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

• ClinicalTrials.gov Identifier: NCT01661270
• Recruitment Status: Completed
• First Posted: August 9, 2012
• Results First Posted: November 26, 2015
• Last Update Posted: October 18, 2016
• Sponsor: Sanofi
• Collaborator: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Sanofi

Tracking Information

• First Submitted Date: August 7, 2012
• First Posted Date: August 9, 2012
• Results First Submitted Date: October 22, 2015
• Results First Posted Date: November 26, 2015
• Last Update Posted Date: October 18, 2016
• Study Start Date: July 2012
• Actual Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 22, 2015)

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.

• Original Primary Outcome Measures (submitted: August 8, 2012): Progression Free Survival [ Time Frame: 7 months (the average) ]

Current Secondary Outcome Measures (submitted: August 24, 2016)

• 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.

Original Secondary Outcome Measures (submitted: August 8, 2012)

• Overall Survival [ Time Frame: 14 months (the average) ]
• Overall Response Rate [ Time Frame: 7 months (the average) ]
• Assess Immunogenicity of IV Aflibercept Patients [ Time Frame: Up to 90 days after last aflibercept/placebo administration ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

Brief Summary

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.

• 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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Colorectal Cancer Metastatic

Intervention

• Drug: Aflibercept
  Pharmaceutical form: Concentrate for Solution for infusion; Route of administration: Intravenous
  Other Names:

  • AVE0005
  • Zaltrap
• Drug: Placebo
  Pharmaceutical form: Concentrate for Solution for infusion; Route of administration: Intravenous

Study Arms

• 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.
  Intervention: Drug: Placebo
• 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.
  Intervention: Drug: Aflibercept

• Publications *: Li J, Xu R, Qin S, Liu T, Pan H, Xu J, Bi F, Lim R, Zhang S, Ba Y, Bai Y, Fan N, Tsuji A, Yeh KH, Ma B, Wei V, Shi D, Magherini E, Shen L. Aflibercept plus FOLFIRI in Asian patients with pretreated metastatic colorectal cancer: a randomized Phase III study. Future Oncol. 2018 Aug;14(20):2031-2044. doi: 10.2217/fon-2017-0669. Epub 2018 Aug 17. Erratum In: Future Oncol. 2019 Feb;15(4):451.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 22, 2015): 332
• Original Estimated Enrollment (submitted: August 8, 2012): 300
• Actual Study Completion Date: July 2015
• Actual Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China, Hong Kong, Japan, Singapore, Taiwan

Administrative Information

• NCT Number: NCT01661270
• Other Study ID Numbers: EFC11338; U1111-1115-7227 ( Other Identifier: UTN )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Sanofi
• Original Responsible Party: Same as current
• Current Study Sponsor: Sanofi
• Original Study Sponsor: Same as current
• Collaborators: Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

• PRS Account: Sanofi
• Verification Date: August 2016