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

In previously-untreated subjects with CLL, fludarabine and rituximab with or without cyclophosphamide (FR or FCR) produces complete responses (CR) of 40-80%. The major complication of FCR has been grade 3/4 neutropenia which was reduced using a lower dose of fludarabine and cyclophosphamide (FCR-Lite) The objective of this study is to evaluate the minimal residual disease (MRD) complete response rate (using the 2008 IWCLL guidelines) after 4 cycles of FCR-Lite plus lenalidomide in subjects with previously untreated CLL. Lenalidomide is active in frontline treatment of CLL as well as in patients with refractory disease. MRD has been demonstrated to be a sensitive surrogate marker for progression-free survival. If patients are MRD negative complete responders (CR) they will stop at 4 cycles of FCR-Lite followed by the lenalidomide consolidation/maintenance arm of the study. If they have a MRD positive CR or partial response (PR) they will continue with 2 additional cycles of FCR-Lite plus lenalidomide followed by lenalidomide consolidation/maintenance. They will be re-tested for MRD after the 6th cycle of FCR-Lite and after 6 and 12 months of lenalidomide monotherapy If they have no response (NR) or progressive disease (PD) following 4 cycles of FCR-Lite plus lenalidomide they will be removed from the study.

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.

Eligibility Criteria:
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.