA is a protein produced by the cells of the prostate gland. PSA is present in small quantities in the serum of men with healthy prostates, but is often elevated in the presence of prostate cancer and in other prostate disorders. A blood test to measure PSA is considered the most effective test currently available for the early detection of prostate cancer. PSA velocity is computed for each participant by means of linear regression on the logarithm of PSA. The linear regression fits a line through the logarithm of the PSA value on the y-axis, and the time from baseline on the x-axis with the baseline PSA value at time zero. The resulting slope is PSA velocity. | Baseline up to 3 months | 
| Part 2: Progression Free Survival (PFS) | PFS was defined as the time from the date of study enrollment to the first date of objectively determined progressive disease (PD) or death from any cause. PD was determined using Response Evaluation Criteria In Solid Tumors (RECIST version 1.0). PD is ≥20% increase in the sum of the longest diameter (LD) of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions. For participants not known to have died and who did not have PD, PFS was censored at the date of the last progression-free assessment. For participants who received subsequent systemic anticancer therapy (after discontinuation from the study treatment) prior to disease progression or death, PFS was censored at the date of last progression-free assessment prior to the initiation of post-discontinuation systemic anticancer therapy. No participant completed a full cycle of therapy and thus no formal analysis was performed. | Baseline to measured PD (up to 487 days) | 
| Part 2: Overall Survival (OS) | Overall survival (OS) time is defined as the time from the date of diagnosis to the date of death from any cause. For participants who are still alive at the time of analysis, survival time will be censored at the last contact date. | Baseline to death (up to 642 days) | 
| Part 2: Duration of Response | Duration of response is defined as the time from date of objective response to progressive disease (PD) or death or prostate-specific androgen (PSA) returning to at least 50% from original baseline value. | First objective response to PD/death/PSA returning to 50% or more than the original baseline value (up to 616 days) | 
| Number of Participants With Adverse Events (AEs) | A listing of serious AEs (SAEs) and all other non-serious AEs is included in the Reported Adverse Event Module. | Baseline through 3 years | 
| Part I: Pharmacokinetic (PK) Parameter: Maximum Observed Drug Concentration During a Dosing Interval at Steady State (Cmax,ss) of Enzastaurin, LSN326020, and Total Analyte (Enzastaurin + LSN326020) | Cmax,ss was calculated using concentration versus time data of enzastaurin, LSN326020, and total analyte (enzastaurin + LSN326020). Data are reported as Geometric Mean and Geometric Coefficient of Variation (%). | Part 1: Cycle 1, Day 21 - predose 2, 4, 6, 8, and 24 hours postdose; Cycle 2, Day 1 - predose, 2, 3, 4, 8, and 24 hours postdose | 
| Pharmacokinetic (PK) Parameter: Area Under the Concentration Versus Time Curve During 1 Dosing Interval at Steady State (AUCτ,ss) of Enzastaurin, LSN326020, and Total Analyte (Enzastaurin + LSN326020) | AUCτ,ss was calculated using concentration versus time data of enzastaurin, LSN326020, and total analyte (enzastaurin + LSN326020). Data are reported as Geometric Mean and Geometric Coefficient of Variation (%). | Part 1: Cycle 1, Day 21 - predose 2, 4, 6, 8, and 24 hours postdose; Cycle 2, Day 1 - predose, 2, 3, 4, 8, and 24 hours postdose; Part 2: Cycle 2, Day 1 - predose, 1-3, and 4-9 hours postdose | 
| Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) of Docetaxel | Cmax was calculated using concentration versus time data of docetaxel. Data are reported as Geometric Mean and Geometric Coefficient of Variation (%). | Part 1: Cycle 1, Day 1 - predose 0.5, 1, 1.5, 2, 3, 4, 8, and 24 hours postdose; Cycle 2, Day 1 - predose, 0.5, 1, 1.5, 2, 3, 4, 8, and 24 hours postdose | 
| Pharmacokinetic (PK) Parameter: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC[0-∞]) of Docetaxel | AUC(0-∞) was calculated using concentration versus time data of docetaxel. Data are reported as Geometric Mean and Geometric Coefficient of Variation (%). | Part 1: Cycle 1, Day 1 - predose 0.5, 1, 1.5, 2, 3, 4, 8, and 24 hours postdose; Cycle 2, Day 1 - predose, 0.5, 1, 1.5, 2, 3, 4, 8, and 24 hours postdose | 
| Tumor Markers | Pharmacogenomic (PGx) work on S032 was cancelled due to the limited number of tissue samples collected and the lack of clinical efficacy (responders) to enzastaurin. Potential biomarkers would have been assessed by dividing participants into low and high expression classes. | Baseline up to 36 months |