Trial Outcomes & Findings for 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 (NCT NCT00533429)

Last Updated: 2021-05-13

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

40 participants

Primary outcome timeframe

Randomization to measured PD or death from any cause up to 12.2 months

Results posted on

2021-05-13

Participant Flow

Participant flow reports those participants who discontinued from study drug.

Participant milestones

Participant milestones
Measure	Pemetrexed + Carboplatin + Bevacizumab + Enzastaurin Combination biochemotherapy: Pemetrexed: 500 milligrams per square meter (mg/m\^2) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: Area under the curve (AUC) 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 milligrams/kilogram (mg/kg) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Enzastaurin: 1125 milligram (mg) loading dose on Day 1 of Cycle 1 (28 days), followed by 500 mg oral daily dose for 3 cycles Maintenance therapy: Enzastaurin: 500 mg oral daily dose for 21-day cycles until disease progression Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression	Pemetrexed + Carboplatin + Bevacizumab + Placebo Combination biochemotherapy: Pemetrexed: 500 mg/m\^2 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: AUC 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 mg/kg intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Placebo: Oral tablets daily to complete Cycle 1 (28 days), then subsequent 21-day cycles for 3 cycles Maintenance therapy: Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression Placebo: Oral tablets daily for 21-day cycles until progressive disease
Overall Study STARTED	20	20
Overall Study Received at Least 1 Dose of Study Drug	20	20
Overall Study Entered Maintenance	8	10
Overall Study COMPLETED	1	4
Overall Study NOT COMPLETED	19	16

Reasons for withdrawal

Reasons for withdrawal
Measure	Pemetrexed + Carboplatin + Bevacizumab + Enzastaurin Combination biochemotherapy: Pemetrexed: 500 milligrams per square meter (mg/m\^2) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: Area under the curve (AUC) 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 milligrams/kilogram (mg/kg) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Enzastaurin: 1125 milligram (mg) loading dose on Day 1 of Cycle 1 (28 days), followed by 500 mg oral daily dose for 3 cycles Maintenance therapy: Enzastaurin: 500 mg oral daily dose for 21-day cycles until disease progression Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression	Pemetrexed + Carboplatin + Bevacizumab + Placebo Combination biochemotherapy: Pemetrexed: 500 mg/m\^2 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: AUC 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 mg/kg intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Placebo: Oral tablets daily to complete Cycle 1 (28 days), then subsequent 21-day cycles for 3 cycles Maintenance therapy: Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression Placebo: Oral tablets daily for 21-day cycles until progressive disease
Overall Study Adverse Event	3	1
Overall Study Death	1	0
Overall Study Withdrawal by Subject	2	0
Overall Study Progressive Disease	12	13
Overall Study Symptomatic deterioration	1	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Pemetrexed + Carboplatin + Bevacizumab + Enzastaurin n=20 Participants Combination biochemotherapy: Pemetrexed: 500 milligrams per square meter (mg/m\^2) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: Area under the curve (AUC) 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 milligrams/kilogram (mg/kg) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Enzastaurin: 1125 milligram (mg) loading dose on Day 1 of Cycle 1 (28 days), followed by 500 mg oral daily dose for 3 cycles Maintenance therapy: Enzastaurin: 500 mg oral daily dose for 21-day cycles until disease progression Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression	Pemetrexed + Carboplatin + Bevacizumab + Placebo n=20 Participants Combination biochemotherapy: Pemetrexed: 500 mg/m\^2 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: AUC 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 mg/kg intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Placebo: Oral tablets daily to complete Cycle 1 (28 days), then subsequent 21-day cycles for 3 cycles Maintenance therapy: Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression Placebo: Oral tablets daily for 21-day cycles until progressive disease	Total n=40 Participants Total of all reporting groups
Age, Continuous	62.1 years STANDARD_DEVIATION 9.3 • n=5 Participants	61.2 years STANDARD_DEVIATION 9.0 • n=7 Participants	61.6 years STANDARD_DEVIATION 9.1 • n=5 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	10 Participants n=7 Participants	19 Participants n=5 Participants
Sex: Female, Male Male	11 Participants n=5 Participants	10 Participants n=7 Participants	21 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	20 Participants n=5 Participants	20 Participants n=7 Participants	40 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	20 Participants n=5 Participants	20 Participants n=7 Participants	40 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	20 Participants n=5 Participants	20 Participants n=7 Participants	40 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - Fully Active	10 Participants n=5 Participants	11 Participants n=7 Participants	21 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 1 - Ambulatory, Restricted Strenuous Activity	10 Participants n=5 Participants	9 Participants n=7 Participants	19 Participants n=5 Participants
Prior therapy Yes	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Prior therapy No	17 Participants n=5 Participants	17 Participants n=7 Participants	34 Participants n=5 Participants
Disease Stage Stage IIIB	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Disease Stage Stage IV	17 Participants n=5 Participants	17 Participants n=7 Participants	34 Participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization to measured PD or death from any cause up to 12.2 months

Population: All randomized participants identified by assigned treatment group. Number of participants censored: Pemetrexed + Carboplatin + Bevacizumab + Enzastaurin = 5; Pemetrexed + Carboplatin + Bevacizumab + Placebo = 2.

Outcome measures

Outcome measures
Measure	Pemetrexed + Carboplatin + Bevacizumab + Enzastaurin n=15 Participants Combination biochemotherapy: Pemetrexed: 500 milligrams per square meter (mg/m\^2) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: Area under the curve (AUC) 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 milligrams/kilogram (mg/kg) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Enzastaurin: 1125 milligram (mg) loading dose on Day 1 of Cycle 1 (28 days), followed by 500 mg oral daily dose for 3 cycles Maintenance therapy: Enzastaurin: 500 mg oral daily dose for 21-day cycles until disease progression Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression	Pemetrexed + Carboplatin + Bevacizumab + Placebo n=18 Participants Combination biochemotherapy: Pemetrexed: 500 mg/m\^2 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: AUC 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 mg/kg intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Placebo: Oral tablets daily to complete Cycle 1 (28 days), then subsequent 21-day cycles for 3 cycles Maintenance therapy: Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression Placebo: Oral tablets daily for 21-day cycles until progressive disease
Progression-Free Survival (PFS)	3.5 months Interval 2.0 to 5.8	4.3 months Interval 2.5 to 5.8

SECONDARY outcome

Timeframe: Randomization to measured progressive disease or death from any cause up to 12.2 months

Population: All randomized participants identified by assigned treatment group.

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.

Outcome measures

Outcome measures
Measure	Pemetrexed + Carboplatin + Bevacizumab + Enzastaurin n=20 Participants Combination biochemotherapy: Pemetrexed: 500 milligrams per square meter (mg/m\^2) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: Area under the curve (AUC) 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 milligrams/kilogram (mg/kg) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Enzastaurin: 1125 milligram (mg) loading dose on Day 1 of Cycle 1 (28 days), followed by 500 mg oral daily dose for 3 cycles Maintenance therapy: Enzastaurin: 500 mg oral daily dose for 21-day cycles until disease progression Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression	Pemetrexed + Carboplatin + Bevacizumab + Placebo n=20 Participants Combination biochemotherapy: Pemetrexed: 500 mg/m\^2 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: AUC 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 mg/kg intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Placebo: Oral tablets daily to complete Cycle 1 (28 days), then subsequent 21-day cycles for 3 cycles Maintenance therapy: Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression Placebo: Oral tablets daily for 21-day cycles until progressive disease
Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Response Rate)	20.0 percentage of participants Interval 2.5 to 37.5	30.0 percentage of participants Interval 9.9 to 50.1

SECONDARY outcome

Timeframe: Randomization to date of death up to 14.3 months

Population: All randomized participants identified by assigned treatment group. Participants censored: Pemetrexed + Carboplatin + Bevacizumab + Enzastaurin = 12; Pemetrexed + Carboplatin + Bevacizumab + Placebo = 9.

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.

Outcome measures

Outcome measures
Measure	Pemetrexed + Carboplatin + Bevacizumab + Enzastaurin n=8 Participants Combination biochemotherapy: Pemetrexed: 500 milligrams per square meter (mg/m\^2) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: Area under the curve (AUC) 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 milligrams/kilogram (mg/kg) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Enzastaurin: 1125 milligram (mg) loading dose on Day 1 of Cycle 1 (28 days), followed by 500 mg oral daily dose for 3 cycles Maintenance therapy: Enzastaurin: 500 mg oral daily dose for 21-day cycles until disease progression Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression	Pemetrexed + Carboplatin + Bevacizumab + Placebo n=11 Participants Combination biochemotherapy: Pemetrexed: 500 mg/m\^2 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: AUC 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 mg/kg intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Placebo: Oral tablets daily to complete Cycle 1 (28 days), then subsequent 21-day cycles for 3 cycles Maintenance therapy: Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression Placebo: Oral tablets daily for 21-day cycles until progressive disease
Overall Survival (OS)	9.1 months Interval 7.8 to Not calculable due to high number of censored participants.	7.6 months Interval 4.2 to Not calculable due to high number of censored participants.

SECONDARY outcome

Timeframe: Randomization to measured PD or death from any cause up to 12.2 months

Population: All randomized participants.

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.

Outcome measures

Outcome measures
Measure	Pemetrexed + Carboplatin + Bevacizumab + Enzastaurin n=20 Participants Combination biochemotherapy: Pemetrexed: 500 milligrams per square meter (mg/m\^2) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: Area under the curve (AUC) 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 milligrams/kilogram (mg/kg) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Enzastaurin: 1125 milligram (mg) loading dose on Day 1 of Cycle 1 (28 days), followed by 500 mg oral daily dose for 3 cycles Maintenance therapy: Enzastaurin: 500 mg oral daily dose for 21-day cycles until disease progression Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression	Pemetrexed + Carboplatin + Bevacizumab + Placebo n=20 Participants Combination biochemotherapy: Pemetrexed: 500 mg/m\^2 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: AUC 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 mg/kg intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Placebo: Oral tablets daily to complete Cycle 1 (28 days), then subsequent 21-day cycles for 3 cycles Maintenance therapy: Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression Placebo: Oral tablets daily for 21-day cycles until progressive disease
Time to Progressive Disease (TTPD)	4.3 Months Interval 1.7 to 5.8	4.8 Months Interval 3.0 to 7.2

SECONDARY outcome

Timeframe: Time of response to disease progression or death from any cause up to 12.2 months

Population: All randomized participants. Participants censored: Pemetrexed + Carboplatin + Bevacizumab + Enzastaurin = 16; Pemetrexed + Carboplatin + Bevacizumab + Placebo = 14.

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.

Outcome measures

Outcome measures
Measure	Pemetrexed + Carboplatin + Bevacizumab + Enzastaurin n=4 Participants Combination biochemotherapy: Pemetrexed: 500 milligrams per square meter (mg/m\^2) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: Area under the curve (AUC) 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 milligrams/kilogram (mg/kg) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Enzastaurin: 1125 milligram (mg) loading dose on Day 1 of Cycle 1 (28 days), followed by 500 mg oral daily dose for 3 cycles Maintenance therapy: Enzastaurin: 500 mg oral daily dose for 21-day cycles until disease progression Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression	Pemetrexed + Carboplatin + Bevacizumab + Placebo n=6 Participants Combination biochemotherapy: Pemetrexed: 500 mg/m\^2 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: AUC 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 mg/kg intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Placebo: Oral tablets daily to complete Cycle 1 (28 days), then subsequent 21-day cycles for 3 cycles Maintenance therapy: Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression Placebo: Oral tablets daily for 21-day cycles until progressive disease
Duration of Response (DoR)	4.7 Months Interval 2.8 to The upper 95% confidence interval was not achieved due to high censoring rate.	3.5 Months Interval 1.3 to The upper 95% confidence interval was not achieved due to high censoring rate.

SECONDARY outcome

Timeframe: Randomization up to 14.3 months and 30-day follow-up

Population: All randomized participants who received at least 1 dose of study drug.

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.

Outcome measures

Outcome measures
Measure	Pemetrexed + Carboplatin + Bevacizumab + Enzastaurin n=20 Participants Combination biochemotherapy: Pemetrexed: 500 milligrams per square meter (mg/m\^2) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: Area under the curve (AUC) 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 milligrams/kilogram (mg/kg) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Enzastaurin: 1125 milligram (mg) loading dose on Day 1 of Cycle 1 (28 days), followed by 500 mg oral daily dose for 3 cycles Maintenance therapy: Enzastaurin: 500 mg oral daily dose for 21-day cycles until disease progression Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression	Pemetrexed + Carboplatin + Bevacizumab + Placebo n=20 Participants Combination biochemotherapy: Pemetrexed: 500 mg/m\^2 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: AUC 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 mg/kg intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Placebo: Oral tablets daily to complete Cycle 1 (28 days), then subsequent 21-day cycles for 3 cycles Maintenance therapy: Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression Placebo: Oral tablets daily for 21-day cycles until progressive disease
Pharmacology Toxicity and Adverse Events (AEs) Non-serious AEs	19 Participants	20 Participants
Pharmacology Toxicity and Adverse Events (AEs) Serious AEs	6 Participants	7 Participants
Pharmacology Toxicity and Adverse Events (AEs) Deaths Due to PD	0 Participants	0 Participants
Pharmacology Toxicity and Adverse Events (AEs) Deaths Due to AEs	1 Participants	1 Participants
Pharmacology Toxicity and Adverse Events (AEs) Deaths within 30-days after treatment	0 Participants	0 Participants

Adverse Events

Pemetrexed + Carboplatin + Bevacizumab + Enzastaurin

Serious events: 6 serious events

Other events: 19 other events

Deaths: 0 deaths

Pemetrexed + Carboplatin + Bevacizumab + Placebo

Serious events: 7 serious events

Other events: 20 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	Pemetrexed + Carboplatin + Bevacizumab + Enzastaurin n=20 participants at risk Combination biochemotherapy: Pemetrexed: 500 milligrams per square meter (mg/m\^2) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: Area under the curve (AUC) 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 milligrams/kilogram (mg/kg) intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Enzastaurin: 1125 milligram (mg) loading dose on Day 1 of Cycle 1 (28 days), followed by 500 mg oral daily dose for 3 cycles Maintenance therapy: Enzastaurin: 500 mg oral daily dose for 21-day cycles until disease progression Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression	Pemetrexed + Carboplatin + Bevacizumab + Placebo n=20 participants at risk Combination biochemotherapy: Pemetrexed: 500 mg/m\^2 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Carboplatin: AUC 6 intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Bevacizumab: 15 mg/kg intravenously on Day 8 of Cycle 1 (28 days), then on Day 1 of subsequent cycles every 21 days for 3 cycles Placebo: Oral tablets daily to complete Cycle 1 (28 days), then subsequent 21-day cycles for 3 cycles Maintenance therapy: Bevacizumab: 15 mg/kg intravenously on Day 1 of every 21-day cycle until disease progression Placebo: Oral tablets daily for 21-day cycles until progressive disease
Gastrointestinal disorders Abdominal pain	0.00% 0/20 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	5.0% 1/20 • Number of events 2 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Gastrointestinal disorders Ascites	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	0.00% 0/20 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Gastrointestinal disorders Colonic obstruction	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	0.00% 0/20 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Gastrointestinal disorders Colonic stenosis	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	0.00% 0/20 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Gastrointestinal disorders Constipation	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	10.0% 2/20 • Number of events 2 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Gastrointestinal disorders Gastrointestinal disorder	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	0.00% 0/20 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Gastrointestinal disorders Ileus	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	0.00% 0/20 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Gastrointestinal disorders Large intestine perforation	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
General disorders Fatigue	0.00% 0/20 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
General disorders Pyrexia	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	0.00% 0/20 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Infections and infestations Infection	0.00% 0/20 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Investigations Haemoglobin decreased	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Investigations Neutrophil count decreased	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Metabolism and nutrition disorders Anorexia	0.00% 0/20 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Metabolism and nutrition disorders Dehydration	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	10.0% 2/20 • Number of events 2 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Metabolism and nutrition disorders Hyponatraemia	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	0.00% 0/20 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Musculoskeletal and connective tissue disorders Back pain	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	0.00% 0/20 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/20 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	0.00% 0/20 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Nervous system disorders Confusional state	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	0.00% 0/20 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	10.0% 2/20 • Number of events 2 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Respiratory, thoracic and mediastinal disorders Pneumonia	0.00% 0/20 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Respiratory, thoracic and mediastinal disorders Respiratory disorder	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	0.00% 0/20 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
Vascular disorders Thrombosis	5.0% 1/20 • Number of events 1 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.	10.0% 2/20 • Number of events 3 • Randomization up to 14.3 months and 30-day follow-up Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.