CLL-Irl Study. CTRIAL-IE (ICORG) 07-01, V7

Study Overview
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Brief Summary
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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. Giving fludarabine together with cyclophosphamide and rituximab may kill more cancer cells. PURPOSE: This phase II trial is studying giving fludarabine together with cyclophosphamide and rituximab to see how well it works in treating patients with chronic lymphocytic leukemia.

Detailed Description
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OBJECTIVES: Primary Evaluate the efficacy, in terms of complete remission rate, of fludarabine phosphate, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia. Secondary Determine the time to treatment failure (TTF) in these patients. Determine the overall survival of these patients until 10th January 2019. Assess the predictive value of immunophenotype, hypermutation analysis, and FISH in determining TTF and OS in these patients. Determine the safety profile of this regimen. OUTLINE: This is a multicenter study. Patients receive fludarabine IV over 30 minutes or orally and cyclophosphamide IV or orally on days 1-3 and pegfilgrastim subcutaneously on day 4. Starting on course 2, patients receive rituximab IV on day 1. Treatment repeats every 28 days for up to 6* courses in the absence of disease progression or unacceptable toxicity. NOTE: *Patients achieving negative minimal residual disease receive 4 courses of treatment. Blood samples are collected periodically for biomarker analysis. Samples are analyzed for protein expression (i.e., CD38, CD20, and ZAP70) by flow cytometry; quantitative immunoglobulins, β2-microglobulin, and T-cell subsets by electrophoresis; IgVH mutation status; and cytogenetics (i.e., +12, del 13q, del 11q, and del 17p) by FISH. After completion of study therapy, patients are followed every 6 months for 5 years and then annually until 10th January 2019.

Official Title
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An Open-label Phase II Study of the Efficacy and Safety of the Combination of Fludarabine, Cyclophosphamide and Rituximab in Patients With Chronic Lymphocytic Leukaemia Who Are Newly Diagnosed, Have Relapsed or Are Resistant to First-Line Treatment

Conditions
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Leukemia

Intervention / Treatment
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* Biological: pegfilgrastim
* Biological: rituximab
* Drug: cyclophosphamide
* Drug: fludarabine phosphate
* Genetic: cytogenetic analysis
* Genetic: fluorescence in situ hybridization
* Genetic: gene expression analysis
* Genetic: mutation analysis
* Genetic: protein expression analysis
* Other: flow cytometry
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of chronic lymphocytic leukemia Stage I-IV disease (Binet stage progressive A, B, C) CD5 and CD23 positive Untreated OR relapsed/resistant disease after combination chemotherapy or rituximab No 17p deletion PATIENT CHARACTERISTICS: WHO performance status 0-2 Life expectancy > 1 year Creatinine clearance ≥ 50 mL/min HIV negative Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other concurrent malignancy except for noninvasive cervical cancer or localized nonmelanomatous skin cancer No history of anaphylaxis to mouse-derived humanized monoclonal antibody No other severe concurrent (e.g., cardiac or pulmonary) diseases or mental disorders that could interfere with ability to participate in the study PRIOR CONCURRENT THERAPY: See Disease Characteristics

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 64 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: Fludarabine, Cylophosphamide and Rituximab<br> | Biological: pegfilgrastim<br> <br> Biological: rituximab<br> <br> Drug: cyclophosphamide<br> <br> Drug: fludarabine phosphate<br> <br> Genetic: cytogenetic analysis<br> <br> Genetic: fluorescence in situ hybridization<br> <br> Genetic: gene expression analysis<br> <br> Genetic: mutation analysis<br> <br> Genetic: protein expression analysis<br> <br> Other: flow cytometry<br> <br> Other: laboratory biomarker analysis<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission rate by NCI response criteria and minimal residual disease (MRD) analysis |  | A formal assessment of response by NCI Criteria (Appendix 3) with the addition of assessment of minimal residual disease in the marrow and if relevant assessment of bulky disease by CT scanning will be made after 4 +/-6 courses of therapy. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to treatment failure (TFF) |  | A clinical assessment of response will be made after 4 courses of therapy, Patients with evidence of progressive disease will stop therapy and will be deemed to have failed treatment. | 
| Overall survival |  | Until 10th January 2019 | 
| Predictive value of immunophenotype, FISH, and hypermutation analysis in determining TTF and OS | Timing and type of response assessment During chemotherapy. A clinical assessment of response will be made after 4 courses of therapy. Patients with evidence of progressive disease will stop therapy and will be deemed to have failed treatment. A formal assessment of response by NCI Criteria (Appendix 3) with the addition of assessment of minimal residual disease in the marrow and if relevant assessment of bulky disease by CT scanning will be made after 4 +/-6 courses of therapy. Following chemotherapy. Disease assessment after the end of therapy will involve a history(recording B-symptoms), complete physical examination, full blood count and blood MRD analysis every 6 months for 5 years and then annually until 10th of January 2019 or until disease progression. | See description | 
| Acute and chronic toxicity as assessed by NCI criteria |  | A formal assessment of response by NCI Criteria (Appendix 3) with the addition of assessment of minimal residual disease in the marrow and if relevant assessment of bulky disease by CT scanning will be made after 4 +/-6 courses of therapy. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory chronic lymphocytic leukemia, stage I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia