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

Colorectal Cancer Metastatic Clinical Trial

— AFLAME  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01661270
• Other study ID #: EFC11338
• Secondary ID: U1111-1115-7227
• Status: Completed
• Phase: Phase 3
• First received: August 7, 2012
• Last updated: October 22, 2015
• Start date: July 2012
• Est. completion date: July 2015

Study information

• Verified date: October 2015
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: China: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

Primary Objective:

To evaluate the improvement in progression-free survival 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 in the 2 treatment arms. To compare the overall response rate in the 2 treatment arms. To assess the safety profile of the 2 treatment arms. To assess immunogenicity of IV aflibercept in selected centers.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 332
• Est. completion date: July 2015
• Est. primary completion date: October 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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, 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 NSAIDS (non steroidal anti-inflammatory agents) 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/24h

• Participants on anticoagulant therapy with unstable dose of warfarin and/or having an out-of-therapeutic range 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 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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Cancer Metastatic
• Colorectal Neoplasms

Intervention

Drug:
• Aflibercept
Pharmaceutical form:Concentrate for Solution for infusion Route of administration: Intravenous
• Placebo
Pharmaceutical form:Concentrate for Solution for infusion Route of administration: Intravenous

Locations

Country	Name	City	State
China	Investigational Site Number 156001	Beijing
China	Investigational Site Number 156002	Beijing
China	Investigational Site Number 156003	Beijing
China	Investigational Site Number 156004	Beijing
China	Investigational Site Number 156016	Chengdu
China	Investigational Site Number 156020	Chongqing
China	Investigational Site Number 156021	Fuzhou
China	Investigational Site Number 156008	Guangzhou
China	Investigational Site Number 156009	Hangzhou
China	Investigational Site Number 156010	Hangzhou
China	Investigational Site Number 156011	Hangzhou
China	Investigational Site Number 156015	Harbin
China	Investigational Site Number 156012	Nanjing
China	Investigational Site Number 156013	Nanjing
China	Investigational Site Number 156006	Shanghai
China	Investigational Site Number 156007	Shanghai
China	Investigational Site Number 156014	Shenyang
China	Investigational Site Number 156005	Tianjin
China	Investigational Site Number 156018	Wuhan
China	Investigational Site Number 156019	Wuhan
China	Investigational Site Number 156017	Xi'An
Hong Kong	Investigational Site Number 344002	Hong Kong
Hong Kong	Investigational Site Number 344001	Shatin, Nt
Japan	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
Singapore	Investigational Site Number 702001	Singapore
Singapore	Investigational Site Number 702002	Singapore
Taiwan	Investigational Site Number 158003	Taipai
Taiwan	Investigational Site Number 158002	Taipei

Sponsors (2)

Lead Sponsor	Collaborator
Sanofi	Regeneron Pharmaceuticals

Countries where clinical trial is conducted

China,  Hong Kong,  Japan,  Singapore,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS)	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.	26.7 months	No