B-cell Lymphoma
Conditions
Brief summary
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).
Detailed description
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.
Interventions
DRUGBevacizumab
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.
DRUGRituximab
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.
DRUGCHOP
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.
DRUGPlacebo
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.
Sponsors
Genentech, Inc.
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 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 | 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. |
Countries
Argentina, Australia, Austria, Brazil, Canada, China, Colombia, Czechia, Ecuador, France, Germany, Greece, Hong Kong, Hungary, Italy, Lithuania, Malaysia, Mexico, New Zealand, Panama, Peru, Philippines, Poland, Portugal, Russia, Slovakia, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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). | 390 |
| 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). | 397 |
| Total | 787 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Safety Follow-up | Administrative/not specified | 8 | 6 |
| Safety Follow-up | Adverse event/intercurrent illness | 4 | 0 |
| Safety Follow-up | Death | 40 | 29 |
| Safety Follow-up | Failure to return | 9 | 6 |
| Safety Follow-up | Insufficient therapeutic response | 40 | 50 |
| Safety Follow-up | Refused treatment/did not cooperate | 6 | 4 |
| Safety Follow-up | Withdrew consent | 32 | 23 |
| Treatment | Administrative/reason not specified | 17 | 21 |
| Treatment | Adverse event/intercurrent illness | 86 | 39 |
| Treatment | Death | 17 | 10 |
| Treatment | Failure to return | 1 | 1 |
| Treatment | Insufficient therapeutic response | 37 | 39 |
| Treatment | Other protocol violation | 1 | 5 |
| Treatment | Refused treatment | 10 | 7 |
| Treatment | Violation of selection criteria at entry | 3 | 3 |
| Treatment | Withdrew consent | 15 | 12 |
Baseline characteristics
| Characteristic | Bevacizumab + Rituximab + CHOP | Placebo + Rituximab + CHOP | Total |
|---|---|---|---|
| Age, Continuous | 57.89 years STANDARD_DEVIATION 14.256 | 56.98 years STANDARD_DEVIATION 15.399 | 57.44 years STANDARD_DEVIATION 14.841 |
| Sex: Female, Male Female | 207 Participants | 193 Participants | 400 Participants |
| Sex: Female, Male Male | 183 Participants | 204 Participants | 387 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 346 / 395 | 331 / 386 |
| serious Total, serious adverse events | 224 / 395 | 173 / 386 |
Outcome results
Primary
Progression-free Survival (PFS)
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + Rituximab + CHOP | Progression-free Survival (PFS) | 40.2 Months |
| Placebo + Rituximab + CHOP | Progression-free Survival (PFS) | 42.9 Months |
Secondary
Overall Response (OR) Assessed According to the Revised Response Criteria for Malignant Lymphoma
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Rituximab + CHOP | Overall Response (OR) Assessed According to the Revised Response Criteria for Malignant Lymphoma | 63.1 Percentage of patients |
| Placebo + Rituximab + CHOP | Overall Response (OR) Assessed According to the Revised Response Criteria for Malignant Lymphoma | 70.5 Percentage of patients |
Secondary
Overall Survival
Overall survival was defined as the time from the date of randomization to the date of death due to any cause.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + Rituximab + CHOP | Overall Survival | NA Months |
| Placebo + Rituximab + CHOP | Overall Survival | NA Months |