Advanced Carcinoma, Non-small Cell Lung Cancer
Conditions
Keywords
advanced cancer, lung cancer, NSCLC, Non-small Cell Lung Cancer, aflibercept, chemotherapy
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).
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.
Interventions
DRUGAflibercept
Administered in combination with the other two interventions via intravenous infusion.
DRUGPemetrexed
Administered in combination with the other two interventions via intravenous infusion.
DRUGCisplatin
Administered in combination with the other two interventions via intravenous infusion.
Sponsors
Sanofi
Regeneron Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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 | — |
| 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 | — |
| 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. |
Countries
Canada, United States
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 4 |
| 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. | 7 |
| 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. | 7 |
| 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. | 42 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| 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 | Other unspecified | 0 | 0 | 0 | 13 |
| 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 |
Baseline characteristics
| Characteristic | 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 |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 6 Participants | 2 Participants | 19 Participants | 27 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 1 Participants | 5 Participants | 23 Participants | 33 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 7 Participants | 7 Participants | 36 Participants | 53 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 2 Participants | 19 Participants | 28 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 5 Participants | 23 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 1 / 7 | 1 / 7 | 5 / 42 |
| other Total, other adverse events | 4 / 4 | 7 / 7 | 7 / 7 | 41 / 42 |
| serious Total, serious adverse events | 1 / 4 | 5 / 7 | 3 / 7 | 16 / 42 |
Outcome results
Primary
Phase 1: Recommended Dose of Aflibercept for Phase 2
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
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: All Participants | Phase 1: Recommended Dose of Aflibercept for Phase 2 | 6 mg/kg |
Secondary
Phase 1 and 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Aflibercept
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
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: All Participants | 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 |
| Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Aflibercept | 330 Day*milligrams per liter (mg/L) | Standard Deviation 251 |
| Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Aflibercept | 442 Day*milligrams per liter (mg/L) | Standard Deviation 152 |
| Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Aflibercept | 402 Day*milligrams per liter (mg/L) | Standard Deviation 100 |
Secondary
Phase 1 and 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Pemetrexed
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)
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: All Participants | 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 |
| Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin | 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 32.5 |
| Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Pemetrexed | 162 Hour*milligrams per liter (mg/L) | Standard Deviation 12.6 |
| Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Pemetrexed | 148 Hour*milligrams per liter (mg/L) | Standard Deviation 24.3 |
Secondary
Phase 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Aflibercept and Pemetrexed
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)
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: All Participants | Phase 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Aflibercept and Pemetrexed | Aflibercept | 53.6 mg/L | Standard Deviation 7.14 |
| Phase 1: All Participants | Phase 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Aflibercept and Pemetrexed | Pemetrexed | 124 mg/L | Standard Deviation 12.6 |
| Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Aflibercept and Pemetrexed | Pemetrexed | 112 mg/L | Standard Deviation 34.7 |
| Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Aflibercept and Pemetrexed | Aflibercept | 68.6 mg/L | Standard Deviation 18.7 |
| Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Aflibercept and Pemetrexed | Aflibercept | 148 mg/L | Standard Deviation 108 |
| Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Aflibercept and Pemetrexed | Pemetrexed | 113 mg/L | Standard Deviation 24.6 |
| Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Aflibercept and Pemetrexed | Aflibercept | 104 mg/L | Standard Deviation 26.2 |
| Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Aflibercept and Pemetrexed | Pemetrexed | 76.8 mg/L | Standard Deviation 40.5 |
Secondary
Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: All Participants | Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities | Hyperglycemia (Non-Fasting) | 4 Participants |
| Phase 1: All Participants | Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities | Hyperglycemia (Fasting) | 1 Participants |
| Phase 1: All Participants | Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities | Hypoglycemia (Non-Fasting) | 0 Participants |
| Phase 1: All Participants | Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities | Hypoglycemia (Fasting) | 0 Participants |
| Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities | Hyperglycemia (Fasting) | 3 Participants |
| Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities | Hypoglycemia (Non-Fasting) | 0 Participants |
| Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities | Hypoglycemia (Fasting) | 0 Participants |
| Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities | Hyperglycemia (Non-Fasting) | 6 Participants |
| Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities | Hypoglycemia (Non-Fasting) | 0 Participants |
| Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities | Hyperglycemia (Fasting) | 6 Participants |
| Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities | Hypoglycemia (Fasting) | 0 Participants |
| Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities | Hyperglycemia (Non-Fasting) | 7 Participants |
| Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities | Hypoglycemia (Fasting) | 0 Participants |
| Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities | Hyperglycemia (Fasting) | 6 Participants |
| Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities | Hyperglycemia (Non-Fasting) | 37 Participants |
| Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Glucose Abnormalities | Hypoglycemia (Non-Fasting) | 5 Participants |
Secondary
Phase 1 and 2: Number of Participants With All Grade Hematology Abnormalities
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: All Participants | Phase 1 and 2: Number of Participants With All Grade Hematology Abnormalities | Absolute Neutrophil Count (ANC) | 2 Participants |
| Phase 1: All Participants | Phase 1 and 2: Number of Participants With All Grade Hematology Abnormalities | Platelet Count | 2 Participants |
| Phase 1: All Participants | Phase 1 and 2: Number of Participants With All Grade Hematology Abnormalities | Hemoglobin | 3 Participants |
| Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Hematology Abnormalities | Absolute Neutrophil Count (ANC) | 4 Participants |
| Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Hematology Abnormalities | Platelet Count | 4 Participants |
| Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Hematology Abnormalities | Hemoglobin | 7 Participants |
| Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Hematology Abnormalities | Hemoglobin | 6 Participants |
| Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Hematology Abnormalities | Absolute Neutrophil Count (ANC) | 7 Participants |
| Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Hematology Abnormalities | Platelet Count | 2 Participants |
| Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Hematology Abnormalities | Absolute Neutrophil Count (ANC) | 13 Participants |
| Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Hematology Abnormalities | Platelet Count | 8 Participants |
| Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With All Grade Hematology Abnormalities | Hemoglobin | 16 Participants |
Secondary
Phase 1 and 2: Number of Participants With Positive Anti-drug Antibody (ADA) of Aflibercept
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
Population: FAS included all participants who were enrolled and received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: All Participants | Phase 1 and 2: Number of Participants With Positive Anti-drug Antibody (ADA) of Aflibercept | 0 Participants |
| Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With Positive Anti-drug Antibody (ADA) of Aflibercept | 0 Participants |
| Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With Positive Anti-drug Antibody (ADA) of Aflibercept | 1 Participants |
| Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With Positive Anti-drug Antibody (ADA) of Aflibercept | 2 Participants |
Secondary
Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
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
Population: FAS included all participants who were enrolled and received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: All Participants | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 4 Participants |
| Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 7 Participants |
| Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 7 Participants |
| Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 42 Participants |
Secondary
Phase 1 and 2: Terminal Half-Life (t1/2) of Aflibercept
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
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: All Participants | Phase 1 and 2: Terminal Half-Life (t1/2) of Aflibercept | 3.16 Days | Standard Deviation 0.57 |
| Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Terminal Half-Life (t1/2) of Aflibercept | 5.53 Days | Standard Deviation 5.43 |
| Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Terminal Half-Life (t1/2) of Aflibercept | 3.72 Days | Standard Deviation 1.04 |
| Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Terminal Half-Life (t1/2) of Aflibercept | 4.62 Days | Standard Deviation 1.46 |
Secondary
Phase 1 and 2: Terminal Half-Life (t1/2) of Pemetrexed
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)
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: All Participants | Phase 1 and 2: Terminal Half-Life (t1/2) of Pemetrexed | 1.47 Hours | Standard Deviation 0.39 |
| Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Terminal Half-Life (t1/2) of Pemetrexed | 1.63 Hours | Standard Deviation 0.22 |
| Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Terminal Half-Life (t1/2) of Pemetrexed | 1.73 Hours | Standard Deviation 0.37 |
| Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Terminal Half-Life (t1/2) of Pemetrexed | 1.48 Hours | Standard Deviation 0.34 |
Secondary
Phase 1 and 2: Total Body Clearance of Aflibercept
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
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: All Participants | Phase 1 and 2: Total Body Clearance of Aflibercept | 0.011 Liter/Day/kg | Standard Deviation 0.004 |
| Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Total Body Clearance of Aflibercept | 0.016 Liter/Day/kg | Standard Deviation 0.007 |
| Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Total Body Clearance of Aflibercept | 0.016 Liter/Day/kg | Standard Deviation 0.009 |
| Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Total Body Clearance of Aflibercept | 0.016 Liter/Day/kg | Standard Deviation 0.004 |
Secondary
Phase 1 and 2: Total Body Clearance of Pemetrexed
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)
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: All Participants | Phase 1 and 2: Total Body Clearance of Pemetrexed | 3.40 Liter/hour/m^2 | Standard Deviation 0.59 |
| Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Total Body Clearance of Pemetrexed | 3.47 Liter/hour/m^2 | Standard Deviation 0.84 |
| Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Total Body Clearance of Pemetrexed | 3.10 Liter/hour/m^2 | Standard Deviation 0.22 |
| Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin | Phase 1 and 2: Total Body Clearance of Pemetrexed | 3.49 Liter/hour/m^2 | Standard Deviation 0.76 |
Secondary
Phase 2: Objective Response Rate
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)
Population: FAS included all participants who were enrolled and received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: All Participants | Phase 2: Objective Response Rate | 23.8 Percentage of Participants |
Secondary
Phase 2: Progression-free Survival (PFS)
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)
Population: FAS included all participants who were enrolled and received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: All Participants | Phase 2: Progression-free Survival (PFS) | 149 Days |