Trial Outcomes & Findings for Study of Aflibercept And Modified FOLFOX6 As First-Line Treatment In Patients With Metastatic Colorectal Cancer (NCT NCT00851084)

Last Updated: 2016-06-07

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

268 participants

Primary outcome timeframe

12 months

Results posted on

2016-06-07

Participant Flow

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.

Participant milestones

Participant milestones
Measure	mFOLFOX6 Only modified FOLFOX6	mFOLFOX6 + Aflibercept modified FOLFOX6 in combination with aflibercept
Overall Study STARTED	117	119
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	117	119

Reasons for withdrawal

Reasons for withdrawal
Measure	mFOLFOX6 Only modified FOLFOX6	mFOLFOX6 + Aflibercept modified FOLFOX6 in combination with aflibercept
Overall Study Randomized but not treated	1	0
Overall Study Adverse Event	26	36
Overall Study Disease progression	52	47
Overall Study Poor compliance to protocol	1	1
Overall Study Physician Decision	13	14
Overall Study Consent withdrawn	0	2
Overall Study Withdrawal by Subject	11	12
Overall Study Metastatic surgery	6	6
Overall Study Other	7	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	mFOLFOX6 Only n=117 Participants modified FOLFOX6	mFOLFOX6 + Aflibercept n=119 Participants modified FOLFOX6 in combination with aflibercept	Total n=236 Participants Total of all reporting groups
Age, Continuous	62.4 Years STANDARD_DEVIATION 9.7 • n=5 Participants	61.8 Years STANDARD_DEVIATION 9.0 • n=7 Participants	62.1 Years STANDARD_DEVIATION 9.4 • n=5 Participants
Age, Customized <65	65 Participants n=5 Participants	70 Participants n=7 Participants	135 Participants n=5 Participants
Age, Customized >=65 but <75	43 Participants n=5 Participants	45 Participants n=7 Participants	88 Participants n=5 Participants
Age, Customized >=75	9 Participants n=5 Participants	4 Participants n=7 Participants	13 Participants n=5 Participants
Sex: Female, Male Female	49 Participants n=5 Participants	43 Participants n=7 Participants	92 Participants n=5 Participants
Sex: Female, Male Male	68 Participants n=5 Participants	76 Participants n=7 Participants	144 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian/White	90 Participants n=5 Participants	97 Participants n=7 Participants	187 Participants n=5 Participants
Race/Ethnicity, Customized Black	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Asian/Oriental	27 Participants n=5 Participants	20 Participants n=7 Participants	47 Participants n=5 Participants
Race/Ethnicity, Customized Other	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment United Kingdom	22 participants n=5 Participants	28 participants n=7 Participants	50 participants n=5 Participants
Region of Enrollment Korea, Republic of	26 participants n=5 Participants	20 participants n=7 Participants	46 participants n=5 Participants
Region of Enrollment Germany	18 participants n=5 Participants	24 participants n=7 Participants	42 participants n=5 Participants
Region of Enrollment Spain	24 participants n=5 Participants	18 participants n=7 Participants	42 participants n=5 Participants
Region of Enrollment Russian Federation	15 participants n=5 Participants	15 participants n=7 Participants	30 participants n=5 Participants
Region of Enrollment Italy	10 participants n=5 Participants	5 participants n=7 Participants	15 participants n=5 Participants
Region of Enrollment Australia	2 participants n=5 Participants	9 participants n=7 Participants	11 participants n=5 Participants
Body Surface Are (BSA)	1.8 m^2 STANDARD_DEVIATION 0.2 • n=5 Participants	1.8 m^2 STANDARD_DEVIATION 0.2 • n=7 Participants	1.8 m^2 STANDARD_DEVIATION 0.2 • n=5 Participants

PRIMARY outcome

Timeframe: 12 months

Population: 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.

Outcome measures

Outcome measures
Measure	mFOLFOX6 Only n=111 Participants modified FOLFOX6	mFOLFOX6 + Aflibercept n=116 Participants modified FOLFOX6 in combination with aflibercept
Progression Free Survival (PFS) Rate at 12 Months	21.2 percentage of participants Interval 12.2 to 30.3	25.8 percentage of participants Interval 17.2 to 34.4

SECONDARY outcome

Timeframe: From the date of the first randomization until the study data cut-off date, 14 April 2011 (approximately 26 months)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	mFOLFOX6 Only n=79 Events modified FOLFOX6	mFOLFOX6 + Aflibercept n=93 Events modified FOLFOX6 in combination with aflibercept
Progression Free Survival (PFS)	8.77 Months Interval 7.622 to 9.265	8.48 Months Interval 7.885 to 9.922

SECONDARY outcome

Timeframe: From the date of the first randomization until the study data cut-off date, 14 April 2011 (approximately 26 months)

Population: Evaluable Patient population.

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).

Outcome measures

Outcome measures
Measure	mFOLFOX6 Only n=111 Participants modified FOLFOX6	mFOLFOX6 + Aflibercept n=116 Participants modified FOLFOX6 in combination with aflibercept
Overall Objective Response Rate (ORR)	45.9 percentage of participants Interval 36.4 to 55.7	49.1 percentage of participants Interval 39.7 to 58.6

SECONDARY outcome

Timeframe: From the date of the first randomization until the study data cut-off date, 14 April 2011 (approximately 26 months)

Population: 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.

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).

Outcome measures

Outcome measures
Measure	mFOLFOX6 Only n=50 Events (Death) modified FOLFOX6	mFOLFOX6 + Aflibercept n=51 Events (Death) modified FOLFOX6 in combination with aflibercept
Overall Survival (OS)	22.31 months Interval 15.57 to Insufficient number of participants with events. Data have limited maturity and the Kaplan-Meier estimates of median OS are inherently imprecise.	19.45 months Interval 15.64 to Insufficient number of participants with events. Data have limited maturity and the Kaplan-Meier estimates of median OS are inherently imprecise.

SECONDARY outcome

Timeframe: From the date of the first randomization up to 30 days after the treatment discontinuation or until TEAE was resolved or stabilized

Population: 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.

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.

Outcome measures

Outcome measures
Measure	mFOLFOX6 Only n=116 Participants modified FOLFOX6	mFOLFOX6 + Aflibercept n=119 Participants modified FOLFOX6 in combination with aflibercept
Number of Participants With Treatment-emergent Adverse Events (TEAE) Premature treatment discontinuation	NA participants Analysis was limited to mFOLFOX6 + aflibercept arm.	34 participants
Number of Participants With Treatment-emergent Adverse Events (TEAE) Treatment Emergent Adverse Event (TEAE)	115 participants	119 participants
Number of Participants With Treatment-emergent Adverse Events (TEAE) Grade 3-4 TEAE	87 participants	108 participants
Number of Participants With Treatment-emergent Adverse Events (TEAE) Treatment emergent Serious Adverse Event (SAE)	32 participants	55 participants
Number of Participants With Treatment-emergent Adverse Events (TEAE) TEAE leading to death	2 participants	8 participants
Number of Participants With Treatment-emergent Adverse Events (TEAE) Permanent treatment discontinuation	26 participants	37 participants

SECONDARY outcome

Timeframe: Any time post baseline and 90 days after the last infusion of aflibercept, according to baseline status

Population: Participants treated with aflibercept and evaluable for antibody assessment.

The antidrug antibody (ADA) assay was evaluated for participants receiving aflibercept.

Outcome measures

Outcome measures
Measure	mFOLFOX6 Only n=112 Participants modified FOLFOX6	mFOLFOX6 + Aflibercept n=3 Participants modified FOLFOX6 in combination with aflibercept
Immunogenicity of Intravenous (IV) Aflibercept ADA Negative post-baseline	105 participants	1 participants
Immunogenicity of Intravenous (IV) Aflibercept ADA Positive (drug specific) post-baseline	7 participants	2 participants
Immunogenicity of Intravenous (IV) Aflibercept ADA Negative 90 days after last dose	45 participants	1 participants
Immunogenicity of Intravenous (IV) Aflibercept ADA Positive 90 days after last dose	0 participants	1 participants

Adverse Events

mFOLFOX6 Only

Serious events: 32 serious events

Other events: 114 other events

Deaths: 0 deaths

mFOLFOX6 + Aflibercept

Serious events: 55 serious events

Other events: 117 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Trial Transparency Team

Sanofi

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The investigator shall have the right to independently publish study results from his site after a multicenter publication, or 12 months after the completion of the study by all sites. He must provide the sponsor a copy of any such publication derived from the study for review and comment at least 45 days (20 days for abstracts) in advance of any submission to a journal, and delay publication till the approval of the publication is given in writing by the Sponsor (not to exceed ninety days).
Publication restrictions are in place

Restriction type: OTHER