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
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
This 2-arm study was designed to compare the efficacy and safety of bevacizumab (Avastin) in
 combination with rituximab (MabThera) and CHOP (cyclophosphamide, hydroxydaunorubicin
 [doxorubicin], Oncovin [vincristine], prednisone) chemotherapy (R-CHOP) versus rituximab plus
 CHOP chemotherapy (R-CHOP) in previously untreated patients with CD20-positive diffuse large
 B-cell lymphoma (DLBCL). Patients were randomized to receive 8 cycles of treatment with
 R-CHOP plus bevacizumab or R-CHOP plus placebo. Treatment with bevacizumab/placebo and R-CHOP
 was given either on a 2-week or 3-week schedule and bevacizumab was given at a weekly average
 dose of 5 mg/kg (10 mg/kg for 2-week cycles and 15 mg/kg for 3-week cycles).
An independent Data and Safety Monitoring Board (DSMB) was established to review safety data
 collected during the study on an ongoing basis. At its meeting in December 2009, the DSMB
 noted a trend for increased cardiac toxicity in the experimental arm (R-CHOP + bevacizumab)
 compared with the control arm (R-CHOP + placebo). Additional efficacy analyses of data from
 720 randomized patients were presented at a DSMB meeting on May 22, 2010; they indicated no
 improvement in efficacy with the addition of bevacizumab to R-CHOP. It was noted, however,
 that there was an apparent increase in the risk of cardiotoxicity, premature treatment
 withdrawal, serious adverse events (SAEs), fatal adverse events (AEs), and perforation/ulcer
 in the experimental arm. Based on its assessment of an increased risk with unlikely benefit
 for patients randomized to the experimental arm, the DSMB recommended that further enrollment
 in the study be permanently halted and that bevacizumab be discontinued for any patients
 randomized to the experimental arm. On May 31, 2010, the sponsor took the decision to stop
 enrollment into the study and the bevacizumab treatment was terminated with immediate effect
 as recommended by the DSMB.

 The study protocol was amended. The primary objective of the study was changed from
 evaluation of efficacy to evaluation of safety and the study was extended to include an
 18-month safety follow-up period. Because enrollment was terminated prematurely resulting in
 fewer enrolled patients than planned, the outcome measure data are premature due to fewer
 than expected events.

 The time frame for the reporting of serious adverse events was modified. Serious adverse
 events (SAE) unrelated to study treatment were reported until 1 year post-treatment or until
 new anti-lymphoma treatment was initiated. SAEs judged to be related to study treatment and
 congestive heart failure events were reported at any time during the study.
Inclusion Criteria:

 -  Adult patients, ≥ 18 and < 80 years of age.

 -  CD20-positive diffuse large B-cell lymphoma.

 -  Low-intermediate, high-intermediate, or high risk disease and/or bulky tumor (largest
 diameter ≥ 7.5 cm).

 -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

 Exclusion Criteria:

 -  Prior treatment for diffuse large B-cell lymphoma.

 -  Types of non-Hodgkin's lymphoma other than diffuse large B-cell lymphoma (DLBCL).

 -  Central nervous system (CNS) involvement of lymphoma.