Phase II Protocol for CLL With Fludarabine and Cyclophosphamide With Rituximab (FCR) Plus Lenalidomide

STUDY OBJECTIVES:

Primary:

The primary objective is to evaluate the complete response rate following 4 cycles of
FCR-Lite plus lenalidomide in previously untreated patients with CLL.

Secondary:

The first secondary objective is to evaluate the toxicity of patients with previously
untreated CLL treated with FCR-Lite plus lenalidomide, followed by lenalidomide. The second
is to evaluate the overall response rate and overall survival of patients with previously
untreated CLL treated with FCR-Lite plus lenalidomide followed by lenalidomide. The third is
to determine whether adding lenalidomide as a consolidation/maintenance therapy will
eliminate bone marrow minimal residual disease in CR patients and whether patients who have a
PR after 6 cycles of FCR-Lite plus lenalidomide will respond to 12 months of lenalidomide.
The final secondary objective is to determine whether the expression of ZAP-70, CD38, and
chromosomes correlate with response rate, duration of response, and survival for previously
untreated patients with CLL.

STUDY DESIGN:

2-stage phase 2 study-design. 19 subjects are treated in stage-1 with FCR-Lite plus 5mg
lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity. If there
are at least 5 CRs the study will accrue an additional 35 subjects (see statistical section).
A secondary objective of this study will be to determine if MRD positive patients will become
MRD negative with lenalidomide consolidation/maintenance and whether PR patients will convert
to CRs Lenalidomide will begin 2 months after the last dose of FCR-Lite in all subjects with
CR. It may begin as soon as 1 month after FCR-Lite plus lenalidomide in subjects with PR.
Lenalidomide is given in 28 d cycles increasing the dose from 5 mg/d to 10 mg/d in cycle 2
and to 15mg in cycles 3-6 if well- tolerated (no grade-3 or -4 toxicity). Patients with
creatinine clearance ≥30ml/min and <60ml/min will start at 2.5mg daily increasing to 5 and
10mg in subsequent cycles . Reduction to the prior dose is allowed for grade-3/-4 toxicity.
MRD will be studied by flow cytometry from bone marrow and peripheral blood samples following
4 and 6 cycles of FCR-Lite and after 6 and 12 months of lenalidomide in CR patients.

Inclusion Criteria:

- Patients must have diagnosis of CLL (as defined by the NCI Criteria below:

- Patients must have peripheral blood absolute lymphocyte count of >5,000/mm3
obtained within 2 weeks prior to start of study.

- The lymphocytosis must consist of small, mature lymphocytes, with ≤55% (not
greater than 55%) prolymphocytes.

- Patients must have phenotypically characterized CLL as defined as:

1. The predominant population of cells share B-cell antigens with CD5 in the absence
of other pan-T-cell markers (CD3, CD2, etc.);

2. Surface immunoglobulin (slg) and CD20 with low-cell surface density expression.

3. If surface immunoglobulin can be demonstrated, the leukemic cells are restricted
to expression of either kappa or lambda.

- Splenomegaly, hepatomegaly or lymphadenopathy are not required for the diagnosis of
CLL

- Patients must require chemotherapy

- Patients must not have received prior treatment cytotoxic, immunotherapy or
investigational therapy.

- Patients must not have history of corticosteroid treatment for CLL, Autoimmune
thrombocytopenia, or autoimmune hemolytic anemia.

- Calculated creatinine clearance ≥30ml/min by Cockcroft-Gault formula

- Bilirubin must be ≤1.5mg/dl, unless secondary to tumor, obtained within 2 weeks prior
to registration

- Platelets ≥75x109/L, unless due to CLL involvement of bone marrow

- Neutrophils ≥1.5x109/L, unless due to CLL involvement of bone marrow

- AST or ALT < 2x upper limit of normal, unless related to CLL

- Age ≥18 years

- ECOG performance status 0-2

- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test

- Men must agree to use a latex condom during sexual contact with a FCBP even if they
have had a successful vasectomy

- Able to take aspirin (81mg or 325mg) daily as prophylactic anticoagulation

- Subject must provide written informed consent

- All study participants must be registered into the mandatory RevAssist® program, and
be willing and able to comply with the requirements of RevAssist®

Exclusion Criteria:

- Patients with autoimmune hemolytic anemia or autoimmune thrombocytopenia are not
eligible

- No prior immunotherapy, investigational or cytotoxic chemotherapy

- Patients with a history of steroid treatment for CLL/SLL autoimmune hemolytic anemia,
or autoimmune thrombocytopenia are not eligible

- Patients with active infections requiring oral or intravenous (IV) antibiotics until
resolution of the infection and completion of therapeutic antibiotics

- Women of childbearing potential and sexually active males who both refuse to use an
accepted and effective method of contraception or women who are breastfeeding

- Patients with a second malignancy other than basal cell carcinoma or squamous cell
carcinoma of the skin or in situ carcinoma of the cervix are not eligible unless the
tumor was treated with curative intent at least two years previously

- History of known HIV

- History or presence CNS disease

- Evidence of laboratory TLS by Cairo-Bishop definition of Tumor Lysis Syndrome

- History of corticosteroid treatment for CLL, Autoimmune thrombocytopenia, or
autoimmune hemolytic anemia.