Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

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. 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.

Further Study Information

PRIMARY OBJECTIVES:

I. 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 OBJECTIVES:

I. 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.

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

III. 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.

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

V. 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.

VI. 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.

Eligibility Criteria

Inclusion Criteria:

• Diagnosis of B-cell chronic lymphocytic leukemia (CLL) meeting the following criteria:

• Absolute lymphocytosis > 5,000/μL

• Lymphocytes must appear mature with < 55% prolymphocytes

• Bone marrow aspirate smear must show > 30% of all nucleated cells as being lymphoid OR bone marrow core biopsy must show lymphoid infiltrates compatible with marrow involvement by CLL

• Overall cellularity must be normocellular or hypercellular

• Lymphocyte phenotype must reveal predominant B-cell monoclonal population sharing a B-cell marker (i.e., CD19, CD20, or CD23) with the CD5 antigen, in the absence of other pan-T-cell markers

• B-cells must be monoclonal with regard to expression of either kappa or lambda light chains and have surface immunoglobulin expression of low density

• Patients with bright surface immunoglobulin levels must have CD23 co-expression

• Must have symptomatic, active disease and meet 1 of the following risk criteria according to the modified three-stage Rai staging system:

• Intermediate-risk disease (i.e., Rai stage I or II) with evidence of active disease as demonstrated by at least one of the following criteria:

• Massive or progressive splenomegaly, hepatomegaly, and/or lymphadenopathy

• Presence of weight loss > 10% within the past 6 months

• Grade 2 or 3 fatigue

• Fevers > 100.5° F or night sweats for > 2 weeks without evidence of infection

• Progressive lymphocytosis with an increase of > 50% over a 2-monthperiod or an anticipated doubling time of < 6 months

• High-risk disease (i.e., Rai stage III or IV)

• Concurrent participation on CALGB-20702 (Leukemia Correlative Studies) required

• Performance status 0-2

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use two effective methods of contraception for ≥ 4 weeks prior to, during, and for ≥ 4 weeks after completion of lenalidomide therapy (for patients randomized to arm II or IV)

• Creatinine ≤ 1.5 times upper limit of normal

• No medical condition requiring chronic use of oral corticosteroids

• Patients with HIV infection may be eligible provided they meet the following criteria:

• CD4-positive cell count > 350/mm³

• HIV viral load< 10,000 copies HIV RNA/mL (if not on anti-HIV therapy) OR < 50 copies HIV RNA/mL (if on anti-HIV therapy)

• No evidence of hepatitis B or C infection

• No evidence of resistant strains of HIV

• No history of AIDS-defining condition

• No prior therapy for CLL, including corticosteroids for autoimmune complications that have developed since the initial diagnosis of CLL

• No concurrent zidovudine or stavudine

• No concurrent hormones or other chemotherapy, except steroids for hypersensitivity reactions or new adrenal failure or hormones for non-disease-related conditions (e.g., insulin for diabetes)

• No concurrent chronic oral steroids

• No concurrent palliative radiotherapy

• No concurrent epoetin alfa or darbepoetin alfa during remission consolidation therapy (for patients randomized to arm II or IV)

• Concurrent participation on CALGB-9665 allowed

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

John Byrd

Principal Investigator

U.S.A.
Missouri
	Cape Girardeau
	Southeast Cancer Center
		Alan Philip Lyss	Ph: 800-392-0936
	Jefferson City
	Goldschmidt Cancer Center
		Alan Philip Lyss	Ph: 800-392-0936
	Saint Louis
	Missouri Baptist Cancer Center
		Alan Philip Lyss	Ph: 800-392-0936
West Virginia
	Wheeling
	Schiffler Cancer Center at Wheeling Hospital
		Manish A Monga	Ph: 304-293-2745
			Email: sfilburn@hsc.wvu.edu

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00602459
Information obtained from ClinicalTrials.gov on April 01, 2013

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