Trial Outcomes & Findings for Induction FOLFOX With or Without Aflibercept Followed by Chemoradiation in High Risk Locally Advanced Rectal Cancer (NCT NCT02340949)

Last Updated: 2021-05-03

Results Overview

The number of patients achieving pCR after induction therapy with mFOLFOX6 +/- aflibercept followed by chemotherapy (CT)/radiotherapy (RT). pCR will be defined as the absence of viable tumor cells in the primary tumor and in the lymph nodes (T0N0)

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

180 participants

Primary outcome timeframe

From baseline until 2 years and 2 months

Results posted on

2021-05-03

Participant Flow

Participant milestones

Participant milestones
Measure	mFOLFOX6 + Aflibercept \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². \- Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days. Aflibercept will be supplied to sites by the study Sponsor as 4 ml vials at a concentration of 25 mg/ml. Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. Aflibercept: Administered I.V. at doses of 4 mg/Kg on Day 1 every 14 days. It will be supplied to sites by Sponsor as 4 ml vials at a concentration of 25 mg/ml 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU	mFOLFOX6 \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU
Overall Study STARTED	115	65
Overall Study COMPLETED	99	61
Overall Study NOT COMPLETED	16	4

Reasons for withdrawal

Reasons for withdrawal
Measure	mFOLFOX6 + Aflibercept \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². \- Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days. Aflibercept will be supplied to sites by the study Sponsor as 4 ml vials at a concentration of 25 mg/ml. Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. Aflibercept: Administered I.V. at doses of 4 mg/Kg on Day 1 every 14 days. It will be supplied to sites by Sponsor as 4 ml vials at a concentration of 25 mg/ml 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU	mFOLFOX6 \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU
Overall Study Adverse Event	4	2
Overall Study Withdrawal by Subject	2	0
Overall Study Progression disease	6	2
Overall Study Death	3	0
Overall Study Physician Decision	1	0

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	mFOLFOX6 + Aflibercept n=115 Participants \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². \- Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days. Aflibercept will be supplied to sites by the study Sponsor as 4 ml vials at a concentration of 25 mg/ml. Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. Aflibercept: Administered I.V. at doses of 4 mg/Kg on Day 1 every 14 days. It will be supplied to sites by Sponsor as 4 ml vials at a concentration of 25 mg/ml 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU	mFOLFOX6 n=65 Participants \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU	Total n=180 Participants Total of all reporting groups
Age, Continuous	58.4 years STANDARD_DEVIATION 10.4 • n=115 Participants	62.2 years STANDARD_DEVIATION 9.2 • n=65 Participants	59.7 years STANDARD_DEVIATION 10 • n=180 Participants
Sex: Female, Male Female	38 Participants n=115 Participants	26 Participants n=65 Participants	64 Participants n=180 Participants
Sex: Female, Male Male	77 Participants n=115 Participants	39 Participants n=65 Participants	116 Participants n=180 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment Spain	115 Participants n=115 Participants	65 Participants n=65 Participants	180 Participants n=180 Participants
Clinical stage Tumor-nodes-metastasis (TNM) Mising	1 Participants n=115 Participants	1 Participants n=65 Participants	2 Participants n=180 Participants
Clinical stage Tumor-nodes-metastasis (TNM) mrT2	1 Participants n=115 Participants	0 Participants n=65 Participants	1 Participants n=180 Participants
Clinical stage Tumor-nodes-metastasis (TNM) mrT3	17 Participants n=115 Participants	12 Participants n=65 Participants	29 Participants n=180 Participants
Clinical stage Tumor-nodes-metastasis (TNM) mrT3B	8 Participants n=115 Participants	8 Participants n=65 Participants	16 Participants n=180 Participants
Clinical stage Tumor-nodes-metastasis (TNM) mrT3A	1 Participants n=115 Participants	0 Participants n=65 Participants	1 Participants n=180 Participants
Clinical stage Tumor-nodes-metastasis (TNM) mrT3C	47 Participants n=115 Participants	22 Participants n=65 Participants	69 Participants n=180 Participants
Clinical stage Tumor-nodes-metastasis (TNM) mrT3D	7 Participants n=115 Participants	4 Participants n=65 Participants	11 Participants n=180 Participants
Clinical stage Tumor-nodes-metastasis (TNM) mrT4	9 Participants n=115 Participants	6 Participants n=65 Participants	15 Participants n=180 Participants
Clinical stage Tumor-nodes-metastasis (TNM) mrT4A	16 Participants n=115 Participants	7 Participants n=65 Participants	23 Participants n=180 Participants
Clinical stage Tumor-nodes-metastasis (TNM) mrT4B	8 Participants n=115 Participants	5 Participants n=65 Participants	13 Participants n=180 Participants
Count of Patients Which Had a Baseline Clinical Stage TNM Nodes (n2)	115 Participants n=115 Participants	65 Participants n=65 Participants	180 Participants n=180 Participants
Location Distal	30 Participants n=115 Participants	18 Participants n=65 Participants	48 Participants n=180 Participants
Location Middle	84 Participants n=115 Participants	46 Participants n=65 Participants	130 Participants n=180 Participants
Location Missing	1 Participants n=115 Participants	1 Participants n=65 Participants	2 Participants n=180 Participants
Histology Adenocarcinoma	115 Participants n=115 Participants	65 Participants n=65 Participants	180 Participants n=180 Participants
Histology other	0 Participants n=115 Participants	0 Participants n=65 Participants	0 Participants n=180 Participants
Mesorectal Fascia (FMR) FMR + (distance <=1 mm)	68 Participants n=115 Participants	37 Participants n=65 Participants	105 Participants n=180 Participants
Mesorectal Fascia (FMR) NR	47 Participants n=115 Participants	28 Participants n=65 Participants	75 Participants n=180 Participants
EMVI score Score 0/1/2	60 Participants n=115 Participants	34 Participants n=65 Participants	94 Participants n=180 Participants
EMVI score Score 3/4	55 Participants n=115 Participants	31 Participants n=65 Participants	86 Participants n=180 Participants

PRIMARY outcome

Timeframe: From baseline until 2 years and 2 months

Outcome measures

Outcome measures
Measure	mFOLFOX6 + Aflibercept n=115 Participants \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². \- Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days. Aflibercept will be supplied to sites by the study Sponsor as 4 ml vials at a concentration of 25 mg/ml. Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. Aflibercept: Administered I.V. at doses of 4 mg/Kg on Day 1 every 14 days. It will be supplied to sites by Sponsor as 4 ml vials at a concentration of 25 mg/ml 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU	mFOLFOX6 n=65 Participants \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU
Number of Patients Achieving Pathologic Complete Response (pCR). Yes	25 Participants	9 Participants
Number of Patients Achieving Pathologic Complete Response (pCR). No	90 Participants	56 Participants

SECONDARY outcome

Timeframe: From baseline until 2 years and 2 months

R0 resection is defined as complete tumor removal, and correlates with good prognosis. Tumor regression grade (TRG) is defined as presence of residual tumor after preoperative therapy. This was assessed by magnetic resonance imaging (MRI) according to the 5-point regression grading scale established by Mandard: TRG1 (complete response with no residual cancer), TRG2 (rare residual cancer), TRG3 (fibrosis outgrowing residual cancer), TRG4 (residual cancer outgrowing fibrosis) and TRG5 (absence of regression). Circular Radial Margin (CRM) is defined as the distance from the margin of normal tissue to the edge of tumor tissue in the resected primary tumor the measured by histopathology study after surgery. A margin of ≤1 mm is considered to be a negative prognostic factor for local recurrence.

Outcome measures

Outcome measures
Measure	mFOLFOX6 + Aflibercept n=115 Participants \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². \- Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days. Aflibercept will be supplied to sites by the study Sponsor as 4 ml vials at a concentration of 25 mg/ml. Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. Aflibercept: Administered I.V. at doses of 4 mg/Kg on Day 1 every 14 days. It will be supplied to sites by Sponsor as 4 ml vials at a concentration of 25 mg/ml 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU	mFOLFOX6 n=65 Participants \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU
Number of Patients Achieving Pathological Parameters of Efficacy: R0 Resection, Tumor Regression Grade, and Circular Radial Margin Rate TRG1-2 · Not available	0 Participants	0 Participants
Number of Patients Achieving Pathological Parameters of Efficacy: R0 Resection, Tumor Regression Grade, and Circular Radial Margin Rate CRM ≤ 1 · Yes	3 Participants	3 Participants
Number of Patients Achieving Pathological Parameters of Efficacy: R0 Resection, Tumor Regression Grade, and Circular Radial Margin Rate CRM ≤ 1 · No	96 Participants	56 Participants
Number of Patients Achieving Pathological Parameters of Efficacy: R0 Resection, Tumor Regression Grade, and Circular Radial Margin Rate CRM ≤ 1 · Not available	16 Participants	6 Participants
Number of Patients Achieving Pathological Parameters of Efficacy: R0 Resection, Tumor Regression Grade, and Circular Radial Margin Rate R0 rate · Yes	101 Participants	60 Participants
Number of Patients Achieving Pathological Parameters of Efficacy: R0 Resection, Tumor Regression Grade, and Circular Radial Margin Rate R0 rate · No	2 Participants	2 Participants
Number of Patients Achieving Pathological Parameters of Efficacy: R0 Resection, Tumor Regression Grade, and Circular Radial Margin Rate R0 rate · Not available	12 Participants	3 Participants
Number of Patients Achieving Pathological Parameters of Efficacy: R0 Resection, Tumor Regression Grade, and Circular Radial Margin Rate TRG1-2 · Yes	59 Participants	30 Participants
Number of Patients Achieving Pathological Parameters of Efficacy: R0 Resection, Tumor Regression Grade, and Circular Radial Margin Rate TRG1-2 · No	56 Participants	35 Participants

SECONDARY outcome

Timeframe: From baseline until 2 years and 2 months

Tumor size is assessed by MRI to determine the T stage. T Downstaging: defined as a lower pathologic T stage compared to pre-treatment T stage.

Outcome measures

Outcome measures
Measure	mFOLFOX6 + Aflibercept n=115 Participants \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². \- Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days. Aflibercept will be supplied to sites by the study Sponsor as 4 ml vials at a concentration of 25 mg/ml. Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. Aflibercept: Administered I.V. at doses of 4 mg/Kg on Day 1 every 14 days. It will be supplied to sites by Sponsor as 4 ml vials at a concentration of 25 mg/ml 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU	mFOLFOX6 n=65 Participants \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU
Number of Participants With Significant MRI Changes Post Intervention, as Defined by T Downstaging Yes	68 Participants	46 Participants
Number of Participants With Significant MRI Changes Post Intervention, as Defined by T Downstaging No	47 Participants	19 Participants

SECONDARY outcome

Timeframe: From baseline until 2 years and 2 months

The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data. AEs were coded and evaluated using the NCI-CTCAE v4.0 toxicity criteria (if NCI-CTCAE are not applicable, MedDRA was used).

Outcome measures

Outcome measures
Measure	mFOLFOX6 + Aflibercept n=115 Participants \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². \- Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days. Aflibercept will be supplied to sites by the study Sponsor as 4 ml vials at a concentration of 25 mg/ml. Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. Aflibercept: Administered I.V. at doses of 4 mg/Kg on Day 1 every 14 days. It will be supplied to sites by Sponsor as 4 ml vials at a concentration of 25 mg/ml 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU	mFOLFOX6 n=65 Participants \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU
Number of Patients Reporting Adverse Events (AEs) At least one AE · Yes	115 Participants	65 Participants
Number of Patients Reporting Adverse Events (AEs) At least one AE · No	0 Participants	0 Participants
Number of Patients Reporting Adverse Events (AEs) At least one Grade 3-4 AE · Yes	83 Participants	31 Participants
Number of Patients Reporting Adverse Events (AEs) At least one Grade 3-4 AE · No	32 Participants	34 Participants
Number of Patients Reporting Adverse Events (AEs) At least one AE that lead to treatment discontinuation · Yes	20 Participants	4 Participants
Number of Patients Reporting Adverse Events (AEs) At least one AE that lead to treatment discontinuation · No	95 Participants	61 Participants
Number of Patients Reporting Adverse Events (AEs) At least one AE that lead to death · Yes	3 Participants	0 Participants
Number of Patients Reporting Adverse Events (AEs) At least one AE that lead to death · No	112 Participants	65 Participants
Number of Patients Reporting Adverse Events (AEs) At least one Serious Adverse Event (SAE) · Yes	45 Participants	16 Participants
Number of Patients Reporting Adverse Events (AEs) At least one Serious Adverse Event (SAE) · No	70 Participants	49 Participants
Number of Patients Reporting Adverse Events (AEs) At least one treatment-related AE · Yes	105 Participants	59 Participants
Number of Patients Reporting Adverse Events (AEs) At least one treatment-related AE · No	10 Participants	6 Participants
Number of Patients Reporting Adverse Events (AEs) At least one treatment-related AE Grade 3-4 · Yes	64 Participants	17 Participants
Number of Patients Reporting Adverse Events (AEs) At least one treatment-related AE Grade 3-4 · No	51 Participants	48 Participants
Number of Patients Reporting Adverse Events (AEs) At least one treatment-related AE that led to death · Yes	0 Participants	0 Participants
Number of Patients Reporting Adverse Events (AEs) At least one treatment-related AE that led to death · No	115 Participants	65 Participants
Number of Patients Reporting Adverse Events (AEs) At least one treatment-related AE that led to permanent treatment discontinuation · Yes	17 Participants	3 Participants
Number of Patients Reporting Adverse Events (AEs) At least one treatment-related AE that led to permanent treatment discontinuation · No	98 Participants	62 Participants
Number of Patients Reporting Adverse Events (AEs) At least one treatment-related Serious Adverse Event (SAE) · Yes	25 Participants	3 Participants
Number of Patients Reporting Adverse Events (AEs) At least one treatment-related Serious Adverse Event (SAE) · No	90 Participants	62 Participants

SECONDARY outcome

Timeframe: From surgical intervention up to 30 days post-surgery, within a general time frame of 2 years and 2 months per study protocol

Surgical complications will be assessed by means of AEs reported during 30 days post surgery.

Outcome measures

Outcome measures
Measure	mFOLFOX6 + Aflibercept n=115 Participants \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². \- Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days. Aflibercept will be supplied to sites by the study Sponsor as 4 ml vials at a concentration of 25 mg/ml. Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. Aflibercept: Administered I.V. at doses of 4 mg/Kg on Day 1 every 14 days. It will be supplied to sites by Sponsor as 4 ml vials at a concentration of 25 mg/ml 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU	mFOLFOX6 n=65 Participants \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU
Number of Patients Reporting Surgical Complications Complications · Yes	60 Participants	30 Participants
Number of Patients Reporting Surgical Complications Postoperative AEs · Yes	3 Participants	1 Participants
Number of Patients Reporting Surgical Complications Postoperative AEs · No	112 Participants	64 Participants
Number of Patients Reporting Surgical Complications Postoperative AEs Grade 3-4 · Yes	2 Participants	0 Participants
Number of Patients Reporting Surgical Complications Postoperative AEs Grade 3-4 · No	113 Participants	65 Participants
Number of Patients Reporting Surgical Complications Complications · No	55 Participants	35 Participants
Number of Patients Reporting Surgical Complications Anastomosis fistula · Yes	4 Participants	1 Participants
Number of Patients Reporting Surgical Complications Anastomosis fistula · No	111 Participants	64 Participants
Number of Patients Reporting Surgical Complications wound infection · Yes	5 Participants	5 Participants
Number of Patients Reporting Surgical Complications wound infection · No	110 Participants	60 Participants
Number of Patients Reporting Surgical Complications intraabdominal infection · Yes	10 Participants	1 Participants
Number of Patients Reporting Surgical Complications intraabdominal infection · No	105 Participants	64 Participants
Number of Patients Reporting Surgical Complications Stoma complications · Yes	2 Participants	0 Participants
Number of Patients Reporting Surgical Complications Stoma complications · No	113 Participants	65 Participants
Number of Patients Reporting Surgical Complications Reoperation · Yes	9 Participants	5 Participants
Number of Patients Reporting Surgical Complications Reoperation · No	106 Participants	60 Participants

SECONDARY outcome

Timeframe: At 3 years after study treatment completion, within a general time frame of 5 years and two months

DFS rate is defined as the percentage of participants without local recurrences at 3-years post study treatment. Here we report the DFS rate at 3-years after completing the Study treatment.

Outcome measures

Outcome measures
Measure	mFOLFOX6 + Aflibercept n=115 Participants \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². \- Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days. Aflibercept will be supplied to sites by the study Sponsor as 4 ml vials at a concentration of 25 mg/ml. Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. Aflibercept: Administered I.V. at doses of 4 mg/Kg on Day 1 every 14 days. It will be supplied to sites by Sponsor as 4 ml vials at a concentration of 25 mg/ml 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU	mFOLFOX6 n=65 Participants \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU
Disease Free Survival (DFS) Rate at 3 Years	75.2 percentage of participants Interval 66.1 to 82.2	81.5 percentage of participants Interval 69.8 to 89.1

Adverse Events

mFOLFOX6 + Aflibercept

Serious events: 45 serious events

Other events: 115 other events

Deaths: 12 deaths

mFOLFOX6

Serious events: 16 serious events

Other events: 65 other events

Deaths: 7 deaths

Serious adverse events

Other adverse events

Additional Information

Pau Doñate Macian

MFAR Clinical Research

Phone: 0034934344412

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	mFOLFOX6 + Aflibercept n=115 participants at risk \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². \- Aflibercept, will be administered intravenously (I.V.) at doses of 4 mg/Kg on Day 1 every 14 days. Aflibercept will be supplied to sites by the study Sponsor as 4 ml vials at a concentration of 25 mg/ml. Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. Aflibercept: Administered I.V. at doses of 4 mg/Kg on Day 1 every 14 days. It will be supplied to sites by Sponsor as 4 ml vials at a concentration of 25 mg/ml 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU	mFOLFOX6 n=65 participants at risk \- mFOLFOX-6 scheme: 5-Fluoruracil \[5-FU\], oxaliplatin and leucovorin will be administered intravenously once every 14 days according to mFOLFOX-6 scheme: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250-500 mL and leucovorin 200 mg/m² IV, both over two hours, followed by 5-FU 400 mg/m² IV bolus and a 46 h infusion of 5-FU 2400 mg/m². Treatment will continue until six cycles are administered unless unacceptable toxicity or progression occurs. 5-Fluoruracil: Once every 14 days. Day 1: 400 mg/m2 I.V. bolus and a 46 h infusion of 5-FU 2400 mg/m2 Oxaliplatin: Once every 14 days. Day 1: 85 mg/m2 I.V. infusion in 250-500 mL, over two hours, followed by 5-FU Leucovorin: Once every 14 days. Day 1: 200 mg/m2 I.V., over two hours, followed by 5-FU
General disorders Asthenia	1.7% 2/115 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.	0.00% 0/65 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.
Nervous system disorders Peripheral neuropathy	1.7% 2/115 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.	1.5% 1/65 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.
Gastrointestinal disorders Diarrhoea	7.0% 8/115 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.	6.2% 4/65 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.
Gastrointestinal disorders Mucosal inflamation	3.5% 4/115 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.	0.00% 0/65 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.
General disorders Nausea	0.00% 0/115 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.	1.5% 1/65 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.
Vascular disorders Hypertension	29.6% 34/115 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.	3.1% 2/65 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.
Blood and lymphatic system disorders Neutropenia	21.7% 25/115 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.	21.5% 14/65 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysesthesia syndrome	2.6% 3/115 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.	0.00% 0/65 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.
General disorders Abdominal pain	0.87% 1/115 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.	0.00% 0/65 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.
General disorders Dysphonia	0.87% 1/115 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.	0.00% 0/65 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.
Blood and lymphatic system disorders Thrombocytopenia	0.87% 1/115 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.	3.1% 2/65 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.
Gastrointestinal disorders Proctalgia	0.87% 1/115 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.	1.5% 1/65 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.
Gastrointestinal disorders Rectal hemorrage	1.7% 2/115 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.	0.00% 0/65 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.
General disorders Pyrexia	0.87% 1/115 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.	0.00% 0/65 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.
Infections and infestations Stomatitis	0.00% 0/115 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.	1.5% 1/65 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.
Blood and lymphatic system disorders Anemia	0.87% 1/115 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.	1.5% 1/65 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.
General disorders Fatigue	0.87% 1/115 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.	0.00% 0/65 • From Baseline to study completion, within an general time frame of 3 years per study protocol For the statistical tables, adverse events have been coded according to the Medical Dictionary of Regulatory Activities (MedDRA 20.1) system. Their intensity has been coded by (NCI-CTCAE) v4.0 toxicity criteria. The safety and tolerability of the study therapy were assessed by means of AEs and changes in laboratory data that were reported in the AEs page. Grade 3 or higher AEs were reported as serious. All the grade 1 and 2 as non serious.