AXEBEAM: Neoadjuvant Bevacizumab, Capecitabine and Radiation Therapy With or Without Oxaliplatin Locally Advanced Rectal Cancer

• Sponsor: Universitaire Ziekenhuizen Leuven (Other)
• Overall Status: Completed
• CT.gov ID: NCT00828672
• Collaborator: (none)
• Enrollment: 84
• Locations: 9
• Arms: 2
• Actual Duration (Months): 117
• Patients Per Site: 9.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Phase II clinical trial, open-label, randomized, two arms, multicentre (possibly multinational). Academic, investigator initiated.

To assess the activity of bevacizumab (AvastinTM) in combination with capecitabine (XelodaTM) and radiation therapy with or without oxaliplatin (EloxatinTM) in the pre-operative treatment of locally advanced rectal cancer, followed by TME (total mesorectal excision).

Condition or Disease	Intervention/Treatment	Phase
Locally Advanced Rectal Cancer	Drug: Oxaliplatin; Drug: Bevacizumab; Drug: Capecitabine; Radiation: radiotherapy	Phase 2

Detailed Description

See Synopsis

Study Design

• Study Type: Interventional
• Actual Enrollment: 84 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Study of Bevacizumab, Capecitabine and Radiation Therapy With or Without Oxaliplatin in the Preoperative Treatment of Locally Advanced Rectal Cancer
• Actual Study Start Date: Jun 1, 2009
• Actual Primary Completion Date: Mar 1, 2014
• Actual Study Completion Date: Mar 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: AXE (ARM 1) Oxaliplatin, Bevacizumab and Capecitabine concurrently with radiotherapy.	Drug: Oxaliplatin; Administered on days 15,22,29,36 en 43; 50 mg/m2; Other Names: Eloxatin ; Drug: Bevacizumab; Administered on days 1,15,29 and 43 ; 5mg/kg; Other Names: Avastin ; Drug: Capecitabine; 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy; Other Names: Xeloda ; Radiation: radiotherapy; Total dose 45Gy
Active Comparator: AX (ARM 2) Bevacizumab and Capecitabine concurrently with radiotherapy	Drug: Bevacizumab; Administered on days 1,15,29 and 43 ; 5mg/kg; Other Names: Avastin ; Drug: Capecitabine; 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy; Other Names: Xeloda ; Radiation: radiotherapy; Total dose 45Gy

Outcome Measures

Primary Outcome Measures

1. Pathologic Response at Surgery. Overview of Complete Pathologic Responses, Good and Little Tumour Regression Rates at Surgery. [4 months]

   Dworak tumour regression grades (TRG) were used to assess pathologic response: TRG0=no regression. TRG1=dominant tumor mass with obvious fibrosis and/or vasculopathy; TRG2=dominant fibrotic changes with few tumour cells or groups; TRG3=very few (difficult to find microscopically) tumour cells in fibrotic tissue with or without mucus substance. TRG4=no intact viable tumour cells, only fibrotic mass or presence of mucin lakes without associated malignant cells (total tumour regression). Pathologic assessments of tumour response post chemoradiotherapy as provided by investigators (read by local pathologists on operative specimens) were reviewed centrally for all pts for whom surgical materials were available (centrally reviewed set). The diagnosis of independent central reviewers primed. Pathologic complete response rates (TRG4) are reported (%). Good (TRG3 and TRG4 together) and little (TRG 0,1 and 2) tumour regression rates are summarized. For these 2 last rows, % add to 100.

Secondary Outcome Measures

1. Number of Participants With Histopathologic R0 and Negative CRM Resection [4 months]

   Histopathologic R0 resection rate was defined as margins histologically negative for tumour involvement after resection. The circumferential resection margin (CRM) is considered to be involved if microscopic tumour is present <1mm from or at the inked circumferential or radial resection margin. Data on quality of mesorectal excision were expected but not collected consistently.

2. Number of Participants With Pathologic Complete Response at Surgery. Number of Participants With Good or Little Pathological Tumour Regression at Surgery. [4 months]

   Dworak tumour regression grades (TRG) were used to assess pathologic response: TRG0=no regression. TRG1=dominant tumor mass with obvious fibrosis and/or vasculopathy; TRG2=dominant fibrotic changes with few tumour cells or groups; TRG3=very few (difficult to find microscopically) tumour cells in fibrotic tissue with or without mucus substance. TRG4=no intact viable tumour cells, only fibrotic mass or presence of mucin lakes without associated malignant cells (total tumour regression). Pathologic assessments of tumour response post chemoradiotherapy as provided by investigators (read by local pathologists on operative specimens) were reviewed centrally for all pts for whom surgical materials were available (centrally reviewed set). The diagnosis of independent central reviewers primed. Pathologic complete response rates (TRG4) are reported (%). Good (TRG3 and TRG4 together) and little (TRG 0,1 and 2) tumour regression rates are summarized. For these 2 last rows, % add to 100.

3. Clinical Response Rate [3 months]

   Baseline tumour measurements were performed within 4 weeks prior to treatment start (RECIST). The same methods of assessment (CT and/or MRI) were used for each measurable lesion at baseline and during follow-up. Complete Response (CR) is disappearance of all clinical and radiological evidence of tumour (both target and non-target lesions). Partial Response (PR) is at least a 30% decrease in the sum of LD of target lesions, taking as reference the baseline sum of tumour longest diameters (LD). Stable Disease (SD) is steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Progressive Disease (PD) is at least a 20% increase in the sum of LD of measured lesions taking as references the smallest sum LD recorded since the treatment started. Appearance of new lesions constitutes PD. In exceptional circumstances, unequivocal progression of non-target lesions was considered evidence of PD.

4. Types and Numbers of Adverse Events - General Overview [continuous up to 1 year]

   Adverse events graded as per NCI CTCAE (US National Cancer Institute Common Terminology Criteria for Adverse Events) version 3.0. All Serious Adverse Events occurrences are reported and counts are summarized here; all Adverse Events (all grades) related and not related to study treatment are reported and summarized here; all severe laboratory events (hematology and biochemistry Gr 3 and higher) are reported and summarized here; all severe postoperative complications (Gr 3 and higher) occurred within the first month post surgery are reported and summarized here. See section Adverse events for details.

5. Recurrence Rates and Disease Free Survival [up to 5 years]

   Counts and proportions of patients experiencing recurrence of disease (local and distant).

6. Death Rates and Overall Survival [up to 5 years]

   Counts and proportions of patients deceased (post-study).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Adenocarcinoma of rectum measurable (RECIST), locally advanced (defined by MRI - Tumour beyond mesorectal fascia (T4) or Tumour ≤ 2 mm from mesorectal fascia or T3 tumour < 5 cm from anal verge

• Patient is at least 18 years of age

• Good organ function

Exclusion Criteria:

• Evidence of distant metastases

• Contraindication for bevacizumab

• Pregnant or breastfeeding women.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Onze Lieve Vrouwziekenhuis	Aalst		Belgium	9300
2	ZNA Middelheim	Antwerp		Belgium	ZNA Middelheim
3	AZ St- Lucas	Brugge		Belgium	8310
4	Erasme Hospital	Brussels		Belgium	1070
5	Cliniques Universitaires St Luc	Brussels		Belgium	1200
6	AZ Groeninge	Kortrijk		Belgium	8500
7	C.H.U. Sart-Tilman	Liege		Belgium	4000
8	Clinique Sainte Elisabeth	Namur		Belgium	5000
9	H. Hartziekenhuis	Roeselare		Belgium	8800

Sponsors and Collaborators

• Universitaire Ziekenhuizen Leuven

Investigators

• Principal Investigator: Eric Van Cutsem, Prof. Dr., UZ Leuven

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Universitaire Ziekenhuizen Leuven
• ClinicalTrials.gov Identifier: NCT00828672
• Other Study ID Numbers: s51104 - ML5194; 2007-007177-23; MO19051
• First Posted: Jan 26, 2009
• Last Update Posted: Jul 10, 2019
• Last Verified: Jul 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Universitaire Ziekenhuizen Leuven: bevacizumab; capecitabine; radiation therapy; oxaliplatin; multimodality treatments; TME (total mesorectal excision); Axe Beam; rectal cancer; neoadjuvant; pathological complete response; postoperative complications
• Additional relevant MeSH terms: Rectal Neoplasms; Bevacizumab; Capecitabine; Oxaliplatin

Study Results

Participant Flow

Recruitment Details	Eighty-four patients were included. First patient enrolled: 22-Jun-2009. Last patient enrolled: 29-Sep-2013. Participating sites: UZ Leuven, Erasme Hospital Bruxelles, Cliniques Universitaires St-Luc Bruxelles, AZ St. Lucas Brugge, AZ Groeninge Kortrijk, CHU Sart-Tilman Liege, OLVZ Aalst, H. Hart Ziekenhuis Roeselare, Cl. Saint Elisabeth Namur
Pre-assignment Detail	Target population was represented by patients with locally advanced rectal cancer (tumour beyond mesorectal fascia (T4) or tumour ≤ 2 mm from mesorectal fascia or T3 tumour < 5 cm from anal verge by MRI), histologically confirmed. Pts were screened as per incl and excl criteria per protocol. Screening failures were not recorded in the eCRF.

Arm/Group Title	AXE (ARM 1)	AX (ARM 2)
Arm/Group Description	Oxaliplatin, Bevacizumab and Capecitabine concurrently with radiotherapy. Oxaliplatin: Administered on days 15,22,29,36 en 43; 50 mg/m2 Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy	Bevacizumab and Capecitabine concurrently with radiotherapy Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy
Period Title: Pre-treatment (Baseline)
STARTED	43	41
COMPLETED	43	41
NOT COMPLETED	0	0
Period Title: Pre-treatment (Baseline)
STARTED	43	41
COMPLETED	41	39
NOT COMPLETED	2	2
Period Title: Pre-treatment (Baseline)
STARTED	41	39
COMPLETED	41	38
NOT COMPLETED	0	1
Period Title: Pre-treatment (Baseline)
STARTED	42	41
COMPLETED	42	41
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	AXE (ARM 1)	AX (ARM 2)	Total
Arm/Group Description	Oxaliplatin, Bevacizumab and Capecitabine concurrently with radiotherapy. Oxaliplatin: Administered on days 15,22,29,36 en 43; 50 mg/m2 Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy	Bevacizumab and Capecitabine concurrently with radiotherapy Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy	Total of all reporting groups
Overall Participants	43	41	84
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	29 67.4%	29 70.7%	58 69%
>=65 years	14 32.6%	12 29.3%	26 31%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61	59	60
Sex: Female, Male (Count of Participants)
Female	14 32.6%	12 29.3%	26 31%
Male	29 67.4%	29 70.7%	58 69%
ECOG PS (Performance Status) (Count of Participants)
ECOG PS=0	36 83.7%	37 90.2%	73 86.9%
ECOG PS=1	7 16.3%	4 9.8%	11 13.1%
Distance from tumour to anal verge (Count of Participants)
<5cm	18 41.9%	15 36.6%	33 39.3%
>=5cm	13 30.2%	15 36.6%	28 33.3%
NA	12 27.9%	11 26.8%	23 27.4%
Distance to CRM (Count of Participants)
0mm	21 48.8%	24 58.5%	45 53.6%
<2mm	6 14%	2 4.9%	8 9.5%
>=2mm	9 20.9%	10 24.4%	19 22.6%
NA	7 16.3%	5 12.2%	12 14.3%
Tumour stage (Count of Participants)
T2 (Tumor invades muscularis propria)	2 4.7%	2 4.9%	4 4.8%
T3 (tumor invades into pericolorectal tissues)	34 79.1%	31 75.6%	65 77.4%
T4 (tumor invades through peritoneum/other organs)	7 16.3%	8 19.5%	15 17.9%
Nodal stage (Count of Participants)
N0 (no regional lymph node metastase)	7 16.3%	5 12.2%	12 14.3%
N1 (metastasis in 1-3 regional lymp nodes)	15 34.9%	18 43.9%	33 39.3%
N2 (metastasis in 4 or more regional lymph nodes)	20 46.5%	17 41.5%	37 44%
Nx (regional nodes cannot be assessed)	1 2.3%	1 2.4%	2 2.4%

Outcome Measures

1. Primary Outcome

Title	Pathologic Response at Surgery. Overview of Complete Pathologic Responses, Good and Little Tumour Regression Rates at Surgery.
Description	Dworak tumour regression grades (TRG) were used to assess pathologic response: TRG0=no regression. TRG1=dominant tumor mass with obvious fibrosis and/or vasculopathy; TRG2=dominant fibrotic changes with few tumour cells or groups; TRG3=very few (difficult to find microscopically) tumour cells in fibrotic tissue with or without mucus substance. TRG4=no intact viable tumour cells, only fibrotic mass or presence of mucin lakes without associated malignant cells (total tumour regression). Pathologic assessments of tumour response post chemoradiotherapy as provided by investigators (read by local pathologists on operative specimens) were reviewed centrally for all pts for whom surgical materials were available (centrally reviewed set). The diagnosis of independent central reviewers primed. Pathologic complete response rates (TRG4) are reported (%). Good (TRG3 and TRG4 together) and little (TRG 0,1 and 2) tumour regression rates are summarized. For these 2 last rows, % add to 100.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

Patients who had undertaken surgery and had pathology materials available for central review (centrally reviewed subset)

Arm/Group Title	AXE (ARM 1)	AX (ARM 2)
Arm/Group Description	Oxaliplatin, Bevacizumab and Capecitabine concurrently with radiotherapy. Oxaliplatin: Administered on days 15,22,29,36 en 43; 50 mg/m2 Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy	Bevacizumab and Capecitabine concurrently with radiotherapy Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy
Measure Participants	41	38
Pathological complete response (Dworak TRG=4) %	34	11
Good tumour regression (Dworak TRG=3-4) %	41	24
Little tumour regression (Dworak TRG=0-1-2) %	59	76

2. Secondary Outcome

Title	Number of Participants With Histopathologic R0 and Negative CRM Resection
Description	Histopathologic R0 resection rate was defined as margins histologically negative for tumour involvement after resection. The circumferential resection margin (CRM) is considered to be involved if microscopic tumour is present <1mm from or at the inked circumferential or radial resection margin. Data on quality of mesorectal excision were expected but not collected consistently.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

Patient in Arm 2 that discontinued chemoradiotherapy due to major toxicity and had surgery off protocol is counted here as well

Arm/Group Title	AXE (ARM 1)	AX (ARM 2)
Arm/Group Description	Oxaliplatin, Bevacizumab and Capecitabine concurrently with radiotherapy. Oxaliplatin: Administered on days 15,22,29,36 en 43; 50 mg/m2 Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy	Bevacizumab and Capecitabine concurrently with radiotherapy Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy
Measure Participants	41	39
Negative resection margins	40 93%	37 90.2%
Positive resection margins	1 2.3%	2 4.9%

3. Secondary Outcome

Title	Number of Participants With Pathologic Complete Response at Surgery. Number of Participants With Good or Little Pathological Tumour Regression at Surgery.
Description	Dworak tumour regression grades (TRG) were used to assess pathologic response: TRG0=no regression. TRG1=dominant tumor mass with obvious fibrosis and/or vasculopathy; TRG2=dominant fibrotic changes with few tumour cells or groups; TRG3=very few (difficult to find microscopically) tumour cells in fibrotic tissue with or without mucus substance. TRG4=no intact viable tumour cells, only fibrotic mass or presence of mucin lakes without associated malignant cells (total tumour regression). Pathologic assessments of tumour response post chemoradiotherapy as provided by investigators (read by local pathologists on operative specimens) were reviewed centrally for all pts for whom surgical materials were available (centrally reviewed set). The diagnosis of independent central reviewers primed. Pathologic complete response rates (TRG4) are reported (%). Good (TRG3 and TRG4 together) and little (TRG 0,1 and 2) tumour regression rates are summarized. For these 2 last rows, % add to 100.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

Centrally reviewed subset

Arm/Group Title	AXE (ARM 1)	AX (ARM 2)
Arm/Group Description	Oxaliplatin, Bevacizumab and Capecitabine concurrently with radiotherapy. Oxaliplatin: Administered on days 15,22,29,36 en 43; 50 mg/m2 Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy	Bevacizumab and Capecitabine concurrently with radiotherapy Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy
Measure Participants	41	38
Complete response, no tumour left Dworak TRG=4	14 32.6%	4 9.8%
Good tumour regression TRG=3-4	17 39.5%	9 22%
No or little tumour regression Dworak TRG=0-1-2	24 55.8%	29 70.7%

4. Secondary Outcome

Title	Clinical Response Rate
Description	Baseline tumour measurements were performed within 4 weeks prior to treatment start (RECIST). The same methods of assessment (CT and/or MRI) were used for each measurable lesion at baseline and during follow-up. Complete Response (CR) is disappearance of all clinical and radiological evidence of tumour (both target and non-target lesions). Partial Response (PR) is at least a 30% decrease in the sum of LD of target lesions, taking as reference the baseline sum of tumour longest diameters (LD). Stable Disease (SD) is steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Progressive Disease (PD) is at least a 20% increase in the sum of LD of measured lesions taking as references the smallest sum LD recorded since the treatment started. Appearance of new lesions constitutes PD. In exceptional circumstances, unequivocal progression of non-target lesions was considered evidence of PD.
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

Intent to treat, all registered patients

Arm/Group Title	AXE (ARM 1)	AX (ARM 2)
Arm/Group Description	Oxaliplatin, Bevacizumab and Capecitabine concurrently with radiotherapy. Oxaliplatin: Administered on days 15,22,29,36 en 43; 50 mg/m2 Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy	Bevacizumab and Capecitabine concurrently with radiotherapy Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy
Measure Participants	43	41
CR	3 7%	5 12.2%
PR	24 55.8%	17 41.5%
SD	9 20.9%	13 31.7%
PD	0 0%	1 2.4%
NA	7 16.3%	5 12.2%

5. Secondary Outcome

Title	Types and Numbers of Adverse Events - General Overview
Description	Adverse events graded as per NCI CTCAE (US National Cancer Institute Common Terminology Criteria for Adverse Events) version 3.0. All Serious Adverse Events occurrences are reported and counts are summarized here; all Adverse Events (all grades) related and not related to study treatment are reported and summarized here; all severe laboratory events (hematology and biochemistry Gr 3 and higher) are reported and summarized here; all severe postoperative complications (Gr 3 and higher) occurred within the first month post surgery are reported and summarized here. See section Adverse events for details.
Time Frame	continuous up to 1 year

Outcome Measure Data

Analysis Population Description

Intent to treat

Arm/Group Title	AXE (ARM 1)	AX (ARM 2)
Arm/Group Description	Oxaliplatin, Bevacizumab and Capecitabine concurrently with radiotherapy. Oxaliplatin: Administered on days 15,22,29,36 en 43; 50 mg/m2 Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy	Bevacizumab and Capecitabine concurrently with radiotherapy Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy
Measure Participants	43	41
Serious adverse events	22	12
All adverse events	564	426
Severe lab events	27	16
Post operative complications at 1 month	14	9

6. Secondary Outcome

Title	Recurrence Rates and Disease Free Survival
Description	Counts and proportions of patients experiencing recurrence of disease (local and distant).
Time Frame	up to 5 years

Outcome Measure Data

Analysis Population Description

Intent to treat (one patient lost to follow-up)

Arm/Group Title	AXE (ARM 1)	AX (ARM 2)
Arm/Group Description	Oxaliplatin, Bevacizumab and Capecitabine concurrently with radiotherapy. Oxaliplatin: Administered on days 15,22,29,36 en 43; 50 mg/m2 Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy	Bevacizumab and Capecitabine concurrently with radiotherapy Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy
Measure Participants	43	41
Recurred Dec 2017	9 20.9%	9 22%
Not recurred Dec 2017	33 76.7%	32 78%
Lost to FU	1 2.3%	0 0%

7. Secondary Outcome

Title	Death Rates and Overall Survival
Description	Counts and proportions of patients deceased (post-study).
Time Frame	up to 5 years

Outcome Measure Data

Analysis Population Description

Intent to treat in follow up (one patient in Arm 1 lost to follow up).

Arm/Group Title	AXE (ARM 1)	AX (ARM 2)
Arm/Group Description	Oxaliplatin, Bevacizumab and Capecitabine concurrently with radiotherapy. Oxaliplatin: Administered on days 15,22,29,36 en 43; 50 mg/m2 Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy	Bevacizumab and Capecitabine concurrently with radiotherapy Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy
Measure Participants	43	41
Deceased (Dec 2017)	6 14%	7 17.1%
Alive (Dec 2017)	36 83.7%	34 82.9%
Lost to FU	1 2.3%	0 0%

Adverse Events

Time Frame	From signature of ICF to 30 days post surgery with follow-up for residual toxicity after this period if applicable
Adverse Event Reporting Description	All SAE occurences are reported and displayed below. Only Gr 3-4-5 adverse events (serious and non serious) are reported in this report.
Arm/Group Title	AXE (ARM 1)		AX (ARM 2)
Arm/Group Description	Oxaliplatin, Bevacizumab and Capecitabine concurrently with radiotherapy. Oxaliplatin: Administered on days 15,22,29,36 en 43; 50 mg/m2 Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy		Bevacizumab and Capecitabine concurrently with radiotherapy Bevacizumab: Administered on days 1,15,29 and 43 ; 5mg/kg Capecitabine: 825 mg/m2 ; 25 days - 5days per week, concurrent with radiotherapy Radiotherapy: Total dose 45Gy
All Cause Mortality
	AXE (ARM 1)		AX (ARM 2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/43 (0%)		1/41 (2.4%)
Serious Adverse Events
	AXE (ARM 1)		AX (ARM 2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/43 (48.8%)		12/41 (29.3%)
Gastrointestinal disorders
Rectal haemorrhage	0/43 (0%)	0	1/41 (2.4%)	1
Diarrhea	3/43 (7%)	3	0/41 (0%)	0
Fistula	0/43 (0%)	0	1/41 (2.4%)	1
Leak	2/43 (4.7%)	2	3/41 (7.3%)	3
Obstruction	2/43 (4.7%)	2	0/41 (0%)	0
Presacral hematoma	0/43 (0%)	0	1/41 (2.4%)	1
General disorders
Fever	3/43 (7%)	4	0/41 (0%)	0
Infections and infestations
Febrile neutropenia	1/43 (2.3%)	1	0/41 (0%)	0
Septic shock	1/43 (2.3%)	1	0/41 (0%)	0
Urinary tract infection	2/43 (4.7%)	2	1/41 (2.4%)	1
Catheter site infection	1/43 (2.3%)	1	0/41 (0%)	0
Wound infection	5/43 (11.6%)	5	2/41 (4.9%)	2
Nervous system disorders
Neuropathy motor	0/43 (0%)	0	1/41 (2.4%)	1
Seizure	1/43 (2.3%)	1	0/41 (0%)	0
Psychiatric disorders
Depression	0/43 (0%)	0	1/41 (2.4%)	1
Vascular disorders
Lung embolism	0/43 (0%)	0	1/41 (2.4%)	1
Other (Not Including Serious) Adverse Events
	AXE (ARM 1)		AX (ARM 2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/43 (41.9%)		15/41 (36.6%)
Blood and lymphatic system disorders
Platelet count decreased	1/43 (2.3%)	2	0/41 (0%)	0
Haemorrhage	0/43 (0%)	0	1/41 (2.4%)	1
Dissiminated Intravascular Coagulation	1/43 (2.3%)	1	0/41 (0%)	0
Hematoma postoperative	0/43 (0%)	0	1/41 (2.4%)	1
Hematoma	0/43 (0%)	0	1/41 (2.4%)	1
Cardiac disorders
Hypertension b	1/43 (2.3%)	1	0/41 (0%)	0
Hypertension	0/43 (0%)	0	2/41 (4.9%)	2
Cardiopulmonary arrest	0/43 (0%)	0	1/41 (2.4%)	1
Ear and labyrinth disorders
Meniere's disease	1/43 (2.3%)	1	0/41 (0%)	0
Gastrointestinal disorders
Anorexia	1/43 (2.3%)	1	0/41 (0%)	0
Diarrhea	4/43 (9.3%)	4	0/41 (0%)	0
Anal pain	0/43 (0%)	0	1/41 (2.4%)	1
Leak Gi	2/43 (4.7%)	2	3/41 (7.3%)	3
Obstruction Gi	2/43 (4.7%)	2	1/41 (2.4%)	1
Pain GI	2/43 (4.7%)	2	0/41 (0%)	0
Discharge from the anus	0/43 (0%)	0	1/41 (2.4%)	1
Ascites	0/43 (0%)	0	1/41 (2.4%)	1
Dysphagia	0/43 (0%)	0	1/41 (2.4%)	1
General disorders
Fatigue	2/43 (4.7%)	2	1/41 (2.4%)	1
Sweating	1/43 (2.3%)	1	0/41 (0%)	0
Infections and infestations
Febrile neutropenia	1/43 (2.3%)	1	0/41 (0%)	0
Catheter site infection	1/43 (2.3%)	1	0/41 (0%)	0
Sepsis	2/43 (4.7%)	2	0/41 (0%)	0
Wound infection	5/43 (11.6%)	5	2/41 (4.9%)	2
Peritonitis	0/43 (0%)	0	1/41 (2.4%)	1
Infection due to leak of anastomosis	1/43 (2.3%)	1	0/41 (0%)	0
Metabolism and nutrition disorders
Hypocalcemia	1/43 (2.3%)	1	0/41 (0%)	0
Hyponatremia	1/43 (2.3%)	1	0/41 (0%)	0
Musculoskeletal and connective tissue disorders
Pain musculoskeletal	1/43 (2.3%)	1	0/41 (0%)	0
Pain muskuloskeletal Gr 3	1/43 (2.3%)	1	0/41 (0%)	0
Hypokalemia	1/43 (2.3%)	1	0/41 (0%)	0
Nervous system disorders
Neuropathy sensory	1/43 (2.3%)	1	0/41 (0%)	0
Syncope	1/43 (2.3%)	1	0/41 (0%)	0
Neuropathy - cranial	0/43 (0%)	0	1/41 (2.4%)	1
Psychiatric disorders
Depression	0/43 (0%)	0	1/41 (2.4%)	1
Renal and urinary disorders
Leak GU	0/43 (0%)	0	1/41 (2.4%)	1
Respiratory, thoracic and mediastinal disorders
Pain pumonary/respiratory	0/43 (0%)	0	1/41 (2.4%)	2
Skin and subcutaneous tissue disorders
Dermatitis	1/43 (2.3%)	1	3/41 (7.3%)	3
Rash	0/43 (0%)	0	1/41 (2.4%)	1
Vascular disorders
Deep venous thrombosis	0/43 (0%)	0	1/41 (2.4%)	1
Embolism	0/43 (0%)	0	2/41 (4.9%)	2

Limitations/Caveats

The study was not powered to allow for formal statistical comparisons between arms

More Information

Certain Agreements

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

The Sponsor is an academic institution and not the drug market authorization holder. Participating PIs were selected from other academic institutions. Participating PIs cannot publish full or partial study results before final publication by Sponsor, but they will be nominated as co-authors based on patient accrual at each participating site. Own results can be published afterwards by participant PIs, with the agreement of the Sponsor.