Phase III, Multicentre, Randomised Study of Fludarabine/Cyclophosphamide Combination With or Without Rituximab in Patients With Untreated Mantle Cell Lymphoma

Study Overview
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Brief Summary
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This randomized phase III trial is comparing how well fludarabine and cyclophosphamide work when given together with or without rituximab in treating patients with previously untreated mantle cell lymphoma.

Detailed Description
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RATIONALE: Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. It is not yet known whether giving combination chemotherapy together with rituximab is more effective than combination chemotherapy alone in treating mantle cell lymphoma. OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive fludarabine phosphate IV or orally once daily and oral cyclophosphamide once daily on days 1-3. Treatment repeats every 28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive rituximab IV on day 1 and fludarabine phosphate IV or orally once daily and oral cyclophosphamide once daily on days 1-3. Treatment repeats every 28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow and blood sample collection periodically for molecular studies. Samples are analyzed for morphology; sIgM, sIgD, CD19, CD20, CD5, CD10, CD23, bcl-1, bcl-6 via immunophenotyping and immunohistochemistry; and t(11,14) translocation via interphase fluorescence in situ hybridization (FISH) mutational analysis. After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter. This trial follows on from the Phase II randomised study of fludarabine/cyclophosphamide combination with or without Rituximab in patients with untreated mantle cell lymphoma. ISRCTN number: NCT00053092 Peer Reviewed and Funded or Endorsed by Cancer Research UK

Official Title
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Phase III, Multicentre, Randomised Study of Fludarabine/Cyclophosphamide Combination With or Without Rituximab in Patients With Untreated Mantle Cell Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: rituximab
* Drug: Cyclophosphamide
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed mantle cell lymphoma (MCL), meeting the following criteria: Diagnosis confirmed by examination of representative material (lymph nodes or bone marrow) together with a typical immunophenotype CD5+, CD23-, sIgM, cyclin D1 nuclear positivity is desirable but not essential Central review of histology will be performed on diagnostic material Molecular or cytogenetic confirmation of diagnosis is not required Previously untreated disease at any stage requiring therapy in the opinion of the treating physician PATIENT CHARACTERISTICS: Life expectancy ≥ 3 months Life expectancy not severely limited by other illness Creatinine clearance ≥ 30 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during study therapy No known serological positivity for HBV, HCV, or HIV No concurrent uncontrolled serious medical conditions No severe impairment of renal or liver function (alkaline phosphatase, bilirubin or creatinine > 2.5 times upper limit of normal) not related to lymphoma No known hypersensitivity to murine proteins No prior malignancy in the past 5 years, except for nonmelanoma skin tumor or curatively resected carcinoma in situ of the uterine cervix No history of a psychological illness or condition that, in the opinion of the investigator, may adversely affect compliance with study medication PRIOR CONCURRENT THERAPY: No prior chemotherapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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 |
| --- | --- |
| Experimental: Fludarabine/Cyclophosphamide/Rituximab<br>Fludarabine 40mgs/m2 oral days 1-3 Cyclophosphamide 250mgs/m2 oral days 1-3 Rituximab 375mgs/m2 day 1 iv infusion Every 28 days | Biological: rituximab<br>* concentrate for solution for infusion<br>Drug: Cyclophosphamide<br>* Tablets<br>Drug: Fludarabine<br>* Film coated tablet<br>|
| Active Comparator: Fludarabine/Cyclophosphamide<br>Fludarabine 40mgs/m2 oral days 1-3 Cyclophosphamide 250mgs/m2 oral days 1-3 Every 28 days | Drug: Cyclophosphamide<br>* Tablets<br>Drug: Fludarabine<br>* Film coated tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival - Time from date of first administration of treatment until death from any cause | From date of first administration of treatment until the date of death from any cause, assessed up to a maximum of 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Progression-free survival - Time from date of first administration of treatment to Disease Progression or replapse | From date of first treatment administration until the date of first documented progression or relapse, whichever came first, assessed up to a maximum of 60 months | 
| Toxicity - Number of patients with >=grade 3 toxicity | Toxicity - Number of patients who suffer grade 3 or 4 toxicities | Within 30 days after last dose of treatment | 
| Toxicity - Percentage of patients with >=grade 3 toxicity | Toxicity - Percentage of patients who suffer grade 3 or 4 toxicities | Within 30 days after last dose of treatment | 
| Tumor response duration | Tumor response duration - Time from Complete or Partial Response to disease progression | From date of first documentation of PR or CR until the date of first progression up to a maximum of 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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contiguous stage II mantle cell lymphoma, noncontiguous stage II mantle cell lymphoma, stage I mantle cell lymphoma, stage III mantle cell lymphoma, stage IV mantle cell lymphoma