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A Study of Pemetrexed, Carboplatin and Bevacizumab in Participants With Nonsquamous Non-Small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT00762034
Recruitment Status : Completed
First Posted : September 30, 2008
Results First Posted : November 28, 2013
Last Update Posted : December 21, 2015
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Non-small Cell Lung Cancer
Interventions Drug: Pemetrexed
Drug: Paclitaxel
Drug: Carboplatin
Biological: Bevacizumab
Enrollment 939
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Period Title: Induction Period
Started 472 467
Received at Least 1 Dose of Study Drug 442 443
Completed 294 298
Not Completed 178 169
Reason Not Completed
Protocol Violation             1             2
Entry Criterion Not Met             12             11
Adverse Event             27             38
Lost to Follow-up             1             1
Progressive Disease             73             55
Physician Decision             21             20
Withdrawal by Subject             15             19
Deaths Not Due to Study Disease             19             14
Deaths Due to Study Disease             9             9
Period Title: Maintenance Period
Started 294 298
Received at Least 1 Dose of Study Drug 294 298
Completed 0 0
Not Completed 294 298
Reason Not Completed
Protocol Violation             1             3
Entry Criterion Not Met             0             2
Adverse Event             42             26
Progressive Disease             186             224
Physician Decision             25             20
Withdrawal by Subject             34             14
Death not due to study disease             2             5
Death due to study disease             3             3
Other             1             1
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev Total
Hide Arm/Group Description

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Total of all reporting groups
Overall Number of Baseline Participants 472 467 939
Hide Baseline Analysis Population Description
All randomized participants.
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 472 participants 467 participants 939 participants
<=65 years 249 236 485
>65 years 223 231 454
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 472 participants 467 participants 939 participants
Female
221
  46.8%
218
  46.7%
439
  46.8%
Male
251
  53.2%
249
  53.3%
500
  53.2%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 472 participants 467 participants 939 participants
Caucasian 409 396 805
Black or African American 42 52 94
Asian 15 14 29
American Indian or Alaska Native 1 1 2
Multiple race/ethnicities 2 3 5
Information not provided 3 1 4
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 472 participants 467 participants 939 participants
472 467 939
Previously Treated Brain Metastasis  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 472 participants 467 participants 939 participants
Yes 52 52 104
No 420 415 835
Histological Subtype   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 472 participants 467 participants 939 participants
Adenocarcinoma, Lung 367 360 727
Bronchioalveolar Carcinoma 4 3 7
Large Cell Lung Carcinoma 8 15 23
NSCLC Not Otherwise Specified 47 39 86
NSCLC Poorly Differentiated 39 47 86
Predominantly Adenocarcinoma 7 2 9
Unknown 0 1 1
[1]
Measure Description: Non-small Cell Lung Carcinoma (NSCLC)
Histological Category for Subgroup Analyses  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 472 participants 467 participants 939 participants
Adenocarcinoma 378 365 743
Large Cell Carcinoma 8 15 23
Other or Indeterminant 86 86 172
Unknown 0 1 1
1.Primary Outcome
Title Overall Survival
Hide Description Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive.
Time Frame Baseline to date of death from any cause (up to 37.06 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants using the intent-to-treat principle. Number of participants censored: n=131, 127 in Pem/Carbo/Bev and Pac/Carbo/Bev arms, respectively.
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 472 467
Median (95% Confidence Interval)
Unit of Measure: months
12.55
(11.30 to 14.03)
13.40
(11.86 to 14.91)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pem/Carbo/Bev, Pac/Carbo/Bev
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.94896
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.00
Confidence Interval (2-Sided) 95%
0.86 to 1.16
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Participants With a Complete Response (CR) and Partial Response (PR) (Overall Response Rate)
Hide Description Overall Response Rate (ORR) is the number of participants with a Complete Response (CR) and Partial Response (PR) divided by the total number of randomized participants per arm, then multiplied by 100. Response is based on the Response Evaluation Criteria In Solid Tumors (RECIST 1.0) criteria. Complete Response (CR) was defined as the disappearance of all target lesions. Partial Response (PR) was defined as at least a 30% decrease in sum of longest diameter of target lesions compared to baseline or the complete disappearance of target lesions, with persistence of 1 or more nontarget lesion(s) and no new lesions.
Time Frame Baseline to measured progressive disease (up to 37.06 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants using the intent-to-treat principle
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 472 467
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
34.1
(29.8 to 38.6)
33.0
(28.7 to 37.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pem/Carbo/Bev, Pac/Carbo/Bev
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.72997
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
3.Secondary Outcome
Title Percentage of Participants With a Complete Response (CR), Partial Response (PR), and Stable Disease (SD) (Disease Control Rate)
Hide Description Disease Control Rate (DCR) is the number of participants with a Complete Response (CR), Partial Response (PR), and Stable Disease (SD) divided by the total number of randomized participants per arm, then multiplied by 100. Response is based on the Response Evaluation Criteria In Solid Tumors (RECIST 1.0) criteria. Complete Response (CR) was defined as the disappearance of all target lesions. Partial Response (PR) was defined as at least a 30% decrease in sum of longest diameter of target lesions compared with baseline or the complete disappearance of target lesions, with persistence of 1 or more nontarget lesion(s) and no new lesions. Progressive Disease (PD) was defined as at least 20% increase in sum of longest diameter of target lesions compared with the smallest sum of the longest diameter recorded since the start of treatment or the appearance of 1 or more new lesion(s). Stable Disease (SD) was defined as small changes that did not meet above criteria.
Time Frame Baseline to measured progressive disease (up to 37.06 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants using the intent-to-treat principle
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 472 467
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
65.9
(61.4 to 70.2)
69.8
(65.4 to 73.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pem/Carbo/Bev, Pac/Carbo/Bev
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.20892
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
4.Secondary Outcome
Title Progression Free Survival Time
Hide Description Progression free survival (PFS) is defined as the time from date of randomization to the date of objective disease progression or death due to any cause. Participants were censored at date of last PFS assessment prior to the cutoff date or the date of initiation of subsequent systemic anticancer therapy, whichever was earlier.
Time Frame Baseline to measured progressive disease or date of death from any cause (up to 33.54 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants using the intent-to-treat principle. Number of participants censored: n=127, 109 in Pem/Carbo/Bev and Pac/Carbo/Bev arms, respectively.
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 472 467
Median (95% Confidence Interval)
Unit of Measure: months
6.04
(5.55 to 6.87)
5.55
(5.39 to 5.98)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pem/Carbo/Bev, Pac/Carbo/Bev
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.01206
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
0.71 to 0.96
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Time to Progressive Disease
Hide Description Time to progressive disease was defined as the time from randomization to the first date of objective disease progression. Participants were censored at date of last PFS assessment prior to the cutoff date or the date of initiation of subsequent systemic anticancer therapy, whichever was earlier.
Time Frame Baseline to measured progressive disease (up to 37.06 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants using the intent-to-treat principle. Number of participants censored: n=198, 172 in Pem/Carbo/Bev and Pac/Carbo/Bev arms, respectively.
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 472 467
Median (95% Confidence Interval)
Unit of Measure: months
7.03
(6.24 to 8.05)
6.04
(5.58 to 6.87)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pem/Carbo/Bev, Pac/Carbo/Bev
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.006
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.79
Confidence Interval (2-Sided) 95%
0.67 to 0.94
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Safety and Toxicity Profile of Study Treatments
Hide Description Safety and toxicity profile was defined as serious and other non-serious adverse events. A summary of serious and all other non-serious adverse events is located in the Reported Adverse Event module.
Time Frame Baseline to study endpoint (up to 37.06 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least 1 dose of study drug during the specified treatment phase.
Arm/Group Title Pem/Carbo/Bev; Induction Phase Pem/Carbo/Bev; Maintenance Phase Pac/Carbo/Bev; Induction Phase Pac/Carbo/Bev; Maintenance Phase
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 442 292 443 298
Measure Type: Number
Unit of Measure: participants
Serious Adverse Events (SAEs) 111 83 123 68
Other Adverse Events (AEs) 432 288 431 296
7.Secondary Outcome
Title Duration of Hospitalizations Per Participant
Hide Description Length of hospitalization in participants hospitalized during the study or within 30 days of discontinuation regardless of whether the hospitalization was or was not due to study drug.
Time Frame Baseline to study endpoint (up to 37.06 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least 1 dose of study drug and had at least one hospitalization while on study or within 30 days of discontinuation.
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 177 172
Mean (Standard Deviation)
Unit of Measure: days
9.4  (9.8) 8.0  (6.7)
8.Secondary Outcome
Title Number of Participants Who Received a Transfusion
Hide Description [Not Specified]
Time Frame Baseline to study endpoint (up to 37.06 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least 1 dose of study drug.
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 442 443
Measure Type: Number
Unit of Measure: participants
116 44
9.Secondary Outcome
Title Number of Participants Receiving Concomitant Medication
Hide Description [Not Specified]
Time Frame Baseline to study endpoint (up to 37.06 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 472 467
Measure Type: Number
Unit of Measure: participants
406 421
10.Secondary Outcome
Title Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy - General (FACT-G)
Hide Description The FACT-G is a validated instrument used to measure quality of life (QOL) in participants with cancer consisting of the 27-item questionnaire and is organized into subscales, each designed to assess a QOL domain: physical well-being (PWB)-7 items; social/family well-being (SWB)-7 items; emotional well-being (EWB)-6 items; functional well-being (FWB)-7 items. Each item uses a 5 point rating scale (0="not at all" and 4=equals "very much"). FACT-G Total is the sum of the scores of all 4 subscales and ranges from 0 to 108. Higher scores indicate better QOL. Least squares mean (LSmean) change is calculated using the linear-mixed model (LMM) analysis controlled for treatment, baseline value, time point and treatment by time point interaction.
Time Frame Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
The LMM analysis includes data from all participants in each arm for whom a validated translation is available in a language in which the completer (participant) is fluent and have evaluable FACT-G data, using the intent-to-treat principle.
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 472 462
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
0.51  (0.54) 0.18  (0.54)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pem/Carbo/Bev, Pac/Carbo/Bev
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.667
Comments Mixed Model Analysis has treatment, baseline, time point, and treatment by timepoint interaction as fixed effects.
Method Mixed Models Analysis
Comments [Not Specified]
11.Secondary Outcome
Title Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy - Lung (FACT-L)
Hide Description FACT-L is a valid instrument used to measure quality of life (QOL) in participants with cancer consisting of the 27-item FACT-General (G) and 9-item lung cancer subscale (LCS). FACT-G is organized into subscales: physical well-being (PWB)–7 items; social/family well-being (SWB)–7 items; emotional well-being (EWB)–6 items; functional well-being (FWB)–7 items. Each item uses a 5 point rating scale (0=“not at all” and 4=equals “very much”). FACT-L Total Score=4 subscales + LCS and ranges from 0 to 144. Trial Outcome Index-Lung (TOI-L)=PWB+FWB+LCS and ranges from 0 to 92. Higher scores indicate better QOL. Least squares mean (LSmean) change is calculated using the linear-mixed model (LMM) analysis controlled for treatment, baseline value, time point and treatment by time point interaction.
Time Frame Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
The LMM analysis includes data from all participants in each arm for whom a validated translation is available in a language in which the completer (participant) is fluent and have evaluable FACT-L, using the intent-to-treat principle.
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 472 467
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
FACT-L Total Score (n=397, 392) 1.88  (0.65) 1.66  (0.66)
Trial Outcome Index-Lung (TOI-L) (n=396, 394) -0.38  (0.50) -0.40  (0.50)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pem/Carbo/Bev, Pac/Carbo/Bev
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.815
Comments p-value for FACT-L Total; Mixed Model Analysis has treatment, baseline, time point, and treatment by timepoint interaction as fixed effects.
Method Mixed Models Analysis
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pem/Carbo/Bev, Pac/Carbo/Bev
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.978
Comments p-value for FACT-L TOI; Mixed Model Analysis has treatment, baseline, time point, and treatment by timepoint interaction as fixed effects.
Method Mixed Models Analysis
Comments [Not Specified]
12.Secondary Outcome
Title Change From Baseline in Participant Reported Outcomes as Assessed by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group- Neurotoxicity (FACT/GOG-Ntx)
Hide Description FACT/GOG-Ntx is a validated instrument used to measure quality of life (QOL) in participants with cancer and neurotoxicity (Ntx) consisting of 27-item FACT-General (G) and 11-item Ntx subscale. FACT-G is organized into domain subscales: physical well-being (PWB)–7 items; social/family well-being (SWB)–7 items; emotional well-being (EWB)–6 items; functional well-being (FWB)–7 items; each uses a 5 point rating scale (0=“not at all” and 4=equals “very much”). FACT/GOG-Ntx Total Score=sum 5 subscales and ranges from 0-152. Ntx Trial Outcome Index (TOI-Ntx)=PWB+FWB+NTX and range from 0-100. For all FACT scales, higher scores indicate better QOL. Least squares mean (LSmean) change is calculated using the linear-mixed model (LMM) analysis controlled for treatment, baseline value, time point and treatment by time point interaction.
Time Frame Baseline, up to first 10 cycles (4 induction and 6 maintenance cycles, cycle=21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
The LMM analysis includes data from all participants in each arm for whom a validated translation is available in a language in which the completer (participant) is fluent and have evaluable FACT/GOG-Ntx data, using the intent-to-treat principle.
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 472 467
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
FACT/GOG-Ntx Total Score (n=393, 389) -0.60  (0.70) -5.48  (0.70)
Ntx Trial Outcome Index (TOI-Ntx)(n=393, 390) -2.79  (0.55) -7.60  (0.55)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pem/Carbo/Bev, Pac/Carbo/Bev
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value for FACT/GOG-Ntx Total; Mixed Model Analysis has treatment, baseline, time point, and treatment by timepoint interaction as fixed effects.
Method Mixed Models Analysis
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pem/Carbo/Bev, Pac/Carbo/Bev
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value for FACT/GOG-Ntx TOI; Mixed Model Analysis has treatment, baseline, time point, and treatment by timepoint interaction as fixed effects.
Method Mixed Models Analysis
Comments [Not Specified]
13.Secondary Outcome
Title Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Pemetrexed
Hide Description [Not Specified]
Time Frame Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who were randomized to Pem/Carbo/Bev, who received study drug, and had evaluable Cmax data.
Arm/Group Title Pem/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev)followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 14
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: micrograms per milliliter (μg/mL)
122
(20%)
14.Secondary Outcome
Title Pharmacokinetics (PK): Elimination Half-life (t1/2) for Pemetrexed
Hide Description [Not Specified]
Time Frame Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who were randomized to Pem/Carbo/Bev, who received study drug, and had evaluable t1/2 data.
Arm/Group Title Pem/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 15
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours (hr)
2.88
(13%)
15.Secondary Outcome
Title Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) for Pemetrexed
Hide Description [Not Specified]
Time Frame Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who were randomized to Pem/Carbo/Bev, who received study drug, and had evaluable AUC(0-∞) data.
Arm/Group Title Pem/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 15
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: microgram*hour per milliliter (μg•hr/mL)
203
(23%)
16.Secondary Outcome
Title Pharmacokinetics (PK): Pemetrexed Clearance (CL)
Hide Description [Not Specified]
Time Frame Cycle 1 (pre-dose, 0.17, 0.33, 0.58, 0.83, 1, 1.75, 2.5, 4. 6. 8, and 24 hours post-dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who were randomized to Pem/Carbo/Bev, who received study drug, and had evaluable CL data.
Arm/Group Title Pem/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 15
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: milliliters per minute (mL/min)
72.1
(25%)
17.Secondary Outcome
Title Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Total (Bound and Unbound) Platinum and Unbound Platinum
Hide Description Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form.
Time Frame Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who received study drug and had evaluable Cmax data.
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 20 16
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: micrograms per milliliter (μg/mL)
Total (Bound and Unbound)
18.4
(24%)
17.8
(33%)
Unbound (n=18, 15)
21.1
(31%)
17.1
(34%)
18.Secondary Outcome
Title Pharmacokinetics (PK): Elimination Half-life (t1/2) for Total (Bound and Unbound) Platinum and Unbound Platinum
Hide Description Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form.
Time Frame Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who received study drug and had evaluable t1/2 data.
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 18 16
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours (hr)
Total (Bound and Unbound)
65.6
(69%)
86.4
(21%)
Unbound (n=17, 13)
2.03
(15%)
1.95
(21%)
19.Secondary Outcome
Title Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) for Total (Bound and Unbound) Platinum and Unbound Platinum
Hide Description Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form.
Time Frame Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who received study drug and had evaluable AUC(0-∞) data.
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 18 16
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: microgram*hour per milliliter (μg•hr/mL)
Total (Bound and Unbound)
160
(32%)
182
(24%)
Unbound (n=17, 13)
55.7
(33%)
62.9
(34%)
20.Secondary Outcome
Title Pharmacokinetics (PK): Platinum Clearance (CL) for Total (Bound and Unbound) and Unbound Forms
Hide Description Platinum is a metabolite of Carboplatin (Carbo) and is found in the blood as both a bound and unbound form.
Time Frame Cycle 1 (pre-dose, 0.25, 0.5, 0.67, 1.42, 2.17, 4, 6, 8, 24, 48, and 72 hours post-dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who received study drug and had evaluable CL data.
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 18 16
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liters per hour (L/hr)
Total (Bound and Unbound)
2.02
(39%)
1.87
(28%)
Unbound (n=17, 13)
5.81
(35%)
5.36
(47%)
21.Secondary Outcome
Title Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) for Bevacizumab
Hide Description [Not Specified]
Time Frame Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who received study drug and had evaluable Cmax data.
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 20 16
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: micrograms per milliliter (μg/mL)
276
(18%)
302
(20%)
22.Secondary Outcome
Title Pharmacokinetics (PK): Elimination Half-life (t1/2) for Bevacizumab
Hide Description [Not Specified]
Time Frame Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who received study drug and had evaluable t1/2 data.
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 17 16
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: days
14.8
(36%)
12.8
(46%)
23.Secondary Outcome
Title Pharmacokinetics (PK): Area Under the Concentration Time Curve From Zero to Infinity (AUC(0-∞)) Bevacizumab
Hide Description [Not Specified]
Time Frame Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who received study drug and had evaluable AUC(0-∞) data.
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 17 16
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: microgram*day per milliliter (μg•day/mL)
3070
(29%)
3160
(33%)
24.Secondary Outcome
Title Pharmacokinetics (PK): Bevacizumab Clearance (CL)
Hide Description [Not Specified]
Time Frame Cycle 1 (pre-dose, 0.75, 1.5, 3, 5, 7, 24, 48, 72, 168, 336, and 503 hours post-dose)
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who received study drug and had evaluable CL data.
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 17 16
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liters per day (L/day)
0.341
(31%)
0.376
(38%)
25.Secondary Outcome
Title Translational Research: Number of Participants With Epidermal Growth Factor Receptor (EGFR) Mutations
Hide Description Epidermal Growth Factor Receptor (EGFR) mutations were measured by polymerase chain reaction (PCR).
Time Frame Baseline
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with EGFR data regardless of study treatment.
Arm/Group Title Pem or Pac Plus Carbo/Bev
Hide Arm/Group Description:

Participants who received either Pem/Carbo/Bev or Pac/Carbo/Bev treatment.

Pem/Carbo/Bev Treatment-500 mg per meter squared (mg/m^2) Pem IV every 21 days, plus Carbo AUC 6 IV every 21 days for up to first 4 cycles of 21 days, plus 15 mg/kg Bev IV every 21.

OR

Pac/Carbo/Bev Treatment-200 mg/m^2 Pac IV and AUC 6 Carbo IV every 21 days for up to first 4 cycles of 21 days, plus 15 mg/kg Bev IV every 21 days.

Overall Number of Participants Analyzed 132
Measure Type: Number
Unit of Measure: participants
EGFR mutation positive 11
EGFR mutation negative 121
26.Secondary Outcome
Title Translational Research: Overall Survival (OS) Based on Nuclear Thyroid Transcription Factor-1 (TTF-1) Expression Regardless of Study Treatment
Hide Description Nuclear Thyroid Transcription Factor-1 (TTF-1) expression was measured using an Immunohistochemistry (IHC) assay which were scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system, and H score is a calculated using formula: 1x(percentage of cells stained 1+) + 2x(percentage of cells stained 2+) + 3x(percentage of cells stained 3+). TTF-1 Positive have an H score >0 and TTF-1 Negative have an H score=0. Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive.
Time Frame Baseline to date of death from any cause (up to 37.06 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with TTF-1 H scores regardless of study treatment. Participants censored: n=38, 11 in the TTF-1 Nuclear Positive and Negative arms, respectively.
Arm/Group Title TTF-1 Positive (H Score > 0) TTF-1 Negative (H Score = 0)
Hide Arm/Group Description:

Participants who were TTF-1 Positive (H score > 0) and received either Pem/Carbo/Bev or Pac/Carbo/Bev treatment.

Pem/Carbo/Bev Treatment-500 mg per meter squared (mg/m^2) Pem IV every 21 days, plus Carbo AUC 6 IV every 21 days for up to first 4 cycles of 21 days, plus 15 mg/kg Bev IV every 21.

OR

Pac/Carbo/Bev Treatment-200 mg/m^2 Pac IV and AUC 6 Carbo IV every 21 days for up to first 4 cycles of 21 days, plus 15 mg/kg Bev IV every 21 days.

Participants who were TTF-1 Negative (H score = 0) and received either Pem/Carbo/Bev or Pac/Carbo/Bev treatment.

Pem/Carbo/Bev Treatment-500 mg per meter squared (mg/m^2) Pem IV every 21 days, plus Carbo AUC 6 IV every 21 days for up to first 4 cycles of 21 days, plus 15 mg/kg Bev IV every 21.

OR

Pac/Carbo/Bev Treatment-200 mg/m^2 Pac IV and AUC 6 Carbo IV every 21 days for up to first 4 cycles of 21 days, plus 15 mg/kg Bev IV every 21 days.

Overall Number of Participants Analyzed 139 66
Median (95% Confidence Interval)
Unit of Measure: months
14.9
(12.8 to 17.6)
8.7
(6.4 to 10.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TTF-1 Positive (H Score > 0), TTF-1 Negative (H Score = 0)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments p-value was not adjusted for multiple comparisons.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.480
Confidence Interval (2-Sided) 95%
0.338 to 0.681
Estimation Comments [Not Specified]
27.Secondary Outcome
Title Translational Research: Overall Survival (OS) Based on Cytoplasmic and Nuclear Thymidylate Synthase (TS) Expression
Hide Description Cytoplasmic and nuclear Thymidylate Synthase (TS) expression was measured using an Immunohistochemistry (IHC) assay which were scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system for cytoplasmic and nuclear staining, and H score was calculated using formula: 1x(percentage of cells stained 1+) + 2x(percentage of cells stained 2+) + 3x(percentage of cells stained 3+). TS Positive have an H score >0 and TS Negative have an H score=0. Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive.
Time Frame Baseline to date of death from any cause (up to 37.06 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with TS Cytoplasm and Nucleus H scores. Participants censored: TS Cytoplasm Positive n=23, 20 and Negative n=4, 1; TS Nucleus Positive n=17, 9 and Negative n=10, 12 for the Pem/Carbo/Bev and Pac/Carbo/Bev arms, respectively.
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 100 89
Median (95% Confidence Interval)
Unit of Measure: months
TS Cytoplasm Positive (H score > 0; n=90, 83)
12.9
(10.8 to 16.9)
12.4
(10.9 to 15.5)
TS Cytoplasm Negative (H score = 0; n=10, 6)
18.2 [1] 
(12.5 to NA)
11.6
(9.1 to 14.7)
TS Nucleus Positive (H score > 0; n=68, 51)
12.7
(9.7 to 15.4)
12.4
(8.4 to 15.5)
TS Nucleus Negative (H score = 0; n=32, 38)
19.2
(12.5 to 24.1)
12.4
(10.1 to 17.1)
[1]
Not calculable due to the low number of participants reaching endpoint event of death.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pem/Carbo/Bev, Pac/Carbo/Bev
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.673
Comments p-value is for TS Cytoplasm Positive (H score > 0) comparing treatment arms and was not adjusted for multiple comparisons.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.927
Confidence Interval (2-Sided) 95%
0.654 to 1.316
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pem/Carbo/Bev, Pac/Carbo/Bev
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.287
Comments p-value is for TS Cytoplasm Negative (H score = 0) comparing treatment arms and was not adjusted for multiple comparisons.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.521
Confidence Interval (2-Sided) 95%
0.157 to 1.729
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Pem/Carbo/Bev, Pac/Carbo/Bev
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2
Comments p-value is for TS Nucleus Positive (H score > 0) comparing treatment arms and was not adjusted for multiple comparisons.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.759
Confidence Interval (2-Sided) 95%
0.498 to 1.157
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Pem/Carbo/Bev, Pac/Carbo/Bev
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.915
Comments p-value is for TS Nucleus Negative (H score = 0) comparing treatment arms and was not adjusted for multiple comparisons.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.969
Confidence Interval (2-Sided) 95%
0.540 to 1.738
Estimation Comments [Not Specified]
28.Secondary Outcome
Title Translational Research: Overall Survival (OS) Based on Cytoplasmic and Membrane Folate Receptor Alpha (FR-α) Expression
Hide Description Cytoplasmic and membrane Folate Receptor Alpha (FR-α) expression was measured using an Immunohistochemistry (IHC) assay which were scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system for cytoplasmic or membrane staining, and H score is a calculated using formula: 1x(percentage of cells stained 1+) + 2x(percentage of cells stained 2+) + 3x(percentage of cells stained 3+). FR-α Positive have an H score >0 and FR-α Negative have an H score=0. Overall survival (OS) is the duration from date of randomization to date of death from any cause. Participants were censored at the date they were last known to be alive.
Time Frame Baseline to date of death from any cause (up to 37.06 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with FR-α Cytoplasm or Membrane H scores. Participants censored: FR-α Positive Cytoplasm n=21, 15 and Negative n=4, 3; FR-α Membrane Positive n=16, 8 and Negative n=9, 10 for Pem/Carbo/Bev and Pac/Carbo/Bev arms, respectively.
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description:

Pemetrexed (Pem), carboplatin (Carbo) and bevacizumab (Bev) followed by pemetrexed and bevacizumab

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation

Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Paclitaxel (Pac), carboplatin (Carbo) and bevacizumab (Bev) followed by bevacizumab

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m^2) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days

Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Overall Number of Participants Analyzed 98 82
Median (95% Confidence Interval)
Unit of Measure: months
FR-α Cytoplasm Positive (H score > 0; n=64, 53)
14.4
(11.4 to 22.2)
14.3
(11.2 to 18.2)
FR-α Cytoplasm Negative (H score = 0; n=34, 29)
12.0
(9.6 to 16.9)
11.2
(5.7 to 14.4)
FR-α Membrane Positive (H score > 0; n=39, 22)
19.2
(10.5 to 30.8)
15.5 [1] 
(11.2 to NA)
FR-α Membrane Negative (H score = 0; n=59, 60)
12.9
(9.6 to 16.7)
11.3
(8.8 to 14.7)
[1]
Not calculable due to the low number of participants reaching endpoint event of death.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pac/Carbo/Bev
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.891
Comments p-value for FR-α Cytoplasm Positive (H score > 0) comparing treatment arms and was not adjusted for multiple comparisons.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.970
Confidence Interval (2-Sided) 95%
0.622 to 1.511
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pem/Carbo/Bev, Pac/Carbo/Bev
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.060
Comments p-value for FR-α Cytoplasm Negative (H score = 0) comparing treatment arms and was not adjusted for multiple comparisons.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.592
Confidence Interval (2-Sided) 95%
0.342 to 1.023
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Pem/Carbo/Bev, Pac/Carbo/Bev
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.905
Comments p-value for FR-α Membrane Positive (H score > 0) comparing treatment arms and was not adjusted for multiple comparisons.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.960
Confidence Interval (2-Sided) 95%
0.490 to 1.880
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Pem/Carbo/Bev, Pac/Carbo/Bev
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.455
Comments p-value for FR-α Membrane Negative (H score = 0) comparing treatment arms and was not adjusted for multiple comparisons.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.859
Confidence Interval (2-Sided) 95%
0.575 to 1.281
Estimation Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description Deaths due to progressive disease are not considered adverse events and reported in the participant flow. All randomized participants who received at least 1 dose of study drug during the specified treatment phase.
 
Arm/Group Title Pem/Carbo/Bev Pac/Carbo/Bev
Hide Arm/Group Description

Induction:

Bevacizumab: Induction therapy 15 milligrams per kilogram (mg/kg) intravenously (IV) every 21 days for up to 4 cycles of 21 days Pemetrexed: Induction therapy 500 milligram per meter squared (mg/m^2) IV every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Carboplatin: Induction therapy of 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Maintenance:

Pemetrexed: Maintenance therapy 500 mg/m^2 IV every 21 days (with bevacizumab) until progressive disease or treatment discontinuation Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

Induction:

Paclitaxel: Induction therapy 200 milligram per meter squared (mg/m ²) intravenously (IV) every 21 days (with carboplatin and bevacizumab) for up to 4 cycles of 21 days Bevacizumab: Induction therapy 15 mg/kg IV every 21 days for up to 4 cycles of 21 days Carboplatin: Induction therapy 6 area under the concentration curve (AUC 6) IV every 21 days for up to 4 cycles of 21 days

Maintenance:

Bevacizumab: Maintenance therapy 15 mg/kg IV every 21 days until progressive disease or treatment discontinuation.

All-Cause Mortality
Pem/Carbo/Bev Pac/Carbo/Bev
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Pem/Carbo/Bev Pac/Carbo/Bev
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   188/442 (42.53%)      181/443 (40.86%)    
Blood and lymphatic system disorders     
Anaemia  1  18/442 (4.07%)  50 5/443 (1.13%)  10
Febrile neutropenia  1  6/442 (1.36%)  7 13/443 (2.93%)  13
Haemorrhagic anaemia  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Leukocytosis  1  1/442 (0.23%)  2 0/443 (0.00%)  0
Leukopenia  1  3/442 (0.68%)  7 0/443 (0.00%)  0
Microangiopathic haemolytic anaemia  1  1/442 (0.23%)  2 0/443 (0.00%)  0
Neutropenia  1  10/442 (2.26%)  15 9/443 (2.03%)  9
Pancytopenia  1  3/442 (0.68%)  5 3/443 (0.68%)  3
Thrombocytopenia  1  12/442 (2.71%)  20 3/443 (0.68%)  3
Cardiac disorders     
Acute myocardial infarction  1  0/442 (0.00%)  0 2/443 (0.45%)  4
Angina pectoris  1  1/442 (0.23%)  1 3/443 (0.68%)  3
Atrial fibrillation  1  1/442 (0.23%)  4 3/443 (0.68%)  3
Atrial flutter  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Cardiac arrest  1  3/442 (0.68%)  3 2/443 (0.45%)  3
Cardiac failure congestive  1  3/442 (0.68%)  3 3/443 (0.68%)  3
Cardio-respiratory arrest  1  0/442 (0.00%)  0 3/443 (0.68%)  3
Cardiomegaly  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Cardiomyopathy  1  1/442 (0.23%)  4 1/443 (0.23%)  2
Myocardial infarction  1  6/442 (1.36%)  6 2/443 (0.45%)  2
Myocardial ischaemia  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Palpitations  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Pericardial effusion  1  1/442 (0.23%)  1 2/443 (0.45%)  3
Pericarditis  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Sinus bradycardia  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Supraventricular tachycardia  1  4/442 (0.90%)  4 1/443 (0.23%)  2
Ear and labyrinth disorders     
Vertigo  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Endocrine disorders     
Addison's disease  1  0/442 (0.00%)  0 1/443 (0.23%)  8
Goitre  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Hypercalcaemia of malignancy  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Inappropriate antidiuretic hormone secretion  1  2/442 (0.45%)  3 1/443 (0.23%)  1
Eye disorders     
Diplopia  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Gastrointestinal disorders     
Abdominal pain  1  3/442 (0.68%)  5 6/443 (1.35%)  7
Abdominal pain upper  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Anal haemorrhage  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Constipation  1  5/442 (1.13%)  6 4/443 (0.90%)  4
Diarrhoea  1  4/442 (0.90%)  9 7/443 (1.58%)  9
Diverticular perforation  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Duodenal ulcer  1  0/442 (0.00%)  0 1/443 (0.23%)  6
Duodenal ulcer haemorrhage  1  2/442 (0.45%)  2 0/443 (0.00%)  0
Duodenitis  1  0/442 (0.00%)  0 1/443 (0.23%)  2
Dysphagia  1  1/442 (0.23%)  4 0/443 (0.00%)  0
Faecaloma  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Gastric ulcer  1  0/442 (0.00%)  0 1/443 (0.23%)  2
Gastritis  1  1/442 (0.23%)  1 1/443 (0.23%)  1
Gastrointestinal haemorrhage  1  3/442 (0.68%)  4 5/443 (1.13%)  5
Gastrointestinal perforation  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Haematemesis  1  1/442 (0.23%)  1 1/443 (0.23%)  1
Haemorrhoids  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Ileus  1  1/442 (0.23%)  1 2/443 (0.45%)  4
Ileus paralytic  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Inguinal hernia  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Intestinal perforation  1  2/442 (0.45%)  7 1/443 (0.23%)  1
Large intestine perforation  1  1/442 (0.23%)  1 1/443 (0.23%)  1
Lower gastrointestinal haemorrhage  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Nausea  1  9/442 (2.04%)  17 11/443 (2.48%)  21
Oesophageal obstruction  1  0/442 (0.00%)  0 1/443 (0.23%)  2
Oesophagitis  1  1/442 (0.23%)  2 0/443 (0.00%)  0
Pancreatitis  1  0/442 (0.00%)  0 2/443 (0.45%)  2
Peptic ulcer  1  1/442 (0.23%)  2 0/443 (0.00%)  0
Proctalgia  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Rectal haemorrhage  1  2/442 (0.45%)  4 1/443 (0.23%)  1
Small intestinal obstruction  1  2/442 (0.45%)  3 1/443 (0.23%)  1
Small intestinal perforation  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Stomatitis  1  0/442 (0.00%)  0 2/443 (0.45%)  3
Upper gastrointestinal haemorrhage  1  3/442 (0.68%)  6 1/443 (0.23%)  1
Vomiting  1  13/442 (2.94%)  20 11/443 (2.48%)  12
General disorders     
Asthenia  1  2/442 (0.45%)  4 9/443 (2.03%)  15
Chest pain  1  1/442 (0.23%)  1 2/443 (0.45%)  2
Death  1  1/442 (0.23%)  1 2/443 (0.45%)  2
Device dislocation  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Device malfunction  1  1/442 (0.23%)  2 0/443 (0.00%)  0
Fatigue  1  1/442 (0.23%)  4 3/443 (0.68%)  5
Hypothermia  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Impaired healing  1  0/442 (0.00%)  0 1/443 (0.23%)  7
Malaise  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Mucosal inflammation  1  2/442 (0.45%)  3 0/443 (0.00%)  0
Multi-organ failure  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Non-cardiac chest pain  1  5/442 (1.13%)  6 1/443 (0.23%)  1
Pain  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Pyrexia  1  3/442 (0.68%)  4 4/443 (0.90%)  5
Hepatobiliary disorders     
Acute hepatic failure  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Bile duct obstruction  1  1/442 (0.23%)  1 1/443 (0.23%)  1
Cholecystitis  1  0/442 (0.00%)  0 2/443 (0.45%)  3
Cholelithiasis  1  0/442 (0.00%)  0 3/443 (0.68%)  3
Hepatic haemorrhage  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Hyperbilirubinaemia  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Immune system disorders     
Drug hypersensitivity  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Hypersensitivity  1  1/442 (0.23%)  2 0/443 (0.00%)  0
Infections and infestations     
Appendicitis perforated  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Bacteraemia  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Bronchitis  1  1/442 (0.23%)  1 2/443 (0.45%)  3
Cellulitis  1  3/442 (0.68%)  5 3/443 (0.68%)  3
Clostridial infection  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Clostridium colitis  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Clostridium difficile colitis  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Device related sepsis  1  2/442 (0.45%)  2 0/443 (0.00%)  0
Diverticulitis  1  1/442 (0.23%)  1 3/443 (0.68%)  8
Empyema  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Enterobacter sepsis  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Gastroenteritis  1  1/442 (0.23%)  1 2/443 (0.45%)  2
Hepatitis c  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Infection  1  2/442 (0.45%)  2 0/443 (0.00%)  0
Infectious peritonitis  1  2/442 (0.45%)  2 0/443 (0.00%)  0
Liver abscess  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Lobar pneumonia  1  2/442 (0.45%)  2 1/443 (0.23%)  1
Lung infection pseudomonal  1  1/442 (0.23%)  7 0/443 (0.00%)  0
Meningitis herpes  1  0/442 (0.00%)  0 1/443 (0.23%)  2
Osteomyelitis  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Perirectal abscess  1  1/442 (0.23%)  10 1/443 (0.23%)  2
Pneumonia  1  28/442 (6.33%)  39 27/443 (6.09%)  42
Pneumonia pneumococcal  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Pneumonia streptococcal  1  0/442 (0.00%)  0 1/443 (0.23%)  17
Pseudomonal sepsis  1  1/442 (0.23%)  1 1/443 (0.23%)  2
Respiratory tract infection  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Retroperitoneal abscess  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Sepsis  1  6/442 (1.36%)  7 2/443 (0.45%)  2
Sepsis syndrome  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Septic shock  1  2/442 (0.45%)  3 0/443 (0.00%)  0
Staphylococcal bacteraemia  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Staphylococcal infection  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Staphylococcal sepsis  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Streptococcal bacteraemia  1  1/442 (0.23%)  2 0/443 (0.00%)  0
Tooth abscess  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Upper respiratory tract infection  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Urinary tract infection  1  0/442 (0.00%)  0 3/443 (0.68%)  4
Urinary tract infection bacterial  1  1/442 (0.23%)  1 1/443 (0.23%)  1
Viral upper respiratory tract infection  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Wound abscess  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Injury, poisoning and procedural complications     
Accidental overdose  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Compression fracture  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Fall  1  1/442 (0.23%)  1 2/443 (0.45%)  3
Femur fracture  1  2/442 (0.45%)  2 0/443 (0.00%)  0
Head injury  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Hip fracture  1  1/442 (0.23%)  1 1/443 (0.23%)  2
Humerus fracture  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Lower limb fracture  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Overdose  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Radiation oesophagitis  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Rib fracture  1  0/442 (0.00%)  0 1/443 (0.23%)  14
Road traffic accident  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Spinal compression fracture  1  2/442 (0.45%)  15 1/443 (0.23%)  2
Wrong drug administered  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Investigations     
Alanine aminotransferase increased  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Aspartate aminotransferase increased  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Aspiration pleural cavity  1  1/442 (0.23%)  1 0/443 (0.00%)  0
International normalised ratio increased  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Platelet count decreased  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Troponin i increased  1  0/442 (0.00%)  0 1/443 (0.23%)  2
Metabolism and nutrition disorders     
Decreased appetite  1  1/442 (0.23%)  2 2/443 (0.45%)  3
Dehydration  1  20/442 (4.52%)  27 21/443 (4.74%)  26
Electrolyte imbalance  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Failure to thrive  1  1/442 (0.23%)  3 0/443 (0.00%)  0
Hypercalcaemia  1  1/442 (0.23%)  2 0/443 (0.00%)  0
Hyperglycaemia  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Hyperkalaemia  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Hypocalcaemia  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Hypoglycaemia  1  2/442 (0.45%)  3 1/443 (0.23%)  1
Hypokalaemia  1  5/442 (1.13%)  8 2/443 (0.45%)  2
Hypomagnesaemia  1  0/442 (0.00%)  0 1/443 (0.23%)  2
Hyponatraemia  1  3/442 (0.68%)  4 8/443 (1.81%)  9
Hypophosphataemia  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Lactic acidosis  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Malnutrition  1  1/442 (0.23%)  2 0/443 (0.00%)  0
Metabolic acidosis  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Metabolic alkalosis  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Starvation  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Tumour lysis syndrome  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Musculoskeletal and connective tissue disorders     
Arthralgia  1  1/442 (0.23%)  2 2/443 (0.45%)  11
Back pain  1  2/442 (0.45%)  8 4/443 (0.90%)  9
Bone pain  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Fracture nonunion  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Groin pain  1  0/442 (0.00%)  0 1/443 (0.23%)  2
Muscular weakness  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Musculoskeletal pain  1  1/442 (0.23%)  1 2/443 (0.45%)  3
Pathological fracture  1  1/442 (0.23%)  1 1/443 (0.23%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Colon cancer  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Malignant pleural effusion  1  2/442 (0.45%)  6 1/443 (0.23%)  1
Metastases to central nervous system  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Metastases to liver  1  0/442 (0.00%)  0 1/443 (0.23%)  8
Metastases to meninges  1  0/442 (0.00%)  0 1/443 (0.23%)  2
Metastatic pain  1  3/442 (0.68%)  5 1/443 (0.23%)  1
Neoplasm malignant  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Neurilemmoma  1  0/442 (0.00%)  0 1/443 (0.23%)  2
Pericardial effusion malignant  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Prostate cancer  1  0/442 (0.00%)  0 1/235 (0.43%)  3
Tumour pain  1  2/442 (0.45%)  2 0/443 (0.00%)  0
Nervous system disorders     
Ataxia  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Cerebral haemorrhage  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Cerebral infarction  1  1/442 (0.23%)  1 2/443 (0.45%)  3
Cerebral ischaemia  1  1/442 (0.23%)  2 2/443 (0.45%)  3
Cerebrovascular accident  1  5/442 (1.13%)  9 3/443 (0.68%)  4
Convulsion  1  0/442 (0.00%)  0 2/443 (0.45%)  2
Dizziness  1  1/442 (0.23%)  1 2/443 (0.45%)  2
Encephalopathy  1  0/442 (0.00%)  0 1/443 (0.23%)  2
Grand mal convulsion  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Haemorrhage intracranial  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Haemorrhagic stroke  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Ischaemic cerebral infarction  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Lethargy  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Metabolic encephalopathy  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Nerve compression  1  0/442 (0.00%)  0 1/443 (0.23%)  7
Neuropathy peripheral  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Paraesthesia  1  0/442 (0.00%)  0 1/443 (0.23%)  3
Parkinson's disease  1  0/442 (0.00%)  0 1/443 (0.23%)  11
Somnolence  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Status epilepticus  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Subarachnoid haemorrhage  1  2/442 (0.45%)  2 0/443 (0.00%)  0
Syncope  1  3/442 (0.68%)  3 1/443 (0.23%)  1
Transient ischaemic attack  1  3/442 (0.68%)  3 2/443 (0.45%)  2
Unresponsive to stimuli  1  1/442 (0.23%)  2 0/443 (0.00%)  0
Psychiatric disorders     
Anxiety  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Confusional state  1  5/442 (1.13%)  5 2/443 (0.45%)  2
Delirium  1  0/442 (0.00%)  0 1/443 (0.23%)  2
Mental status changes  1  4/442 (0.90%)  4 2/443 (0.45%)  3
Renal and urinary disorders     
Nephrotic syndrome  1  1/442 (0.23%)  3 0/443 (0.00%)  0
Renal failure  1  1/442 (0.23%)  7 0/443 (0.00%)  0
Renal failure acute  1  7/442 (1.58%)  10 4/443 (0.90%)  5
Renal tubular necrosis  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Urinary retention  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Urinary tract obstruction  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Respiratory, thoracic and mediastinal disorders     
Acquired tracheo-oesophageal fistula  1  1/442 (0.23%)  2 0/443 (0.00%)  0
Acute respiratory distress syndrome  1  1/442 (0.23%)  1 2/443 (0.45%)  2
Acute respiratory failure  1  1/442 (0.23%)  3 2/443 (0.45%)  2
Aspiration  1  1/442 (0.23%)  4 0/443 (0.00%)  0
Bronchial fistula  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Bronchospasm  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Chronic obstructive pulmonary disease  1  7/442 (1.58%)  30 2/443 (0.45%)  22
Dyspnoea  1  7/442 (1.58%)  14 8/443 (1.81%)  18
Emphysema  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Epistaxis  1  6/442 (1.36%)  7 2/443 (0.45%)  2
Haemoptysis  1  8/442 (1.81%)  11 3/443 (0.68%)  6
Hydropneumothorax  1  0/442 (0.00%)  0 4/443 (0.90%)  10
Hypoxia  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Pleural effusion  1  3/442 (0.68%)  6 6/443 (1.35%)  9
Pleuritic pain  1  1/442 (0.23%)  1 1/443 (0.23%)  2
Pneumonia aspiration  1  1/442 (0.23%)  2 3/443 (0.68%)  3
Pneumothorax  1  2/442 (0.45%)  2 2/443 (0.45%)  2
Pulmonary embolism  1  10/442 (2.26%)  21 9/443 (2.03%)  14
Pulmonary haemorrhage  1  2/442 (0.45%)  2 1/443 (0.23%)  1
Pulmonary hypertension  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Respiratory distress  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Respiratory failure  1  11/442 (2.49%)  13 4/443 (0.90%)  4
Skin and subcutaneous tissue disorders     
Skin disorder  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Surgical and medical procedures     
Lung neoplasm surgery  1  1/442 (0.23%)  2 0/443 (0.00%)  0
Vascular disorders     
Arterial thrombosis  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Deep vein thrombosis  1  5/442 (1.13%)  16 14/443 (3.16%)  34
Haemorrhage  1  1/442 (0.23%)  1 1/443 (0.23%)  1
Hypertension  1  2/442 (0.45%)  5 1/443 (0.23%)  7
Hypertensive crisis  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Hypotension  1  3/442 (0.68%)  3 3/443 (0.68%)  5
Intra-abdominal haemorrhage  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Jugular vein thrombosis  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Orthostatic hypotension  1  0/442 (0.00%)  0 1/443 (0.23%)  1
Post thrombotic syndrome  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Shock  1  1/442 (0.23%)  1 0/443 (0.00%)  0
Superior vena cava syndrome  1  1/442 (0.23%)  5 0/443 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Pem/Carbo/Bev Pac/Carbo/Bev
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   430/442 (97.29%)      433/443 (97.74%)    
Blood and lymphatic system disorders     
Anaemia  1  177/442 (40.05%)  1367 136/443 (30.70%)  793
Leukopenia  1  73/442 (16.52%)  387 76/443 (17.16%)  362
Neutropenia  1  170/442 (38.46%)  733 219/443 (49.44%)  790
Thrombocytopenia  1  159/442 (35.97%)  829 105/443 (23.70%)  452
Eye disorders     
Lacrimation increased  1  31/442 (7.01%)  405 2/443 (0.45%)  12
Gastrointestinal disorders     
Abdominal pain  1  42/442 (9.50%)  171 39/443 (8.80%)  113
Constipation  1  181/442 (40.95%)  1380 166/443 (37.47%)  931
Diarrhoea  1  100/442 (22.62%)  536 118/443 (26.64%)  338
Dyspepsia  1  49/442 (11.09%)  419 30/443 (6.77%)  155
Gastrooesophageal reflux disease  1  25/442 (5.66%)  249 22/443 (4.97%)  178
Nausea  1  236/442 (53.39%)  1465 223/443 (50.34%)  1157
Stomatitis  1  61/442 (13.80%)  321 44/443 (9.93%)  159
Vomiting  1  114/442 (25.79%)  369 108/443 (24.38%)  310
General disorders     
Asthenia  1  40/442 (9.05%)  230 29/443 (6.55%)  178
Fatigue  1  268/442 (60.63%)  2793 257/443 (58.01%)  2273
Mucosal inflammation  1  51/442 (11.54%)  229 35/443 (7.90%)  110
Oedema peripheral  1  66/442 (14.93%)  466 40/443 (9.03%)  249
Pain  1  22/442 (4.98%)  87 31/443 (7.00%)  196
Pyrexia  1  35/442 (7.92%)  104 42/443 (9.48%)  57
Infections and infestations     
Sinusitis  1  33/442 (7.47%)  111 19/443 (4.29%)  53
Upper respiratory tract infection  1  32/442 (7.24%)  103 26/443 (5.87%)  53
Urinary tract infection  1  32/442 (7.24%)  84 42/443 (9.48%)  108
Investigations     
Alanine aminotransferase increased  1  37/442 (8.37%)  291 12/443 (2.71%)  47
Aspartate aminotransferase increased  1  33/442 (7.47%)  207 17/443 (3.84%)  52
Blood creatinine increased  1  25/442 (5.66%)  163 13/443 (2.93%)  29
Haemoglobin decreased  1  39/442 (8.82%)  322 22/443 (4.97%)  102
Platelet count decreased  1  29/442 (6.56%)  106 14/443 (3.16%)  39
Weight decreased  1  77/442 (17.42%)  464 68/443 (15.35%)  470
Metabolism and nutrition disorders     
Decreased appetite  1  133/442 (30.09%)  865 145/443 (32.73%)  912
Dehydration  1  68/442 (15.38%)  194 54/443 (12.19%)  155
Hyperglycaemia  1  38/442 (8.60%)  251 45/443 (10.16%)  236
Hypokalaemia  1  28/442 (6.33%)  70 33/443 (7.45%)  76
Hypomagnesaemia  1  34/442 (7.69%)  169 30/443 (6.77%)  186
Musculoskeletal and connective tissue disorders     
Arthralgia  1  46/442 (10.41%)  272 107/443 (24.15%)  967
Back pain  1  60/442 (13.57%)  299 64/443 (14.45%)  441
Bone pain  1  16/442 (3.62%)  83 33/443 (7.45%)  204
Musculoskeletal chest pain  1  33/442 (7.47%)  197 21/443 (4.74%)  141
Musculoskeletal pain  1  42/442 (9.50%)  273 31/443 (7.00%)  246
Myalgia  1  25/442 (5.66%)  150 60/443 (13.54%)  394
Pain in extremity  1  25/442 (5.66%)  200 44/443 (9.93%)  413
Nervous system disorders     
Dizziness  1  77/442 (17.42%)  404 63/443 (14.22%)  298
Dysgeusia  1  67/442 (15.16%)  551 47/443 (10.61%)  283
Headache  1  82/442 (18.55%)  516 67/443 (15.12%)  343
Neuropathy peripheral  1  42/442 (9.50%)  413 145/443 (32.73%)  1394
Paraesthesia  1  11/442 (2.49%)  85 24/443 (5.42%)  255
Peripheral sensory neuropathy  1  19/442 (4.30%)  218 73/443 (16.48%)  888
Psychiatric disorders     
Anxiety  1  52/442 (11.76%)  407 44/443 (9.93%)  379
Confusional state  1  19/442 (4.30%)  95 23/443 (5.19%)  48
Depression  1  52/442 (11.76%)  402 47/443 (10.61%)  414
Insomnia  1  69/442 (15.61%)  535 87/443 (19.64%)  719
Renal and urinary disorders     
Proteinuria  1  63/442 (14.25%)  435 54/443 (12.19%)  449
Respiratory, thoracic and mediastinal disorders     
Cough  1  91/442 (20.59%)  549 86/443 (19.41%)  568
Dysphonia  1  32/442 (7.24%)  257 17/443 (3.84%)  126
Dyspnoea  1  88/442 (19.91%)  558 85/443 (19.19%)  503
Epistaxis  1  117/442 (26.47%)  800 98/443 (22.12%)  599
Oropharyngeal pain  1  41/442 (9.28%)  140 33/443 (7.45%)  115
Rhinorrhoea  1  29/442 (6.56%)  205 19/443 (4.29%)  153
Skin and subcutaneous tissue disorders     
Alopecia  1  34/442 (7.69%)  445 193/443 (43.57%)  2024
Pruritus  1  15/442 (3.39%)  72 30/443 (6.77%)  91
Rash  1  42/442 (9.50%)  239 56/443 (12.64%)  177
Vascular disorders     
Hypertension  1  74/442 (16.74%)  800 70/443 (15.80%)  678
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Chief Medical Officer
Organization: Eli Lilly and Company
Phone: 800-545-5979
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT00762034     History of Changes
Other Study ID Numbers: 9707
H3E-MC-JMHD ( Other Identifier: Eli Lilly and Company )
First Submitted: September 26, 2008
First Posted: September 30, 2008
Results First Submitted: March 28, 2013
Results First Posted: November 28, 2013
Last Update Posted: December 21, 2015