Phase II Protocol for CLL With Fludarabine and Cyclophosphamide With Rituximab (FCR) Plus Lenalidomide
Condition: Chronic Lymphocytic Leukemia (CLL)
MeSH terms: Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide
Intervention description: 19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity.
Intervention MeSH terms: Cyclophosphamide; Rituximab; Fludarabine; Lenalidomide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 21.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: CLL; FCR; Rituximab; Lenalidomide; Cyclophosphamide

Summary:

      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.
    

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.