Non-Hodgkin's Lymphoma
Conditions
Brief summary
This 2 arm study will compare the efficacy and safety of the standard chemotherapy of the East German Study Group for Hematology and Oncology versus standard chemotherapy plus MabThera (375mg/m2 iv, once monthly for 8 cycles) in patients with indolent non-Hodgkin's and mantle cell lymphoma. The anticipated time on study treatment is 3-12 months, and the target sample size is 100-500 individuals.
Interventions
DRUGrituximab [MabThera/Rituxan]
375mg/m2 iv monthly for 8 cycles
DRUGStandard chemotherapy
As prescribed
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* adult patients \>=18 years of age; * advanced, low-grade non-Hodgkin's and mantle cell lymphoma.
Exclusion criteria
* possibility of curative radiation therapy; * secondary NHL; * participation in another clinical trial eg with cytostatic chemotherapy or cytokines; * concomitant diseases and/or restricted organ function precluding therapy according to the study protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving CR or PR at the End of Therapy | Following completion of 6 cycles (24 weeks) | CR was defined as a complete remission of all objective medical findings at the time of restaging, with complete resolution of pre-existing swelling of the lymph nodes, as well as a pre-existing hepatomegaly and splenomegaly, for at least 4 weeks. This was in exclusion of persistent lymphoma infiltration of the bone marrow by means of bone marrow biopsy; normalization of blood counts with granulocytes greater than (\>)1.5 giga particles per liter (Gpt/L) (which is the equivalent of 10\^9/L), hemoglobin (Hb) \>7.5 millimoles per liter (mmol/L), and platelets less than (\<) 100 Gpt/L. PR was defined as greater than or equal to (≥)50 percent (%) reduction of all measurable and evaluable lymphoma manifestations (sum of the products of the 2 largest perpendicular diameters) for at least 4 weeks without occurrence of new manifestations and normalization of blood counts. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) - Percentage of Participants Alive at 24 Months | Month 24 | OS was defined as interval from randomization to date of death of any cause. Data were analyzed by means of Kaplan-Meier estimators and log-rank tests at the significance level of alpha=5% for difference between the treatment groups. |
| Event-Free Survival (EFS) - Percentage of Participants Event Free at 24 Months | Month 24 | EFS was defined as the interval from randomization date to therapy failure. Therapy failure was defined after 2 cycles as no change (NC) or progression of disease (PD); after 6 cycles as minimal response \[MR\], NC, or PD); or death from any cause. NC is defined as tumor regression of \<25%, stable disease and progression ≤25%. PD was defined as the increase in the frequency and severity of disease symptoms, occurrence of new nodal or extranodal lymphoma manifestations, volume increase of pre-existing lymphoma manifestations by more than 25%, and increase of splenomegaly by more than 25%. MR was defined as tumor regression between 50% (\<50%) and 25% (≥25%) for at least 4 weeks without occurrence of new manifestations. Data were analyzed by means of Kaplan-Meier estimators and log-rank tests at the significance level of alpha=5% for difference between the treatment groups. |
| Progression-Free Survival (PFS) - Percentage of Participants Event Free at 24 Months | 24 months | PFS was defined as the interval from randomization date to progression of disease or death from non-Hodgkin's Lymphoma (NHL). Progression of disease was defined as: increase in the frequency and severity of disease symptoms; occurrence of new nodal or extranodal lymphoma manifestations; volume increase of pre-existing lymphoma manifestations by more than 25%; or increase of splenomegaly by more than 25%. Data were analyzed by means of Kaplan-Meier estimators and log-rank tests at the significance level of alpha equals (=) 5% for difference between the treatment groups. |
| Response Duration - Percentage of Participants Event Free at 24 Months | Month 24 | Response duration defined as interval from first assessment of CR/PR to PD. PD is an increase in the frequency and severity of disease symptoms, occurrence of new nodal or extranodal lymphoma manifestations, volume increase of pre-existing lymphoma manifestations by more than 25%, increase of splenomegaly by more than 25%. Data were analyzed by means of Kaplan-Meier estimators and log-rank tests at the significance level of alpha=5% for difference between the treatment groups. |
| Time to Next Treatment - Percentage of Participants Who Did Not Need New Treatment at 24 Months | Month 24 | Time to next treatment was defined as the interval from randomization date to the time when new treatment was needed. Data were analyzed by means of Kaplan-Meier estimators and log-rank tests at the significance level of alpha=5% for difference between the treatment groups. |
| Disease-Free Survival (DFS) - Percentage of Participants Event Free at 24 Months | Month 24 | DFS was defined as the interval from first assessment of CR to PD. PD is an increase in the frequency and severity of disease symptoms, the occurrence of new nodal or extranodal lymphoma manifestations, the volume increase of pre-existing lymphoma manifestations by more than 25%, increase of splenomegaly by more than 25%. Data were analyzed by means of Kaplan-Meier estimators and log-rank tests at the significance level of alpha=5% for difference between the treatment groups. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Mitoxantrone, Chlorambucil, Prednisolone (MCP) Participants received mitoxantrone 8 mg/m\^2, IV, on Days 1 and 2, chlorambucil 3 x 3 mg/m\^2, PO, every 8 hours on Days 1 through 5, and prednisolone at 25 mg/m\^2, PO on Days 1 through 5. This cycle was repeated at 4-week intervals for a minimum of 6 cycles and a maximum of 8 cycles. After Cycles 2 and 6, participants were assessed for response; participants with no change or with progressive disease (or with minimal response at Cycle 6) were withdrawn from therapy. Participants achieving a CR or PR following induction therapy with MCP were administered maintenance therapy (per standard of care and at the discretion of the investigator) with IFN alpha 3 x 4.5 mIU per week, SC, until progression or withdrawal. Participants could have also received 3 x 500 mg of paracetamol/day during the first weeks of IFN therapy. | 177 |
| Rituximab + MCP Participants received rituximab 375 mg/m\^2, IV on Day 1, mitoxantrone 8 mg/m\^2, IV, on Days 3 and 4, chlorambucil 3 x 3 mg/m\^2, PO every 8 hours on Days 3 through 7, and prednisolone 25 mg/m\^2, PO on Days 3 through 7. This cycle was repeated at 4-week intervals for a minimum of 6 cycles and a maximum of 8 cycles. After Cycles 2 and 6, participants were assessed for response; participants with no change or with progressive disease (or with minimal response at Cycle 6) were withdrawn from therapy. Participants achieving a CR or PR following induction therapy with MCP were administered maintenance therapy (per standard of care and at the discretion of the investigator) with IFN alpha 3 x 4.5 mIU per week, SC, until progression or withdrawal. Participants could have also received 3 x 500 mg of paracetamol/day during the first weeks of IFN therapy. | 181 |
| Total | 358 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 14 | 7 |
| Overall Study | Death | 6 | 2 |
| Overall Study | Early Improvement | 2 | 0 |
| Overall Study | Lack of Efficacy | 35 | 18 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Other | 0 | 2 |
| Overall Study | Protocol Violation | 15 | 5 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Mitoxantrone, Chlorambucil, Prednisolone (MCP) | Rituximab + MCP | Total |
|---|---|---|---|
| Age, Continuous | 60.1 years STANDARD_DEVIATION 8.7 | 60.4 years STANDARD_DEVIATION 8.3 | 60.4 years STANDARD_DEVIATION 8.5 |
| Sex: Female, Male Female | 89 Participants | 79 Participants | 168 Participants |
| Sex: Female, Male Male | 88 Participants | 102 Participants | 190 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 146 / 177 | 163 / 183 |
| serious Total, serious adverse events | 20 / 177 | 18 / 183 |
Outcome results
Primary
Percentage of Participants Achieving CR or PR at the End of Therapy
CR was defined as a complete remission of all objective medical findings at the time of restaging, with complete resolution of pre-existing swelling of the lymph nodes, as well as a pre-existing hepatomegaly and splenomegaly, for at least 4 weeks. This was in exclusion of persistent lymphoma infiltration of the bone marrow by means of bone marrow biopsy; normalization of blood counts with granulocytes greater than (\>)1.5 giga particles per liter (Gpt/L) (which is the equivalent of 10\^9/L), hemoglobin (Hb) \>7.5 millimoles per liter (mmol/L), and platelets less than (\<) 100 Gpt/L. PR was defined as greater than or equal to (≥)50 percent (%) reduction of all measurable and evaluable lymphoma manifestations (sum of the products of the 2 largest perpendicular diameters) for at least 4 weeks without occurrence of new manifestations and normalization of blood counts.
Time frame: Following completion of 6 cycles (24 weeks)
Population: The ITT centroblastic-centrocytic (cbcc)/Follicular Lymphoma (FL) (collectively, ITTcbcc/FL) population included all participants in the ITT population with cbcc lymphoma (target population).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mitoxantrone, Chlorambucil, Prednisolone (MCP) | Percentage of Participants Achieving CR or PR at the End of Therapy | 75.0 percentage of participants |
| Rituximab + MCP | Percentage of Participants Achieving CR or PR at the End of Therapy | 92.4 percentage of participants |
p-value: 0.000995% CI: [6.4, 28.4]Fisher Exact
Secondary
Disease-Free Survival (DFS) - Percentage of Participants Event Free at 24 Months
DFS was defined as the interval from first assessment of CR to PD. PD is an increase in the frequency and severity of disease symptoms, the occurrence of new nodal or extranodal lymphoma manifestations, the volume increase of pre-existing lymphoma manifestations by more than 25%, increase of splenomegaly by more than 25%. Data were analyzed by means of Kaplan-Meier estimators and log-rank tests at the significance level of alpha=5% for difference between the treatment groups.
Time frame: Month 24
Population: ITTcbcc/FL Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mitoxantrone, Chlorambucil, Prednisolone (MCP) | Disease-Free Survival (DFS) - Percentage of Participants Event Free at 24 Months | 69.6 percentage of participants |
| Rituximab + MCP | Disease-Free Survival (DFS) - Percentage of Participants Event Free at 24 Months | 86.5 percentage of participants |
p-value: 0.0186Log Rank
Secondary
Event-Free Survival (EFS) - Percentage of Participants Event Free at 24 Months
EFS was defined as the interval from randomization date to therapy failure. Therapy failure was defined after 2 cycles as no change (NC) or progression of disease (PD); after 6 cycles as minimal response \[MR\], NC, or PD); or death from any cause. NC is defined as tumor regression of \<25%, stable disease and progression ≤25%. PD was defined as the increase in the frequency and severity of disease symptoms, occurrence of new nodal or extranodal lymphoma manifestations, volume increase of pre-existing lymphoma manifestations by more than 25%, and increase of splenomegaly by more than 25%. MR was defined as tumor regression between 50% (\<50%) and 25% (≥25%) for at least 4 weeks without occurrence of new manifestations. Data were analyzed by means of Kaplan-Meier estimators and log-rank tests at the significance level of alpha=5% for difference between the treatment groups.
Time frame: Month 24
Population: ITTcbcc/FL Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mitoxantrone, Chlorambucil, Prednisolone (MCP) | Event-Free Survival (EFS) - Percentage of Participants Event Free at 24 Months | 50.9 percentage of participants |
| Rituximab + MCP | Event-Free Survival (EFS) - Percentage of Participants Event Free at 24 Months | 83.6 percentage of participants |
p-value: <0.0001Log Rank
Secondary
Overall Survival (OS) - Percentage of Participants Alive at 24 Months
OS was defined as interval from randomization to date of death of any cause. Data were analyzed by means of Kaplan-Meier estimators and log-rank tests at the significance level of alpha=5% for difference between the treatment groups.
Time frame: Month 24
Population: ITTcbcc/FL Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mitoxantrone, Chlorambucil, Prednisolone (MCP) | Overall Survival (OS) - Percentage of Participants Alive at 24 Months | 78.8 percentage of participants |
| Rituximab + MCP | Overall Survival (OS) - Percentage of Participants Alive at 24 Months | 93.7 percentage of participants |
p-value: 0.0127Log Rank
Secondary
Progression-Free Survival (PFS) - Percentage of Participants Event Free at 24 Months
PFS was defined as the interval from randomization date to progression of disease or death from non-Hodgkin's Lymphoma (NHL). Progression of disease was defined as: increase in the frequency and severity of disease symptoms; occurrence of new nodal or extranodal lymphoma manifestations; volume increase of pre-existing lymphoma manifestations by more than 25%; or increase of splenomegaly by more than 25%. Data were analyzed by means of Kaplan-Meier estimators and log-rank tests at the significance level of alpha equals (=) 5% for difference between the treatment groups.
Time frame: 24 months
Population: ITTcbcc/FL Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mitoxantrone, Chlorambucil, Prednisolone (MCP) | Progression-Free Survival (PFS) - Percentage of Participants Event Free at 24 Months | 57.6 percentage of participants |
| Rituximab + MCP | Progression-Free Survival (PFS) - Percentage of Participants Event Free at 24 Months | 86.7 percentage of participants |
p-value: <0.0001Log Rank
Secondary
Response Duration - Percentage of Participants Event Free at 24 Months
Response duration defined as interval from first assessment of CR/PR to PD. PD is an increase in the frequency and severity of disease symptoms, occurrence of new nodal or extranodal lymphoma manifestations, volume increase of pre-existing lymphoma manifestations by more than 25%, increase of splenomegaly by more than 25%. Data were analyzed by means of Kaplan-Meier estimators and log-rank tests at the significance level of alpha=5% for difference between the treatment groups.
Time frame: Month 24
Population: ITTcbcc/FL Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mitoxantrone, Chlorambucil, Prednisolone (MCP) | Response Duration - Percentage of Participants Event Free at 24 Months | 60.3 percentage of participants |
| Rituximab + MCP | Response Duration - Percentage of Participants Event Free at 24 Months | 87.7 percentage of participants |
p-value: 0.0002Log Rank
Secondary
Time to Next Treatment - Percentage of Participants Who Did Not Need New Treatment at 24 Months
Time to next treatment was defined as the interval from randomization date to the time when new treatment was needed. Data were analyzed by means of Kaplan-Meier estimators and log-rank tests at the significance level of alpha=5% for difference between the treatment groups.
Time frame: Month 24
Population: ITTcbcc/FL Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mitoxantrone, Chlorambucil, Prednisolone (MCP) | Time to Next Treatment - Percentage of Participants Who Did Not Need New Treatment at 24 Months | 54.6 percentage of participants |
| Rituximab + MCP | Time to Next Treatment - Percentage of Participants Who Did Not Need New Treatment at 24 Months | 72.0 percentage of participants |
p-value: 0.0017Log Rank