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

• Progression-free Survival (PFS) [ Time Frame: Baseline to end of the study (up to 4 years, 4 months) ] [ Designated as safety issue: No ]
  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.
  
  

• Overall Survival [ Time Frame: Baseline to end of the study (up to 4 years, 4 months) ] [ Designated as safety issue: No ]
  Overall survival was defined as the time from the date of randomization to the date of death due to any cause.
  
  
• Overall Response (OR) Assessed According to the Revised Response Criteria for Malignant Lymphoma [ Time Frame: At the end of treatment (Cycle 8, up to 12 months) ] [ Designated as safety issue: No ]
  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.
  
  

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.