Study of Pemetrexed + Carboplatin + Bevacizumab + Enzastaurin Versus Pemetrexed + Carboplatin + Bevacizumab + Placebo in Participants With Non-Small Cell Lung Cancer Who Have Not Been Previously Treated With Chemotherapy

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine if Pemetrexed plus Carboplatin plus Bevacizumab plus Enzastaurin, followed by maintenance Bevacizumab plus Enzastaurin can extend survival time without disease progression in the first-line treatment of participants with advanced stage non-small cell lung cancer.

Official Title
-----------------
Protocol H6Q-MC-S034(a) Randomized, Double-Blind, Phase 2 Study of Pemetrexed + Carboplatin + Bevacizumab + Enzastaurin Versus Pemetrexed + Carboplatin + Bevacizumab + Placebo in Chemonaive Patients With Stage IIIB or IV Non-Small Cell Lung Cancer

Conditions
-----------------
Non-small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: enzastaurin
* Drug: pemetrexed
* Drug: carboplatin
* Drug: bevacizumab
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: participants or their legal representative must have signed an informed consent document for clinical research have laboratory confirmed diagnosis of advanced, nonsquamous cell non-small cell lung cancer (NSCLC) (Stage IIIB or IV disease) which is not curable have not received any prior systemic chemotherapy, immunotherapy, targeted therapy, or biological therapy for advanced NSCLC, prior radiation therapy is allowed to less than 25% of the bone marrow have measurable disease have adequate organ function and estimated life expectancy of 12 weeks Exclusion Criteria: have known central nervous system (CNS) disease; major surgery within 28 days; minor surgery within 7 days; serious concomitant systemic disorder; serious cardiac condition; have a serious, nonhealing wound, ulcer, or bone fracture have received treatment within the last 30 days with any drug that has not received regulatory approval for any indication at the time of study entry have previously received treatment with enzastaurin, pemetrexed, or bevacizumab are pregnant or breast-feeding are unable to swallow tablets

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>Pemetrexed + Carboplatin + Bevacizumab + Enzastaurin | Drug: enzastaurin<br>* 1125 milligram (mg) loading dose then 500 mg, oral, daily until disease progression<br>* Other names: LY317615;Drug: pemetrexed<br>* 500 milligrams per square meter (mg/m^2), intravenously ( IV), Day 8 of cycle 1 - 28 days, Day 1 of subsequent cycles every (q) 21 days x 3 cycles<br>* Other names: Alimta;Drug: carboplatin<br>* Area under the curve (AUC) 6, IV, Day 8 cycle 1 - 28 days, Day 1 of subsequent cycles q 21 days x 3 cycles<br>Drug: bevacizumab<br>* 15 milligrams/kilogram (mg/kg), IV, Day 8 of cycle 1 - 28 days, Day 1 of subsequent cycles q 21 days x 3 cycles<br>|
| Placebo Comparator: B<br>Pemetrexed + Carboplatin + Bevacizumab + Placebo | Drug: pemetrexed<br>* 500 milligrams per square meter (mg/m^2), intravenously ( IV), Day 8 of cycle 1 - 28 days, Day 1 of subsequent cycles every (q) 21 days x 3 cycles<br>* Other names: Alimta;Drug: carboplatin<br>* Area under the curve (AUC) 6, IV, Day 8 cycle 1 - 28 days, Day 1 of subsequent cycles q 21 days x 3 cycles<br>Drug: bevacizumab<br>* 15 milligrams/kilogram (mg/kg), IV, Day 8 of cycle 1 - 28 days, Day 1 of subsequent cycles q 21 days x 3 cycles<br>Drug: Placebo<br>* oral, daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS was defined as the time from date of randomization to the first observation of progressive disease (PD) or death due to any cause. For participants not known to have died as of the data cutoff date and who did not have objective PD, PFS was censored at the date of the last objective progression-free assessment. For participants who received subsequent anticancer therapy (after discontinuation from all study treatment) prior to objective disease progression or death, PFS was censored at the date of the last objective progression-free assessment prior to the initiation of post-discontinuation anticancer therapy. | Randomization to measured PD or death from any cause up to 12.2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Response Rate) | Tumor response rate was defined as number of participants with overall best response of CR or PR over number of protocol qualified participants using the Response Evaluation Criteria in Solid Tumors (RECIST v1.0) criteria. CR was defined as the disappearance of all tumor lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum of LDs or complete disappearance of target lesions, with persistence (but not worsening) of 1 or more non-target lesions. In either case, no new lesions may have appeared. Percentage of participants was calculated as: (number of participants with CR or PR/ number of participants qualified for tumor response analysis) × 100. | Randomization to measured progressive disease or death from any cause up to 12.2 months | 
| Overall Survival (OS) | OS was defined as the time from the date of randomization to the date of death from any cause. For participants who were not known to have died as of the data cutoff, OS was censored at the last contact date. | Randomization to date of death up to 14.3 months | 
| Time to Progressive Disease (TTPD) | TTPD was defined as the time from the date of randomization until the first date of objectively determined progressive disease (PD). For participants who died without objective PD (including death from study disease), TTPD was censored at the date of the last objective progression-free disease assessment. For participants not known to have died as of the data cutoff and did not have PD, TTPD was censored at the date of the last objective progression-free disease assessment. | Randomization to measured PD or death from any cause up to 12.2 months | 
| Duration of Response (DoR) | The duration of a complete response (CR) or partial response (PR) was defined as the time from first objective status assessment of CR or PR to the first time of progression or death from any cause. Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST v1.0) criteria. CR was defined as the disappearance of all target lesions and PR was defined as having at least a 30% decrease in sum of longest diameter (LD) of target lesions taking as reference the baseline sum of LDs. For participants who died without progressive disease or who were alive, DoR was censored at the last contact of progression free assessment. For participants who received subsequent anticancer therapy (after discontinuation from all study treatment) prior to PD, DoR was censored at the date of last progression-free assessment prior to the initiation of post-discontinuation anticancer therapy. Due to early study closure, DoR was not analyzed. | Time of response to disease progression or death from any cause up to 12.2 months | 
| Pharmacology Toxicity and Adverse Events (AEs) | Clinically significant events were defined as serious AEs (SAEs) and other non-serious AEs. Participants who died due to progressive disease (PD) or an AE while on treatment and or died during the 30 day post-treatment follow-up are included. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. | Randomization up to 14.3 months and 30-day follow-up |