A Study of Induction and Maintenance Treatment With MabThera (Rituximab) in Patients With Indolent B-Cell Nonfollicular Lymphomas

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of MabThera in combination chemotherapy, followed by maintenance treatment with MabThera. The anticipated time on study treatment is 1-2 years, and the target sample size is <100 individuals.

Official Title
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An Open-label Study of Fludarabine and Cyclophosphamide Plus MabThera Followed by Maintenance With MabThera on Failure-free Survival in Treatment-naïve Patients With Advanced Indolent B-cell Nonfollicular Lymphoma

Conditions
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Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients 18-65 years of age; previously untreated indolent nonfollicular non-Hodgkin's lymphoma; active disease; >=3 involved sites. Exclusion Criteria: typical chronic lymphocytic leukemia; other malignancies within 3 years before study, except basal or squamous cell skin cancer or cancer in situ of the cervix; systemic corticosteroid use for >1 month; significant cardiovascular disease; central nervous system involvement; hepatitis B or C virus infection, or HIV infection.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: rituximab<br>* 1<br>* Other names: MabThera/Rituxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Remaining Failure-Free After 2 Years From Treatment Start Date | Percentage of participants who at 2 years from the start of treatment remained free from documented disease progression, relapse, or death. Failure status was based on tumor evaluation performed on Month 28. Participants who did not have a tumor evaluation at Month 28 were counted as failures. | Month 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving a Best Overall Response of CR, CRu, or PR by Study Phase | CR: complete disappearance of all symptoms/objective signs of disease (enlarged lymph nodes, hepatomegaly, splenomegaly) for at least 3 months following definitive re-evaluation at end of therapy. For initial bone marrow involvement, clearance of bone marrow documented by biopsy, normalization of blood counts with granulocytes greater than (>)1,500 per microliter (/µL), hemoglobin >12 grams per deciliter (g/dL), platelets >100,000/µL. CRu: disappearance of all symptoms and nearly all measurable lesions, but persistence of some radiologic abnormalities with normalization of all biologic abnormalities; normalization of the performance status for at least 3 months after the definite evaluation of therapy. PR: at least 50 percent (%) reduction of measurable and evaluable lymphoma involvement for at least 4 weeks without occurrence of new manifestations, normalization of blood counts. Participants without evaluation at end of induction/maintenance phase were considered nonresponders. | Baseline, Months 4, 7 (Induction Phase), 11, 16 (Maintenance Phase),22, 28, 34, and 40(Follow-Up Phase) | 
| Percentage of Participants Achieving a Response by Response Type and Study Phase | CR: complete disappearance of all symptoms/objective signs of disease (enlarged lymph nodes, hepatomegaly, splenomegaly) for at least 3 months following definitive re-evaluation at end of therapy. For initial bone marrow involvement, clearance of bone marrow documented by biopsy, normalization of blood counts with granulocytes greater than (>)1,500 per microliter (/µL), hemoglobin >12 grams per deciliter (g/dL), platelets >100,000/µL. CRu: disappearance of all symptoms and nearly all measurable lesions, but persistence of some radiologic abnormalities with normalization of all biologic abnormalities; normalization of the performance status for at least 3 months after the definite evaluation of therapy. PR: at least 50 percent (%) reduction of measurable and evaluable lymphoma involvement for at least 4 weeks without occurrence of new manifestations, normalization of blood counts. Participants without evaluation at end of induction/maintenance phase were considered nonresponders. | Baseline, Months 4, 7, 11, 16, 22, 28, 34, and 40 | 
| Failure-Free Survival (FFS), Percentage of Participants Estimated to be Free of Documented Disease Progression, Relapse, or Death | FFS data were analyzed using Kaplan-Meier survival analysis. FFS was measured from the date of treatment start to the date of documented disease progression, relapse, or death from any cause. Responding participants, participants who were lost to follow up, who withdrew consent, or dropped out due to adverse events (AE) were censored at their last assessment date. The reported data refer to values up to 40 months. | Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40 | 
| FFS - Percentage of Participants With an Event | FFS was measured from the date of treatment start to the date of documented disease progression, relapse, or death from any cause. Responding participants, participants who were lost to follow up, who withdrew consent, or who dropped out due to AEs were censored at their last assessment date. | Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40 | 
| FFS - Time to Event | FFS was measured from the date of treatment start to the date of documented disease progression, relapse or death from any cause. Responding participants, participants who were lost to follow up, who withdrew consent or dropped out due to AEs were censored at their last assessment date. NOTE: The mean survival time and its standard error were underestimated because the largest observation was censored and the estimation was restricted to the largest event time. | Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40 | 
| Overall Survival (OS) - Percentage of Participants Estimated to be Alive | OS data were analyzed using Kaplan-Meier survival analysis. OS was defined as the time from first dosage of study drug to the date of death from any cause. Reported data refer to values up to 40 months. | Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40 | 
| OS - Percentage of Participants With an Event | OS was defined as the time from first dosage of study drug to the date of death from any cause. | Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40. | 
| OS - Time to Event | Overall survival was defined as the time from first dosage of study drug to the date of death from any cause. | Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40. | 
| Disease-Free Survival (DFS) - Percentage of Participants Estimated to be Disease-Free | DFS data were analyzed using Kaplan-Meier survival analysis. DFS was defined for all participants who achieved a complete response (CR/CRu) at month 1 after the completion of treatment of the induction phase (Month 7 of the study) and was measured from the time of CR to the date of relapse. Participants without relapse were censored at their last assessment date. Participants who died due to tumour burden were considered in relapse. Participants who died due to any other causes were censored as of the death date. The reported data refer to values up to 40 months. | Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40 | 
| DFS - Percentage of Participants With an Event | DFS was defined for all patients who achieved a complete response (CR/CRu) at month 1 after the completion of treatment of the induction phase (month 7 of the study) and was measured from the time of complete response to the date of relapse. Participants without relapse were censored at their last assessment date. Participants who died due to tumour burden were considered in relapse. Participants who died due to any other causes were censored on the death date. | Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40. | 
| DFS - Time to Event | DFS was defined for all participants who achieved a complete response (CR/CRu) at month 1 after the completion of treatment of the induction phase (month 7 of the study) and was measured from the time of complete response to the date of relapse. Participants without relapse were censored at their last assessment date. Participants who died due to tumour burden were considered in relapse. Participants who died due to any other causes were censored on the death date. NOTE: The mean survival time and its standard error were underestimated because the largest observation was censored and the estimation was restricted to the largest event time. | Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40. | 
| Progression-free Survival (PFS) - Percentage of Participants Estimated to Be Progress Free | PFS data were analyzed using Kaplan-Meier survival analysis. PFS was defined as the time from treatment start to the date of documented disease progression. Reported data refer to values up to 40 months. | Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40 | 
| PFS - Percentage of Participants With an Event | Progression-free survival was defined as the time from the date of treatment start to the date of documented disease progression. | Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40 | 
| PFS - Time to Event | Progression-free survival was defined as the time from treatment start to the date of documented disease progression. NOTE: The mean survival time and its standard error were underestimated because the largest observation was censored and the estimation was restricted to the largest event time. | Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40 | 
| Duration of Response (DR) - Percentage of Participants Expected to Maintain a Response | DR data were analyzed using Kaplan-Meier survival analysis. DR was defined for all participants who achieved a response (CR, CRu and PR) at month 1 after the completion of treatment of the induction phase (Month 7 of the study) and was measured from the time of response until the date of progression or relapse. Participants without relapse or progression were censored at their last assessment date. Participants who died due to tumour were considered in progression. Participants who died for any other cause were censored to the death date. | Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40 | 
| DR - Percentage of Participants With an Event | DR was defined for all participants who achieved a response (CR, CRu and PR) at month 1 after the completion of treatment of the induction phase (Month 7 of the study) and was measured from the time of response until the date of progression or relapse. Participants without relapse or progression were censored at their last assessment date. Participants who died due to tumour were considered in progression. Participants who died for any other cause were censored to the death date. | Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40 | 
| DR - Time to Event | DR was defined for all participants who achieved a response (CR, CRu and PR) at month 1 after the completion of treatment of the induction phase (Month 7 of the study) and was measured from the time of response until the date of progression or relapse. Participants without relapse or progression were censored at their last assessment date. Participants who died due to tumour were considered in progression. Participants who died for any other cause were censored to the death date. | Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40 |