Trial Outcomes & Findings for A Study of Bevacizumab (Avastin) in Participants With Newly Diagnosed Locally Advanced Rectal Cancer (NCT NCT00865189)

Last Updated: 2017-08-04

Results Overview

Tumor sterilization was defined as the absence of residual tumor cells in the resected specimen including lymph nodes (ypT0-N0). The rate of sterilization of the tumoral specimen was assessed after surgery on the surgical specimen by local review. Analyses were performed for participants who have been operated as defined by the protocol (within the study and TME technique) and for all participants who have been operated. Reported is the percentage of participants with tumor sterilization.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

91 participants

Primary outcome timeframe

After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment)

Results posted on

2017-08-04

Participant Flow

A total of 92 participants with resectable rectal cancer were selected and 91 participants were randomized into the study. One participant was not randomized due to non-compliance with the inclusion/exclusion criteria.

Participant milestones

Participant milestones
Measure	Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (intravenous \[IV\] infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the total mesorectal excision (TME) technique.	Arm B (Bevacizumab, Chemoradiotherapy) In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.
Overall Study STARTED	46	45
Overall Study COMPLETED	34	26
Overall Study NOT COMPLETED	12	19

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (intravenous \[IV\] infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the total mesorectal excision (TME) technique.	Arm B (Bevacizumab, Chemoradiotherapy) In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.
Overall Study Other	1	2
Overall Study Death	4	11
Overall Study Lost to Follow-up	6	6
Overall Study Withdrawal by Subject	1	0

Baseline Characteristics

A Study of Bevacizumab (Avastin) in Participants With Newly Diagnosed Locally Advanced Rectal Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) n=46 Participants In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the TME technique.	Arm B (Bevacizumab, Chemoradiotherapy) n=45 Participants In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.	Total n=91 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	33 Participants n=5 Participants	29 Participants n=7 Participants	62 Participants n=5 Participants
Age, Categorical >=65 years	13 Participants n=5 Participants	16 Participants n=7 Participants	29 Participants n=5 Participants
Sex: Female, Male Female	15 Participants n=5 Participants	15 Participants n=7 Participants	30 Participants n=5 Participants
Sex: Female, Male Male	31 Participants n=5 Participants	30 Participants n=7 Participants	61 Participants n=5 Participants

PRIMARY outcome

Timeframe: After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment)

Population: ITT population. Here, number of participants analyzed = participants who were evaluable for this outcome.

Outcome measures

Outcome measures
Measure	Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) n=42 Participants In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the TME technique.	Arm B (Bevacizumab, Chemoradiotherapy) n=44 Participants In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.
Percentage of Participants With Tumor Sterilization Defined by ypT0-N0	23.8 percentage of participants Interval 12.1 to 39.5	11.4 percentage of participants Interval 3.8 to 24.6

SECONDARY outcome

Timeframe: After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment)

Population: ITT population. Here, number of participants analyzed = participants who were evaluable for this outcome. "n" = participants who were evaluable for specified category.

A participant with a downstaging was defined as a participant with T3 (T describes the size of the original \[primary\] tumor) at inclusion and T2 or T1 or T0 after surgery, or with N+ (N describes lymph nodes involvement) at inclusion and N- after surgery and if T is equal at inclusion and after surgery. The clinical tumor-node-metastasis (cTNM) classification was used at inclusion and the pathological staging tumor and nodes (ypTN) classification after surgery. Reported is the percentage of participants with tumor downstaging of the surgical specimen according to the local review and centralized review.

Outcome measures

Outcome measures
Measure	Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) n=41 Participants In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the TME technique.	Arm B (Bevacizumab, Chemoradiotherapy) n=44 Participants In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.
Percentage of Participants With Tumor Down-Staging (ypT0-pT2) Downstaging, local review (n=41, 44)	65.9 percentage of participants Interval 51.3 to 80.4	54.5 percentage of participants Interval 39.8 to 69.3
Percentage of Participants With Tumor Down-Staging (ypT0-pT2) Downstaging, centralized review (n=39, 43)	64.1 percentage of participants Interval 49.0 to 79.2	55.8 percentage of participants Interval 41.0 to 70.7

SECONDARY outcome

Timeframe: After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment)

Population: ITT population

The percentage of participants with a recurrence was described by type of recurrence (local and distant recurrence).

Outcome measures

Outcome measures
Measure	Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) n=46 Participants In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the TME technique.	Arm B (Bevacizumab, Chemoradiotherapy) n=45 Participants In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.
Percentage of Participants With Local and Distant Recurrences Local recurrence	2.2 percentage of participants Interval 0.1 to 11.5	6.7 percentage of participants Interval 1.4 to 18.3
Percentage of Participants With Local and Distant Recurrences Distant recurrence	17.4 percentage of participants Interval 7.8 to 31.4	13.3 percentage of participants Interval 5.1 to 26.8

SECONDARY outcome

Timeframe: Baseline up to approximately 6 years

Population: ITT population

Outcome measures

Outcome measures
Measure	Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) n=46 Participants In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the TME technique.	Arm B (Bevacizumab, Chemoradiotherapy) n=45 Participants In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.
Percentage of Participants With Second Cancer, Local or Regional Recurrence, Distant Metastasis, or Death	30.4 percentage of participants Interval 1.4 to 18.3	33.3 percentage of participants

SECONDARY outcome

Timeframe: From first time of the treatment administration to the date of second cancer, local or regional recurrence, distant metastasis or death from any cause (up to approximately 6 years)

Population: ITT population

The DFS was defined as the time from the first treatment intake to disease recurrence assessed (second primary cancer, local or distant recurrence, distant metastases) or death from any cause. The DFS was analyzed using Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) n=46 Participants In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the TME technique.	Arm B (Bevacizumab, Chemoradiotherapy) n=45 Participants In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.
Disease-Free Survival (DFS)	68.3 months Interval 68.3 to Upper limit of 95% CI was not reached due to low number of DFS-events.	NA months Interval 53.0 to Median and upper limit of 95% CI were not reached due to low number of DFS-events.

SECONDARY outcome

Timeframe: Baseline up to approximately 6 years

Population: ITT population

Outcome measures

Outcome measures
Measure	Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) n=46 Participants In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the TME technique.	Arm B (Bevacizumab, Chemoradiotherapy) n=45 Participants In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.
Percentage of Participants Who Died	8.7 percentage of participants Interval 1.4 to 18.3	24.4 percentage of participants

SECONDARY outcome

Timeframe: From the first treatment administration to the date of death (up to approximately 6 years)

Population: ITT population

The overall survival was defined as the time from the first treatment intake to death from any cause.

Outcome measures

Outcome measures
Measure	Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) n=46 Participants In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the TME technique.	Arm B (Bevacizumab, Chemoradiotherapy) n=45 Participants In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.
Overall Survival	NA months Median and 95% CI were not reached due to low number of deaths.	NA months Median and 95% CI were not reached due to low number of deaths.

SECONDARY outcome

Timeframe: 6 cycles (12 weeks; cycle length = 14 days)

Population: ITT population. Only Arm A participants received induction treatment.

Outcome measures

Outcome measures
Measure	Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) n=46 Participants In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the TME technique.	Arm B (Bevacizumab, Chemoradiotherapy) In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.
Number of Cycles of Induction Chemotherapy	5.8 cycles Standard Deviation 0.7	—

SECONDARY outcome

Timeframe: Arm A: Week 16 to Week 23; Arm B: Week 1 to Week 7

Population: ITT population

Outcome measures

Outcome measures
Measure	Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) n=46 Participants In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the TME technique.	Arm B (Bevacizumab, Chemoradiotherapy) n=45 Participants In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.
Number of Cycles of Chemotherapy	4.4 cycles Standard Deviation 1.5	4.8 cycles Standard Deviation 0.5

SECONDARY outcome

Timeframe: Arm A: Week 16 to Week 23; Arm B: Week 1 to Week 7

Population: ITT population

Outcome measures

Outcome measures
Measure	Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) n=46 Participants In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the TME technique.	Arm B (Bevacizumab, Chemoradiotherapy) n=45 Participants In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.
Number of Cycles of Radiotherapy	4.5 cycles Standard Deviation 1.5	5.0 cycles Standard Deviation 0.0

SECONDARY outcome

Timeframe: Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment

Population: ITT population

The surgery involving a radical rectal excision using the TME technique.

Outcome measures

Outcome measures
Measure	Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) n=46 Participants In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the TME technique.	Arm B (Bevacizumab, Chemoradiotherapy) n=45 Participants In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.
Percentage of Participants With Surgery	91.3 percentage of participants 0.0	97.8 percentage of participants

Adverse Events

Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy)

Serious events: 21 serious events

Other events: 46 other events

Deaths: 0 deaths

Arm B (Bevacizumab, Chemoradiotherapy)

Serious events: 18 serious events

Other events: 44 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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 that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy) n=46 participants at risk In this arm, participants underwent 3 phases of treatment. During the Phase 1, participants received induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 was surgery involving a radical rectal excision using the TME technique.	Arm B (Bevacizumab, Chemoradiotherapy) n=45 participants at risk In this arm, participants received the Phase 2 and Phase 3 treatments only. The phase 2 consisted of 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy \[5-FU + radiotherapy\], with administration of bevacizumab every two weeks \[Cycles 1, 3 and 5\]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 was surgery involving a radical rectal excision using the TME technique.
Gastrointestinal disorders Diarrhoea	54.3% 25/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	53.3% 24/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Gastrointestinal disorders Nausea	52.2% 24/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	15.6% 7/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Gastrointestinal disorders Constipation	32.6% 15/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	6.7% 3/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Gastrointestinal disorders Abdominal pain	15.2% 7/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	11.1% 5/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Gastrointestinal disorders Rectal haemorrhage	19.6% 9/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	4.4% 2/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Gastrointestinal disorders Abdominal pain upper	10.9% 5/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	8.9% 4/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Gastrointestinal disorders Anorectal discomfort	2.2% 1/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	15.6% 7/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Gastrointestinal disorders Proctalgia	8.7% 4/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	6.7% 3/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Gastrointestinal disorders Haemorrhoids	8.7% 4/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	4.4% 2/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Gastrointestinal disorders Vomiting	13.0% 6/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	0.00% 0/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Gastrointestinal disorders Rectal tenesmus	2.2% 1/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	6.7% 3/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Gastrointestinal disorders Stomatitis	6.5% 3/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	2.2% 1/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Gastrointestinal disorders Abdominal pain lower	0.00% 0/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	6.7% 3/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Gastrointestinal disorders Gingivitis	6.5% 3/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	0.00% 0/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Renal and urinary disorders Proteinuria	43.5% 20/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	28.9% 13/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Renal and urinary disorders Dysuria	26.1% 12/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	22.2% 10/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Renal and urinary disorders Pollakiuria	4.3% 2/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	6.7% 3/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
General disorders Asthenia	37.0% 17/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	13.3% 6/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
General disorders Mucosal inflammation	15.2% 7/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	8.9% 4/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
General disorders Fatigue	8.7% 4/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	4.4% 2/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
General disorders Pyrexia	6.5% 3/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	0.00% 0/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Nervous system disorders Neuropathy peripheral	47.8% 22/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	0.00% 0/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Nervous system disorders Paraesthesia	23.9% 11/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	4.4% 2/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Nervous system disorders Headache	15.2% 7/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	4.4% 2/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Nervous system disorders Dysaesthesia	8.7% 4/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	0.00% 0/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Infections and infestations Urinary tract infection	4.3% 2/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	8.9% 4/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Injury, poisoning and procedural complications Wound dehiscence	4.3% 2/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	11.1% 5/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Injury, poisoning and procedural complications Anastomotic fistula	6.5% 3/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	4.4% 2/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Injury, poisoning and procedural complications Wound complication	8.7% 4/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	2.2% 1/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Injury, poisoning and procedural complications Radiation skin injury	6.5% 3/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	2.2% 1/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Investigations Neutrophil count decreased	26.1% 12/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	2.2% 1/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Investigations Blood potassium decreased	10.9% 5/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	2.2% 1/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Investigations Weight decreased	6.5% 3/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	4.4% 2/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Respiratory, thoracic and mediastinal disorders Epistaxis	32.6% 15/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	4.4% 2/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	8.7% 4/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	0.00% 0/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Skin and subcutaneous tissue disorders Alopecia	6.5% 3/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	0.00% 0/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Skin and subcutaneous tissue disorders Pruritus	6.5% 3/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	0.00% 0/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Vascular disorders Hypertension	23.9% 11/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	15.6% 7/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Musculoskeletal and connective tissue disorders Muscle spasms	6.5% 3/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	0.00% 0/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Reproductive system and breast disorders Erectile dysfunction	6.5% 3/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	2.2% 1/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Metabolism and nutrition disorders Decreased appetite	13.0% 6/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	6.7% 3/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.
Gastrointestinal disorders Proctitis	45.7% 21/46 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.	40.0% 18/45 • Baseline up to approximately 6 years The safety population included all selected participants who received at least one dose of treatment and corresponded to the ITT population.