A Study of Avastin (Bevacizumab) Plus Xeloda (Capecitabine) in Patients With Locally Advanced Rectal Cancer.

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01227707
• Collaborator: (none)
• Enrollment: 43
• Locations: 9
• Arm: 1
• Duration (Months): 57
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This open-label study will assess the efficacy and safety of Avastin (bevacizumab) plus Xeloda (capecitabine) in combination with standard technique radiotherapy of the pelvic region in the neo-adjuvant setting in patients with locally advanced primary rectal cancer. Patients will receive 4 courses of Avastin at a dose of 5 mg/kg intravenously (iv) every 2 weeks and for 38 days Xeloda at dose of 825 mg/kg twice daily orally, plus radiation therapy. After surgery, adjuvant treatment with 5-fluorouracil/leucovorin and, at the discretion of the investigator, with Avastin 5 mg/kg iv every 2 weeks for at least 6 months will be given.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Drug: bevacizumab [Avastin]; Drug: capecitabine [Xeloda]; Radiation: Radiation therapy; Procedure: Mesorectal excision; Drug: bevacizumab [Avastin]; Drug: 5-fluorouracil; Drug: leucovorin	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label Study to Assess the Effect of Combination Treatment With Avastin and Xeloda, Plus Pre-operative Standard Radiotherapy, on Response Rate in Patients With Locally Advanced Rectal Cancer.
• Study Start Date: Nov 1, 2005
• Actual Primary Completion Date: Aug 1, 2010
• Actual Study Completion Date: Aug 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Single Arm

Drug: bevacizumab [Avastin]; 5 mg/kg intravenously every 2 weeks, 4 cycles; Drug: capecitabine [Xeloda]; 825 mg/m2 twice daily orally, 38 days; Radiation: Radiation therapy; Total dose of 45 Gy over 38 days; Procedure: Mesorectal excision; 6-8 weeks after completion of neoadjuvant treatment; Drug: bevacizumab [Avastin]; Post-surgery adjuvant treatment at the discretion of the investigator: 5 mg/kg iv every 2 weeks for at least 6 months; Drug: 5-fluorouracil; Post-surgery adjuvant therapy: bolus of 400mg/m2 iv plus iv infusion of 600 mg/m2 on Days 1 and 2 of each 2-week cycle for 6 months; Drug: leucovorin; Post-surgery adjuvant treatment: 100 mg/m2 iv on Days 1 and 2 of each 2-week cycle for 6 months

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Pathological Complete Response (pCR) [6 to 8 weeks following completion of neoadjuvant treatment]

   pCR was defined as the absence of viable tumor cells, as determined by standard histologic procedure, in the tumor specimen (including regional lymph nodes) obtained at surgery. In order to minimize evaluation bias, tumor specimens were analyzed by both a central and local pathologist. The number of participants with pathological tumor stage 0 (pT0) and regional lymph nodes stage 0 (pN0) at surgery was determined. pCR was defined as the number of participants with pT0 and pN0 at surgery divided by the total number of participants with pathological tumor stage data collected.

Secondary Outcome Measures

1. Percentage of Participants by Primary Tumor (T), Regional Lymph Nodes (N), and Distant Metastasis (M) Clinical Stage at Baseline and at the End of Neo-Adjuvant Treatment (NAT) [Baseline (BL) and end of neoadjuvant treatment (within 6 weeks after the completion of study treatment)]

   The frequencies of clinical tumor stage T (0, 1, 2, 3, 4, or X), regional lymph nodes stage N (0, 1, 2, 3, or 4), and distant metastasis clinical stage M (0, 1, or X) at baseline and at the end of NAT were assessed. The frequencies of pathological tumor stage T and regional lymph nodes stage N at surgery were evaluated. The clinical tumor and lymph node status was assessed by clinical examination, endosonography, and/or rectosigmoidoscopy, and pelvic and abdomen computerized tomography (CT) scan or magnetic resonance imaging (MRI). Response to treatment had to be assessed within 6 weeks after end of treatment by using the same techniques performed at baseline.

2. Percentage of Participants Undergoing Sphincter-Saving Surgery by Type of Procedure [6 to 8 weeks after completion of study treatment]

3. Percentage of Participants With Complete Response (CR) at the End of Neoadjuvant Treatment [BL and within 6 weeks after the completion of study treatment]

   Percentage of participants with CR was evaluated as the proportion of participants with complete response for the target and non-target lesions, separately, at the end of NAT according to the Response Evaluation Criteria in Solid Tumors (RECIST). CR was defined as disappearance of all target lesions or all non-target lesions and normalization of tumor marker levels.

4. Percentage of Participants With an Overall Response of CR at the End of Neoadjuvant Treatment [BL and within 6 weeks after the completion of study treatment]

   Percentage of participants with an overall response of CR was evaluated as the proportion of participants with CR for the target and non-target lesions plus absence of new lesions at the end of NAT according to RECIST. CR was defined as disappearance of all target lesions, all non-target lesions, and normalization of tumor marker levels.

5. Percentage of Participants With New Lesions at the Primary Tumor Site at the End of Neoadjuvant Treatment [BL and within 6 weeks after the completion of study treatment]

   The percentage of participants with new lesions located at the primary tumor site were evaluated at the end of NAT.

6. Percentage of Participants With Relapse During Follow-Up [BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until progression, up to 45 months]

   The percentage of participants with local and/or regional relapse during follow-up. New lesions located at rectum or at colon or at lymph node detected at the end of NAT were evaluated as local and/or regional relapse.

7. Disease-Free Survival (DFS) - Percentage of Participants With an Event [BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until progression, up to 45 months]

   DFS was defined as the time from treatment start date to the date of first progression of disease or date of death due to any cause.

8. DFS - Time to Event [BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until progression, up to 45 months]

   The time in months from date of start-of-treatment to the date of event defined as the first documented disease progression or death due to any cause. If a participant did not have an event, the time was censored at the date of last adequate tumor assessment. DFS was estimated using the Kaplan-Meier method.

9. Overall Survival (OS) - Percentage of Participants With an Event [BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until death, up to 45 months]

   OS was defined as the time from the date of first day of treatment until death due to any cause or the last date the participant was known to be alive.

10. OS - Time to Event [BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until death, up to 45 months]

    OS was defined as the time from the date of first day of treatment until death due to any cause or the last date the participant was known to be alive. OS was estimated using the Kaplan-Meier method.

11. Time to Disease Progression (TTP) - Percentage of Participants With an Event [BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until death, up to 45 months]

    TTP was defined as the time from date of treatment start until first documented progression of disease or death due to underlying cancer.

12. TTP - Time to Event [BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until death, up to 45 months]

    TTP was defined as the time from date of treatment start until first documented progression of disease or death due to underlying cancer. TTP was estimated using the Kaplan-Meier method.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Adult patients, >=18 years of age

• Patients with confirmed rectal cancer who are subject to surgery and would benefit from pre-operative combined chemo-radiotherapy

• Measurable and/or evaluable lesions according to RECIST criteria

• EOCG performance status 0-1

Exclusion Criteria:

• Prior radiotherapy or chemotherapy for rectal cancer

• Untreated brain metastases or spinal cord compression or primary brain tumors

• Chronic daily treatment with high-dose aspirin (>325 mg/day) or other medications known to predispose to gastrointestinal ulceration

• Co-existing malignancies, or malignancies diagnosed within the last 5 years, with the exception of basal and squamous cell cancer, or cervical cancer in situ.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Ancona		Italy	60121
2		Bologna		Italy	40139
3		Cuneo		Italy	12100
4		Genova		Italy	16132
5		Napoli		Italy	80131
6		Paola		Italy	87027
7		Pisa		Italy	56100
8		Roma		Italy	00135
9		Siena		Italy	53100

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Chair: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01227707
• Other Study ID Numbers: ML18522
• First Posted: Oct 25, 2010
• Last Update Posted: Aug 17, 2015
• Last Verified: Jul 1, 2015

• Additional relevant MeSH terms: Rectal Neoplasms; Leucovorin; Bevacizumab; Fluorouracil; Capecitabine

Study Results

Participant Flow

Arm/Group Title	Bevacizumab (Bv)+Capecitabine/Bv+Leucovorin+5-fluorouracil
Arm/Group Description	Participants received bevacizumab 5 milligrams per kilogram (mg/kg) intravenously (IV) on Days -14, 1, 15, and 29 and capecitabine 825 milligrams per square meter (mg/m^2) orally (PO) twice daily (BID) from Days 1 to 38. Participants also received radiation therapy given at a daily fraction of 1.8 Gray (Gy) administered in 5 weekly fractions starting at Week 1 (through Week 6) for a maximum total dose of 45 Gy. Six to 8 weeks following all above treatments, participants received complete mesorectal excision surgery. After surgery, participants received bevacizumab 5 mg/kg IV on Day 1 and leucovorin 100 mg/m^2 IV (over 2 hours) followed by 5-fluorouracil (5-FU) 400 mg/m^2 IV bolus and then 5-FU 600 mg/m^2 IV (over 22 hours) on Days 1 and 2 every 2 weeks for a maximum of 12 cycles.
Period Title: Overall Study
STARTED	43
COMPLETED	19
NOT COMPLETED	24

Baseline Characteristics

Arm/Group Title	Bv+Capecitabine/Bv+Leucovorin+5-FU
Arm/Group Description	Participants received bevacizumab 5 mg/kg IV on Days -14, 1, 15, and 29 and capecitabine 825 mg/m^2 PO BID from Days 1 to 38. Participants also received radiation therapy given at a daily fraction of 1.8 Gy administered in 5 weekly fractions starting at Week 1 (through Week 6) for a maximum total dose of 45 Gy. Six to 8 weeks following all above treatments, participants received complete mesorectal excision surgery. After surgery, participants received bevacizumab 5 mg/kg IV on Day 1 and leucovorin 100 mg/m^2 IV (over 2 hours) followed by 5-FU 400 mg/m^2 IV bolus and then 5-FU 600 mg/m^2 IV (over 22 hours) on Days 1 and 2 every 2 weeks for a maximum of 12 cycles.
Overall Participants	43
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.49 (10.85)
Sex: Female, Male (Count of Participants)
Female	18 41.9%
Male	25 58.1%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Pathological Complete Response (pCR)
Description	pCR was defined as the absence of viable tumor cells, as determined by standard histologic procedure, in the tumor specimen (including regional lymph nodes) obtained at surgery. In order to minimize evaluation bias, tumor specimens were analyzed by both a central and local pathologist. The number of participants with pathological tumor stage 0 (pT0) and regional lymph nodes stage 0 (pN0) at surgery was determined. pCR was defined as the number of participants with pT0 and pN0 at surgery divided by the total number of participants with pathological tumor stage data collected.
Time Frame	6 to 8 weeks following completion of neoadjuvant treatment

Outcome Measure Data

Analysis Population Description

ITT population; only participants who underwent surgery and had pathological tumor stage data were included in the analysis.

Arm/Group Title	Bv+Capecitabine/Bv+Leucovorin+5-FU
Arm/Group Description	Participants received bevacizumab 5 mg/kg IV on Days -14, 1, 15, and 29 and capecitabine 825 mg/m^2 PO BID from Days 1 to 38. Participants also received radiation therapy given at a daily fraction of 1.8 Gy administered in 5 weekly fractions starting at Week 1 (through Week 6) for a maximum total dose of 45 Gy. Six to 8 weeks following all above treatments, participants received complete mesorectal excision surgery. After surgery, participants received bevacizumab 5 mg/kg IV on Day 1 and leucovorin 100 mg/m^2 IV (over 2 hours) followed by 5-FU 400 mg/m^2 IV bolus and then 5-FU 600 mg/m^2 IV (over 22 hours) on Days 1 and 2 every 2 weeks for a maximum of 12 cycles.
Measure Participants	40
Number (95% Confidence Interval) [percentage of participants]	10.00 23.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bv+Capecitabine/Bv+Leucovorin+5-FU
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments
	Method	one sample binomial test
	Comments

2. Secondary Outcome

Title	Percentage of Participants by Primary Tumor (T), Regional Lymph Nodes (N), and Distant Metastasis (M) Clinical Stage at Baseline and at the End of Neo-Adjuvant Treatment (NAT)
Description	The frequencies of clinical tumor stage T (0, 1, 2, 3, 4, or X), regional lymph nodes stage N (0, 1, 2, 3, or 4), and distant metastasis clinical stage M (0, 1, or X) at baseline and at the end of NAT were assessed. The frequencies of pathological tumor stage T and regional lymph nodes stage N at surgery were evaluated. The clinical tumor and lymph node status was assessed by clinical examination, endosonography, and/or rectosigmoidoscopy, and pelvic and abdomen computerized tomography (CT) scan or magnetic resonance imaging (MRI). Response to treatment had to be assessed within 6 weeks after end of treatment by using the same techniques performed at baseline.
Time Frame	Baseline (BL) and end of neoadjuvant treatment (within 6 weeks after the completion of study treatment)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Bv+Capecitabine/Bv+Leucovorin+5-FU
Arm/Group Description	Participants received bevacizumab 5 mg/kg IV on Days -14, 1, 15, and 29 and capecitabine 825 mg/m^2 PO BID from Days 1 to 38. Participants also received radiation therapy given at a daily fraction of 1.8 Gy administered in 5 weekly fractions starting at Week 1 (through Week 6) for a maximum total dose of 45 Gy. Six to 8 weeks following all above treatments, participants received complete mesorectal excision surgery. After surgery, participants received bevacizumab 5 mg/kg IV on Day 1 and leucovorin 100 mg/m^2 IV (over 2 hours) followed by 5-FU 400 mg/m^2 IV bolus and then 5-FU 600 mg/m^2 IV (over 22 hours) on Days 1 and 2 every 2 weeks for a maximum of 12 cycles.
Measure Participants	43
Baseline: T0, N0	0 0%
End of NAT: T0, N0	4.65 10.8%
Baseline: T1, N0	0 0%
End of NAT: T1, N0	4.65 10.8%
Baseline: T1, NX	0 0%
End of NAT: T1, NX	2.33 5.4%
Baseline: T2, N0	0 0%
End of NAT: T2, N0	18.60 43.3%
Baseline: T2, N1	9.30 21.6%
End of NAT: T2, N1	9.30 21.6%
Baseline: T2, NX	0 0%
End of NAT: T2, NX	6.98 16.2%
Baseline: T3, N0	32.56 75.7%
End of NAT: T3, N0	18.60 43.3%
Baseline: T3, N1	46.51 108.2%
End of NAT: T3, N1	9.30 21.6%
Baseline: T3, N2	0 0%
End of NAT: T3, N2	2.33 5.4%
Baseline: T3, NX	2.33 5.4%
End of NAT: T3, NX	6.98 16.2%
Baseline: T4, N0	0 0%
End of NAT: T4, N0	4.65 10.8%
Baseline: T4, N1	2.33 5.4%
End of NAT: T4, N1	0 0%
Baseline: T4, N2	2.33 5.4%
End of NAT: T4, N2	0 0%
Baseline: T4, N3	2.33 5.4%
End of NAT: T4, N3	0 0%
Baseline: TX, N0	0 0%
End of NAT: TX, N0	2.33 5.4%
Baseline: TX, N2	2.33 5.4%
End of NAT: TX, N2	0 0%
Baseline: M0	97.67 227.1%
End of NAT: M0	81.40 189.3%
Baseline: M1	2.33 5.4%
End of NAT: M1	2.33 5.4%
Baseline: MX	0 0%
End of NAT: MX	9.30 21.6%

3. Secondary Outcome

Title	Percentage of Participants Undergoing Sphincter-Saving Surgery by Type of Procedure
Time Frame	6 to 8 weeks after completion of study treatment

Outcome Measure Data

Analysis Population Description

ITT population; only participants who underwent surgery were included in the analysis. n (number) equals (=) number of participants assessed for the specified parameter (colostomy)

Arm/Group Title	Bv+Capecitabine/Bv+Leucovorin+5-FU
Arm/Group Description	Participants received bevacizumab 5 mg/kg IV on Days -14, 1, 15, and 29 and capecitabine 825 mg/m^2 PO BID from Days 1 to 38. Participants also received radiation therapy given at a daily fraction of 1.8 Gy administered in 5 weekly fractions starting at Week 1 (through Week 6) for a maximum total dose of 45 Gy. Six to 8 weeks following all above treatments, participants received complete mesorectal excision surgery. After surgery, participants received bevacizumab 5 mg/kg IV on Day 1 and leucovorin 100 mg/m^2 IV (over 2 hours) followed by 5-FU 400 mg/m^2 IV bolus and then 5-FU 600 mg/m^2 IV (over 22 hours) on Days 1 and 2 every 2 weeks for a maximum of 12 cycles.
Measure Participants	40
Anterior resection	70.0 162.8%
Abdomen-peritoneal amputation (Miles)	22.5 52.3%
Other	3.0 7%
Colostomy, temporary (n=32)	47.50 110.5%
Colostomy, definitive (n=32)	32.50 75.6%
No colostomy	20.0 46.5%

4. Secondary Outcome

Title	Percentage of Participants With Complete Response (CR) at the End of Neoadjuvant Treatment
Description	Percentage of participants with CR was evaluated as the proportion of participants with complete response for the target and non-target lesions, separately, at the end of NAT according to the Response Evaluation Criteria in Solid Tumors (RECIST). CR was defined as disappearance of all target lesions or all non-target lesions and normalization of tumor marker levels.
Time Frame	BL and within 6 weeks after the completion of study treatment

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Bv+Capecitabine/Bv+Leucovorin+5-FU
Arm/Group Description	Participants received bevacizumab 5 mg/kg IV on Days -14, 1, 15, and 29 and capecitabine 825 mg/m^2 PO BID from Days 1 to 38. Participants also received radiation therapy given at a daily fraction of 1.8 Gy administered in 5 weekly fractions starting at Week 1 (through Week 6) for a maximum total dose of 45 Gy. Six to 8 weeks following all above treatments, participants received complete mesorectal excision surgery. After surgery, participants received bevacizumab 5 mg/kg IV on Day 1 and leucovorin 100 mg/m^2 IV (over 2 hours) followed by 5-FU 400 mg/m^2 IV bolus and then 5-FU 600 mg/m^2 IV (over 22 hours) on Days 1 and 2 every 2 weeks for a maximum of 12 cycles.
Measure Participants	43
CR of target lesion(s)	11.63 27%
CR of non-target lesion(s)	18.60 43.3%

5. Secondary Outcome

Title	Percentage of Participants With an Overall Response of CR at the End of Neoadjuvant Treatment
Description	Percentage of participants with an overall response of CR was evaluated as the proportion of participants with CR for the target and non-target lesions plus absence of new lesions at the end of NAT according to RECIST. CR was defined as disappearance of all target lesions, all non-target lesions, and normalization of tumor marker levels.
Time Frame	BL and within 6 weeks after the completion of study treatment

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Bv+Capecitabine/Bv+Leucovorin+5-FU
Arm/Group Description	Participants received bevacizumab 5 mg/kg IV on Days -14, 1, 15, and 29 and capecitabine 825 mg/m^2 PO BID from Days 1 to 38. Participants also received radiation therapy given at a daily fraction of 1.8 Gy administered in 5 weekly fractions starting at Week 1 (through Week 6) for a maximum total dose of 45 Gy. Six to 8 weeks following all above treatments, participants received complete mesorectal excision surgery. After surgery, participants received bevacizumab 5 mg/kg IV on Day 1 and leucovorin 100 mg/m^2 IV (over 2 hours) followed by 5-FU 400 mg/m^2 IV bolus and then 5-FU 600 mg/m^2 IV (over 22 hours) on Days 1 and 2 every 2 weeks for a maximum of 12 cycles.
Measure Participants	43
Number [percentage of participants]	9.30 21.6%

6. Secondary Outcome

Title	Percentage of Participants With New Lesions at the Primary Tumor Site at the End of Neoadjuvant Treatment
Description	The percentage of participants with new lesions located at the primary tumor site were evaluated at the end of NAT.
Time Frame	BL and within 6 weeks after the completion of study treatment

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Bv+Capecitabine/Bv+Leucovorin+5-FU
Arm/Group Description	Participants received bevacizumab 5 mg/kg IV on Days -14, 1, 15, and 29 and capecitabine 825 mg/m^2 PO BID from Days 1 to 38. Participants also received radiation therapy given at a daily fraction of 1.8 Gy administered in 5 weekly fractions starting at Week 1 (through Week 6) for a maximum total dose of 45 Gy. Six to 8 weeks following all above treatments, participants received complete mesorectal excision surgery. After surgery, participants received bevacizumab 5 mg/kg IV on Day 1 and leucovorin 100 mg/m^2 IV (over 2 hours) followed by 5-FU 400 mg/m^2 IV bolus and then 5-FU 600 mg/m^2 IV (over 22 hours) on Days 1 and 2 every 2 weeks for a maximum of 12 cycles.
Measure Participants	43
Number [percentage of participants]	4.65 10.8%

7. Secondary Outcome

Title	Percentage of Participants With Relapse During Follow-Up
Description	The percentage of participants with local and/or regional relapse during follow-up. New lesions located at rectum or at colon or at lymph node detected at the end of NAT were evaluated as local and/or regional relapse.
Time Frame	BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until progression, up to 45 months

Outcome Measure Data

Analysis Population Description

ITT population; only participants who underwent radical surgery were included in the analysis

Arm/Group Title	Bv+Capecitabine/Bv+Leucovorin+5-FU
Arm/Group Description	Participants received bevacizumab 5 mg/kg IV on Days -14, 1, 15, and 29 and capecitabine 825 mg/m^2 PO BID from Days 1 to 38. Participants also received radiation therapy given at a daily fraction of 1.8 Gy administered in 5 weekly fractions starting at Week 1 (through Week 6) for a maximum total dose of 45 Gy. Six to 8 weeks following all above treatments, participants received complete mesorectal excision surgery. After surgery, participants received bevacizumab 5 mg/kg IV on Day 1 and leucovorin 100 mg/m^2 IV (over 2 hours) followed by 5-FU 400 mg/m^2 IV bolus and then 5-FU 600 mg/m^2 IV (over 22 hours) on Days 1 and 2 every 2 weeks for a maximum of 12 cycles.
Measure Participants	38
No Relapse	84.21 195.8%
1 Relapse	7.89 18.3%
2 Relapses	7.89 18.3%

8. Secondary Outcome

Title	Disease-Free Survival (DFS) - Percentage of Participants With an Event
Description	DFS was defined as the time from treatment start date to the date of first progression of disease or date of death due to any cause.
Time Frame	BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until progression, up to 45 months

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Bv+Capecitabine/Bv+Leucovorin+5-FU
Arm/Group Description	Participants received bevacizumab 5 mg/kg IV on Days -14, 1, 15, and 29 and capecitabine 825 mg/m^2 PO BID from Days 1 to 38. Participants also received radiation therapy given at a daily fraction of 1.8 Gy administered in 5 weekly fractions starting at Week 1 (through Week 6) for a maximum total dose of 45 Gy. Six to 8 weeks following all above treatments, participants received complete mesorectal excision surgery. After surgery, participants received bevacizumab 5 mg/kg IV on Day 1 and leucovorin 100 mg/m^2 IV (over 2 hours) followed by 5-FU 400 mg/m^2 IV bolus and then 5-FU 600 mg/m^2 IV (over 22 hours) on Days 1 and 2 every 2 weeks for a maximum of 12 cycles.
Measure Participants	43
Number [percentage of participants]	30.23 70.3%

9. Secondary Outcome

Title	DFS - Time to Event
Description	The time in months from date of start-of-treatment to the date of event defined as the first documented disease progression or death due to any cause. If a participant did not have an event, the time was censored at the date of last adequate tumor assessment. DFS was estimated using the Kaplan-Meier method.
Time Frame	BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until progression, up to 45 months

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Bv+Capecitabine/Bv+Leucovorin+5-FU
Arm/Group Description	Participants received bevacizumab 5 mg/kg IV on Days -14, 1, 15, and 29 and capecitabine 825 mg/m^2 PO BID from Days 1 to 38. Participants also received radiation therapy given at a daily fraction of 1.8 Gy administered in 5 weekly fractions starting at Week 1 (through Week 6) for a maximum total dose of 45 Gy. Six to 8 weeks following all above treatments, participants received complete mesorectal excision surgery. After surgery, participants received bevacizumab 5 mg/kg IV on Day 1 and leucovorin 100 mg/m^2 IV (over 2 hours) followed by 5-FU 400 mg/m^2 IV bolus and then 5-FU 600 mg/m^2 IV (over 22 hours) on Days 1 and 2 every 2 weeks for a maximum of 12 cycles.
Measure Participants	43
Mean (Standard Deviation) [months]	27.43 (1.71)

10. Secondary Outcome

Title	Overall Survival (OS) - Percentage of Participants With an Event
Description	OS was defined as the time from the date of first day of treatment until death due to any cause or the last date the participant was known to be alive.
Time Frame	BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until death, up to 45 months

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Bv+Capecitabine/Bv+Leucovorin+5-FU
Arm/Group Description	Participants received bevacizumab 5 mg/kg IV on Days -14, 1, 15, and 29 and capecitabine 825 mg/m^2 PO BID from Days 1 to 38. Participants also received radiation therapy given at a daily fraction of 1.8 Gy administered in 5 weekly fractions starting at Week 1 (through Week 6) for a maximum total dose of 45 Gy. Six to 8 weeks following all above treatments, participants received complete mesorectal excision surgery. After surgery, participants received bevacizumab 5 mg/kg IV on Day 1 and leucovorin 100 mg/m^2 IV (over 2 hours) followed by 5-FU 400 mg/m^2 IV bolus and then 5-FU 600 mg/m^2 IV (over 22 hours) on Days 1 and 2 every 2 weeks for a maximum of 12 cycles.
Measure Participants	43
Number [percentage of participants]	25.58 59.5%

11. Secondary Outcome

Title	OS - Time to Event
Description	OS was defined as the time from the date of first day of treatment until death due to any cause or the last date the participant was known to be alive. OS was estimated using the Kaplan-Meier method.
Time Frame	BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until death, up to 45 months

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Bv+Capecitabine/Bv+Leucovorin+5-FU
Arm/Group Description	Participants received bevacizumab 5 mg/kg IV on Days -14, 1, 15, and 29 and capecitabine 825 mg/m^2 PO BID from Days 1 to 38. Participants also received radiation therapy given at a daily fraction of 1.8 Gy administered in 5 weekly fractions starting at Week 1 (through Week 6) for a maximum total dose of 45 Gy. Six to 8 weeks following all above treatments, participants received complete mesorectal excision surgery. After surgery, participants received bevacizumab 5 mg/kg IV on Day 1 and leucovorin 100 mg/m^2 IV (over 2 hours) followed by 5-FU 400 mg/m^2 IV bolus and then 5-FU 600 mg/m^2 IV (over 22 hours) on Days 1 and 2 every 2 weeks for a maximum of 12 cycles.
Measure Participants	43
Mean (Standard Deviation) [months]	32.14 (1.46)

12. Secondary Outcome

Title	Time to Disease Progression (TTP) - Percentage of Participants With an Event
Description	TTP was defined as the time from date of treatment start until first documented progression of disease or death due to underlying cancer.
Time Frame	BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until death, up to 45 months

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Bv+Capecitabine/Bv+Leucovorin+5-FU
Arm/Group Description	Participants received bevacizumab 5 mg/kg IV on Days -14, 1, 15, and 29 and capecitabine 825 mg/m^2 PO BID from Days 1 to 38. Participants also received radiation therapy given at a daily fraction of 1.8 Gy administered in 5 weekly fractions starting at Week 1 (through Week 6) for a maximum total dose of 45 Gy. Six to 8 weeks following all above treatments, participants received complete mesorectal excision surgery. After surgery, participants received bevacizumab 5 mg/kg IV on Day 1 and leucovorin 100 mg/m^2 IV (over 2 hours) followed by 5-FU 400 mg/m^2 IV bolus and then 5-FU 600 mg/m^2 IV (over 22 hours) on Days 1 and 2 every 2 weeks for a maximum of 12 cycles.
Measure Participants	43
Number [percentage of participants]	27.91 64.9%

13. Secondary Outcome

Title	TTP - Time to Event
Description	TTP was defined as the time from date of treatment start until first documented progression of disease or death due to underlying cancer. TTP was estimated using the Kaplan-Meier method.
Time Frame	BL, within 6 weeks after the completion of neoadjuvant treatment, every 2 weeks for 1 year following surgery, every 3 months thereafter until death, up to 45 months

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Bv+Capecitabine/Bv+Leucovorin+5-FU
Arm/Group Description	Participants received bevacizumab 5 mg/kg IV on Days -14, 1, 15, and 29 and capecitabine 825 mg/m^2 PO BID from Days 1 to 38. Participants also received radiation therapy given at a daily fraction of 1.8 Gy administered in 5 weekly fractions starting at Week 1 (through Week 6) for a maximum total dose of 45 Gy. Six to 8 weeks following all above treatments, participants received complete mesorectal excision surgery. After surgery, participants received bevacizumab 5 mg/kg IV on Day 1 and leucovorin 100 mg/m^2 IV (over 2 hours) followed by 5-FU 400 mg/m^2 IV bolus and then 5-FU 600 mg/m^2 IV (over 22 hours) on Days 1 and 2 every 2 weeks for a maximum of 12 cycles.
Measure Participants	43
Mean (Standard Deviation) [months]	27.68 (1.72)

Adverse Events

Time Frame	Adverse events were collected from the date of first study-drug administration until 28 days after the last dose of study drug administration.
Adverse Event Reporting Description	All enrolled participants who received at least 1 dose of study medication were included in the safety population.
Arm/Group Title	Bv+Capecitabine/Bv+Leucovorin+5-FU
Arm/Group Description	Participants received bevacizumab 5 mg/kg IV on Days -14, 1, 15, and 29 and capecitabine 825 mg/m^2 PO BID from Days 1 to 38. Participants also received radiation therapy given at a daily fraction of 1.8 Gy administered in 5 weekly fractions starting at Week 1 (through Week 6) for a maximum total dose of 45 Gy. Six to 8 weeks following all above treatments, participants received complete mesorectal excision surgery. After surgery, participants received bevacizumab 5 mg/kg IV on Day 1 and leucovorin 100 mg/m^2 IV (over 2 hours) followed by 5-FU 400 mg/m^2 IV bolus and then 5-FU 600 mg/m^2 IV (over 22 hours) on Days 1 and 2 every 2 weeks for a maximum of 12 cycles.
All Cause Mortality
	Bv+Capecitabine/Bv+Leucovorin+5-FU
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bv+Capecitabine/Bv+Leucovorin+5-FU
	Affected / at Risk (%)	# Events
Total	8/42 (19%)
Cardiac disorders
Miocardic ischemia	1/42 (2.4%)
Cardiac ischemia	1/42 (2.4%)
Gastrointestinal disorders
Diarrhoea	1/42 (2.4%)
Bowel perforation	1/42 (2.4%)
Intestinal occlusion	1/42 (2.4%)
Injury, poisoning and procedural complications
Anastomosis dehiscence	1/42 (2.4%)
Postoperative abscess	1/42 (2.4%)
Metabolism and nutrition disorders
Ipokaliemia	1/42 (2.4%)
Other (Not Including Serious) Adverse Events
	Bv+Capecitabine/Bv+Leucovorin+5-FU
	Affected / at Risk (%)	# Events
Total	39/42 (92.9%)
Blood and lymphatic system disorders
Anemia	5/42 (11.9%)
Leukopenia	7/42 (16.7%)
Neutropenia	6/42 (14.3%)
Thrombocytopenia	1/42 (2.4%)
Cardiac disorders
Tachycardia	1/42 (2.4%)
Ear and labyrinth disorders
Vertigo	2/42 (4.8%)
Eye disorders
Conjunctivitis	1/42 (2.4%)
Gastrointestinal disorders
Abdominal pain	6/42 (14.3%)
Constipation	4/42 (9.5%)
Diarrhea	18/42 (42.9%)
Hematochezia	8/42 (19%)
Nausea	9/42 (21.4%)
Proctalgia	10/42 (23.8%)
Proctitis	5/42 (11.9%)
Rectal hemorrhage	3/42 (7.1%)
Rectal tenesmus	7/42 (16.7%)
Anal fistula	1/42 (2.4%)
Anorectal discomfort	2/42 (4.8%)
Haemorrhoids	1/42 (2.4%)
Mucous stools	2/42 (4.8%)
Perianal erythema	1/42 (2.4%)
Stomatitis	1/42 (2.4%)
Vomiting	1/42 (2.4%)
General disorders
Asthenia	6/42 (14.3%)
Fatigue	4/42 (9.5%)
Pyrexia	3/42 (7.1%)
Chest pain	2/42 (4.8%)
Mucosal inflammation	2/42 (4.8%)
Hepatobiliary disorders
Hyperbilirubinaemia	2/42 (4.8%)
Hypertransaminasaemia	1/42 (2.4%)
Infections and infestations
Cystitis	4/42 (9.5%)
Iatrogenic infection	1/42 (2.4%)
Influenza	1/42 (2.4%)
Oral herpes	1/42 (2.4%)
Injury, poisoning and procedural complications
Gastrointestinal stoma complication	1/42 (2.4%)
Investigations
Blood lactate dehydrogenase increased	1/42 (2.4%)
Transaminases abnormal	1/42 (2.4%)
Metabolism and nutrition disorders
Hypokalaemia	2/42 (4.8%)
Hyperuricaemia	1/42 (2.4%)
Hypocalcaemia	1/42 (2.4%)
Musculoskeletal and connective tissue disorders
Back pain	2/42 (4.8%)
Fistula	1/42 (2.4%)
Muscular weakness	1/42 (2.4%)
Musculoskeletal pain	1/42 (2.4%)
Pain in extremity	1/42 (2.4%)
Nervous system disorders
Headache	2/42 (4.8%)
Neurotoxicity	1/42 (2.4%)
Paraesthesia	2/42 (4.8%)
Psychiatric disorders
Anxiety	1/42 (2.4%)
Renal and urinary disorders
Dysuria	3/42 (7.1%)
Haematuria	1/42 (2.4%)
Pollakiuria	1/42 (2.4%)
Proteinuria	1/42 (2.4%)
Strangury	2/42 (4.8%)
Reproductive system and breast disorders
Prostatitis	1/42 (2.4%)
Vulvovaginal burning sensation	1/42 (2.4%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	2/42 (4.8%)
Hypoxia	1/42 (2.4%)
Oropharyngeal swelling	1/42 (2.4%)
Skin and subcutaneous tissue disorders
Dermatitis	1/42 (2.4%)
Dermatitis exfoliative	1/42 (2.4%)
Palmar-plantar erythrodysaesthesia syndrome	1/42 (2.4%)
Rash	1/42 (2.4%)
Vascular disorders
Hypertension	6/42 (14.3%)
Arterial thrombosis	1/42 (2.4%)
Hypotension	1/42 (2.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Study being conducted under this agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request the Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.