A Multicenter, Randomized, Double-blind, Placebo-controlled Phase III Trial Comparing the Efficacy of Bevacizumab in Combination With Rituximab and CHOP (R-CHOP + Bevacizumab) Versus Rituximab and CHOP (R-CHOP) in Previously Untreated Patients With CD20-positive Diffuse Large B-cell Lymphoma (DLBCL)
A Multicenter, Randomized, Double-blind, Placebo-controlled Phase III Trial Comparing the Efficacy of Bevacizumab in Combination With Rituximab and CHOP (R-CHOP + Bevacizumab) Versus Rituximab and CHOP (R-CHOP) in Previously Untreated Patients With CD20-positive Diffuse Large B-cell Lymphoma (DLBCL)
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:
Exclusion Criteria:
La Jolla, California 92093, United States
Kansas City, Kansas 66160, United States
Winston-Salem, North Carolina 27103, United States
Woolloongabba, Queensland 4102, Australia
Adelaide, South Australia 5000, Australia
Vienna, 1090, Austria
Santo André, São Paulo 09060-650, Brazil
São Paulo, São Paulo 01221-020, Brazil
Toronto, Ontario M5G 2M9, Canada
Greenfield Park, Quebec J4V 2H1, Canada
Montreal, Quebec H3T 1E2, Canada
Shanghai, 200127, China
Xi'an, 710032, China
Medellin-Antioquia, Colombia
Plzen - Lochotin, 304 60, Czechia
Berlin, 10117, Germany
Bremen, 28239, Germany
Dortmund, 44137, Germany
Göttingen, 37075, Germany
Greifswald, 17475, Germany
Homburg/Saar, 66421, Germany
Leipzig, 04103, Germany
Lübeck, 23562, Germany
München, 81377, Germany
Münster, 48149, Germany
Trier, 54292, Germany
Ulm, 89081, Germany
Wiesbaden, 65199, Germany
Budapest, 1097, Hungary
Debrecen, 4032, Hungary
Aviano, Friuli Venezia Giulia 33081, Italy
Udine, Friuli Venezia Giulia 33100, Italy
Campobasso, Molise 86100, Italy
Orbassano, Piedmont 10043, Italy
Turin, Piedmont 10126, Italy
Via S. Sofia 78, Sicily 95123, Italy
Chiclayo, CIX, Peru
Lima, Lima11, Peru
Diliman, Quezon City, 1100, Philippines
Lublin, 20-081, Poland
Warsaw, 02-507, Poland
Moscow, 115478, Russia
Seoul, 138-736, South Korea
Santander, Cantabria 39008, Spain
A Coruña, La Coruña 15006, Spain
San Cristóbal de La Laguna, Tenerife 38320, Spain
Galdakano, Vizcaya 48960, Spain
Jaén, 23007, Spain
Malmö, 205 02, Sweden
Bangkok, 10330, Thailand
Chiang Mai, 50200, Thailand
Hampshire, RG24 9NA, United Kingdom
Middx, UB8 3NN, United Kingdom