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

Sponsor
Regeneron Pharmaceuticals (Industry)
Overall Status
Terminated
CT.gov ID
NCT00794417
Collaborator
Sanofi (Industry)
60
Enrollment
15
Locations
4
Arms
30.9
Actual Duration (Months)
4
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of the study was to determine whether the combination of aflibercept, pemetrexed and cisplatin is safe and effective in treating non-small cell lung cancer (NSCLC).

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

The study was conducted in two phases. In phase 1, patients with advanced cancer received different doses of aflibercept in combination with approved doses of pemetrexed and cisplatin. The objective of phase 1 was to determine the safest dose of the combined study medications. This dose was administered to patients with previously untreated NSCLC in phase 2. The phase 2 portion of the study determined if the combination is effective in treating NSCLC.

Study Design

Study Type:
Interventional
Actual Enrollment :
60 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1/2 Study of Aflibercept Administered in Combination With Pemetrexed and Cisplatin in Patients With Advanced Carcinoma
Actual Study Start Date :
Nov 30, 2008
Actual Primary Completion Date :
Jun 30, 2011
Actual Study Completion Date :
Jun 30, 2011

Arms and Interventions

Arm Intervention/Treatment
Experimental: 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.

Drug: Aflibercept
Administered in combination with the other two interventions via intravenous infusion.

Drug: Pemetrexed
Administered in combination with the other two interventions via intravenous infusion.
Other Names:
  • Alimta

    • Drug: Cisplatin
    Administered in combination with the other two interventions via intravenous infusion.
    Other Names:
  • Platinol

    		•
    Experimental: 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.

    Drug: Aflibercept
    Administered in combination with the other two interventions via intravenous infusion.

    Drug: Pemetrexed
    Administered in combination with the other two interventions via intravenous infusion.
    Other Names:
  • Alimta

    • Drug: Cisplatin
    Administered in combination with the other two interventions via intravenous infusion.
    Other Names:
  • Platinol

    		•
    Experimental: 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.

    Drug: Aflibercept
    Administered in combination with the other two interventions via intravenous infusion.

    Drug: Pemetrexed
    Administered in combination with the other two interventions via intravenous infusion.
    Other Names:
  • Alimta

    • Drug: Cisplatin
    Administered in combination with the other two interventions via intravenous infusion.
    Other Names:
  • Platinol

    		•
    Experimental: 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.

    Drug: Aflibercept
    Administered in combination with the other two interventions via intravenous infusion.

    Drug: Pemetrexed
    Administered in combination with the other two interventions via intravenous infusion.
    Other Names:
  • Alimta

    • Drug: Cisplatin
    Administered in combination with the other two interventions via intravenous infusion.
    Other Names:
  • Platinol

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Phase 1: Recommended Dose of Aflibercept for Phase 2 [Phase 1: Baseline up to 315 Days]

      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.

    Secondary Outcome Measures

    1. Phase 2: Objective Response Rate [Phase 2: Baseline (Day 421) up to end of study (Day 972)]

      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.

    2. Phase 2: Progression-free Survival (PFS) [Phase 2: Baseline (Day 421) up to end of study (Day 972)]

      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.

    3. Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) [Phase 1: Baseline up to 751 Days; Phase 2: Baseline (Day 421) up to 972 Days]

      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.

    4. Phase 1 and 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Aflibercept [Phase 1 and 2: Pre-dose up to Day 22 post-dose]

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

    5. Phase 1 and 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Pemetrexed [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.

    6. Phase 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Aflibercept and Pemetrexed [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)]

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

    7. Phase 1 and 2: Total Body Clearance of Aflibercept [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.

    8. Phase 1 and 2: Total Body Clearance of Pemetrexed [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.

    9. Phase 1 and 2: Terminal Half-Life (t1/2) of Aflibercept [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.

    10. Phase 1 and 2: Terminal Half-Life (t1/2) of Pemetrexed [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.

    11. Phase 1 and 2: Number of Participants With Positive Anti-drug Antibody (ADA) of Aflibercept [Phase 1: Baseline up to 315 Days; Phase 2: Baseline (Day 421) up to Day 739]

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

    12. Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities [Phase 1: Baseline up to 751 Days; Phase 2: Baseline (Day 421) up to 972 Days]

    13. Phase 1 and 2: Number of Participants With All Grade Hematology Abnormalities [Phase 1: Baseline up to 751 Days; Phase 2: Baseline (Day 421) up to 972 Days]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Confirmation of cancer by biopsy (tissue sample)

    • Phase 1: patients with advanced or metastatic disease that have failed conventional therapy

    • Phase 2: patients with previously untreated NSCLC, excluding squamous cell histology and cavitating lesions

    • Age ≥18 years

    • Eastern Cooperative Oncology Group (ECOG) performance status 0-1

    • Adequate renal, liver and bone marrow function.

    • Negative pregnancy test (serum or urine) in females of childbearing potential within 7 days of the initial dose of aflibercept

    • Ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures

    • Institutional Review Board (IRB) approved, signed and dated informed consent form

    Exclusion Criteria:

    • Prior treatment with study medications

    • Untreated, symptomatic, or progressive Central Nervous System cancer and/or spinal cord compression. Patients with treated brain metastases must have been without symptoms for at least 3 months

    • Surgery up to 4 weeks prior to the initial administration of aflibercept and/or incomplete wound healing

    • Anti-VEGF therapy up to 4 weeks prior to the initial administration of aflibercept (for phase 1 only)

    • Chemotherapy up to 4 weeks prior to the initial administration of aflibercept (for phase 1 only)

    • Other investigational treatment up to 4 weeks prior to the initial administration of aflibercept

    • Any of the following up to 6 months (24 weeks) prior to the initial administration of aflibercept:

    • Severe cardiovascular disease or event

    • Cerebrovascular accident, transient ischemic attack, or moderate to severe peripheral neuropathy

    • Erosive esophagitis or gastritis, infectious or inflammatory bowel disease, and diverticulitis

    • Deep vein thrombosis, pulmonary embolism, or other clotting event

    • Episode(s)of moderate to severe, continuous bleeding

    • Breast-feeding or pregnancy

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Arizona Cancer Institute, LLC Tucson Arizona United States 85715
    2 University of Arkansas for Medical Science Little Rock Arkansas United States 72205
    3 Stanford University Medical Center Stanford California United States 94305
    4 Palm Beach Institute of Hematology and Oncology Boynton Beach Florida United States 33435
    5 Edward Hines Jr. VA Medical Center Hines Illinois United States 60141
    6 Kentucky Cancer Clinic Hazard Kentucky United States 41701
    7 Sidney Kimmel Comprehensive Cancer Center Baltimore Maryland United States 21231-1000
    8 Dartmouth-Hitchcock Medical Center Lebanon New Hampshire United States 03756
    9 UNM Cancer Clinic Albuquerque New Mexico United States 87131
    10 Montefiore Medical Center Bronx New York United States 10467
    11 Roswell Park Cancer Institute Buffalo New York United States 14263
    12 Presbyterian Hospital Center for Cancer Research Charlotte North Carolina United States 28204
    13 Erie Regional Cancer Center Erie Pennsylvania United States 16505
    14 Schiffler Cancer Center - Medical Oncology Division Wheeling West Virginia United States 26003
    15 Princess Margaret Hospital Toronto Ontario Canada M5G 2M9

    Sponsors and Collaborators

    • Regeneron Pharmaceuticals
    • Sanofi

    Investigators

    • Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Regeneron Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT00794417
    Other Study ID Numbers:
    • VGFT-ST-0708
    • TCD10767
    First Posted:
    Nov 20, 2008
    Last Update Posted:
    Dec 10, 2020
    Last Verified:
    Nov 1, 2020
    Keywords provided by Regeneron Pharmaceuticals
    advanced cancer
    lung cancer
    NSCLC
    Non-small Cell Lung Cancer
    aflibercept
    chemotherapy
    Additional relevant MeSH terms:
    Carcinoma
    Lung Neoplasms
    Carcinoma, Non-Small-Cell Lung
    Pemetrexed
    Aflibercept

    Study Results

    Participant Flow

    Recruitment Details 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.
    Pre-assignment Detail
    Arm/Group Title Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin
    Arm/Group Description 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. 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. 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. 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.
    Period Title: Phase 1: Baseline (Day 1) up to Day 751
    STARTED 4 7 7 0
    COMPLETED 1 4 4 0
    NOT COMPLETED 3 3 3 0
    Period Title: Phase 1: Baseline (Day 1) up to Day 751
    STARTED 0 0 0 42
    COMPLETED 0 0 0 7
    NOT COMPLETED 0 0 0 35

    Baseline Characteristics

    Arm/Group Title Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Total
    Arm/Group Description 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. 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. 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. 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 of all reporting groups
    Overall Participants 4 7 7 42 60
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    4
    100%
    1
    14.3%
    5
    71.4%
    23
    54.8%
    33
    55%
    >=65 years
    0
    0%
    6
    85.7%
    2
    28.6%
    19
    45.2%
    27
    45%
    Sex: Female, Male (Count of Participants)
    Female
    3
    75%
    4
    57.1%
    2
    28.6%
    19
    45.2%
    28
    46.7%
    Male
    1
    25%
    3
    42.9%
    5
    71.4%
    23
    54.8%
    32
    53.3%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    4
    9.5%
    4
    6.7%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    2
    4.8%
    2
    3.3%
    White
    3
    75%
    7
    100%
    7
    100%
    36
    85.7%
    53
    88.3%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    1
    25%
    0
    0%
    0
    0%
    0
    0%
    1
    1.7%

    Outcome Measures

    1. Primary Outcome
    Title Phase 1: Recommended Dose of Aflibercept for Phase 2
    Description 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.
    Time Frame Phase 1: Baseline up to 315 Days

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Phase 1: All Participants
    Arm/Group Description 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.
    Measure Participants 18
    Number [mg/kg]
    6
    2. Secondary Outcome
    Title Phase 2: Objective Response Rate
    Description 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.
    Time Frame Phase 2: Baseline (Day 421) up to end of study (Day 972)

    Outcome Measure Data

    Analysis Population Description
    FAS included all participants who were enrolled and received at least one dose of study drug.
    Arm/Group Title Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin
    Arm/Group Description 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.
    Measure Participants 42
    Number [Percentage of Participants]
    23.8
    595%
    3. Secondary Outcome
    Title Phase 2: Progression-free Survival (PFS)
    Description 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.
    Time Frame Phase 2: Baseline (Day 421) up to end of study (Day 972)

    Outcome Measure Data

    Analysis Population Description
    FAS included all participants who were enrolled and received at least one dose of study drug.
    Arm/Group Title Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin
    Arm/Group Description 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.
    Measure Participants 42
    Median (95% Confidence Interval) [Days]
    149
    4. Secondary Outcome
    Title Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
    Description 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.
    Time Frame Phase 1: Baseline up to 751 Days; Phase 2: Baseline (Day 421) up to 972 Days

    Outcome Measure Data

    Analysis Population Description
    FAS included all participants who were enrolled and received at least one dose of study drug.
    Arm/Group Title Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin
    Arm/Group Description 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. 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. 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. 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.
    Measure Participants 4 7 7 42
    Count of Participants [Participants]
    4
    100%
    7
    100%
    7
    100%
    42
    100%
    5. Secondary Outcome
    Title Phase 1 and 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Aflibercept
    Description The AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.
    Time Frame Phase 1 and 2: Pre-dose up to Day 22 post-dose

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin
    Arm/Group Description 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. 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. 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. 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.
    Measure Participants 4 6 6 7
    Mean (Standard Deviation) [Day*milligrams per liter (mg/L)]
    201
    (96.5)
    330
    (251)
    442
    (152)
    402
    (100)
    6. Secondary Outcome
    Title Phase 1 and 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Pemetrexed
    Description The AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.
    Time Frame Phase 1 and 2: Pre-dose up to Day 1 post-dose, Day 2 post-dose (only in Phase 1)

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin
    Arm/Group Description 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. 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. 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. 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.
    Measure Participants 4 7 7 10
    Mean (Standard Deviation) [Hour*milligrams per liter (mg/L)]
    151
    (30.0)
    151
    (32.5)
    162
    (12.6)
    148
    (24.3)
    7. Secondary Outcome
    Title Phase 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Aflibercept and Pemetrexed
    Description Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve.
    Time Frame 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)

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin
    Arm/Group Description 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. 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. 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. 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.
    Measure Participants 4 7 7 21
    Aflibercept
    53.6
    (7.14)
    68.6
    (18.7)
    148
    (108)
    104
    (26.2)
    Pemetrexed
    124
    (12.6)
    112
    (34.7)
    113
    (24.6)
    76.8
    (40.5)
    8. Secondary Outcome
    Title Phase 1 and 2: Total Body Clearance of Aflibercept
    Description Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
    Time Frame Phase 1 and 2: Pre-dose up to Day 22 post-dose

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin
    Arm/Group Description 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. 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. 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. 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.
    Measure Participants 4 6 6 7
    Mean (Standard Deviation) [Liter/Day/kg]
    0.011
    (0.004)
    0.016
    (0.007)
    0.016
    (0.009)
    0.016
    (0.004)
    9. Secondary Outcome
    Title Phase 1 and 2: Total Body Clearance of Pemetrexed
    Description Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
    Time Frame Phase 1 and 2: Pre-dose up to Day 1 post-dose, Day 2 post-dose (only in Phase 1)

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin
    Arm/Group Description 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. 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. 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. 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.
    Measure Participants 4 7 7 10
    Mean (Standard Deviation) [Liter/hour/m^2]
    3.40
    (0.59)
    3.47
    (0.84)
    3.10
    (0.22)
    3.49
    (0.76)
    10. Secondary Outcome
    Title Phase 1 and 2: Terminal Half-Life (t1/2) of Aflibercept
    Description 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.
    Time Frame Phase 1 and 2: Pre-dose up to Day 22 post-dose

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin
    Arm/Group Description 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. 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. 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. 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.
    Measure Participants 4 6 6 7
    Mean (Standard Deviation) [Days]
    3.16
    (0.570)
    5.53
    (5.43)
    3.72
    (1.04)
    4.62
    (1.46)
    11. Secondary Outcome
    Title Phase 1 and 2: Terminal Half-Life (t1/2) of Pemetrexed
    Description 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.
    Time Frame Phase 1 and 2: Pre-dose up to Day 1 post-dose, Day 2 post-dose (only in Phase 1)

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin
    Arm/Group Description 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. 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. 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. 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.
    Measure Participants 4 7 7 10
    Mean (Standard Deviation) [Hours]
    1.47
    (0.39)
    1.63
    (0.22)
    1.73
    (0.37)
    1.48
    (0.34)
    12. Secondary Outcome
    Title Phase 1 and 2: Number of Participants With Positive Anti-drug Antibody (ADA) of Aflibercept
    Description Serum samples were analyzed by a validated electrochemiluminescence immunoassay to detect the presence of ADA.
    Time Frame Phase 1: Baseline up to 315 Days; Phase 2: Baseline (Day 421) up to Day 739

    Outcome Measure Data

    Analysis Population Description
    FAS included all participants who were enrolled and received at least one dose of study drug.
    Arm/Group Title Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin
    Arm/Group Description 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. 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. 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. 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.
    Measure Participants 4 7 7 42
    Count of Participants [Participants]
    0
    0%
    0
    0%
    1
    14.3%
    2
    4.8%
    13. Secondary Outcome
    Title Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities
    Description
    Time Frame Phase 1: Baseline up to 751 Days; Phase 2: Baseline (Day 421) up to 972 Days

    Outcome Measure Data

    Analysis Population Description
    FAS included all participants who were enrolled and received at least one dose of study drug.
    Arm/Group Title Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin
    Arm/Group Description 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. 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. 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. 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.
    Measure Participants 4 7 7 42
    Hyperglycemia (Non-Fasting)
    4
    100%
    6
    85.7%
    7
    100%
    37
    88.1%
    Hyperglycemia (Fasting)
    1
    25%
    3
    42.9%
    6
    85.7%
    6
    14.3%
    Hypoglycemia (Non-Fasting)
    0
    0%
    0
    0%
    0
    0%
    5
    11.9%
    Hypoglycemia (Fasting)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    14. Secondary Outcome
    Title Phase 1 and 2: Number of Participants With All Grade Hematology Abnormalities
    Description
    Time Frame Phase 1: Baseline up to 751 Days; Phase 2: Baseline (Day 421) up to 972 Days

    Outcome Measure Data

    Analysis Population Description
    FAS included all participants who were enrolled and received at least one dose of study drug.
    Arm/Group Title Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin
    Arm/Group Description 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. 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. 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. 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.
    Measure Participants 4 7 7 42
    Absolute Neutrophil Count (ANC)
    2
    50%
    4
    57.1%
    7
    100%
    13
    31%
    Hemoglobin
    3
    75%
    7
    100%
    6
    85.7%
    16
    38.1%
    Platelet Count
    2
    50%
    4
    57.1%
    2
    28.6%
    8
    19%

    Adverse Events

    Time Frame All Adverse Events (AEs) were collected from signature of the informed consent form up to 751 Days for Phase 1 and 972 Days for Phase 2 regardless of seriousness or relationship to investigational product.
    Adverse Event Reporting Description Reported AEs are treatment-emergent adverse events (TEAEs). A TEAE is an AE that either begins on or after study drug administration or is a pre-existing condition that worsens on or after study drug administration.
    Arm/Group Title Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin
    Arm/Group Description 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. 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. 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. 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.
    All Cause Mortality
    Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/4 (0%) 1/7 (14.3%) 1/7 (14.3%) 5/42 (11.9%)
    Serious Adverse Events
    Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/4 (25%) 5/7 (71.4%) 3/7 (42.9%) 16/42 (38.1%)
    Blood and lymphatic system disorders
    FEBRILE NEUTROPENIA 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    Cardiac disorders
    ATRIAL FIBRILLATION 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    Gastrointestinal disorders
    NAUSEA 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    General disorders
    FATIGUE 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    DISEASE PROGRESSION 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 3/42 (7.1%) 4
    CHEST PAIN 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    METASTATIC PAIN 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    Hepatobiliary disorders
    CHOLANGITIS 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    CHOLECYSTITIS 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/42 (0%) 0
    Immune system disorders
    ANAPHYLACTIC REACTION 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    Infections and infestations
    GINGIVAL INFECTION 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    PNEUMONIA 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 2/42 (4.8%) 2
    BRONCHITIS 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    PNEUMOCOCCAL SEPSIS 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    URINARY TRACT INFECTION 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    Metabolism and nutrition disorders
    DEHYDRATION 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    HYPERKALAEMIA 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    HYPOGLYCAEMIA 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    HYPOKALAEMIA 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    Musculoskeletal and connective tissue disorders
    MUSCULOSKELETAL CHEST PAIN 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    METASTATIC PAIN 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    Nervous system disorders
    REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 3/42 (7.1%) 3
    HEADACHE 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 2/42 (4.8%) 2
    ALTERED STATE OF CONSCIOUSNESS 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    SPEECH DISORDER 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    Renal and urinary disorders
    RENAL FAILURE ACUTE 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 3/42 (7.1%) 3
    Respiratory, thoracic and mediastinal disorders
    PULMONARY EMBOLISM 0/4 (0%) 0 2/7 (28.6%) 2 0/7 (0%) 0 1/42 (2.4%) 1
    PLEURAL EFFUSION 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    DYSPNOEA 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 2/42 (4.8%) 2
    PNEUMOTHORAX 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 2/42 (4.8%) 3
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    HAEMOPTYSIS 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    HYDROPNEUMOTHORAX 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    Vascular disorders
    HYPOTENSION 0/4 (0%) 0 1/7 (14.3%) 1 1/7 (14.3%) 1 0/42 (0%) 0
    HYPERTENSION 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 3/42 (7.1%) 3
    Other (Not Including Serious) Adverse Events
    Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/4 (100%) 7/7 (100%) 7/7 (100%) 41/42 (97.6%)
    Blood and lymphatic system disorders
    ANAEMIA 2/4 (50%) 3 2/7 (28.6%) 2 0/7 (0%) 0 5/42 (11.9%) 18
    NEUTROPENIA 1/4 (25%) 2 0/7 (0%) 0 0/7 (0%) 0 7/42 (16.7%) 11
    THROMBOCYTOPENIA 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 7/42 (16.7%) 19
    LEUKOPENIA 1/4 (25%) 2 0/7 (0%) 0 0/7 (0%) 0 3/42 (7.1%) 6
    Cardiac disorders
    TACHYCARDIA 1/4 (25%) 1 0/7 (0%) 0 1/7 (14.3%) 1 4/42 (9.5%) 4
    BRADYCARDIA 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    Ear and labyrinth disorders
    TINNITUS 1/4 (25%) 1 0/7 (0%) 0 2/7 (28.6%) 4 3/42 (7.1%) 3
    DEAFNESS 1/4 (25%) 1 0/7 (0%) 0 2/7 (28.6%) 2 1/42 (2.4%) 1
    EAR PAIN 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    AURICULAR SWELLING 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    EAR CANAL STENOSIS 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    HYPOACUSIS 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 3/42 (7.1%) 3
    Eye disorders
    VISION BLURRED 2/4 (50%) 2 0/7 (0%) 0 2/7 (28.6%) 3 4/42 (9.5%) 4
    EYE IRRITATION 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 2
    PHOTOPHOBIA 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    DRY EYE 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 2/42 (4.8%) 2
    VISUAL IMPAIRMENT 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 1/42 (2.4%) 1
    MYODESOPSIA 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    Gastrointestinal disorders
    NAUSEA 4/4 (100%) 6 5/7 (71.4%) 6 6/7 (85.7%) 11 28/42 (66.7%) 42
    VOMITING 4/4 (100%) 4 4/7 (57.1%) 4 4/7 (57.1%) 6 10/42 (23.8%) 19
    CONSTIPATION 3/4 (75%) 4 3/7 (42.9%) 4 6/7 (85.7%) 10 22/42 (52.4%) 29
    DIARRHOEA 2/4 (50%) 3 2/7 (28.6%) 4 4/7 (57.1%) 7 16/42 (38.1%) 27
    STOMATITIS 1/4 (25%) 2 3/7 (42.9%) 4 1/7 (14.3%) 6 15/42 (35.7%) 18
    DYSPEPSIA 1/4 (25%) 1 3/7 (42.9%) 4 1/7 (14.3%) 1 12/42 (28.6%) 14
    ABDOMINAL PAIN 1/4 (25%) 2 2/7 (28.6%) 2 1/7 (14.3%) 1 2/42 (4.8%) 2
    ODYNOPHAGIA 1/4 (25%) 1 1/7 (14.3%) 2 0/7 (0%) 0 2/42 (4.8%) 2
    ABDOMINAL DISTENSION 1/4 (25%) 2 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    ORAL PAIN 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    ABDOMINAL DISCOMFORT 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/42 (0%) 0
    ASCITES 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/42 (0%) 0
    OESOPHAGEAL VARICES HAEMORRHAGE 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/42 (0%) 0
    ABDOMINAL PAIN UPPER 0/4 (0%) 0 2/7 (28.6%) 2 0/7 (0%) 0 2/42 (4.8%) 2
    RECTAL HAEMORRHAGE 0/4 (0%) 0 1/7 (14.3%) 1 2/7 (28.6%) 2 0/42 (0%) 0
    GINGIVAL PAIN 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 1/42 (2.4%) 1
    HAEMORRHOIDS 0/4 (0%) 0 0/7 (0%) 0 2/7 (28.6%) 2 2/42 (4.8%) 2
    GASTROOESOPHAGEAL REFLUX DISEASE 0/4 (0%) 0 0/7 (0%) 0 2/7 (28.6%) 2 1/42 (2.4%) 1
    DRY MOUTH 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 5/42 (11.9%) 5
    MOUTH ULCERATION 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 1/42 (2.4%) 1
    TOOTHACHE 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 1/42 (2.4%) 1
    RETCHING 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    DYSPHAGIA 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 3/42 (7.1%) 3
    FLATULENCE 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 3/42 (7.1%) 3
    OROPHARYNGEAL PAIN 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 3/42 (7.1%) 4
    General disorders
    FATIGUE 4/4 (100%) 12 6/7 (85.7%) 12 6/7 (85.7%) 29 28/42 (66.7%) 40
    FEELING ABNORMAL 4/4 (100%) 4 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    PYREXIA 2/4 (50%) 3 1/7 (14.3%) 1 0/7 (0%) 0 3/42 (7.1%) 3
    OEDEMA PERIPHERAL 2/4 (50%) 3 0/7 (0%) 0 1/7 (14.3%) 1 5/42 (11.9%) 6
    MUCOSAL INFLAMMATION 1/4 (25%) 1 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    NON-CARDIAC CHEST PAIN 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 2/42 (4.8%) 2
    XEROSIS 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 1/42 (2.4%) 1
    INFUSION SITE WARMTH 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/42 (0%) 0
    LOCALISED OEDEMA 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/42 (0%) 0
    TEMPERATURE INTOLERANCE 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/42 (0%) 0
    CHEST PAIN 0/4 (0%) 0 3/7 (42.9%) 5 3/7 (42.9%) 8 2/42 (4.8%) 2
    GAIT DISTURBANCE 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 3/42 (7.1%) 3
    INJECTION SITE REACTION 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    CHILLS 0/4 (0%) 0 0/7 (0%) 0 2/7 (28.6%) 2 3/42 (7.1%) 3
    CHEST DISCOMFORT 0/4 (0%) 0 0/7 (0%) 0 2/7 (28.6%) 2 0/42 (0%) 0
    ASTHENIA 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 4/42 (9.5%) 11
    PAIN 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 2/42 (4.8%) 2
    CYST 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    INFLUENZA LIKE ILLNESS 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    OEDEMA 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    Hepatobiliary disorders
    CHOLECYSTITIS 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    Infections and infestations
    STAPHYLOCOCCAL INFECTION 1/4 (25%) 1 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    NASOPHARYNGITIS 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/42 (0%) 0
    SKIN INFECTION 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/42 (0%) 0
    PNEUMONIA 0/4 (0%) 0 1/7 (14.3%) 1 1/7 (14.3%) 2 4/42 (9.5%) 4
    URINARY TRACT INFECTION 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 3/42 (7.1%) 4
    ORAL HERPES 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 1/42 (2.4%) 1
    BRONCHITIS 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    HERPES SIMPLEX 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    HERPES VIRUS INFECTION 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    RHINITIS 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 1/42 (2.4%) 1
    RASH PUSTULAR 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    SINUSITIS 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    UPPER RESPIRATORY TRACT INFECTION 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 4/42 (9.5%) 6
    Injury, poisoning and procedural complications
    SCRATCH 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    CONTUSION 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    OPEN WOUND 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    Investigations
    CREATININE RENAL CLEARANCE DECREASED 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 2/42 (4.8%) 2
    HEART RATE DECREASED 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/42 (0%) 0
    WEIGHT DECREASED 0/4 (0%) 0 2/7 (28.6%) 5 4/7 (57.1%) 12 1/42 (2.4%) 1
    ASPARTATE AMINOTRANSFERASE INCREASED 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 5 2/42 (4.8%) 3
    BLOOD ALKALINE PHOSPHATASE INCREASED 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 3 2/42 (4.8%) 3
    ALANINE AMINOTRANSFERASE INCREASED 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 6 1/42 (2.4%) 1
    NEUTROPHIL COUNT DECREASED 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 2 1/42 (2.4%) 1
    BLOOD CREATININE INCREASED 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 8/42 (19%) 21
    Metabolism and nutrition disorders
    ANOREXIA 3/4 (75%) 3 4/7 (57.1%) 9 5/7 (71.4%) 12 13/42 (31%) 14
    HYPOMAGNESAEMIA 1/4 (25%) 2 2/7 (28.6%) 2 0/7 (0%) 0 6/42 (14.3%) 12
    HYPERNATRAEMIA 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/42 (0%) 0
    DECREASED APPETITE 0/4 (0%) 0 1/7 (14.3%) 1 2/7 (28.6%) 2 3/42 (7.1%) 3
    DEHYDRATION 0/4 (0%) 0 1/7 (14.3%) 1 1/7 (14.3%) 1 12/42 (28.6%) 19
    HYPOPHOSPHATAEMIA 0/4 (0%) 0 1/7 (14.3%) 4 1/7 (14.3%) 1 4/42 (9.5%) 5
    HYPONATRAEMIA 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 7/42 (16.7%) 8
    HYPOKALAEMIA 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 5/42 (11.9%) 14
    GOUT 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 1/42 (2.4%) 1
    WEIGHT LOSS POOR 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 10/42 (23.8%) 15
    HYPERGLYCAEMIA 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 6/42 (14.3%) 13
    HYPERKALAEMIA 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 5/42 (11.9%) 10
    HYPOCALCAEMIA 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 5/42 (11.9%) 9
    Musculoskeletal and connective tissue disorders
    FLANK PAIN 1/4 (25%) 1 0/7 (0%) 0 1/7 (14.3%) 4 0/42 (0%) 0
    BONE PAIN 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 2/42 (4.8%) 3
    MUSCLE TWITCHING 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/42 (0%) 0
    MUSCULOSKELETAL PAIN 0/4 (0%) 0 2/7 (28.6%) 2 3/7 (42.9%) 4 5/42 (11.9%) 7
    MYALGIA 0/4 (0%) 0 1/7 (14.3%) 2 2/7 (28.6%) 2 5/42 (11.9%) 5
    PAIN IN EXTREMITY 0/4 (0%) 0 1/7 (14.3%) 2 2/7 (28.6%) 7 5/42 (11.9%) 6
    BACK PAIN 0/4 (0%) 0 1/7 (14.3%) 1 1/7 (14.3%) 1 4/42 (9.5%) 5
    MUSCULOSKELETAL CHEST PAIN 0/4 (0%) 0 1/7 (14.3%) 1 1/7 (14.3%) 1 4/42 (9.5%) 4
    ARTHRALGIA 0/4 (0%) 0 0/7 (0%) 0 3/7 (42.9%) 4 2/42 (4.8%) 3
    NECK PAIN 0/4 (0%) 0 0/7 (0%) 0 2/7 (28.6%) 2 3/42 (7.1%) 4
    MUSCLE SPASMS 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 4/42 (9.5%) 7
    MUSCULAR WEAKNESS 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 4/42 (9.5%) 5
    MUSCULOSKELETAL STIFFNESS 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 3 1/42 (2.4%) 1
    Nervous system disorders
    DYSGEUSIA 4/4 (100%) 4 1/7 (14.3%) 1 4/7 (57.1%) 4 15/42 (35.7%) 16
    HEADACHE 3/4 (75%) 4 1/7 (14.3%) 1 4/7 (57.1%) 8 13/42 (31%) 18
    DIZZINESS 1/4 (25%) 1 2/7 (28.6%) 4 4/7 (57.1%) 4 6/42 (14.3%) 6
    MEMORY IMPAIRMENT 1/4 (25%) 1 2/7 (28.6%) 3 1/7 (14.3%) 1 1/42 (2.4%) 1
    NEUROPATHY PERIPHERAL 1/4 (25%) 1 0/7 (0%) 0 2/7 (28.6%) 4 4/42 (9.5%) 5
    TREMOR 1/4 (25%) 1 0/7 (0%) 0 2/7 (28.6%) 3 0/42 (0%) 0
    PERIPHERAL SENSORY NEUROPATHY 1/4 (25%) 1 0/7 (0%) 0 1/7 (14.3%) 1 3/42 (7.1%) 3
    HYPERSOMNIA 0/4 (0%) 0 1/7 (14.3%) 2 1/7 (14.3%) 1 0/42 (0%) 0
    SINUS HEADACHE 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 1/42 (2.4%) 1
    CLONUS 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    PARAESTHESIA 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 3 0/42 (0%) 0
    INSOMNIA 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 6/42 (14.3%) 7
    Psychiatric disorders
    ANXIETY 0/4 (0%) 0 2/7 (28.6%) 2 0/7 (0%) 0 4/42 (9.5%) 5
    INSOMNIA 0/4 (0%) 0 0/7 (0%) 0 3/7 (42.9%) 3 0/42 (0%) 0
    DEPRESSION 0/4 (0%) 0 0/7 (0%) 0 2/7 (28.6%) 2 3/42 (7.1%) 4
    ABNORMAL DREAMS 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    HALLUCINATION 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    LOSS OF LIBIDO 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    CONFUSIONAL STATE 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 4/42 (9.5%) 4
    MENTAL STATUS CHANGES 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 4/42 (9.5%) 6
    Renal and urinary disorders
    BLADDER DISCOMFORT 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/42 (0%) 0
    DYSURIA 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 1/42 (2.4%) 1
    URINARY RETENTION 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 1/42 (2.4%) 1
    PROTEINURIA 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 14/42 (33.3%) 21
    RENAL FAILURE 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 1/42 (2.4%) 1
    Reproductive system and breast disorders
    VAGINAL HAEMORRHAGE 1/4 (25%) 2 0/7 (0%) 0 0/7 (0%) 0 0/42 (0%) 0
    AMENORRHOEA 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    DYSPHONIA 2/4 (50%) 2 3/7 (42.9%) 3 4/7 (57.1%) 4 14/42 (33.3%) 14
    DYSPNOEA 2/4 (50%) 2 3/7 (42.9%) 5 3/7 (42.9%) 3 7/42 (16.7%) 7
    OROPHARYNGEAL PAIN 2/4 (50%) 2 2/7 (28.6%) 4 2/7 (28.6%) 2 0/42 (0%) 0
    HICCUPS 2/4 (50%) 3 2/7 (28.6%) 4 1/7 (14.3%) 1 5/42 (11.9%) 6
    EPISTAXIS 2/4 (50%) 2 1/7 (14.3%) 1 5/7 (71.4%) 5 11/42 (26.2%) 12
    NASAL CONGESTION 2/4 (50%) 2 0/7 (0%) 0 0/7 (0%) 0 0/42 (0%) 0
    COUGH 1/4 (25%) 1 0/7 (0%) 0 3/7 (42.9%) 3 7/42 (16.7%) 9
    RHINORRHOEA 1/4 (25%) 1 0/7 (0%) 0 2/7 (28.6%) 2 6/42 (14.3%) 6
    RESPIRATORY DISORDER 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/42 (0%) 0
    DYSPNOEA EXERTIONAL 0/4 (0%) 0 1/7 (14.3%) 1 1/7 (14.3%) 1 2/42 (4.8%) 2
    HYPOVENTILATION 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    PRODUCTIVE COUGH 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    NASAL DRYNESS 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    NASAL ULCER 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    RHONCHI 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    HAEMOPTYSIS 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 3/42 (7.1%) 3
    WHEEZING 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 3/42 (7.1%) 3
    Skin and subcutaneous tissue disorders
    HYPERKERATOSIS 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/42 (0%) 0
    SKIN ODOUR ABNORMAL 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/42 (0%) 0
    RASH 0/4 (0%) 0 1/7 (14.3%) 1 1/7 (14.3%) 1 1/42 (2.4%) 1
    ERYTHEMA 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    SWELLING FACE 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    ALOPECIA 0/4 (0%) 0 0/7 (0%) 0 2/7 (28.6%) 2 3/42 (7.1%) 3
    NIGHT SWEATS 0/4 (0%) 0 0/7 (0%) 0 2/7 (28.6%) 2 0/42 (0%) 0
    DRY SKIN 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 2 4/42 (9.5%) 4
    PRURITUS 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 3/42 (7.1%) 3
    DERMATITIS ACNEIFORM 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 1/42 (2.4%) 1
    BLISTER 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    HAIR TEXTURE ABNORMAL 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    HYPERHIDROSIS 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    PAIN OF SKIN 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    RASH PAPULAR 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/42 (0%) 0
    Vascular disorders
    HYPERTENSION 2/4 (50%) 6 3/7 (42.9%) 3 5/7 (71.4%) 8 22/42 (52.4%) 34
    HYPOTENSION 1/4 (25%) 1 1/7 (14.3%) 2 0/7 (0%) 0 2/42 (4.8%) 2
    DEEP VEIN THROMBOSIS 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    HAEMATOMA 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/42 (0%) 0
    HOT FLUSH 0/4 (0%) 0 0/7 (0%) 0 2/7 (28.6%) 2 1/42 (2.4%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    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.

    Results Point of Contact

    Name/Title Clinical Trial Administrator
    Organization Regeneron Pharmaceuticals, Inc.
    Phone 844-734-6643
    Email clinicaltrials@regeneron.com
    Responsible Party:
    Regeneron Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT00794417
    Other Study ID Numbers:
    • VGFT-ST-0708
    • TCD10767
    First Posted:
    Nov 20, 2008
    Last Update Posted:
    Dec 10, 2020
    Last Verified:
    Nov 1, 2020