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

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

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).

Study Overview

• Status: Terminated
• Conditions: Non-small Cell Lung Cancer; Advanced Carcinoma
• Intervention / Treatment: Drug: Aflibercept; Drug: Pemetrexed; Drug: Cisplatin

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 Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Regeneron Pharmaceuticals
• Collaborators: Sanofi

Publications and helpful links

General Publications

• Diaz-Padilla I, Siu LL, San Pedro-Salcedo M, Razak AR, Colevas AD, Shepherd FA, Leighl NB, Neal JW, Thibault A, Liu L, Lisano J, Gao B, Lawson EB, Wakelee HA. A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours. Br J Cancer. 2012 Aug 7;107(4):604-11. doi: 10.1038/bjc.2012.319. Epub 2012 Jul 17.
• Chen H, Modiano MR, Neal JW, Brahmer JR, Rigas JR, Jotte RM, Leighl NB, Riess JW, Kuo CJ, Liu L, Gao B, Dicioccio AT, Adjei AA, Wakelee HA. A phase II multicentre study of ziv-aflibercept in combination with cisplatin and pemetrexed in patients with previously untreated advanced/metastatic non-squamous non-small cell lung cancer. Br J Cancer. 2014 Feb 4;110(3):602-8. doi: 10.1038/bjc.2013.735. Epub 2013 Nov 28.

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2008
• Primary Completion (Actual): June 30, 2011
• Study Completion (Actual): June 30, 2011

Study Registration Dates

• First Submitted: November 19, 2008
• First Submitted That Met QC Criteria: November 19, 2008
• First Posted (Estimate): November 20, 2008

Study Record Updates

• Last Update Posted (Actual): December 10, 2020
• Last Update Submitted That Met QC Criteria: November 13, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: chemotherapy; NSCLC; lung cancer; advanced cancer; Non-small Cell Lung Cancer; aflibercept
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Folic Acid Antagonists; Pemetrexed; Aflibercept
• Other Study ID Numbers: VGFT-ST-0708; TCD10767