Fludarabine and Rituximab With or Without Lenalidomide or Cyclophosphamide in Treating Patients With Symptomatic Chronic Lymphocytic Leukemia

Official Title

A Genetic Risk-Stratified, Randomized Phase II Study of Four Fludarabine/Antibody Combinations for Patients With Symptomatic, Previously Untreated Chronic Lymphocytic Leukemia

Summary:

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. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. Giving fludarabine and rituximab together with lenalidomide or cyclophosphamide may kill more cancer cells. PURPOSE: This randomized phase II trial is studying fludarabine and rituximab to compare how well they work with or without lenalidomide or cyclophosphamide in treating patients with symptomatic chronic lymphocytic leukemia.

Trial Description

Primary Outcome:

• 2-year progression-free survival rate

Secondary Outcome:

• Response rate (complete response and partial response)
• Toxicity as assessed by NCI CTCAE v4.0
• 2-year progression-free survival in patients with del (11q22.3)
• Toxicity of FRC in patients with del (11q22.3)

OBJECTIVES:
Primary

• To determine the two-year progression-free survival (PFS) after remission induction (RI) with four different chemo-immunotherapy combinations for patients with untreated, symptomatic, lower-risk and high-risk chronic lymphocytic leukemia (CLL) to decide which of the four arms, if any, to take forward into a randomized phase III trial. Secondary

• To determine the induction response to fludarabine phosphate and rituximab (FR) and fludarabine phosphate, cyclophosphamide, and rituximab (FCR) in each of these arms, along with the consolidation response to lenalidomide in patients with CLL.

• To determine the toxicity from these four chemoimmunotherapy combinations and that of consolidation therapy with lenalidomide.

• To determine the induction response and toxicity of FCR in patients with del(11q22.3) along with consolidation response, 2-year PFS and toxicity of lenalidomide in this specific genetic group.

• To determine the effect of pretreatment biologic characteristics on clinical outcomes, such as attaining a complete response to induction therapy and progression-free survival.

• To collect relapse samples to determine the frequency of clonal evolution among patients with IgVH mutated and unmutated disease and to study mechanisms of resistance to chemoimmunotherapy.

• To determine if flow cytometry-negative status immediately post-therapy and at 24 months after study entry is an effective surrogate marker for prolonged progression-free survival and overall survival.

OUTLINE:

This is a multicenter study. Patients are stratified according to risk group (intermediate vs high). Patients are randomized to 1 of 3 treatment arms or assigned to arm IV if found to be del(11q22.3) positive.

• Arm I (remission-induction [RI] therapy with fludarabine and rituximab): Patients receive rituximab IV on days 1, 3, and 5 of course 1 and on day 1 of all subsequent courses. Patients also receive fludarabine phosphate IV over 30 minutes or orally on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression.

• Arm II (RI therapy with fludarabine and rituximab followed by remission-consolidation [RC] therapy with lenalidomide): Patients undergo RI therapy as in arm I. Patients with a complete or partial response or stable disease proceed to RC therapy beginning approximately 4 months after completion of RI, comprising oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 3-6 courses in the absence of disease progression.

• Arm III (RI therapy with fludarabine phosphate, rituximab, and cyclophosphamide): Patients receive rituximab IV on days 1 and 3 of course 1 and on day 1 of all subsequent courses. Patients also receive fludarabine phosphate IV over 30 minutes or orally followed by cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression.

• Arm IV [del(11q22.3)-positive] (RI therapy with fludarabine, rituximab, and cyclophosphamide followed by RC therapy with lenalidomide): Patients undergo the first course of RI therapy as in arm I or II, followed by rituximab IV on day 1 of all subsequent courses, and fludarabine IV over 30 minutes and cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression. Beginning approximately 4 months after completion of RI therapy, patients receive RC therapy comprising oral lenalidomide as in arm II. Patients undergo bone marrow aspirate and blood sample collection at baseline; 3 months after completion of RI therapy; 2 months after completion of lenalidomide consolidation therapy (arm II and IV only); 2 years after study enrollment; and then at the time of relapse. Samples are assessed for interphase cytogenetic abnormalities; clonal evolution; IgV_H gene mutational status; CD38, CD49d, and ZAP-70 expression; p53 dysfunction, gene expression profile, and epigenetic changes in methylation. Samples are also assessed for flow cytometry negativity status. Studies include fluorescence in situ hybridization, chromosomal translocation, flow cytometry, and cytogenetics. After completion of study therapy, patients are followed every 3 months for 1 year and then every 6 months for up to 15 years.

View this trial on ClinicalTrials.gov