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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1/2 Study of Aflibercept Administered in Combination With Pemetrexed and Cisplatin in Patients With Advanced Carcinoma

Conditions
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Advanced Carcinoma, Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Aflibercept
* Drug: Pemetrexed
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin<br>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<br>* Administered in combination with the other two interventions via intravenous infusion.<br>Drug: Pemetrexed<br>* Administered in combination with the other two interventions via intravenous infusion.<br>* Other names: Alimta;Drug: Cisplatin<br>* Administered in combination with the other two interventions via intravenous infusion.<br>* Other names: Platinol;|
| Experimental: Phase 1: Aflibercept 2 mg/kg and Pemetrexed and Cisplatin<br>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<br>* Administered in combination with the other two interventions via intravenous infusion.<br>Drug: Pemetrexed<br>* Administered in combination with the other two interventions via intravenous infusion.<br>* Other names: Alimta;Drug: Cisplatin<br>* Administered in combination with the other two interventions via intravenous infusion.<br>* Other names: Platinol;|
| Experimental: Phase 1: Aflibercept 4 mg/kg and Pemetrexed and Cisplatin<br>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<br>* Administered in combination with the other two interventions via intravenous infusion.<br>Drug: Pemetrexed<br>* Administered in combination with the other two interventions via intravenous infusion.<br>* Other names: Alimta;Drug: Cisplatin<br>* Administered in combination with the other two interventions via intravenous infusion.<br>* Other names: Platinol;|
| Experimental: Phase 2: Aflibercept 6 mg/kg and Pemetrexed and Cisplatin<br>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<br>* Administered in combination with the other two interventions via intravenous infusion.<br>Drug: Pemetrexed<br>* Administered in combination with the other two interventions via intravenous infusion.<br>* Other names: Alimta;Drug: Cisplatin<br>* Administered in combination with the other two interventions via intravenous infusion.<br>* Other names: Platinol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Phase 1: Baseline up to 315 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Phase 2: Baseline (Day 421) up to end of study (Day 972) | 
| 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. | Phase 2: Baseline (Day 421) up to end of study (Day 972) | 
| 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. | Phase 1: Baseline up to 751 Days; Phase 2: Baseline (Day 421) up to 972 Days | 
| 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. | Phase 1 and 2: Pre-dose up to Day 22 post-dose | 
| 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. | Phase 1 and 2: Pre-dose up to Day 1 post-dose, Day 2 post-dose (only in Phase 1) | 
| 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. | 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) | 
| 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. | Phase 1 and 2: Pre-dose up to Day 22 post-dose | 
| 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. | Phase 1 and 2: Pre-dose up to Day 1 post-dose, Day 2 post-dose (only in Phase 1) | 
| 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. | Phase 1 and 2: Pre-dose up to Day 22 post-dose | 
| 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. | Phase 1 and 2: Pre-dose up to Day 1 post-dose, Day 2 post-dose (only in Phase 1) | 
| 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. | Phase 1: Baseline up to 315 Days; Phase 2: Baseline (Day 421) up to Day 739 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced cancer, lung cancer, NSCLC, Non-small Cell Lung Cancer, aflibercept, chemotherapy