Trial Outcomes & Findings for A Study of Aflibercept Administered in Combination With Pemetrexed and Cisplatin in Participants With Advanced Carcinoma (NCT NCT00794417)

Last Updated: 2020-12-10

Results Overview

Recommended Dose was defined as the highest combination dose at which fewer than 33 percent (%) of participants experienced dose limiting toxicity during the first cycle of therapy.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

60 participants

Primary outcome timeframe

Phase 1: Baseline up to 315 Days

Results posted on

2020-12-10

Participant Flow

The study consisted of 2 phases: phase 1 and phase 2. A total of 18 participants were enrolled in phase 1 of the study and 42 participants were enrolled in phase 2 of the study. Participants enrolled in phase 1 were not eligible for enrollment in phase 2.

Participant milestones

Participant milestones
Measure	Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Participants received intravenous infusion of aflibercept 2 milligrams per kilogram (mg/kg) followed by pemetrexed 500 mg/square meter (m\^2) and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Participants received intravenous infusion of aflibercept 4 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) for 6 cycles.
Phase 1: Baseline (Day 1) up to Day 751 STARTED	4	7	7	0
Phase 1: Baseline (Day 1) up to Day 751 COMPLETED	1	4	4	0
Phase 1: Baseline (Day 1) up to Day 751 NOT COMPLETED	3	3	3	0
Phase 2: Baseline (Day 421) to Day 972 STARTED	0	0	0	42
Phase 2: Baseline (Day 421) to Day 972 COMPLETED	0	0	0	7
Phase 2: Baseline (Day 421) to Day 972 NOT COMPLETED	0	0	0	35

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Participants received intravenous infusion of aflibercept 2 milligrams per kilogram (mg/kg) followed by pemetrexed 500 mg/square meter (m\^2) and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Participants received intravenous infusion of aflibercept 4 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) for 6 cycles.
Phase 1: Baseline (Day 1) up to Day 751 Death	0	0	2	0
Phase 1: Baseline (Day 1) up to Day 751 Other un-specified	3	3	1	0
Phase 2: Baseline (Day 421) to Day 972 Death	0	0	0	7
Phase 2: Baseline (Day 421) to Day 972 Physician Decision	0	0	0	11
Phase 2: Baseline (Day 421) to Day 972 Withdrawal by Subject	0	0	0	4
Phase 2: Baseline (Day 421) to Day 972 Other unspecified	0	0	0	13

Baseline Characteristics

A Study of Aflibercept Administered in Combination With Pemetrexed and Cisplatin in Participants With Advanced Carcinoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin n=4 Participants Participants received intravenous infusion of aflibercept 2 milligrams per kilogram (mg/kg) followed by pemetrexed 500 mg/square meter (m\^2) and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 4 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=42 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) for 6 cycles.	Total n=60 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	4 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants	23 Participants n=4 Participants	33 Participants n=21 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	6 Participants n=7 Participants	2 Participants n=5 Participants	19 Participants n=4 Participants	27 Participants n=21 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	4 Participants n=7 Participants	2 Participants n=5 Participants	19 Participants n=4 Participants	28 Participants n=21 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants	23 Participants n=4 Participants	32 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	4 Participants n=4 Participants	4 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants	2 Participants n=21 Participants
Race (NIH/OMB) White	3 Participants n=5 Participants	7 Participants n=7 Participants	7 Participants n=5 Participants	36 Participants n=4 Participants	53 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants

PRIMARY outcome

Timeframe: Phase 1: Baseline up to 315 Days

Population: Full analysis set (FAS) included all participants who were enrolled and received at least one dose of study drug. Data for this outcome measure has been reported for all participants in single arm.

Recommended Dose was defined as the highest combination dose at which fewer than 33 percent (%) of participants experienced dose limiting toxicity during the first cycle of therapy.

Outcome measures

Outcome measures
Measure	Phase 1: All Participants n=18 Participants All participants who received intravenous infusion of aflibercept 2 mg/kg or 4 mg/kg or 6 mg/kg followed by pemetrexed 500 mg/square metere (m\^2) and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Participants received intravenous infusion of aflibercept 4 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) for 6 cycles.
Phase 1: Recommended Dose of Aflibercept for Phase 2	6 mg/kg	—	—	—

SECONDARY outcome

Timeframe: Phase 2: Baseline (Day 421) up to end of study (Day 972)

Population: FAS included all participants who were enrolled and received at least one dose of study drug.

Objective response rate was defined as the percentage of participants who achieved complete response (CR) or partial response (PR) as assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST). CR was defined as disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking the Baseline sum LD as reference.

Outcome measures

Outcome measures
Measure	Phase 1: All Participants n=42 Participants All participants who received intravenous infusion of aflibercept 2 mg/kg or 4 mg/kg or 6 mg/kg followed by pemetrexed 500 mg/square metere (m\^2) and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Participants received intravenous infusion of aflibercept 4 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) for 6 cycles.
Phase 2: Objective Response Rate	23.8 Percentage of Participants	—	—	—

SECONDARY outcome

Timeframe: Phase 2: Baseline (Day 421) up to end of study (Day 972)

Population: FAS included all participants who were enrolled and received at least one dose of study drug.

PFS was defined as the time in days from the date of first study drug administration to the date of first documentation of tumor progression or death from any cause, whichever occurs first, as assessed by the modified RECIST. Median time of PFS was estimated using Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Phase 1: All Participants n=42 Participants All participants who received intravenous infusion of aflibercept 2 mg/kg or 4 mg/kg or 6 mg/kg followed by pemetrexed 500 mg/square metere (m\^2) and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Participants received intravenous infusion of aflibercept 4 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) for 6 cycles.
Phase 2: Progression-free Survival (PFS)	149 Days Interval 130.0 to 212.0	—	—	—

SECONDARY outcome

Timeframe: Phase 1: Baseline up to 751 Days; Phase 2: Baseline (Day 421) up to 972 Days

Population: FAS included all participants who were enrolled and received at least one dose of study drug.

An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (for example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) was defined as an adverse event with an onset that occurs after receiving study drug. Any TEAE included participants with both serious and non-serious AEs.

Outcome measures

Outcome measures
Measure	Phase 1: All Participants n=4 Participants All participants who received intravenous infusion of aflibercept 2 mg/kg or 4 mg/kg or 6 mg/kg followed by pemetrexed 500 mg/square metere (m\^2) and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 4 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=42 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) for 6 cycles.
Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs)	4 Participants	7 Participants	7 Participants	42 Participants

SECONDARY outcome

Timeframe: Phase 1 and 2: Pre-dose up to Day 22 post-dose

Population: FAS included all participants who were enrolled and received at least one dose of study drug. Here "Overall number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

The AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.

Outcome measures

Outcome measures
Measure	Phase 1: All Participants n=4 Participants All participants who received intravenous infusion of aflibercept 2 mg/kg or 4 mg/kg or 6 mg/kg followed by pemetrexed 500 mg/square metere (m\^2) and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin n=6 Participants Participants received intravenous infusion of aflibercept 4 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=6 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) for 6 cycles.
Phase 1 and 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Aflibercept	201 Day*milligrams per liter (mg/L) Standard Deviation 96.5	330 Day*milligrams per liter (mg/L) Standard Deviation 251	442 Day*milligrams per liter (mg/L) Standard Deviation 152	402 Day*milligrams per liter (mg/L) Standard Deviation 100

SECONDARY outcome

Timeframe: Phase 1 and 2: Pre-dose up to Day 1 post-dose, Day 2 post-dose (only in Phase 1)

The AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.

Outcome measures

Outcome measures
Measure	Phase 1: All Participants n=4 Participants All participants who received intravenous infusion of aflibercept 2 mg/kg or 4 mg/kg or 6 mg/kg followed by pemetrexed 500 mg/square metere (m\^2) and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 4 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=10 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) for 6 cycles.
Phase 1 and 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Pemetrexed	151 Hour*milligrams per liter (mg/L) Standard Deviation 30.0	151 Hour*milligrams per liter (mg/L) Standard Deviation 32.5	162 Hour*milligrams per liter (mg/L) Standard Deviation 12.6	148 Hour*milligrams per liter (mg/L) Standard Deviation 24.3

SECONDARY outcome

Timeframe: Phase 1 and 2: Aflibercept: Pre-dose up to Day 22 post-dose; Pemetrexed: Pre-dose up to Day 1 post-dose, Day 2 post-dose (only in Phase 1)

Population: FAS included all participants who were enrolled and received at least one dose of study drug. Here "Overall number of participants analyzed" signifies participants who were evaluable for this outcome measure and "Number analyzed" signifies those participants who were evaluable for specific category.

Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve.

Outcome measures

Outcome measures
Measure	Phase 1: All Participants n=4 Participants All participants who received intravenous infusion of aflibercept 2 mg/kg or 4 mg/kg or 6 mg/kg followed by pemetrexed 500 mg/square metere (m\^2) and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 4 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=21 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) for 6 cycles.
Phase 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Aflibercept and Pemetrexed Aflibercept	53.6 mg/L Standard Deviation 7.14	68.6 mg/L Standard Deviation 18.7	148 mg/L Standard Deviation 108	104 mg/L Standard Deviation 26.2
Phase 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Aflibercept and Pemetrexed Pemetrexed	124 mg/L Standard Deviation 12.6	112 mg/L Standard Deviation 34.7	113 mg/L Standard Deviation 24.6	76.8 mg/L Standard Deviation 40.5

SECONDARY outcome

Timeframe: Phase 1 and 2: Pre-dose up to Day 22 post-dose

Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.

Outcome measures

Outcome measures
Measure	Phase 1: All Participants n=4 Participants All participants who received intravenous infusion of aflibercept 2 mg/kg or 4 mg/kg or 6 mg/kg followed by pemetrexed 500 mg/square metere (m\^2) and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin n=6 Participants Participants received intravenous infusion of aflibercept 4 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=6 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) for 6 cycles.
Phase 1 and 2: Total Body Clearance of Aflibercept	0.011 Liter/Day/kg Standard Deviation 0.004	0.016 Liter/Day/kg Standard Deviation 0.007	0.016 Liter/Day/kg Standard Deviation 0.009	0.016 Liter/Day/kg Standard Deviation 0.004

SECONDARY outcome

Timeframe: Phase 1 and 2: Pre-dose up to Day 1 post-dose, Day 2 post-dose (only in Phase 1)

Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.

Outcome measures

Outcome measures
Measure	Phase 1: All Participants n=4 Participants All participants who received intravenous infusion of aflibercept 2 mg/kg or 4 mg/kg or 6 mg/kg followed by pemetrexed 500 mg/square metere (m\^2) and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 4 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=10 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) for 6 cycles.
Phase 1 and 2: Total Body Clearance of Pemetrexed	3.40 Liter/hour/m^2 Standard Deviation 0.59	3.47 Liter/hour/m^2 Standard Deviation 0.84	3.10 Liter/hour/m^2 Standard Deviation 0.22	3.49 Liter/hour/m^2 Standard Deviation 0.76

SECONDARY outcome

Timeframe: Phase 1 and 2: Pre-dose up to Day 22 post-dose

Terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination.

Outcome measures

Outcome measures
Measure	Phase 1: All Participants n=4 Participants All participants who received intravenous infusion of aflibercept 2 mg/kg or 4 mg/kg or 6 mg/kg followed by pemetrexed 500 mg/square metere (m\^2) and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin n=6 Participants Participants received intravenous infusion of aflibercept 4 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=6 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) for 6 cycles.
Phase 1 and 2: Terminal Half-Life (t1/2) of Aflibercept	3.16 Days Standard Deviation 0.570	5.53 Days Standard Deviation 5.43	3.72 Days Standard Deviation 1.04	4.62 Days Standard Deviation 1.46

SECONDARY outcome

Timeframe: Phase 1 and 2: Pre-dose up to Day 1 post-dose, Day 2 post-dose (only in Phase 1)

Terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination.

Outcome measures

Outcome measures
Measure	Phase 1: All Participants n=4 Participants All participants who received intravenous infusion of aflibercept 2 mg/kg or 4 mg/kg or 6 mg/kg followed by pemetrexed 500 mg/square metere (m\^2) and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 4 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=10 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) for 6 cycles.
Phase 1 and 2: Terminal Half-Life (t1/2) of Pemetrexed	1.47 Hours Standard Deviation 0.39	1.63 Hours Standard Deviation 0.22	1.73 Hours Standard Deviation 0.37	1.48 Hours Standard Deviation 0.34

SECONDARY outcome

Timeframe: Phase 1: Baseline up to 315 Days; Phase 2: Baseline (Day 421) up to Day 739

Population: FAS included all participants who were enrolled and received at least one dose of study drug.

Serum samples were analyzed by a validated electrochemiluminescence immunoassay to detect the presence of ADA.

Outcome measures

Outcome measures
Measure	Phase 1: All Participants n=4 Participants All participants who received intravenous infusion of aflibercept 2 mg/kg or 4 mg/kg or 6 mg/kg followed by pemetrexed 500 mg/square metere (m\^2) and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 4 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=42 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) for 6 cycles.
Phase 1 and 2: Number of Participants With Positive Anti-drug Antibody (ADA) of Aflibercept	0 Participants	0 Participants	1 Participants	2 Participants

SECONDARY outcome

Timeframe: Phase 1: Baseline up to 751 Days; Phase 2: Baseline (Day 421) up to 972 Days

Population: FAS included all participants who were enrolled and received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	Phase 1: All Participants n=4 Participants All participants who received intravenous infusion of aflibercept 2 mg/kg or 4 mg/kg or 6 mg/kg followed by pemetrexed 500 mg/square metere (m\^2) and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 4 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=42 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) for 6 cycles.
Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities Hyperglycemia (Non-Fasting)	4 Participants	6 Participants	7 Participants	37 Participants
Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities Hyperglycemia (Fasting)	1 Participants	3 Participants	6 Participants	6 Participants
Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities Hypoglycemia (Non-Fasting)	0 Participants	0 Participants	0 Participants	5 Participants
Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities Hypoglycemia (Fasting)	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Phase 1: Baseline up to 751 Days; Phase 2: Baseline (Day 421) up to 972 Days

Population: FAS included all participants who were enrolled and received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	Phase 1: All Participants n=4 Participants All participants who received intravenous infusion of aflibercept 2 mg/kg or 4 mg/kg or 6 mg/kg followed by pemetrexed 500 mg/square metere (m\^2) and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 4 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=7 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) until disease progression, unacceptable toxicity, withdrawal of consent or if another study withdrawal criterion has been met.	Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin n=42 Participants Participants received intravenous infusion of aflibercept 6 mg/kg followed by pemetrexed 500 mg/m\^2 and then cisplatin 75 mg/m\^2 on Day 1 of each 3 week cycle (1 Cycle = 21 Days in this study) for 6 cycles.
Phase 1 and 2: Number of Participants With All Grade Hematology Abnormalities Absolute Neutrophil Count (ANC)	2 Participants	4 Participants	7 Participants	13 Participants
Phase 1 and 2: Number of Participants With All Grade Hematology Abnormalities Hemoglobin	3 Participants	7 Participants	6 Participants	16 Participants
Phase 1 and 2: Number of Participants With All Grade Hematology Abnormalities Platelet Count	2 Participants	4 Participants	2 Participants	8 Participants

Adverse Events

Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin

Serious events: 1 serious events

Other events: 4 other events

Deaths: 0 deaths

Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin

Serious events: 5 serious events

Other events: 7 other events

Deaths: 1 deaths

Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin

Serious events: 3 serious events

Other events: 7 other events

Deaths: 1 deaths

Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin

Serious events: 16 serious events

Other events: 41 other events

Deaths: 5 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Trial Administrator

Regeneron Pharmaceuticals, Inc.

Phone: 844-734-6643

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The investigator has the right to independently publish study results from the investigator's site after a multi-center publication, or a defined period after the completion of the study by all sites. The investigator must provide the sponsor a copy of any such publication derived from the study for review and comment in advance of any submission, and delay publication, if requested, to allow the Sponsor to preserve its proprietary rights.
Publication restrictions are in place

Restriction type: OTHER