A Study of MabThera/Rituxan (Rituximab) Alone and in Combination With Roferon-A in Patients With Follicular or Other CD20+ Low-Grade (Indolent) Lymphoma

Study Overview
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Brief Summary
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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.

Official Title
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Rituximab (Mabthera®) as Single Agent and in Combination With Interferon Alfa-2a (Roferon-A®), a Phase-III Randomized Trial in Patients With Follicular or Other CD20+ Low-grade (Indolent) Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Drug: rituximab
* Drug: interferon-a-2a


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rituximab Monotherapy<br>Participants received 375 milligrams per square meter (mg/m2) rituximab intravenously (i.v.) weekly for 4 weeks. Participants achieving minor response (MR), partial response (PR), or completer response (CR) received a second cycle of treatment. | Drug: rituximab<br>* 375 mg/m2 rituximab i.v. weekly for 4 weeks<br>* Other names: Rituxan;|
| Experimental: Rituximab, Interferon<br>Participants received 375 mg/m2 rituximab i.v. weekly for 4 weeks; and 3 million international units per day (MIU/day) interferon-a2a subcutaneously (s.c.) during Week 1, and 4.5 MIU/day s.c. 6 days per week during Weeks 2 through 5. Interferon-a2a was not administered on days of rituximab administration. Participants achieving MR, PR, or CR received a second cycle of treatment. | Drug: rituximab<br>* 375 mg/m2 rituximab i.v. weekly for 4 weeks<br>* Other names: Rituxan;Drug: interferon-a-2a<br>* 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<br>* Other names: Roferon-A;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline (BL), Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period | 
| Treatment Failure - Time to Event | The median time, in months, between randomization and treatment failure event determined using Kaplan-Meier estimates. | BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Weeks 10 and 16 | 
| 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. | Weeks 10 and 16 | 
| 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. | BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period | 
| 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. | BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period | 
| 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). | BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period | 
| 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 | BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period | 
| Overall Survival (OS) - Percentage of Participants With an Event | An overall survival event was defined as death due to any cause. | BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period | 
| Overall Survival | The median time, in months, from randomization to OS event assessed using Kaplan-Meier estimates. One month=30.4 days | BL, Week 10 and 16, and Months 6, 12, 18, 24, 30, and 42 of the follow-up period |