Lymphoma
Conditions
Brief summary
This randomized, open-label study will compare the efficacy and safety of MabThera/Rituxan (rituximab) alone, and in combination with Roferon-A (interferon alfa-2a) in patients with follicular or other CD20+ low-grade lymphoma. Patients will be randomized to receive either MabThera/Rituxan 375 mg/m2 intravenously weekly for 4 weeks or Roferon-A 3 MIU/day subcutaneously in Week 1 followed by 4.5 MIU/day sc in Weeks 2-5 plus MabThera/Rituxan 375 mg/m2 weekly iv in Weeks 3-6. Patients who have a response will receive an additional cycle of treatment. The anticipated time on study treatment is up to 6 months.
Interventions
DRUGrituximab
375 mg/m2 rituximab i.v. weekly for 4 weeks
DRUGinterferon-a-2a
3 MIU/day interferon-a2a s.c. during Week 1, and 4.5 MIU/day s.c. 6 days per week during Weeks 2 through 5
Sponsors
Nordic Lymphoma Group
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients \>18 years of age * CD20+ low-grade (indolent) lymphoma of follicular and marginal zone type, small lymphocytic lymphoma without a B-CLL phenotype, or indolent lymphoma not otherwise specified * Stage II (with bulky disease), III, or IV lymphoma * No previous chemotherapy or a maximum of 6 months chlorambucil or cyclophosphamide * Indication for treatment: symptomatic enlarged lymph nodes, spleen or other lymphoma manifestations, progression \>6 months of lymphadenopathy or splenomegaly, anemia or thrombocytopenia or decreased hemoglobin or platelets due to lymphoma, general symptoms (weight loss, night sweats or fever) * WHO performance status 0-2
Exclusion criteria
* Prior treatment with rituximab or an interferon * B-CLL, mantle cell lymphoma, lymphoplasmacytic lymphoma (Waldenstroem's disease), or central nervous system lymphoma * Indolent lymphoma transformed into aggressive lymphoma * Indolent lymphoma with bulky tumor requiring urgent therapy * Prior malignancies, except non-melanoma skin tumors, in situ cervical cancer, or curative surgery \>5 years ago * Positive for HIV infection * Uncontrolled asthma or allergy requiring corticosteroids
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Failure - Percentage of Participants With an Event | Baseline (BL), Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period | Treatment failure was defined as an event of any of the following: progressive disease while receiving study treatment, death due to any cause, or the initiation of another type of treatment due to stable disease, progressive disease or relapse, or intolerance to study treatment. |
| Treatment Failure - Time to Event | BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period | The median time, in months, between randomization and treatment failure event determined using Kaplan-Meier estimates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response - Percentage of Participants With an Event | BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period | Response duration was defined as the period between the date for first observation of CR, CRu or PR and the date of progressive disease (PD), censored observation or death of any cause. Response duration was also assessed for response defined as CR only. Response duration was calculated among responders (CR+CRu+PR) with cutoffs for follow-up applied. |
| Duration of Response | BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period | The median time, in months, from the date of the first observation of CR, CRu, or PR and the date of progressive disease (PD), censored observation, or death due to any cause. PD was defined as an increase of \>50% compared to BL in the sum of the product of the two largest perpendicular parameters of measurable lymphoma, or the occurrence of new lesions. One month=30.4 days. Response duration was calculated amongst responders (CR+CRu+PR) with cutoffs for follow-up applied. |
| Disease Progression - Percentage of Participants With an Event | BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period | A disease progression event was defined as tumor progression or death due to any cause (or a censored observation). |
| Percentage of Participants Achieving Complete Response (CR), Unconfirmed CR (CRu), or Partial Response (PR) | Weeks 10 and 16 | CR was defined as the complete disappearance of all previously detectable disease signs; the absence of palpable lymph nodes greater than (\>) 1 centimeter (cm) or nodes \>1.5 cm observed in computerized axial tomography (CAT) scan; and negative bone marrow pathology, if initially positive. CRu was defined as CR, except that bone marrow results were indeterminate. PR was defined as a decrease of greater than or equal to (≥) 50 percent (%) compared with the BL value in the sum of the products of the two largest perpendicular diameters in all measurable and evaluable lesions; and a ≥50% reduction of the size from BL if hepato-splenomegaly was present. |
| Overall Survival (OS) - Percentage of Participants With an Event | BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period | An overall survival event was defined as death due to any cause. |
| Overall Survival | BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period | The median time, in months, from randomization to OS event assessed using Kaplan-Meier estimates. One month=30.4 days |
| Time to Disease Progression | BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period | The median time, in months, from randomization to disease progression event assessed using Kaplan-Meier estimates. One month=30.4 days |
| Percentage of Participants Achieving CR or CRu | Weeks 10 and 16 | CR was defined as the complete disappearance of all previously detectable disease signs; the absence of palpable lymph nodes \>1 cm or nodes \>1.5 cm observed in CATscan; and negative bone marrow pathology, if initially positive. CRu was defined as CR, except that bone marrow results were indeterminate. |
Countries
Denmark, Norway, Sweden
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rituximab Monotherapy Participants rituximab received 375 mg/m\^2, IV, once weekly for 4 weeks. Participants who achieved MR, PR, or CR after the first cycle received a second cycle of treatment for a maximum of 2 cycles. | 156 |
| Rituximab + IFN Participants received rituximab 375 mg/m\^2, IV, once weekly for 4 weeks. Participants also received IFN-α2a 3 MIU/day, SC, during Week 1, and 4.5 MIU/day, SC, 6 days per week during Weeks 2 through 5. IFN-α2a was not administered on days of rituximab administration. Participants who achieved MR, PR, or CR during the first cycle received a second cycle of treatment for a maximum of 2 cycles. | 157 |
| Total | 313 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 6 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | New cancer | 1 | 0 |
| Overall Study | Other | 2 | 0 |
| Overall Study | Other malignancy | 1 | 0 |
| Overall Study | Pathology review | 2 | 1 |
| Overall Study | Progressive disease (PD) | 8 | 10 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Stable disease (SD) | 22 | 16 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Rituximab Monotherapy | Rituximab + IFN | Total |
|---|---|---|---|
| Age, Continuous | 59.1 years STANDARD_DEVIATION 11.6 | 57.2 years STANDARD_DEVIATION 10.8 | 58.1 years STANDARD_DEVIATION 11.2 |
| Sex: Female, Male Female | 78 Participants | 82 Participants | 160 Participants |
| Sex: Female, Male Male | 78 Participants | 75 Participants | 153 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 138 / 156 | 155 / 157 |
| serious Total, serious adverse events | 13 / 156 | 34 / 157 |
Outcome results
Primary
Treatment Failure - Percentage of Participants With an Event
Treatment failure was defined as an event of any of the following: progressive disease while receiving study treatment, death due to any cause, or the initiation of another type of treatment due to stable disease, progressive disease or relapse, or intolerance to study treatment.
Time frame: Baseline (BL), Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab Monotherapy | Treatment Failure - Percentage of Participants With an Event | 68 percentage of participants |
| Rituximab + IFN | Treatment Failure - Percentage of Participants With an Event | 67 percentage of participants |
Primary
Treatment Failure - Time to Event
The median time, in months, between randomization and treatment failure event determined using Kaplan-Meier estimates.
Time frame: BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab Monotherapy | Treatment Failure - Time to Event | 21.5 months |
| Rituximab + IFN | Treatment Failure - Time to Event | 28.0 months |
p-value: 0.3023Log Rank
Secondary
Disease Progression - Percentage of Participants With an Event
A disease progression event was defined as tumor progression or death due to any cause (or a censored observation).
Time frame: BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab Monotherapy | Disease Progression - Percentage of Participants With an Event | 60 percentage of participants |
| Rituximab + IFN | Disease Progression - Percentage of Participants With an Event | 62 percentage of participants |
Secondary
Duration of Response
The median time, in months, from the date of the first observation of CR, CRu, or PR and the date of progressive disease (PD), censored observation, or death due to any cause. PD was defined as an increase of \>50% compared to BL in the sum of the product of the two largest perpendicular parameters of measurable lymphoma, or the occurrence of new lesions. One month=30.4 days. Response duration was calculated amongst responders (CR+CRu+PR) with cutoffs for follow-up applied.
Time frame: BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period
Population: ITT population; n=number of participants assessed for the specified parameter at a given visit. Only participants with a response (CR+CRu+PR, CR+CRu, or CR only) were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Rituximab Monotherapy | Duration of Response | CR+CRu+PR (n=102,113) | 22.0 months |
| Rituximab Monotherapy | Duration of Response | CR+CRu only (n=62,73) | NA months |
| Rituximab Monotherapy | Duration of Response | CR only (n=50,62) | 59.5 months |
| Rituximab + IFN | Duration of Response | CR+CRu only (n=62,73) | 44.4 months |
| Rituximab + IFN | Duration of Response | CR+CRu+PR (n=102,113) | 30.0 months |
| Rituximab + IFN | Duration of Response | CR only (n=50,62) | 50.7 months |
Comparison: CR+CRu+PRp-value: 0.784Log Rank
Comparison: CR+CRup-value: 0.4419Log Rank
Comparison: CR onlyp-value: 0.5942Log Rank
Secondary
Duration of Response - Percentage of Participants With an Event
Response duration was defined as the period between the date for first observation of CR, CRu or PR and the date of progressive disease (PD), censored observation or death of any cause. Response duration was also assessed for response defined as CR only. Response duration was calculated among responders (CR+CRu+PR) with cutoffs for follow-up applied.
Time frame: BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab Monotherapy | Duration of Response - Percentage of Participants With an Event | CR, CRu, and PR (n=102,113) | 63 percentage of participants |
| Rituximab Monotherapy | Duration of Response - Percentage of Participants With an Event | CR and CRu only (n=62,73) | 44 percentage of participants |
| Rituximab Monotherapy | Duration of Response - Percentage of Participants With an Event | CR only (n=50,62) | 38 percentage of participants |
| Rituximab + IFN | Duration of Response - Percentage of Participants With an Event | CR, CRu, and PR (n=102,113) | 65 percentage of participants |
| Rituximab + IFN | Duration of Response - Percentage of Participants With an Event | CR and CRu only (n=62,73) | 53 percentage of participants |
| Rituximab + IFN | Duration of Response - Percentage of Participants With an Event | CR only (n=50,62) | 48 percentage of participants |
Secondary
Overall Survival
The median time, in months, from randomization to OS event assessed using Kaplan-Meier estimates. One month=30.4 days
Time frame: BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab Monotherapy | Overall Survival | NA months |
| Rituximab + IFN | Overall Survival | NA months |
p-value: 0.4963Log Rank
Secondary
Overall Survival (OS) - Percentage of Participants With an Event
An overall survival event was defined as death due to any cause.
Time frame: BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab Monotherapy | Overall Survival (OS) - Percentage of Participants With an Event | 13 percentage of participants |
| Rituximab + IFN | Overall Survival (OS) - Percentage of Participants With an Event | 11 percentage of participants |
Secondary
Percentage of Participants Achieving Complete Response (CR), Unconfirmed CR (CRu), or Partial Response (PR)
CR was defined as the complete disappearance of all previously detectable disease signs; the absence of palpable lymph nodes greater than (\>) 1 centimeter (cm) or nodes \>1.5 cm observed in computerized axial tomography (CAT) scan; and negative bone marrow pathology, if initially positive. CRu was defined as CR, except that bone marrow results were indeterminate. PR was defined as a decrease of greater than or equal to (≥) 50 percent (%) compared with the BL value in the sum of the products of the two largest perpendicular diameters in all measurable and evaluable lesions; and a ≥50% reduction of the size from BL if hepato-splenomegaly was present.
Time frame: Weeks 10 and 16
Population: ITT population; number (n) equals (=) number of participants assessed for the specified parameter at a given visit.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab Monotherapy | Percentage of Participants Achieving Complete Response (CR), Unconfirmed CR (CRu), or Partial Response (PR) | Week 10, Cycle 1 (n=156,157) | 54 percentage of participants |
| Rituximab Monotherapy | Percentage of Participants Achieving Complete Response (CR), Unconfirmed CR (CRu), or Partial Response (PR) | Week 16, Cycle 2 (n=123,124) | 74 percentage of participants |
| Rituximab + IFN | Percentage of Participants Achieving Complete Response (CR), Unconfirmed CR (CRu), or Partial Response (PR) | Week 10, Cycle 1 (n=156,157) | 59 percentage of participants |
| Rituximab + IFN | Percentage of Participants Achieving Complete Response (CR), Unconfirmed CR (CRu), or Partial Response (PR) | Week 16, Cycle 2 (n=123,124) | 82 percentage of participants |
Comparison: Week 10, Cycle 1p-value: 0.3362Chi-squared
Comparison: Week 16, Cycle 2p-value: 0.1157Chi-squared
Secondary
Percentage of Participants Achieving CR or CRu
CR was defined as the complete disappearance of all previously detectable disease signs; the absence of palpable lymph nodes \>1 cm or nodes \>1.5 cm observed in CATscan; and negative bone marrow pathology, if initially positive. CRu was defined as CR, except that bone marrow results were indeterminate.
Time frame: Weeks 10 and 16
Population: ITT population; n=number of participants assessed for the specified parameter at a given visit.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab Monotherapy | Percentage of Participants Achieving CR or CRu | Week 10, Cycle 1 (n=156,157) | 8 percentage of participants |
| Rituximab Monotherapy | Percentage of Participants Achieving CR or CRu | Week 16, Cycle 2 (n=123,124) | 24 percentage of participants |
| Rituximab + IFN | Percentage of Participants Achieving CR or CRu | Week 10, Cycle 1 (n=156,157) | 9 percentage of participants |
| Rituximab + IFN | Percentage of Participants Achieving CR or CRu | Week 16, Cycle 2 (n=123,124) | 41 percentage of participants |
Comparison: Week 10, Cycle 1p-value: 0.854Chi-squared
Comparison: Week 16, Cycle 2p-value: 0.0051Chi-squared
Secondary
Time to Disease Progression
The median time, in months, from randomization to disease progression event assessed using Kaplan-Meier estimates. One month=30.4 days
Time frame: BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab Monotherapy | Time to Disease Progression | 25.0 months |
| Rituximab + IFN | Time to Disease Progression | 32.0 months |
p-value: 0.8946Log Rank