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

• Sponsor: Sanofi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01661270
• Collaborator: Regeneron Pharmaceuticals (Industry)
• Enrollment: 332
• Locations: 37
• Arms: 2
• Duration (Months): 36
• Patients Per Site: 9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer Metastatic	Drug: Aflibercept; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 332 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Study Start Date: Jul 1, 2012
• Actual Primary Completion Date: Oct 1, 2014
• Actual Study Completion Date: Jul 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: Placebo; Pharmaceutical form: Concentrate for Solution for infusion; Route of administration: Intravenous
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.	Drug: Aflibercept; Pharmaceutical form: Concentrate for Solution for infusion; Route of administration: Intravenous; Other Names: AVE0005 Zaltrap

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) [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.

Secondary Outcome Measures

1. Overall Survival (OS) [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.

2. Percentage of Participants With Objective Response [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.

Eligibility Criteria

Criteria

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

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number 156003	Beijing		China	100071
2	Investigational Site Number 156001	Beijing		China	100142
3	Investigational Site Number 156002	Beijing		China	100210
4	Investigational Site Number 156004	Beijing		China	100853
5	Investigational Site Number 156016	Chengdu		China	610041
6	Investigational Site Number 156020	Chongqing		China	400038
7	Investigational Site Number 156021	Fuzhou		China	350014
8	Investigational Site Number 156008	Guangzhou		China	510060
9	Investigational Site Number 156010	Hangzhou		China	310003
10	Investigational Site Number 156011	Hangzhou		China	310009
11	Investigational Site Number 156009	Hangzhou		China	310016
12	Investigational Site Number 156015	Harbin		China	150081
13	Investigational Site Number 156012	Nanjing		China	210002
14	Investigational Site Number 156013	Nanjing		China	210029
15	Investigational Site Number 156006	Shanghai		China	200032
16	Investigational Site Number 156007	Shanghai		China	200032
17	Investigational Site Number 156014	Shenyang		China	110001
18	Investigational Site Number 156005	Tianjin		China	300060
19	Investigational Site Number 156019	Wuhan		China	430022
20	Investigational Site Number 156018	Wuhan		China	430030
21	Investigational Site Number 156017	Xi'An		China	710032
22	Investigational Site Number 344002	Hong Kong		Hong Kong
23	Investigational Site Number 344001	Shatin, Nt		Hong Kong
24	Investigational Site Number 392006	Amagasaki-Shi		Japan
25	Investigational Site Number 392003	Bunkyo-Ku		Japan
26	Investigational Site Number 392004	Bunkyo-Ku		Japan
27	Investigational Site Number 392009	Gifu-Shi		Japan
28	Investigational Site Number 392002	Kitaadachi-Gun		Japan
29	Investigational Site Number 392001	Kobe-Shi		Japan
30	Investigational Site Number 392005	Kochi-Shi		Japan
31	Investigational Site Number 392007	Kumamoto-Shi		Japan
32	Investigational Site Number 392008	Nagakute-Shi		Japan
33	Investigational Site Number 392010	Takatsuki-Shi		Japan
34	Investigational Site Number 702002	Singapore		Singapore	119228
35	Investigational Site Number 702001	Singapore		Singapore	169610
36	Investigational Site Number 158003	Taipai		Taiwan	10043
37	Investigational Site Number 158002	Taipei		Taiwan

Sponsors and Collaborators

• Sanofi
• Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT01661270
• Other Study ID Numbers: EFC11338; U1111-1115-7227
• First Posted: Aug 9, 2012
• Last Update Posted: Oct 18, 2016
• Last Verified: Aug 1, 2016

• Additional relevant MeSH terms: Colorectal Neoplasms; Aflibercept

Study Results

Participant Flow

Recruitment Details	The study was conducted at 37 centers in 5 countries. A total of 332 participants were randomized between 17 July 2012 and 18 March 2014.
Pre-assignment Detail	Due to treatment kit misallocation, part of the patients randomized to placebo received aflibercept for 1/several treatment cycles and are presented as a separate group for safety evaluation. EOT criteria were: disease progression/death, un-tolerable toxicity, consent withdrawal/Investigator decision.

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	109	223
Adverse Event	26	47
Disease Progression	67	118
Physician Decision	1	8
Participant's Request	15	48
Other Reasons	0	2
COMPLETED	109	223
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Placebo	Aflibercept	Total
Arm/Group Description	Placebo for 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.	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.	Total of all reporting groups
Overall Participants	109	223	332
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.0 (11.3)	55.1 (10.9)	54.4 (11.0)
Sex: Female, Male (Count of Participants)
Female	46 42.2%	95 42.6%	141 42.5%
Male	63 57.8%	128 57.4%	191 57.5%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	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.
Time Frame	26.7 months

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) population included all randomized participants.

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description	Placebo for 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.	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.
Measure Participants	109	223
Median (95% Confidence Interval) [months]	5.59	6.93

2. Secondary Outcome

Title	Overall Survival (OS)
Description	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.
Time Frame	31.6 months

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description	Placebo for 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.	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.
Measure Participants	109	233
Median (95% Confidence Interval) [months]	11.93	14.59

3. Secondary Outcome

Title	Percentage of Participants With Objective Response
Description	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.
Time Frame	26.6 months

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description	Placebo for 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.	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.
Measure Participants	109	233
Number (95% Confidence Interval) [percentage of participants]	3.7 3.4%	18.4 8.3%

Adverse Events

Time Frame	All AE collected from signature of informed consent upto resolution/stabilization/death regardless of seriousness/relationship to IMP.After cutoff date for OS,only ongoing AE & SAE were followed until resolution,stabilization/2 follow-ups(about 4 months).
Adverse Event Reporting Description	Reported AEs were treatment-emergent AEs that developed/worsened during 'on-treatment period' (from first dose of Aflibercept to 30 days of follow-up visit). Safety population (subset of ITT population): all participants who received at least one dose of study drug. Due to operational treatment error, 3 arms were reported for safety analysis.
Arm/Group Title	Placebo Only		Aflibercept Only		Mixed Administration (Placebo and Aflibercept)
Arm/Group Description	Placebo for 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.		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.		Participants who were originally randomized to receive either Placebo or Aflibercept, actually received both the treatment (Placebo and Aflibercept).
All Cause Mortality
	Placebo Only		Aflibercept Only		Mixed Administration (Placebo and Aflibercept)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo Only		Aflibercept Only		Mixed Administration (Placebo and Aflibercept)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/33 (27.3%)		30/111 (27%)		43/188 (22.9%)
Blood and lymphatic system disorders
Neutropenia	1/33 (3%)		2/111 (1.8%)		1/188 (0.5%)
Thrombocytopenia	0/33 (0%)		2/111 (1.8%)		1/188 (0.5%)
Bone marrow failure	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Febrile neutropenia	0/33 (0%)		0/111 (0%)		2/188 (1.1%)
Cardiac disorders
Acute left ventricular failure	0/33 (0%)		1/111 (0.9%)		1/188 (0.5%)
Acute coronary syndrome	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Acute myocardial infarction	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Angina pectoris	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Cardiopulmonary failure	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Gastrointestinal disorders
Diarrhoea	1/33 (3%)		2/111 (1.8%)		2/188 (1.1%)
Gastrointestinal haemorrhage	0/33 (0%)		2/111 (1.8%)		1/188 (0.5%)
Intestinal obstruction	3/33 (9.1%)		2/111 (1.8%)		5/188 (2.7%)
Abdominal mass	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Ileus	0/33 (0%)		1/111 (0.9%)		1/188 (0.5%)
Intestinal perforation	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Lower gastrointestinal haemorrhage	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Abdominal pain	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Ascites	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Colitis	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Constipation	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Mouth ulceration	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Oesophageal varices haemorrhage	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Rectal perforation	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Small intestinal obstruction	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Stomatitis	0/33 (0%)		0/111 (0%)		2/188 (1.1%)
Vomiting	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
General disorders
Pyrexia	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Fatigue	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Hepatobiliary disorders
Hepatic function abnormal	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Liver injury	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Bile duct stone	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Cholecystitis chronic	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Gallbladder perforation	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Infections and infestations
Anal abscess	1/33 (3%)		1/111 (0.9%)		3/188 (1.6%)
Fungal skin infection	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Hepatitis B	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Lung infection	0/33 (0%)		1/111 (0.9%)		1/188 (0.5%)
Peritonitis	0/33 (0%)		1/111 (0.9%)		1/188 (0.5%)
Catheter site abscess	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Gastroenteritis	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Herpes zoster	0/33 (0%)		0/111 (0%)		2/188 (1.1%)
Lobar pneumonia	1/33 (3%)		0/111 (0%)		0/188 (0%)
Lung abscess	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Neutropenic sepsis	0/33 (0%)		0/111 (0%)		3/188 (1.6%)
Sepsis	1/33 (3%)		0/111 (0%)		0/188 (0%)
Urinary tract infection	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Injury, poisoning and procedural complications
Traumatic intracranial haemorrhage	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Investigations
Blood bilirubin increased	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Alanine aminotransferase increased	0/33 (0%)		0/111 (0%)		2/188 (1.1%)
Aspartate aminotransferase increased	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Blood alkaline phosphatase increased	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Blood lactate dehydrogenase increased	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Metabolism and nutrition disorders
Hyperammonaemia	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Hypoglycaemia	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Decreased appetite	0/33 (0%)		0/111 (0%)		2/188 (1.1%)
Musculoskeletal and connective tissue disorders
Back pain	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Musculoskeletal chest pain	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphangiosis carcinomatosa	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Nervous system disorders
Cerebral infarction	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Peroneal nerve palsy	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Posterior reversible encephalopathy syndrome	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Cerebral ischaemia	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Loss of consciousness	1/33 (3%)		0/111 (0%)		1/188 (0.5%)
Psychiatric disorders
Completed suicide	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Depression	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Renal and urinary disorders
Proteinuria	0/33 (0%)		2/111 (1.8%)		1/188 (0.5%)
Calculus urinary	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Bladder outlet obstruction	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Haematuria	0/33 (0%)		0/111 (0%)		2/188 (1.1%)
Reproductive system and breast disorders
Vaginal fistula	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Female genital tract fistula	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Genital rash	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/33 (0%)		2/111 (1.8%)		0/188 (0%)
Epistaxis	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Interstitial lung disease	0/33 (0%)		1/111 (0.9%)		0/188 (0%)
Pneumothorax	0/33 (0%)		1/111 (0.9%)		2/188 (1.1%)
Oropharyngeal pain	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Skin and subcutaneous tissue disorders
Subcutaneous emphysema	0/33 (0%)		0/111 (0%)		1/188 (0.5%)
Vascular disorders
Deep vein thrombosis	0/33 (0%)		2/111 (1.8%)		0/188 (0%)
Hypertension	0/33 (0%)		2/111 (1.8%)		0/188 (0%)
Subclavian vein thrombosis	0/33 (0%)		0/111 (0%)		2/188 (1.1%)
Venous thrombosis limb	1/33 (3%)		0/111 (0%)		0/188 (0%)
Other (Not Including Serious) Adverse Events
	Placebo Only		Aflibercept Only		Mixed Administration (Placebo and Aflibercept)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/33 (97%)		109/111 (98.2%)		188/188 (100%)
Blood and lymphatic system disorders
Neutropenia	22/33 (66.7%)		68/111 (61.3%)		135/188 (71.8%)
Leukopenia	20/33 (60.6%)		59/111 (53.2%)		84/188 (44.7%)
Thrombocytopenia	4/33 (12.1%)		22/111 (19.8%)		24/188 (12.8%)
Anaemia	3/33 (9.1%)		6/111 (5.4%)		12/188 (6.4%)
Gastrointestinal disorders
Nausea	22/33 (66.7%)		61/111 (55%)		110/188 (58.5%)
Diarrhoea	14/33 (42.4%)		60/111 (54.1%)		122/188 (64.9%)
Vomiting	22/33 (66.7%)		56/111 (50.5%)		107/188 (56.9%)
Stomatitis	5/33 (15.2%)		27/111 (24.3%)		60/188 (31.9%)
Abdominal pain	4/33 (12.1%)		19/111 (17.1%)		42/188 (22.3%)
Constipation	8/33 (24.2%)		14/111 (12.6%)		35/188 (18.6%)
Abdominal distension	4/33 (12.1%)		13/111 (11.7%)		11/188 (5.9%)
Mouth ulceration	2/33 (6.1%)		11/111 (9.9%)		29/188 (15.4%)
Abdominal pain upper	0/33 (0%)		7/111 (6.3%)		15/188 (8%)
Gastrointestinal haemorrhage	0/33 (0%)		6/111 (5.4%)		5/188 (2.7%)
Proctalgia	0/33 (0%)		6/111 (5.4%)		3/188 (1.6%)
Toothache	2/33 (6.1%)		2/111 (1.8%)		2/188 (1.1%)
Rectal discharge	2/33 (6.1%)		0/111 (0%)		0/188 (0%)
General disorders
Fatigue	9/33 (27.3%)		37/111 (33.3%)		84/188 (44.7%)
Pyrexia	3/33 (9.1%)		15/111 (13.5%)		33/188 (17.6%)
Asthenia	1/33 (3%)		12/111 (10.8%)		24/188 (12.8%)
Chest discomfort	2/33 (6.1%)		2/111 (1.8%)		4/188 (2.1%)
Pain	2/33 (6.1%)		1/111 (0.9%)		5/188 (2.7%)
Infections and infestations
Upper respiratory tract infection	1/33 (3%)		11/111 (9.9%)		19/188 (10.1%)
Urinary tract infection	0/33 (0%)		3/111 (2.7%)		14/188 (7.4%)
Investigations
Alanine aminotransferase increased	2/33 (6.1%)		11/111 (9.9%)		19/188 (10.1%)
Weight decreased	1/33 (3%)		9/111 (8.1%)		27/188 (14.4%)
Aspartate aminotransferase increased	2/33 (6.1%)		8/111 (7.2%)		21/188 (11.2%)
Blood pressure increased	0/33 (0%)		8/111 (7.2%)		6/188 (3.2%)
White blood cell count decreased	3/33 (9.1%)		7/111 (6.3%)		16/188 (8.5%)
Haemoglobin decreased	1/33 (3%)		5/111 (4.5%)		15/188 (8%)
Platelet count decreased	2/33 (6.1%)		2/111 (1.8%)		7/188 (3.7%)
Metabolism and nutrition disorders
Decreased appetite	15/33 (45.5%)		42/111 (37.8%)		90/188 (47.9%)
Hypokalaemia	0/33 (0%)		15/111 (13.5%)		11/188 (5.9%)
Musculoskeletal and connective tissue disorders
Back pain	4/33 (12.1%)		7/111 (6.3%)		14/188 (7.4%)
Nervous system disorders
Headache	1/33 (3%)		9/111 (8.1%)		17/188 (9%)
Dizziness	4/33 (12.1%)		8/111 (7.2%)		17/188 (9%)
Cholinergic syndrome	4/33 (12.1%)		7/111 (6.3%)		11/188 (5.9%)
Hypoaesthesia	2/33 (6.1%)		4/111 (3.6%)		5/188 (2.7%)
Neuropathy peripheral	2/33 (6.1%)		1/111 (0.9%)		4/188 (2.1%)
Psychiatric disorders
Insomnia	4/33 (12.1%)		9/111 (8.1%)		10/188 (5.3%)
Renal and urinary disorders
Proteinuria	0/33 (0%)		19/111 (17.1%)		37/188 (19.7%)
Haematuria	1/33 (3%)		6/111 (5.4%)		5/188 (2.7%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/33 (0%)		30/111 (27%)		38/188 (20.2%)
Cough	4/33 (12.1%)		13/111 (11.7%)		18/188 (9.6%)
Dysphonia	2/33 (6.1%)		13/111 (11.7%)		26/188 (13.8%)
Productive cough	1/33 (3%)		7/111 (6.3%)		3/188 (1.6%)
Oropharyngeal pain	0/33 (0%)		5/111 (4.5%)		11/188 (5.9%)
Skin and subcutaneous tissue disorders
Rash	3/33 (9.1%)		9/111 (8.1%)		13/188 (6.9%)
Hyperhidrosis	2/33 (6.1%)		8/111 (7.2%)		10/188 (5.3%)
Palmar-plantar erythrodysaesthesia syndrome	0/33 (0%)		8/111 (7.2%)		11/188 (5.9%)
Alopecia	2/33 (6.1%)		5/111 (4.5%)		43/188 (22.9%)
Pigmentation disorder	2/33 (6.1%)		5/111 (4.5%)		6/188 (3.2%)
Skin hyperpigmentation	2/33 (6.1%)		3/111 (2.7%)		13/188 (6.9%)
Dry skin	0/33 (0%)		0/111 (0%)		10/188 (5.3%)
Vascular disorders
Hypertension	1/33 (3%)		43/111 (38.7%)		65/188 (34.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.