Study of Aflibercept And Modified FOLFOX6 As First-Line Treatment In Patients With Metastatic Colorectal Cancer (AFFIRM)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT00851084
First received: February 24, 2009
Last updated: June 21, 2013
Last verified: May 2013
Results First Received: February 19, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Conditions: Colorectal Neoplasms
Neoplasm Metastasis
Interventions: Drug: aflibercept
Drug: oxaliplatin
Drug: 5-FU
Drug: Folinic Acid

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
There were 268 patients screened (informed consent signed) for this study. Of these screened patients, 236 patients were subsequently randomly assigned to treatments. 32 patients were screen failures.

Reporting Groups
  Description
mFOLFOX6 Only modified FOLFOX6
mFOLFOX6 + Aflibercept modified FOLFOX6 in combination with aflibercept

Participant Flow:   Overall Study
    mFOLFOX6 Only     mFOLFOX6 + Aflibercept  
STARTED     117     119  
COMPLETED     0 [1]   0 [1]
NOT COMPLETED     117     119  
Randomized but not treated                 1                 0  
Adverse Event                 26                 36  
Disease progression                 52                 47  
Poor compliance to protocol                 1                 1  
Physician Decision                 13                 14  
Consent withdrawn                 0                 2  
Withdrawal by Subject                 11                 12  
Metastatic surgery                 6                 6  
Not specified                 7                 1  
[1] Participants continued treatment until they met treatment discontinuation criteria.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
mFOLFOX6 Only modified FOLFOX6
mFOLFOX6 + Aflibercept modified FOLFOX6 in combination with aflibercept
Total Total of all reporting groups

Baseline Measures
    mFOLFOX6 Only     mFOLFOX6 + Aflibercept     Total  
Number of Participants  
[units: participants]
  117     119     236  
Age  
[units: Years]
Mean ± Standard Deviation
  62.4  ± 9.7     61.8  ± 9.0     62.1  ± 9.4  
Age, Customized  
[units: Participants]
     
<65     65     70     135  
>=65 but <75     43     45     88  
>=75     9     4     13  
Gender  
[units: Participants]
     
Female     49     43     92  
Male     68     76     144  
Race/Ethnicity, Customized  
[units: Participants]
     
Caucasian/White     90     97     187  
Black     0     1     1  
Asian/Oriental     27     20     47  
Other     0     1     1  
Region of Enrollment  
[units: participants]
     
United Kingdom     22     28     50  
Korea, Republic of     26     20     46  
Germany     18     24     42  
Spain     24     18     42  
Russian Federation     15     15     30  
Italy     10     5     15  
Australia     2     9     11  
Body Surface Are (BSA)  
[units: m^2]
Mean ± Standard Deviation
  1.8  ± 0.2     1.8  ± 0.2     1.8  ± 0.2  



  Outcome Measures
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1.  Primary:   Progression Free Survival (PFS) Rate at 12 Months   [ Time Frame: 12 months ]

Measure Type Primary
Measure Title Progression Free Survival (PFS) Rate at 12 Months
Measure Description PFS rate at 12 months was defined as the percentage of patients alive without disease progression at 12 months after randomization. The primary efficacy analysis was based on assessment by the Independent Review Committee (IRC). The study was not powered for comparison of PFS rate at 12 months between the two arms (non-comparative, open-label study). Progression was defined using Response Evaluation Criteria In Solid Tumors (RECIST v1.0), as at least a 20 percent increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non target-lesions.
Time Frame 12 months  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Analyses of PFS rate was performed in the evaluable patient (EP) population as the primary analysis population. Overall, 9 patients from the randomized population were excluded from the EP population.

Reporting Groups
  Description
mFOLFOX6 Only modified FOLFOX6
mFOLFOX6 + Aflibercept modified FOLFOX6 in combination with aflibercept

Measured Values
    mFOLFOX6 Only     mFOLFOX6 + Aflibercept  
Number of Participants Analyzed  
[units: participants]
  111     116  
Progression Free Survival (PFS) Rate at 12 Months  
[units: percentage of participants]
Number ( 95% Confidence Interval )
  21.2  
  ( 12.2 to 30.3 )  
  25.8  
  ( 17.2 to 34.4 )  

No statistical analysis provided for Progression Free Survival (PFS) Rate at 12 Months



2.  Secondary:   Progression Free Survival (PFS)   [ Time Frame: From the date of the first randomization until the study data cut-off date, 14 April 2011 (approximately 26 months) ]

Measure Type Secondary
Measure Title Progression Free Survival (PFS)
Measure Description

PFS was defined as the time from the date of randomization to the date of tumor progression or death from any cause, whichever occurred first. PFS was based on tumor assessment by the Independent Review Committee (IRC). PFS was estimated from Kaplan-Meier Curves.

The study was not powered for comparison of PFS between the two arms (non-comparative, open-label study).

Progression was defined using Response Evaluation Criteria In Solid Tumors (RECIST v1.0), as at least a 20 percent increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non target-lesions.

Time Frame From the date of the first randomization until the study data cut-off date, 14 April 2011 (approximately 26 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Evaluable patient (EP) population. A total of 55 patients (32 in the mFOLFOX6 group and 23 in the mFOLFOX6 + aflibercept group) were without an event at the cutoff date for the PFS analysis by IRC.

Reporting Groups
  Description
mFOLFOX6 Only modified FOLFOX6
mFOLFOX6 + Aflibercept modified FOLFOX6 in combination with aflibercept

Measured Values
    mFOLFOX6 Only     mFOLFOX6 + Aflibercept  
Number of Participants Analyzed  
[units: participants]
  111     116  
Number of Events Analyzed  
[units: Events]
  79     93  
Progression Free Survival (PFS)  
[units: Months]
Median ( 95% Confidence Interval )
  8.77  
  ( 7.622 to 9.265 )  
  8.48  
  ( 7.885 to 9.922 )  

No statistical analysis provided for Progression Free Survival (PFS)



3.  Secondary:   Overall Objective Response Rate (ORR)   [ Time Frame: From the date of the first randomization until the study data cut-off date, 14 April 2011 (approximately 26 months) ]

Measure Type Secondary
Measure Title Overall Objective Response Rate (ORR)
Measure Description

Summary of overall objective response rate based on tumor assessment by the Independent Review Committee (IRC) as per Response Evaluation Criteria in Solid Tumours (RECIST) criteria. ORR was defined as the proportion of patients with confirmed Complete Response (CR) or confirmed Partial Response (PR) relative to the total number of patients in the analysis population.

Per RECIST v 1.0 target lesions evaluation and assessed by tumor imaging: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): >=30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.

The study was not powered for comparison of ORR between the two arms (non-comparative, open-label study).

Time Frame From the date of the first randomization until the study data cut-off date, 14 April 2011 (approximately 26 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Evaluable Patient population.

Reporting Groups
  Description
mFOLFOX6 Only modified FOLFOX6
mFOLFOX6 + Aflibercept modified FOLFOX6 in combination with aflibercept

Measured Values
    mFOLFOX6 Only     mFOLFOX6 + Aflibercept  
Number of Participants Analyzed  
[units: participants]
  111     116  
Overall Objective Response Rate (ORR)  
[units: percentage of participants]
Number ( 95% Confidence Interval )
  45.9  
  ( 36.4 to 55.7 )  
  49.1  
  ( 39.7 to 58.6 )  

No statistical analysis provided for Overall Objective Response Rate (ORR)



4.  Secondary:   Overall Survival (OS)   [ Time Frame: From the date of the first randomization until the study data cut-off date, 14 April 2011 (approximately 26 months) ]

Measure Type Secondary
Measure Title Overall Survival (OS)
Measure Description

Overall survival was defined as the time from the date of randomization to the date of death due to any cause. In absence of confirmation of death, survival time was censored at the earliest between the last date the patient was known to be alive and the study cutoff date.

The study was not powered for comparison of OS between the two arms (non-comparative, open-label study).

Time Frame From the date of the first randomization until the study data cut-off date, 14 April 2011 (approximately 26 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population (ITT) – all participants who gave informed consent and were randomized. Of the 268 screened participants, 236 were randomly assigned to treatments, whereas 32 participants were screen failures.

Reporting Groups
  Description
mFOLFOX6 Only modified FOLFOX6
mFOLFOX6 + Aflibercept modified FOLFOX6 in combination with aflibercept

Measured Values
    mFOLFOX6 Only     mFOLFOX6 + Aflibercept  
Number of Participants Analyzed  
[units: participants]
  117     119  
Number of Events (Death) Analyzed  
[units: Events (Death)]
  50     51  
Overall Survival (OS)  
[units: months]
Median ( 95% Confidence Interval )
  22.31  
  ( 15.57 to NA ) [1]
  19.45  
  ( 15.64 to NA ) [1]
[1] Insufficient number of participants with events. Data have limited maturity and the Kaplan-Meier estimates of median OS are inherently imprecise.

No statistical analysis provided for Overall Survival (OS)



5.  Secondary:   Number of Participants With Treatment-emergent Adverse Events (TEAE)   [ Time Frame: From the date of the first randomization up to 30 days after the treatment discontinuation or until TEAE was resolved or stabilized ]

Measure Type Secondary
Measure Title Number of Participants With Treatment-emergent Adverse Events (TEAE)
Measure Description Summary of treatment-emergent adverse events in the safety population. The National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE), version 3.0 was used in this study to grade the severity of AEs.
Time Frame From the date of the first randomization up to 30 days after the treatment discontinuation or until TEAE was resolved or stabilized  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Of the total 235 patients included in the safety population, 116 patients received mFOLFOX6 and 119 patients received mFOLFOX6 + aflibercept. One patient, randomly assigned to the mFOLFOX6 arm did not receive any study treatment and was therefore excluded from the safety analyses.

Reporting Groups
  Description
mFOLFOX6 Only modified FOLFOX6
mFOLFOX6 + Aflibercept modified FOLFOX6 in combination with aflibercept

Measured Values
    mFOLFOX6 Only     mFOLFOX6 + Aflibercept  
Number of Participants Analyzed  
[units: participants]
  116     119  
Number of Participants With Treatment-emergent Adverse Events (TEAE)  
[units: participants]
   
Treatment Emergent Adverse Event (TEAE)     115     119  
Grade 3-4 TEAE     87     108  
Treatment emergent Serious Adverse Event (SAE)     32     55  
TEAE leading to death     2     8  
Premature treatment discontinuation     NA [1]   34  
Permanent treatment discontinuation     26     37  
[1] Analysis was limited to mFOLFOX6 + aflibercept arm.

No statistical analysis provided for Number of Participants With Treatment-emergent Adverse Events (TEAE)



6.  Secondary:   Immunogenicity of Intravenous (IV) Aflibercept   [ Time Frame: Any time post baseline and 90 days after the last infusion of aflibercept, according to baseline status ]

Measure Type Secondary
Measure Title Immunogenicity of Intravenous (IV) Aflibercept
Measure Description The antidrug antibody (ADA) assay was evaluated for participants receiving aflibercept.
Time Frame Any time post baseline and 90 days after the last infusion of aflibercept, according to baseline status  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants treated with aflibercept and evaluable for antibody assessment.

Reporting Groups
  Description
Negative or Missing Negative or missing antidrug antibody (ADA) assay status at Baseline for those participants treated with aflibercept.
Positive Positive antidrug antibody (ADA) assay status at Baseline for those participants treated with aflibercept.

Measured Values
    Negative or Missing     Positive  
Number of Participants Analyzed  
[units: participants]
  112     3  
Immunogenicity of Intravenous (IV) Aflibercept  
[units: participants]
   
ADA Negative post-baseline     105     1  
ADA Positive (drug specific) post-baseline     7     2  
ADA Negative 90 days after last dose     45     1  
ADA Positive 90 days after last dose     0     1  

No statistical analysis provided for Immunogenicity of Intravenous (IV) Aflibercept




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
The overall survival (OS) data are severely limited due to the low number of events (<50%) in both arms, therefore median OS cannot be accurately estimated due to limitations of available data.


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