Comparing Two Treatments for Ovarian Cancer: Standard Chemotherapy Plus Enzastaurin, or Placebo (Sugar Pill)

Study Overview
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Brief Summary
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Participants with ovarian cancer usually get the drugs carboplatin and paclitaxel as initial treatment. In many participants the tumor will shrink, or even disappear, after treatment with these drugs. But, unfortunately, the tumor will grow again in many participants. This trial will try to address the question: Can we delay the time till the tumor grows again by adding a 3rd drug to the standard therapy? To answer this question, participants will, by chance, either get the experimental drug enzastaurin or a dummy pill (placebo) during the chemotherapy and for up to 3 years after chemotherapy. Participants and physicians will not know if a participant gets enzastaurin or placebo (double-blinded trial). After a predefined time, the treatment will be uncovered, and the number of participants with tumor growth at a specific time point will be compared between the two treatments.

Official Title
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A Randomized, Phase 2, Placebo-Controlled, Double-Blinded Study With and Without Enzastaurin in Combination With Paclitaxel and Carboplatin as First-Line Treatment, Followed by Maintenance Treatment in Advanced Ovarian Cancer

Conditions
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Ovarian Cancer, Fallopian Tube Neoplasms, Peritoneal Neoplasm

Intervention / Treatment
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* Drug: enzastaurin
* Drug: carboplatin
* Drug: paclitaxel
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have specific stages of disease, known as Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stages IIB, IIC, III or IV Organ functions (blood, renal, liver, cardiac) must meet specific requirements. Participants who could become pregnant must take care not to become pregnant during the study participation and for 6 months after study discontinuation Participants must give written consent for study participation. Exclusion Criteria: Participants received any experimental drug within the last 30 days. Participants received any prior chemotherapy or other drug therapy for the current disease. Participants receive any other treatment for the cancer during study participation. Participants are unable to discontinue concurrent administration of carbamazepine, phenobarbital, or phenytoin. Participants are pregnant, breast feeding, or not using adequate contraceptive methods to prevent pregnancy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: A (Part A)<br>Enzastaurin: 1125 milligram (mg) loading dose then 500 mg oral tablet, daily for six 21-day cycles or up to 3 years Carboplatin: Area under the concentration time curve (AUC) 5 intravenous (IV), every (q) 21 days for six 21-day cycles Paclitaxel:175 milligrams/square meter (mg/m²) IV, q21 days for six 21-day cycles | Drug: enzastaurin<br> <br> * Other names: LY317615;Drug: carboplatin<br> <br> Drug: paclitaxel<br> <br> |
| Placebo Comparator: B (Part B)<br>Carboplatin: AUC5 IV, q21 days for six 21-day cycles Paclitaxel: 175 mg/m², IV, q21 days for six 21-day cycles Placebo: oral tablet | Drug: carboplatin<br> <br> Drug: paclitaxel<br> <br> Drug: placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Progression-Free Survival (PFS) | PFS was defined as time from date of randomization to first date of determined progressive disease (PD) or death from any cause. PD defined using Response Evaluation Criteria in Solid Tumors (RECIST v1.0) and Gynecological Cancer Intergroup (GCIG) criteria. RECIST: ≥20% increase in sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since treatment started or appearance of ≥ 1new lesions and/or unequivocal progression of existing non-target lesions. GCIG: Cancer Antigen-125 (CA-125) serum ≥2 times upper limit of normal (ULN) for those in normal range or nadir for participants who never achieved normal range. Participants not known to have died and did not have PD were censored at last progression-free assessment. Those who received subsequent systemic anticancer therapy (after study drug discontinued) prior to determined PD or death, were censored at date of last progression-free disease assessment prior to post-discontinuation chemotherapy. | Randomization up to date of PD or death (up to 28.6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Percentage of Participants With PFS at 2 Years | PFS was defined as time from date of randomization to first date of determined PD or death from any cause. PD defined using RECIST v1.0 and GCIG criteria. RECIST v1.0: as ≥20% increase in sum of LD of target lesions taking as reference the smallest sum LD recorded since treatment started or appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. GCIG: CA-125 serum ≥2 times ULN for those in normal range or nadir (the lowest value of blood counts after chemotherapy) for participants who never achieved normal range. Participants not known to have died and did not have PD were censored at last progression-free assessment. Those who received subsequent systemic anticancer therapy (after study drug discontinued) prior to determined PD or death, were censored at date of last progression-free disease assessment prior to post-discontinuation chemotherapy. | Randomization to measured PD evaluated at 2 years | 
| Part 2: Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR)] | ORR was the percentage of participants with a CR or PR using RECIST v1.0 and CA-125 GCIG criteria. RECIST v1.0: CR was defined as the disappearance of all tumors. PR was defined ≥30% decrease in the sum of the LD of target lesions taking as reference the baseline sum LD or complete disappearance of target lesions, with persistence (but not worsening) of ≥1 nontarget lesions and appearance of no new lesions. GCIG: CA-125 serum ≥2 times above ULN for those in normal range or nadir for participants who never achieved normal range. ORR calculated as: (CR + PR) / (total number of participants qualified for tumor response analysis per arm) * 100. | Randomization to PD or death from any cause (up to 28.6 months) | 
| Part 2: Percentage of Participants With CR or PR or Stable Disease (SD) (Rate of Response) | Rate of response was defined using RECIST v1.0 and CA-125 GCIG criteria. RECIST v1.0: CR was defined as the disappearance of all target lesions. PR was defined ≥30% decrease in the sum of the LD of target lesions taking as reference the baseline sum LD or complete disappearance of target lesions, with persistence (but not worsening) of ≥1 nontarget lesions and appearance of no new lesions. SD was defined as small changes that did not meet the above criteria. PD was defined as having a ≥20% increase in the sum of the LD of target lesions. GCIG: CA-125 serum ≥2 times above ULN for those in normal range or nadir for participants who never achieved normal range. Rate of response calculated as: (CR + PR + SD)/(total number of participants qualified for tumor response analysis per arm) *100. | Randomization to PD or death from any cause (up to 28.6 months) | 
| Part 2: Translational Research: PFS Based on Protein Expression (PE) (To Assess Biological Markers in Tumors That Could Indicate Who Could Benefit From Enzastaurin Treatment) | PE measured using Immunohistochemistry (IHC) assay, scored 0 (negative, no staining) to 3+ (brightest staining). IHC H-scores for protein biomarkers (PKCβ2, PTEN, pCREB, pGSK3b, pS6) calculated as: [1*(percentage of cells stained [PCS] as 1+)]+[2*(PCS as 2+)]+[3*(PCS as 3+)]. High PE: ≥marker threshold value and Low PE: <marker threshold value. PFS: date of randomization to PD or death. PD defined using RECIST v1.0 and GCIG criteria. RECIST: ≥20% increase in sum of LD of target lesions taking as references smallest sum LD recorded since treatment started or appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. GCIG: CA-125 serum ≥2 times ULN for those in normal range or nadir for those who never achieved normal range. Per protocol, Part 1 was not included as it is an open-label safety lead-in portion with PK characterization. | Randomization up to date of PD or death (up to 28.6 months) | 
| Number of Participants With Serious Adverse Events (SAEs), Other Non-Serious Adverse Events (AEs) and the Number of Participants Who Died (To Compare the Safety of the 2 Treatments) | Clinically significant events were defined as SAEs and other non-serious AEs regardless of causality. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Events module. The number of participants SAEs, other non-serious AEs, and those who died due to PD are included. | Randomization up to 28.6 months | 
| Pharmacokinetics (PK): Maximum Concentration (Cmax) for Carboplatin With and Without Enzastaurin for Part 1 of Study |  | Cycle 1 Day 1 (carb) and Cycle 2 Day 1 (carb + enz); carb 0.25 hours (h) (prior to infusion), 0.5, 1, 2, 3, 5, and 21h after start of infusion | 
| PK: Cmax for Paclitaxel With and Without Enzastaurin for Part 1 of Study |  | Cycle 1 Day 1 (pac) and Cycle 2 Day 1 (pac + enz); pac 1, 2, 3h (immediately after stopping infusion), 3.25, 3.5, 4, 5, 6, 8, 24, and 30h after start of infusion | 
| PK: AUC From Time 0 to Infinity (AUC0-∞) for Carboplatin With and Without Enzastaurin for Part 1 of Study |  | Cycle 1 Day 1 (carb) and Cycle 2 Day 1 (carb + enz); carb at 0.25h (prior to infusion), 0.5, 1, 2, 3, 5, and 21h after start of infusion | 
| PK: AUC0-∞ for Paclitaxel With and Without Enzastaurin for Part 1 of Study |  | Cycle 1 Day 1 (pac) and Cycle 2 Day 1 (pac + enz); pac at 1, 2, 3h (immediately after stopping infusion), 3.25, 3.5, 4, 5, 6, 8, 24, and 30h after start of infusion | 
| PK: Cmax at Steady State (Cmax,ss) for Part 1 of Study | Cmax,ss for enzastaurin, its metabolite LSN326020 (LY326020) and total analytes are reported. | Cycle 1 Day 21 (enz) and Cycle 2 Day 1 (carb + pac + enz) at pre-dose, 2, 4, 6, 8 and 24h after the enz dose | 
| PK: AUC During the Dosing Interval at Steady State (AUCτ,ss) for Part 2 of Study | AUCτ,ss for enzastaurin, its metabolite LSN326020 (LY326020), and total analytes are reported. | Cycle 2 Day 1 (carb + pac + enz) at pre-dose, 2, 4, 6, 8 and 24h after the enz dose |