Trial Information

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

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.