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

• Sponsor: Sanofi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00851084
• Collaborator: (none)
• Enrollment: 268
• Locations: 37
• Arms: 2
• Duration (Months): 35
• Patients Per Site: 7.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The primary objective of the study is to estimate the progression-free survival rate at 12 months for the two arms of the study.

Secondary objectives include the evaluation of overall objective response rate to treatment, progression-free survival, overall survival, safety and documentation of potential immunogenicity of aflibercept.

This study was a non-comparative randomized trial and was not powered for a comparison of any of the efficacy endpoints.

Rather, the aim of the trial was to get, for all endpoints, an estimation of the efficacy and safety of aflibercept combined with a modified FOLFOX6 regimen. In such type of non-comparative randomized trial, the control FOLFOLX6 arm was intended to only act as a check on the similarity of the current patients to the historical controls with respect to clinical outcome when given FOLFOX6 treatment.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Neoplasms; Neoplasm Metastasis	Drug: aflibercept; Drug: oxaliplatin; Drug: 5-FU; Drug: Folinic Acid	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 268 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized, Multinational, Study Of Aflibercept And Modified FOLFOX6 As First-Line Treatment In Patients With Metastatic Colorectal Cancer
• Study Start Date: Feb 1, 2009
• Actual Primary Completion Date: Apr 1, 2011
• Actual Study Completion Date: Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: mFOLFOX6 only modified FOLFOX6 chemotherapy regimen	Drug: oxaliplatin; administration: IV infusion; Drug: 5-FU; administration: IV infusion; Drug: Folinic Acid; administration: IV infusion
Experimental: mFOLFOX6 + aflibercept modified FOLFOX6 chemotherapy regimen in combination with aflibercept	Drug: aflibercept; administration: IV infusion; Other Names: ZALTRAP™ AVE0005 ; Drug: oxaliplatin; administration: IV infusion; Drug: 5-FU; administration: IV infusion; Drug: Folinic Acid; administration: IV infusion

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) Rate at 12 Months [12 months]

   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.

Secondary Outcome Measures

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

   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.

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

   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).

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

   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).

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

   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.

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

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically proven adenocarcinoma of the colon or the rectum

• Metastatic disease not amenable to potentially curative treatment

Exclusion Criteria:

• Prior therapy for metastatic cancer of the colon or the rectum

• Prior treatment with angiogenesis inhibitors

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sanofi-Aventis Investigational Site Number 036004	Douglas		Australia	4814
2	Sanofi-Aventis Investigational Site Number 036001	Hunter Region Mail Centre		Australia	2310
3	Sanofi-Aventis Investigational Site Number 036003	Hunter Region Mail Centre		Australia	2310
4	Sanofi-Aventis Investigational Site Number 276003	Berlin		Germany	13353
5	Sanofi-Aventis Investigational Site Number 276007	Dresden		Germany	01307
6	Sanofi-Aventis Investigational Site Number 276001	Hannover		Germany	30625
7	Sanofi-Aventis Investigational Site Number 276006	Homberg		Germany	66421
8	Sanofi-Aventis Investigational Site Number 276004	Mannheim		Germany	68167
9	Sanofi-Aventis Investigational Site Number 276002	Münster		Germany	48149
10	Sanofi-Aventis Investigational Site Number 276005	Recklinghausen		Germany	45659
11	Sanofi-Aventis Investigational Site Number 380005	Bari		Italy	70126
12	Sanofi-Aventis Investigational Site Number 380001	Firenze		Italy	50141
13	Sanofi-Aventis Investigational Site Number 380002	Milano		Italy	20121
14	Sanofi-Aventis Investigational Site Number 380003	Taormina		Italy	98039
15	Sanofi-Aventis Investigational Site Number 380004	Torino		Italy	10126
16	Sanofi-Aventis Investigational Site Number 410003	Busan		Korea, Republic of	614-735
17	Sanofi-Aventis Investigational Site Number 410004	Cheongju		Korea, Republic of	361-711
18	Sanofi-Aventis Investigational Site Number 410005	Daegu		Korea, Republic of	700-721
19	Sanofi-Aventis Investigational Site Number 410002	Daejeon		Korea, Republic of
20	Sanofi-Aventis Investigational Site Number 410007	Goyang-Si, Gyeonggi-Do		Korea, Republic of	410-769
21	Sanofi-Aventis Investigational Site Number 410006	Seoul		Korea, Republic of	120-752
22	Sanofi-Aventis Investigational Site Number 410001	Seoul		Korea, Republic of	152-703
23	Sanofi-Aventis Investigational Site Number 410008	Ulsan		Korea, Republic of	682-714
24	Sanofi-Aventis Investigational Site Number 643002	Pyatigorsk		Russian Federation	357500
25	Sanofi-Aventis Investigational Site Number 643005	Saint-Petersburg		Russian Federation	197758
26	Sanofi-Aventis Investigational Site Number 643001	Sochi		Russian Federation	354057
27	Sanofi-Aventis Investigational Site Number 724005	Barcelona		Spain	08036
28	Sanofi-Aventis Investigational Site Number 724004	Madrid		Spain	28007
29	Sanofi-Aventis Investigational Site Number 724001	Madrid		Spain	28040
30	Sanofi-Aventis Investigational Site Number 724002	Sabadell		Spain	08208
31	Sanofi-Aventis Investigational Site Number 724007	Santiago De Compostela		Spain	15706
32	Sanofi-Aventis Investigational Site Number 724003	Valencia		Spain	46009
33	Sanofi-Aventis Investigational Site Number 826004	Leeds		United Kingdom	LS9 7TF
34	Sanofi-Aventis Investigational Site Number 826001	Leicester		United Kingdom	LE1 5WW
35	Sanofi-Aventis Investigational Site Number 826002	Manchester		United Kingdom	M20 4BX
36	Sanofi-Aventis Investigational Site Number 826003	Slough		United Kingdom	SL2 4HL
37	Sanofi-Aventis Investigational Site Number 826005	Southampton		United Kingdom	SO16 6YD

Sponsors and Collaborators

• Sanofi

Investigators

• Principal Investigator: John Zalcberg, MD, Peter Mc Callum Cancer Centre, Melbourne, Australia

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT00851084
• Other Study ID Numbers: EFC10668; EudraCT 2008-004178-41
• First Posted: Feb 25, 2009
• Last Update Posted: Jun 7, 2016
• Last Verified: May 1, 2016

• Keywords provided by Sanofi: Angiogenesis; Colon cancer; Rectal cancer; Oxaliplatin
• Additional relevant MeSH terms: Neoplasms; Colorectal Neoplasms; Neoplasm Metastasis; Leucovorin; Folic Acid; Oxaliplatin; Aflibercept; Levoleucovorin

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	mFOLFOX6 Only	mFOLFOX6 + Aflibercept
Arm/Group Description	modified FOLFOX6	modified FOLFOX6 in combination with aflibercept
Period Title: Overall Study
STARTED	117	119
COMPLETED	0	0
NOT COMPLETED	117	119

Baseline Characteristics

Arm/Group Title	mFOLFOX6 Only	mFOLFOX6 + Aflibercept	Total
Arm/Group Description	modified FOLFOX6	modified FOLFOX6 in combination with aflibercept	Total of all reporting groups
Overall Participants	117	119	236
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	62.4 (9.7)	61.8 (9.0)	62.1 (9.4)
Age, Customized (Number) [Number]
<65	65 55.6%	70 58.8%	135 57.2%
>=65 but <75	43 36.8%	45 37.8%	88 37.3%
>=75	9 7.7%	4 3.4%	13 5.5%
Sex: Female, Male (Count of Participants)
Female	49 41.9%	43 36.1%	92 39%
Male	68 58.1%	76 63.9%	144 61%
Race/Ethnicity, Customized (Number) [Number]
Caucasian/White	90 76.9%	97 81.5%	187 79.2%
Black	0 0%	1 0.8%	1 0.4%
Asian/Oriental	27 23.1%	20 16.8%	47 19.9%
Other	0 0%	1 0.8%	1 0.4%
Region of Enrollment (participants) [Number]
United Kingdom	22 18.8%	28 23.5%	50 21.2%
Korea, Republic of	26 22.2%	20 16.8%	46 19.5%
Germany	18 15.4%	24 20.2%	42 17.8%
Spain	24 20.5%	18 15.1%	42 17.8%
Russian Federation	15 12.8%	15 12.6%	30 12.7%
Italy	10 8.5%	5 4.2%	15 6.4%
Australia	2 1.7%	9 7.6%	11 4.7%
Body Surface Are (BSA) (m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m^2]	1.8 (0.2)	1.8 (0.2)	1.8 (0.2)

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS) Rate at 12 Months
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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	mFOLFOX6 Only	mFOLFOX6 + Aflibercept
Arm/Group Description	modified FOLFOX6	modified FOLFOX6 in combination with aflibercept
Measure Participants	111	116
Number (95% Confidence Interval) [percentage of participants]	21.2 18.1%	25.8 21.7%

2. Secondary Outcome

Title	Progression Free Survival (PFS)
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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	mFOLFOX6 Only	mFOLFOX6 + Aflibercept
Arm/Group Description	modified FOLFOX6	modified FOLFOX6 in combination with aflibercept
Measure Participants	111	116
Measure Events	79	93
Median (95% Confidence Interval) [Months]	8.77	8.48

3. Secondary Outcome

Title	Overall Objective Response Rate (ORR)
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)

Outcome Measure Data

Analysis Population Description

Evaluable Patient population.

Arm/Group Title	mFOLFOX6 Only	mFOLFOX6 + Aflibercept
Arm/Group Description	modified FOLFOX6	modified FOLFOX6 in combination with aflibercept
Measure Participants	111	116
Number (95% Confidence Interval) [percentage of participants]	45.9 39.2%	49.1 41.3%

4. Secondary Outcome

Title	Overall Survival (OS)
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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	mFOLFOX6 Only	mFOLFOX6 + Aflibercept
Arm/Group Description	modified FOLFOX6	modified FOLFOX6 in combination with aflibercept
Measure Participants	117	119
Measure Events (Death)	50	51
Median (95% Confidence Interval) [months]	22.31	19.45

5. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAE)
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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	mFOLFOX6 Only	mFOLFOX6 + Aflibercept
Arm/Group Description	modified FOLFOX6	modified FOLFOX6 in combination with aflibercept
Measure Participants	116	119
Treatment Emergent Adverse Event (TEAE)	115 98.3%	119 100%
Grade 3-4 TEAE	87 74.4%	108 90.8%
Treatment emergent Serious Adverse Event (SAE)	32 27.4%	55 46.2%
TEAE leading to death	2 1.7%	8 6.7%
Premature treatment discontinuation	NA NaN	34 28.6%
Permanent treatment discontinuation	26 22.2%	37 31.1%

6. Secondary Outcome

Title	Immunogenicity of Intravenous (IV) Aflibercept
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

Outcome Measure Data

Analysis Population Description

Participants treated with aflibercept and evaluable for antibody assessment.

Arm/Group Title	Negative or Missing	Positive
Arm/Group Description	Negative or missing antidrug antibody (ADA) assay status at Baseline for those participants treated with aflibercept.	Positive antidrug antibody (ADA) assay status at Baseline for those participants treated with aflibercept.
Measure Participants	112	3
ADA Negative post-baseline	105 89.7%	1 0.8%
ADA Positive (drug specific) post-baseline	7 6%	2 1.7%
ADA Negative 90 days after last dose	45 38.5%	1 0.8%
ADA Positive 90 days after last dose	0 0%	1 0.8%

Adverse Events

Adverse Event Reporting Description	Of the total 235 patients included in the safety population, 116 patients received mFOLFOX6 and 119 patients received aflibercept+mFOLFOX6. One patient, randomly assigned to the mFOLFOX6 arm did not receive any study treatment and was therefore excluded from the safety analyses.
Arm/Group Title	mFOLFOX6 Only		mFOLFOX6 + Aflibercept
Arm/Group Description	modified FOLFOX6		modified FOLFOX6 in combination with aflibercept
All Cause Mortality
	mFOLFOX6 Only		mFOLFOX6 + Aflibercept
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	mFOLFOX6 Only		mFOLFOX6 + Aflibercept
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/116 (27.6%)		55/119 (46.2%)
Blood and lymphatic system disorders
Neutropenia	1/116 (0.9%)		3/119 (2.5%)
Febrile neutropenia	2/116 (1.7%)		2/119 (1.7%)
Cardiac disorders
Sinoatrial block	0/116 (0%)		1/119 (0.8%)
Ventricular arrhythmia	0/116 (0%)		1/119 (0.8%)
Endocrine disorders
Adrenal insufficiency	0/116 (0%)		1/119 (0.8%)
Eye disorders
Vision blurred	1/116 (0.9%)		0/119 (0%)
Retinal detachment	1/116 (0.9%)		0/119 (0%)
Gastrointestinal disorders
Nausea	1/116 (0.9%)		0/119 (0%)
Diarrhoea	3/116 (2.6%)		3/119 (2.5%)
Stomatitis	1/116 (0.9%)		0/119 (0%)
Constipation	0/116 (0%)		2/119 (1.7%)
Vomiting	2/116 (1.7%)		3/119 (2.5%)
Abdominal pain	2/116 (1.7%)		2/119 (1.7%)
Rectal haemorrhage	0/116 (0%)		1/119 (0.8%)
Intestinal obstruction	4/116 (3.4%)		2/119 (1.7%)
Dysphagia	1/116 (0.9%)		0/119 (0%)
Haematochezia	0/116 (0%)		1/119 (0.8%)
Ascites	1/116 (0.9%)		0/119 (0%)
Colonic obstruction	3/116 (2.6%)		0/119 (0%)
Melaena	1/116 (0.9%)		1/119 (0.8%)
Anal fistula	0/116 (0%)		1/119 (0.8%)
Ileal perforation	0/116 (0%)		1/119 (0.8%)
Large intestine perforation	0/116 (0%)		1/119 (0.8%)
Mechanical ileus	1/116 (0.9%)		0/119 (0%)
Small intestinal obstruction	0/116 (0%)		1/119 (0.8%)
Subileus	0/116 (0%)		1/119 (0.8%)
General disorders
Fatigue	1/116 (0.9%)		2/119 (1.7%)
Pyrexia	3/116 (2.6%)		6/119 (5%)
Disease progression	1/116 (0.9%)		4/119 (3.4%)
Medical device complication	0/116 (0%)		1/119 (0.8%)
General physical health deterioration	1/116 (0.9%)		0/119 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia	1/116 (0.9%)		0/119 (0%)
Bile duct obstruction	1/116 (0.9%)		0/119 (0%)
Immune system disorders
Drug hypersensitivity	0/116 (0%)		3/119 (2.5%)
Infections and infestations
Urinary tract infection	0/116 (0%)		2/119 (1.7%)
Catheter site infection	3/116 (2.6%)		3/119 (2.5%)
Pneumonia	1/116 (0.9%)		4/119 (3.4%)
Cystitis	1/116 (0.9%)		0/119 (0%)
Device related infection	0/116 (0%)		1/119 (0.8%)
Infection	1/116 (0.9%)		0/119 (0%)
Neutropenic infection	1/116 (0.9%)		0/119 (0%)
Abdominal infection	1/116 (0.9%)		0/119 (0%)
Gastroenteritis norovirus	0/116 (0%)		2/119 (1.7%)
Infectious peritonitis	0/116 (0%)		2/119 (1.7%)
Lower respiratory tract infection	0/116 (0%)		1/119 (0.8%)
Neutropenic sepsis	1/116 (0.9%)		1/119 (0.8%)
Bacterial infection	0/116 (0%)		1/119 (0.8%)
Bronchopneumonia	0/116 (0%)		1/119 (0.8%)
Folliculitis	0/116 (0%)		1/119 (0.8%)
Fungaemia	1/116 (0.9%)		0/119 (0%)
Gastroenteritis	1/116 (0.9%)		0/119 (0%)
Pneumonia viral	0/116 (0%)		1/119 (0.8%)
Pyelonephritis	1/116 (0.9%)		0/119 (0%)
Sepsis	0/116 (0%)		1/119 (0.8%)
Septic shock	0/116 (0%)		1/119 (0.8%)
Staphylococcal sepsis	0/116 (0%)		1/119 (0.8%)
Subcutaneous abscess	0/116 (0%)		1/119 (0.8%)
Urosepsis	0/116 (0%)		1/119 (0.8%)
Injury, poisoning and procedural complications
Anastomotic leak	0/116 (0%)		1/119 (0.8%)
Head injury	0/116 (0%)		1/119 (0.8%)
Postoperative wound complication	0/116 (0%)		1/119 (0.8%)
Investigations
Neutrophil count decreased	0/116 (0%)		1/119 (0.8%)
Metabolism and nutrition disorders
Dehydration	1/116 (0.9%)		1/119 (0.8%)
Malnutrition	0/116 (0%)		1/119 (0.8%)
Musculoskeletal and connective tissue disorders
Pathological fracture	1/116 (0.9%)		0/119 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm progression	0/116 (0%)		1/119 (0.8%)
Nervous system disorders
Peripheral sensory neuropathy	1/116 (0.9%)		0/119 (0%)
Lethargy	1/116 (0.9%)		0/119 (0%)
Presyncope	1/116 (0.9%)		1/119 (0.8%)
Convulsion	0/116 (0%)		1/119 (0.8%)
Haemorrhage intracranial	0/116 (0%)		1/119 (0.8%)
Ischaemic stroke	1/116 (0.9%)		0/119 (0%)
Posterior reversible encephalopathy syndrome	0/116 (0%)		1/119 (0.8%)
Renal and urinary disorders
Proteinuria	0/116 (0%)		1/119 (0.8%)
Haematuria	1/116 (0.9%)		0/119 (0%)
Urinary retention	0/116 (0%)		1/119 (0.8%)
Renal failure	0/116 (0%)		2/119 (1.7%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/116 (0%)		1/119 (0.8%)
Dyspnoea	0/116 (0%)		2/119 (1.7%)
Pulmonary embolism	3/116 (2.6%)		4/119 (3.4%)
Acute respiratory distress syndrome	0/116 (0%)		2/119 (1.7%)
Skin and subcutaneous tissue disorders
Pyoderma gangrenosum	0/116 (0%)		1/119 (0.8%)
Social circumstances
Social stay hospitalisation	0/116 (0%)		1/119 (0.8%)
Surgical and medical procedures
Malignant tumour excision	0/116 (0%)		1/119 (0.8%)
Tumour excision	1/116 (0.9%)		0/119 (0%)
Vascular disorders
Subclavian vein thrombosis	0/116 (0%)		1/119 (0.8%)
Circulatory collapse	1/116 (0.9%)		0/119 (0%)
Hypertensive crisis	0/116 (0%)		1/119 (0.8%)
Lymphatic fistula	0/116 (0%)		1/119 (0.8%)
Other (Not Including Serious) Adverse Events
	mFOLFOX6 Only		mFOLFOX6 + Aflibercept
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	114/116 (98.3%)		117/119 (98.3%)
Blood and lymphatic system disorders
Neutropenia	64/116 (55.2%)		53/119 (44.5%)
Thrombocytopenia	25/116 (21.6%)		14/119 (11.8%)
Anaemia	11/116 (9.5%)		11/119 (9.2%)
Leukopenia	10/116 (8.6%)		11/119 (9.2%)
Febrile neutropenia	2/116 (1.7%)		6/119 (5%)
Eye disorders
Lacrimation increased	3/116 (2.6%)		6/119 (5%)
Gastrointestinal disorders
Nausea	62/116 (53.4%)		62/119 (52.1%)
Diarrhoea	51/116 (44%)		69/119 (58%)
Stomatitis	44/116 (37.9%)		60/119 (50.4%)
Constipation	31/116 (26.7%)		37/119 (31.1%)
Vomiting	28/116 (24.1%)		34/119 (28.6%)
Abdominal pain	25/116 (21.6%)		21/119 (17.6%)
Dyspepsia	12/116 (10.3%)		21/119 (17.6%)
Abdominal pain upper	14/116 (12.1%)		8/119 (6.7%)
Proctalgia	3/116 (2.6%)		6/119 (5%)
Mouth ulceration	1/116 (0.9%)		6/119 (5%)
General disorders
Fatigue	30/116 (25.9%)		41/119 (34.5%)
Asthenia	30/116 (25.9%)		24/119 (20.2%)
Pyrexia	18/116 (15.5%)		15/119 (12.6%)
Oedema peripheral	8/116 (6.9%)		13/119 (10.9%)
Immune system disorders
Drug hypersensitivity	6/116 (5.2%)		4/119 (3.4%)
Infections and infestations
Urinary tract infection	12/116 (10.3%)		12/119 (10.1%)
Nasopharyngitis	8/116 (6.9%)		16/119 (13.4%)
Upper respiratory tract infection	5/116 (4.3%)		6/119 (5%)
Investigations
Weight decreased	6/116 (5.2%)		15/119 (12.6%)
Aspartate aminotransferase increased	6/116 (5.2%)		3/119 (2.5%)
Alanine aminotransferase increased	6/116 (5.2%)		2/119 (1.7%)
Metabolism and nutrition disorders
Decreased appetite	37/116 (31.9%)		41/119 (34.5%)
Musculoskeletal and connective tissue disorders
Back pain	11/116 (9.5%)		9/119 (7.6%)
Musculoskeletal pain	2/116 (1.7%)		8/119 (6.7%)
Arthralgia	6/116 (5.2%)		2/119 (1.7%)
Nervous system disorders
Peripheral sensory neuropathy	35/116 (30.2%)		23/119 (19.3%)
Headache	9/116 (7.8%)		39/119 (32.8%)
Neuropathy peripheral	24/116 (20.7%)		23/119 (19.3%)
Paraesthesia	25/116 (21.6%)		18/119 (15.1%)
Polyneuropathy	16/116 (13.8%)		16/119 (13.4%)
Lethargy	13/116 (11.2%)		14/119 (11.8%)
Dysgeusia	16/116 (13.8%)		11/119 (9.2%)
Dizziness	11/116 (9.5%)		12/119 (10.1%)
Dysaesthesia	7/116 (6%)		7/119 (5.9%)
Neurotoxicity	6/116 (5.2%)		0/119 (0%)
Psychiatric disorders
Insomnia	3/116 (2.6%)		10/119 (8.4%)
Depression	3/116 (2.6%)		7/119 (5.9%)
Renal and urinary disorders
Proteinuria	1/116 (0.9%)		28/119 (23.5%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	15/116 (12.9%)		34/119 (28.6%)
Dyspnoea	8/116 (6.9%)		22/119 (18.5%)
Cough	14/116 (12.1%)		12/119 (10.1%)
Dysphonia	3/116 (2.6%)		22/119 (18.5%)
Oropharyngeal pain	3/116 (2.6%)		8/119 (6.7%)
Rhinorrhoea	2/116 (1.7%)		6/119 (5%)
Skin and subcutaneous tissue disorders
Alopecia	15/116 (12.9%)		13/119 (10.9%)
Palmar-plantar erythrodysaesthesia syndrome	6/116 (5.2%)		20/119 (16.8%)
Rash	7/116 (6%)		6/119 (5%)
Dry skin	6/116 (5.2%)		5/119 (4.2%)
Pruritus	6/116 (5.2%)		5/119 (4.2%)
Skin hyperpigmentation	6/116 (5.2%)		5/119 (4.2%)
Vascular disorders
Hypertension	8/116 (6.9%)		64/119 (53.8%)
Deep vein thrombosis	2/116 (1.7%)		7/119 (5.9%)
Phlebitis	0/116 (0%)		6/119 (5%)

Limitations/Caveats

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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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).