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
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| ClinicalTrials.gov Identifier: NCT00486759 |
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Recruitment Status :
Terminated
(Due to an unfavorable benefit/risk ratio.)
First Posted : June 15, 2007
Results First Posted : December 31, 2012
Last Update Posted : July 25, 2017
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| B-cell Lymphoma | Drug: Bevacizumab Drug: Rituximab Drug: CHOP Drug: Placebo | Phase 3 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 787 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Double (Participant, Investigator) |
| Primary Purpose: | Treatment |
| Official Title: | 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) |
| Actual Study Start Date : | July 26, 2007 |
| Actual Primary Completion Date : | November 30, 2011 |
| Actual Study Completion Date : | November 30, 2011 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: 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).
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Drug: Bevacizumab
Bevacizumab was administered at a dose of 15 mg/kg IV on Day 1 of each 21-day cycle for 8 cycles or at a dose 10 mg/kg IV on Day 1 of each 14-day cycle for 8 cycles. The cycle duration (14- or 21-day) was chosen by each center prior to initiation of the study and was the same for all patients enrolled at that center.
Other Name: Avastin Drug: Rituximab Rituximab was administered at a dose of 375 mg/m^2 IV on Day 1 of each 14- or 21-day cycle for 8 cycles. The cycle duration (14- or 21-day) was chosen by each center prior to initiation of the study and was the same for all patients enrolled at that center.
Other Name: MabThera Drug: CHOP Cyclophosphamide was administered at a dose of 750 mg/m^2 IV on Day 1 of each cycle. Doxorubicin was administered at a dose of 50 mg/m^2 IV on Day 1 of each cycle. Vincristine was administered at a dose of 1.4 mg/m^2 IV (maximum of 2 mg) on Day 1 of each cycle. Prednisone was administered at a dose of 100 mg orally on Days 1-5 of each cycle. All 4 drugs were administered either every 21 days for 8 cycles or every 14 days for 6 cycles. The cycle duration (14- or 21-day) was chosen by each center prior to initiation of the study and was the same for all patients enrolled at that center. |
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Active Comparator: 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).
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Drug: Rituximab
Rituximab was administered at a dose of 375 mg/m^2 IV on Day 1 of each 14- or 21-day cycle for 8 cycles. The cycle duration (14- or 21-day) was chosen by each center prior to initiation of the study and was the same for all patients enrolled at that center.
Other Name: MabThera Drug: CHOP Cyclophosphamide was administered at a dose of 750 mg/m^2 IV on Day 1 of each cycle. Doxorubicin was administered at a dose of 50 mg/m^2 IV on Day 1 of each cycle. Vincristine was administered at a dose of 1.4 mg/m^2 IV (maximum of 2 mg) on Day 1 of each cycle. Prednisone was administered at a dose of 100 mg orally on Days 1-5 of each cycle. All 4 drugs were administered either every 21 days for 8 cycles or every 14 days for 6 cycles. The cycle duration (14- or 21-day) was chosen by each center prior to initiation of the study and was the same for all patients enrolled at that center. Drug: Placebo Placebo to bevacizumab was administered on Day 1 of each 14- or 21-day cycle for 8 cycles. The cycle duration (14- or 21-day) was chosen by each center prior to initiation of the study and was the same for all patients enrolled at that center. |
- Progression-free Survival (PFS) [ Time Frame: Baseline to end of the study (up to 4 years, 4 months) ]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) ]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) ]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.
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| Ages Eligible for Study: | 18 Years to 79 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00486759
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| Study Director: | Clinical Trials | Hoffmann-La Roche |
| Responsible Party: | Hoffmann-La Roche |
| ClinicalTrials.gov Identifier: | NCT00486759 |
| Other Study ID Numbers: |
BO20603 |
| First Posted: | June 15, 2007 Key Record Dates |
| Results First Posted: | December 31, 2012 |
| Last Update Posted: | July 25, 2017 |
| Last Verified: | June 2017 |
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Lymphoma Lymphoma, B-Cell Lymphoma, Large B-Cell, Diffuse Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Lymphoma, Non-Hodgkin Bevacizumab |
Rituximab Antineoplastic Agents, Immunological Antineoplastic Agents Angiogenesis Inhibitors Angiogenesis Modulating Agents Growth Substances Physiological Effects of Drugs Growth Inhibitors Immunologic Factors Antirheumatic Agents |