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A Study of Aflibercept Versus Placebo With FOLFIRI in Patients With Metastatic Colorectal Cancer Previously Treated With an Oxaliplatin Chemotherapy (AFLAME)

This study has been completed.
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi Identifier:
First received: August 7, 2012
Last updated: August 24, 2016
Last verified: August 2016

Primary Objective:

To evaluate the improvement in progression-free survival (PFS) of aflibercept versus placebo in participants with metastatic colorectal cancer treated with FOLFIRI as second-line treatment for metastatic disease.

Secondary Objectives:

To compare the overall survival (OS) in the 2 treatment arms. To compare the overall response rate (ORR) in the 2 treatment arms. To assess the safety profile of the 2 treatment arms. To assess immunogenicity of intravenous (IV) aflibercept in selected centers.

Condition Intervention Phase
Colorectal Cancer Metastatic
Drug: Aflibercept
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Multinational, Randomized, Double-Blind Study of Aflibercept Versus Placebo With Irinotecan/ 5-FU Combination (FOLFIRI) in Patients With Metastatic Colorectal Cancer (MCRC) After Failure of an Oxaliplatin Based Regimen

Resource links provided by NLM:

Further study details as provided by Sanofi:

Primary Outcome Measures:
  • Progression-free Survival (PFS) [ Time Frame: 26.7 months ]
    PFS was defined as the time interval from the date of randomization to the date of first observation of either tumor progression or death due to any cause. Tumor assessment was performed by Independent Review Committee (IRC) as per response evaluation criteria in solid tumors (RECIST) version 1.0. Progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study or absolute increase and at least 5 mm, progression of existing non-target lesions, or presence of new lesions. PFS was calculated by Kaplan-Meier estimates.

Secondary Outcome Measures:
  • Overall Survival (OS) [ Time Frame: 31.6 months ]
    OS was defined as the time interval from the date of randomization to the date of death due to any cause. In the absence of confirmation of death, survival time was censored at the earliest between the last date of the participants was known to be alive and the study cut-off date. Analysis was performed by Kaplan-Meier method.

  • Percentage of Participants With Objective Response [ Time Frame: 26.6 months ]
    Objective response rate was defined as the proportion of participants with confirmed complete response (CR) or confirmed partial response (PR), as assessed by Investigators and the IRC according to RECIST 1.0 criteria, relative to the total number of participants in the relevant analysis population. Complete Response (CR): disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): At least a 30% decrease in the size of target lesions with no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions but persistence of 1 or more non-target lesions not qualifying for either CR or progressive disease (PD) and no new lesions.

Enrollment: 332
Study Start Date: July 2012
Study Completion Date: July 2015
Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
Placebo for aflibercept intravenous (IV) infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m^2 IV infusion and leucovorin 400 mg/m^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m^2 followed by continuous IV infusion 2400 mg/m^2.
Drug: Placebo
Pharmaceutical form: Concentrate for Solution for infusion; Route of administration: Intravenous
Experimental: Aflibercept
Aflibercept 4 mg/kg IV infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m^2 IV infusion and leucovorin 400 mg/m^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m^2 followed by continuous IV infusion 2400 mg/m^2.
Drug: Aflibercept
Pharmaceutical form: Concentrate for Solution for infusion; Route of administration: Intravenous
Other Names:
  • AVE0005
  • Zaltrap

Detailed Description:
Screening occurred from signed informed consent to randomization (up to 21 days). A treatment cycle was defined as a 2 week-period. All participants were followed during the study treatment and follow-up period until death or study cut off date, which ever comes first.

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion criteria:

  • Histological or cytological proven adenocarcinoma of the colon or rectum.
  • Metastatic disease that was not amenable to potentially curative treatment.
  • One and only one prior chemotherapeutic regimen for metastatic disease. This prior chemotherapy must be an oxaliplatin containing regimen. Participants who were relapsed within 6 months of completion of oxaliplatin based adjuvant chemotherapy were eligible.

Exclusion criteria:

  • Prior therapy with irinotecan.
  • Eastern Cooperative Oncology Group (ECOG) performance status >1.
  • Less than 28 days elapsed from prior radiotherapy, from prior surgery and prior chemotherapy to the time of randomization. Less than 42 days elapsed from prior major surgery to the time to randomization.
  • Adverse events (with exception of alopecia, peripheral sensory neuropathy grade ≤ 2 and those listed in specific exclusion criteria) from any prior anticancer therapy of grade >1 (National Cancer Institute Common terminology Criteria [NCI CTCAE] v.3.0) at the time of randomization.
  • Age <18 years.
  • History of brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis or new evidence of brain or leptomeningeal disease.
  • Other prior malignancy. Adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix or any other cancer from which the participants had disease free for > 5 years were allowed.
  • Participation in another clinical trial with an investigational drug and any concurrent treatment with any investigational drug within 30 days prior to randomization.
  • Any of the following within 6 months prior to randomization: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association Functional Classification (NYHA) class III or IV congestive heart failure, stroke or transient ischemic attack.
  • Any of the following within 3 months prior to randomization: treatment resistant peptic or duodenal ulcer disease, erosive oesophagitis or gastritis, grade 3 or 4 gastrointestinal bleeding/hemorrhage, gastrointestinal perforation/fistula, abdominal abscess, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism, or other uncontrolled thromboembolic event.
  • Participants who had given high dose of aspirin or non steroidal anti-inflammatory agents (NSAIDS) or high steroids within 4 weeks prior to randomization. The definition of "high dose" was to be based on the investigator's judgment.
  • Occurrence of deep vein thrombosis within 4 weeks, prior to randomization.
  • Inadequate organ or bone marrow function.
  • Pregnant or breast-feeding woman. Positive serum or urine pregnancy test prior to randomization. Participants with reproductive (M/F) who were not agree to use accepted and effective method of contraception during the study treatment period and for at least 6 months following completion of study treatment.
  • Uncontrolled hypertension.
  • Urine Protein: creatine ratio (UPCR) >1 on morning spot urinalysis or proteinuria > 500mg/24 hours.
  • Participants on anticoagulant therapy with unstable dose of warfarin and/or having an out-of-therapeutic range international normalized ratio (INR) (>3) within 4 weeks prior to randomization.
  • Evidence of clinically significant bleeding diathesis or underlying coagulopathy.
  • Known dihydropyrimidine dehydrogenase deficiency.
  • Predisposing colonic or small bowel disorder in which the symptoms were uncontrolled as indicated by baseline of > 3 loose stools daily.
  • Prior history of chronic enteropathy, inflammatory enteropathy, chronic diarrhea, unresolved bowel obstruction/sub-obstruction, more than hemicolectomy, extensive small intestine resection with chronic diarrhea.
  • History of anaphylaxis or known intolerance to atropine sulphate or loperamide or appropriate antiemetics to be administered in conjunction with FOLFIRI.
  • Treatment with concomitant anticonvulsant agents that were cytochrome P450 3A4 (CYP3A4) inducers (phenytoin, phenobarbital, carbamazepine), unless discontinued > 7 days.
  • Participants with known Gilbert's syndrome.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

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Please refer to this study by its identifier: NCT01661270

Investigational Site Number 156003
Beijing, China, 100071
Investigational Site Number 156001
Beijing, China, 100142
Investigational Site Number 156002
Beijing, China, 100210
Investigational Site Number 156004
Beijing, China, 100853
Investigational Site Number 156016
Chengdu, China, 610041
Investigational Site Number 156020
Chongqing, China, 400038
Investigational Site Number 156021
Fuzhou, China, 350014
Investigational Site Number 156008
Guangzhou, China, 510060
Investigational Site Number 156010
Hangzhou, China, 310003
Investigational Site Number 156011
Hangzhou, China, 310009
Investigational Site Number 156009
Hangzhou, China, 310016
Investigational Site Number 156015
Harbin, China, 150081
Investigational Site Number 156012
Nanjing, China, 210002
Investigational Site Number 156013
Nanjing, China, 210029
Investigational Site Number 156006
Shanghai, China, 200032
Investigational Site Number 156007
Shanghai, China, 200032
Investigational Site Number 156014
Shenyang, China, 110001
Investigational Site Number 156005
Tianjin, China, 300060
Investigational Site Number 156019
Wuhan, China, 430022
Investigational Site Number 156018
Wuhan, China, 430030
Investigational Site Number 156017
Xi'An, China, 710032
Hong Kong
Investigational Site Number 344002
Hong Kong, Hong Kong
Investigational Site Number 344001
Shatin, Nt, Hong Kong
Investigational Site Number 392006
Amagasaki-Shi, Japan
Investigational Site Number 392003
Bunkyo-Ku, Japan
Investigational Site Number 392004
Bunkyo-Ku, Japan
Investigational Site Number 392009
Gifu-Shi, Japan
Investigational Site Number 392002
Kitaadachi-Gun, Japan
Investigational Site Number 392001
Kobe-Shi, Japan
Investigational Site Number 392005
Kochi-Shi, Japan
Investigational Site Number 392007
Kumamoto-Shi, Japan
Investigational Site Number 392008
Nagakute-Shi, Japan
Investigational Site Number 392010
Takatsuki-Shi, Japan
Investigational Site Number 702002
Singapore, Singapore, 119228
Investigational Site Number 702001
Singapore, Singapore, 169610
Investigational Site Number 158003
Taipai, Taiwan, 10043
Investigational Site Number 158002
Taipei, Taiwan
Sponsors and Collaborators
Regeneron Pharmaceuticals
Study Director: Clinical Sciences & Operations Sanofi
  More Information

Responsible Party: Sanofi Identifier: NCT01661270     History of Changes
Other Study ID Numbers: EFC11338
U1111-1115-7227 ( Other Identifier: UTN )
Study First Received: August 7, 2012
Results First Received: October 22, 2015
Last Updated: August 24, 2016

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action processed this record on April 26, 2017