Trial Outcomes & Findings for A Study of Bevacizumab (Avastin) in Combination With Rituximab (MabThera) and CHOP (Cyclophosphamide, Hydroxydaunorubicin [Doxorubicin], Oncovin [Vincristine], Prednisone) Chemotherapy in Patients With Diffuse Large B-cell Lymphoma (NCT NCT00486759)

Last Updated: 2017-07-25

Results Overview

PFS was defined as the time from the date of randomization to the date of disease progression (PD)/relapse, as determined by the investigator, or death from any cause, whichever occurred earlier. A patient with PD/relapse must meet at least 1 of the following criteria: (1) Appearance of any new lesion \> 1.0 cm in the short axis during or at the end of therapy. (2) ≥ 50 % increase from nadir in the sum of the products of diameters (SPD, maximum diameter of a tumor x largest diameter perpendicular to the maximum diameter) of any previously involved nodes, in a single involved node, or the size of other lesions (eg, splenic or hepatic nodules). To be considered progressive disease, a lymph node with a diameter of the short axis \< 1.0 cm must increase by ≥ 50% to a size of 1.5 x 1.5 cm or \> 1.5 cm in the long axis. (3) ≥ 50 % increase in the greatest diameter of any previously identified node \> 1.0 cm in its short axis or in the SPD of more than 1 node.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

787 participants

Primary outcome timeframe

Baseline to end of the study (up to 4 years, 4 months)

Results posted on

2017-07-25

Participant Flow

Participant milestones

Participant milestones
Measure	Bevacizumab + Rituximab + CHOP Patients received bevacizumab 5 mg/kg/week on Day 1 of each cycle + rituximab 375 mg/m\^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin \[doxorubicin\], Oncovin \[vincristine\], prednisone).	Placebo + Rituximab + CHOP Patients received placebo to bevacizumab on Day 1 of each cycle + rituximab 375 mg/m\^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin \[doxorubicin\], Oncovin \[vincristine\], prednisone).
Treatment STARTED	390	397
Treatment COMPLETED	203	260
Treatment NOT COMPLETED	187	137
Safety Follow-up STARTED	203	260
Safety Follow-up COMPLETED	64	142
Safety Follow-up NOT COMPLETED	139	118

Reasons for withdrawal

Reasons for withdrawal
Measure	Bevacizumab + Rituximab + CHOP Patients received bevacizumab 5 mg/kg/week on Day 1 of each cycle + rituximab 375 mg/m\^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin \[doxorubicin\], Oncovin \[vincristine\], prednisone).	Placebo + Rituximab + CHOP Patients received placebo to bevacizumab on Day 1 of each cycle + rituximab 375 mg/m\^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin \[doxorubicin\], Oncovin \[vincristine\], prednisone).
Treatment Adverse event/intercurrent illness	86	39
Treatment Insufficient therapeutic response	37	39
Treatment Death	17	10
Treatment Withdrew consent	15	12
Treatment Administrative/reason not specified	17	21
Treatment Refused treatment	10	7
Treatment Violation of selection criteria at entry	3	3
Treatment Other protocol violation	1	5
Treatment Failure to return	1	1
Safety Follow-up Insufficient therapeutic response	40	50
Safety Follow-up Death	40	29
Safety Follow-up Withdrew consent	32	23
Safety Follow-up Failure to return	9	6
Safety Follow-up Administrative/not specified	8	6
Safety Follow-up Refused treatment/did not cooperate	6	4
Safety Follow-up Adverse event/intercurrent illness	4	0

Baseline Characteristics

A Study of Bevacizumab (Avastin) in Combination With Rituximab (MabThera) and CHOP (Cyclophosphamide, Hydroxydaunorubicin [Doxorubicin], Oncovin [Vincristine], Prednisone) Chemotherapy in Patients With Diffuse Large B-cell Lymphoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bevacizumab + Rituximab + CHOP n=390 Participants Patients received bevacizumab 5 mg/kg/week on Day 1 of each cycle + rituximab 375 mg/m\^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin \[doxorubicin\], Oncovin \[vincristine\], prednisone).	Placebo + Rituximab + CHOP n=397 Participants Patients received placebo to bevacizumab on Day 1 of each cycle + rituximab 375 mg/m\^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin \[doxorubicin\], Oncovin \[vincristine\], prednisone).	Total n=787 Participants Total of all reporting groups
Age, Continuous	57.89 years STANDARD_DEVIATION 14.256 • n=5 Participants	56.98 years STANDARD_DEVIATION 15.399 • n=7 Participants	57.44 years STANDARD_DEVIATION 14.841 • n=5 Participants
Sex: Female, Male Female	207 Participants n=5 Participants	193 Participants n=7 Participants	400 Participants n=5 Participants
Sex: Female, Male Male	183 Participants n=5 Participants	204 Participants n=7 Participants	387 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline to end of the study (up to 4 years, 4 months)

Population: Intent-to-treat population: All randomized patients, regardless whether or not they had actually received the assigned treatments.

Outcome measures

Outcome measures
Measure	Bevacizumab + Rituximab + CHOP n=390 Participants Patients received bevacizumab 5 mg/kg/week on Day 1 of each cycle + rituximab 375 mg/m\^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin \[doxorubicin\], Oncovin \[vincristine\], prednisone).	Placebo + Rituximab + CHOP n=397 Participants Patients received placebo to bevacizumab on Day 1 of each cycle + rituximab 375 mg/m\^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin \[doxorubicin\], Oncovin \[vincristine\], prednisone).
Progression-free Survival (PFS)	40.2 Months Interval 12.1 to The 75th percentile could not be estimated due to a lack of events.	42.9 Months Interval 13.6 to The 75th percentile could not be estimated due to a lack of events.

SECONDARY outcome

Timeframe: Baseline to end of the study (up to 4 years, 4 months)

Population: Intent-to-treat population: All randomized patients, regardless whether or not they had actually received the assigned treatments.

Overall survival was defined as the time from the date of randomization to the date of death due to any cause.

Outcome measures

Outcome measures
Measure	Bevacizumab + Rituximab + CHOP n=390 Participants Patients received bevacizumab 5 mg/kg/week on Day 1 of each cycle + rituximab 375 mg/m\^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin \[doxorubicin\], Oncovin \[vincristine\], prednisone).	Placebo + Rituximab + CHOP n=397 Participants Patients received placebo to bevacizumab on Day 1 of each cycle + rituximab 375 mg/m\^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin \[doxorubicin\], Oncovin \[vincristine\], prednisone).
Overall Survival	NA Months Interval 34.0 to The median and 75th percentile could not be estimated due to a lack of events,	NA Months Interval 42.9 to The median and 75th percentile could not be estimated due to a lack of events,

SECONDARY outcome

Timeframe: At the end of treatment (Cycle 8, up to 12 months)

Population: Intent-to-treat population: All randomized patients, regardless whether or not they had actually received the assigned treatments.

OR = a complete response (CR), an unconfirmed CR, or a partial response (PR). CR = Complete disappearance of disease and disease-related symptoms. All lymph nodes and nodal masses regressed on computed tomography (CT) to normal size (≤ 1.5 cm in their greatest transverse diameter for nodes \> 1.5 cm prior to therapy and ≤ 1.0 cm in their short axis for nodes 1.1-1.5 cm in their long axis and \> 1.0 cm in their short axis prior to therapy). Spleen and/or liver not palpable on physical examination, normal size by imaging, and disappearance of nodules related to lymphoma. If bone marrow was involved prior to therapy, infiltrate must have cleared on repeat biopsy. PR = ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. No increase in the size of the other nodes, liver, or spleen. Splenic and hepatic nodules regressed by ≥ 50% in their SPD or, for single nodules, in the greatest transverse diameter. No new sites of disease.

Outcome measures

Outcome measures
Measure	Bevacizumab + Rituximab + CHOP n=390 Participants Patients received bevacizumab 5 mg/kg/week on Day 1 of each cycle + rituximab 375 mg/m\^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin \[doxorubicin\], Oncovin \[vincristine\], prednisone).	Placebo + Rituximab + CHOP n=397 Participants Patients received placebo to bevacizumab on Day 1 of each cycle + rituximab 375 mg/m\^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin \[doxorubicin\], Oncovin \[vincristine\], prednisone).
Overall Response (OR) Assessed According to the Revised Response Criteria for Malignant Lymphoma	63.1 Percentage of patients	70.5 Percentage of patients

Adverse Events

Bevacizumab + Rituximab + CHOP

Serious events: 224 serious events

Other events: 346 other events

Deaths: 0 deaths

Placebo + Rituximab + CHOP

Serious events: 173 serious events

Other events: 331 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800 821-8590

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

Serious adverse events
Measure	Bevacizumab + Rituximab + CHOP n=395 participants at risk Patients received bevacizumab 5 mg/kg/week on Day 1 of each cycle + rituximab 375 mg/m\^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin \[doxorubicin\], Oncovin \[vincristine\], prednisone).	Placebo + Rituximab + CHOP n=386 participants at risk Patients received placebo to bevacizumab on Day 1 of each cycle + rituximab 375 mg/m\^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin \[doxorubicin\], Oncovin \[vincristine\], prednisone).
Musculoskeletal and connective tissue disorders Myofascial pain syndrome	0.25% 1/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.00% 0/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Musculoskeletal and connective tissue disorders Osteoporosis	0.00% 0/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.26% 1/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Blood and lymphatic system disorders Febrile neutorpenia	15.9% 63/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	12.4% 48/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Blood and lymphatic system disorders Neutropenia	3.0% 12/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	4.4% 17/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Blood and lymphatic system disorders Leukopenia	1.5% 6/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	1.3% 5/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Blood and lymphatic system disorders Anaemia	2.0% 8/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.26% 1/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Blood and lymphatic system disorders Thrombocytopenia	1.3% 5/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	1.0% 4/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Blood and lymphatic system disorders Agranulocytosis	0.76% 3/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.52% 2/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Blood and lymphatic system disorders Febrile bone marrow aplasia	0.00% 0/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.78% 3/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Blood and lymphatic system disorders Pancytopenia	0.51% 2/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.26% 1/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Blood and lymphatic system disorders Lymphopenia	0.51% 2/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.00% 0/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Blood and lymphatic system disorders Splenic vein thrombosis	0.25% 1/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.00% 0/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Blood and lymphatic system disorders Splenomegaly	0.25% 1/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.00% 0/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Pneumonia	5.6% 22/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	4.1% 16/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Septic shock	1.5% 6/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	1.0% 4/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Infection	0.76% 3/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	1.6% 6/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Urinary tract infection	1.5% 6/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.78% 3/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Bronchopneumonia	0.51% 2/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	1.6% 6/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Gastroenteritis	0.51% 2/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	1.0% 4/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Neutropenic sepsis	1.3% 5/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.26% 1/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Sepsis	0.51% 2/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	1.0% 4/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Neutropenic infection	0.25% 1/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	1.0% 4/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Device related infection	0.51% 2/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.26% 1/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Lower respiratory tract infection	0.25% 1/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.52% 2/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Anal abscess	0.51% 2/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.00% 0/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Appendicitis	0.25% 1/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.26% 1/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Bronchitis	0.25% 1/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.26% 1/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Cellulitis	0.00% 0/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.52% 2/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Cystitis	0.25% 1/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.26% 1/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Erysipelas	0.00% 0/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.52% 2/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Escherichia sepsis	0.00% 0/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.52% 2/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Herpes zoster	0.25% 1/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.26% 1/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Oesophageal candidiasis	0.51% 2/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.00% 0/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Pharyngitis	0.25% 1/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.26% 1/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Pneumocystis jiroveci pneumonia	0.00% 0/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.52% 2/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Respiratory tract infection	0.51% 2/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.00% 0/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Abdominal abscess	0.25% 1/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.00% 0/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Acute tonsillitis	0.25% 1/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.00% 0/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Amoebiasis	0.25% 1/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.00% 0/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Appendiceal abscess	0.00% 0/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	0.26% 1/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.

Other adverse events
Measure	Bevacizumab + Rituximab + CHOP n=395 participants at risk Patients received bevacizumab 5 mg/kg/week on Day 1 of each cycle + rituximab 375 mg/m\^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin \[doxorubicin\], Oncovin \[vincristine\], prednisone).	Placebo + Rituximab + CHOP n=386 participants at risk Patients received placebo to bevacizumab on Day 1 of each cycle + rituximab 375 mg/m\^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin \[doxorubicin\], Oncovin \[vincristine\], prednisone).
Respiratory, thoracic and mediastinal disorders Dysphonia	7.3% 29/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	1.8% 7/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Skin and subcutaneous tissue disorders Alopecia	24.3% 96/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	20.7% 80/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Skin and subcutaneous tissue disorders Rash	5.6% 22/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	6.0% 23/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Musculoskeletal and connective tissue disorders Back pain	9.4% 37/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	9.6% 37/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Musculoskeletal and connective tissue disorders Arthralgia	8.9% 35/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	4.9% 19/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Gastrointestinal disorders Nausea	27.1% 107/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	27.5% 106/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Gastrointestinal disorders Diarrhoea	24.1% 95/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	21.0% 81/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Gastrointestinal disorders Constipation	22.3% 88/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	18.1% 70/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Gastrointestinal disorders Vomiting	14.2% 56/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	18.1% 70/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Gastrointestinal disorders Stomatitis	8.4% 33/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	9.3% 36/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Gastrointestinal disorders Dyspepsia	5.8% 23/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	9.1% 35/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Gastrointestinal disorders Abdominal pain	8.1% 32/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	6.5% 25/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Gastrointestinal disorders Abdominal pain upper	4.3% 17/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	8.3% 32/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Gastrointestinal disorders Haemorrhoids	5.8% 23/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	3.1% 12/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
General disorders Fatigue	18.0% 71/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	18.4% 71/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
General disorders Pyrexia	18.0% 71/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	14.2% 55/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
General disorders Asthenia	14.9% 59/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	15.5% 60/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
General disorders Mucosal inflammation	15.4% 61/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	11.7% 45/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
General disorders Oedema peripheral	6.1% 24/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	7.5% 29/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Blood and lymphatic system disorders Neutropenia	22.3% 88/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	30.8% 119/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Blood and lymphatic system disorders Anaemia	16.7% 66/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	24.9% 96/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Blood and lymphatic system disorders Leukopenia	10.6% 42/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	12.7% 49/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Blood and lymphatic system disorders Thrombocytopenia	6.1% 24/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	7.8% 30/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Nervous system disorders Headache	14.9% 59/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	15.3% 59/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Nervous system disorders Neuropathy peripheral	9.6% 38/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	9.8% 38/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Nervous system disorders Paraesthesia	10.6% 42/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	8.0% 31/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Nervous system disorders Peripheral sensory neuropathy	6.3% 25/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	7.3% 28/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Nervous system disorders Dizziness	6.1% 24/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	5.4% 21/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Respiratory, thoracic and mediastinal disorders Cough	13.2% 52/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	11.1% 43/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Respiratory, thoracic and mediastinal disorders Epistaxis	11.9% 47/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	2.6% 10/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Respiratory, thoracic and mediastinal disorders Dyspnoea	4.8% 19/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	7.0% 27/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	6.8% 27/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	4.9% 19/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	6.1% 24/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	3.6% 14/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Musculoskeletal and connective tissue disorders Pain in extremity	5.6% 22/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	4.9% 19/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Musculoskeletal and connective tissue disorders Bone pain	5.8% 23/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	4.4% 17/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Nasopharyngitis	7.6% 30/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	5.7% 22/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Urinary tract infection	6.1% 24/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	6.0% 23/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Infections and infestations Upper respiratory tract infection	6.3% 25/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	4.4% 17/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Metabolism and nutrition disorders Decreased appetite	15.2% 60/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	11.9% 46/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Metabolism and nutrition disorders Hypokalaemia	5.3% 21/395 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.	4.4% 17/386 • All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose. Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.