Alternating Thalidomide and Lenalidomide Therapy Plus Rituximab (ThRiL) as Initial Treatment for Patients With CLL
Condition: Chronic Lymphocytic Leukemia
MeSH terms: Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: thalidomide; lenalidomide; rituximab
Intervention description: 50 mg oral dosing every other day; varying oral doses every other day (max 25 mg/day); 375 mg/m2 intravenously on days 1, 8, 15, and 22 of cycle 1. Then, repeated on days 1, 8, 15, and 22 of every 6th cycle thereafter (Cycle 7, 13, 19, etc.)
Intervention MeSH terms: Thalidomide; Rituximab; Lenalidomide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: CLL

Summary:

      The investigators' hypothesis is that treatment of CLL with an alternating daily dosing
      schedule of thalidomide and lenalidomide may result in better tolerability by decreasing each
      agent's individual toxicities, while preserving efficacy, and therefore lead to a longer
      duration of therapy and improved responses. Additionally, the combination of the 2 agents may
      have additive or synergistic effects therapeutically.

      In Cycle -1, odd numbered patients will receive oral thalidomide daily days 1-14 followed by
      no treatment on days 15-28. Even numbered patients will receive oral lenalidomide daily on
      days 1-14 and then no treatment on days 15-28. Starting with cycle 1, patients will alternate
      daily thalidomide (every odd day) with daily lenalidomide (every even day) for days 1-28.
      Rituximab will be given on days 1, 8, 15, and 22 starting with Cycle 1, and then again every
      6th cycle thereafter (cycles 7, 13, 19, etc.)
    

Eligibility criteria:

        Inclusion criteria:

        1. Confirmed diagnosis of CLL or SLL based upon standard criteria as outlined in the IWCLL
        Update of the 1996 NCI-Working Group criteria for CLL:

        a) Presence of one of the following:

        1. more than or equal to 5 x 10^9 B lymphocytes/L in the peripheral blood for a duration of
        at least 3 months. Patients with a B lymphocytosis will be characterized as CLL, while
        those without will be characterized as SLL

        2. the presence of lymphadenopathy resulting from infiltration with lymphocytes with the
        phenotype of CLL

        3. bone marrow infiltration with lymphocytes with the phenotype of CLL

        b) Lymphocytes with the morphologic appearance of small, mature appearing lymphocytes, with
        less or equal to 55 percent prolymphocytes (blood or bone marrow)

        c) Cellular phenotype characterized by the:

          1. co-expression of the CD5, CD20, and CD23 surface antigens

          2. clonal kappa or lambda light chain expression

          3. dim surface immunoglobulin expression

        2. No prior therapy for CLL, including treatment for autoimmune conditions that have
        developed since the initial diagnosis of CLL.

        3. Active disease requiring therapy as defined by the IWCLL Update of the 1996 NCIWG
        guidelines:

          1. Evidence of progressive marrow failure as manifested by the development of worsening
             of anemia and / or thrombocytopenia

          2. Massive, progressive, or symptomatic splenomegaly

          3. Massive, progressive, or symptomatic lymphadenopathy

          4. Progressive lymphocytosis with an increase of more than 50 percent over a 2-month
             period or a lymphocyte doubling time of less than 6 months.

          5. Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroids or
             other standard therapy

          6. Presence of disease related symptoms: unintentional weight loss of more than 10
             percent within previous six months, significant fatigue, fevers greater than 100.5 F
             or 38.0 C for 2 or more weeks without evidence of infection, night sweats for more
             than 1 month without evidence of infection.

             4. Understand and voluntarily sign an informed consent form.

             5. Age at least 18 years at the time of signing the informed consent form.

             6. Able to adhere to the study visit schedule and other protocol requirements.

             7. ECOG performance status of at most 2 at study entry.

             8. Laboratory test results within these ranges:

               -  Absolute neutrophil count at least 1000/mm³

               -  Platelet count at least 50,000/mm³

               -  Creatinine clearance of at least 30 mL/min by Cockroft-Gault formula. Patients
                  with a baseline creatinine clearance of greater than 30 and less than 60 mL/min
                  will have a starting dose of lenalidomide 5 mg PO every other day per the defined
                  schedule. Patients with a baseline creatinine clearance of ≥ 60 mL/min will have
                  a starting dose of lenalidomide 5 mg PO daily per the defined schedule.

               -  Total bilirubin at most 1.5 times the ULN, unless abnormality is the result of
                  Gilbert's disease or the result of the CLL.

               -  AST (SGOT) and ALT (SGPT) at most 3 x ULN (or at most 5 x ULN if due to the CLL)

                  9. Disease free of prior malignancies for at least 2 years with exception of
                  curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, or
                  carcinoma "in situ" of the cervix or breast.

                  10. All study participants must be registered into the mandatory Revlimid REMS
                  and S.T.E.P.S. ( P-TAP: Protocol Therapy Assistance Program) program(s), and be
                  willing and able to comply with the requirements of Revlimid REMS and S.T.E.P.S.

                  11. Females of childbearing potential (FCBP) must have a negative serum or urine
                  pregnancy test with a sensitivity of at least 25 mIU/mL within 10 -14 days prior
                  to and again within 24 hours of starting treatment and again within 24 hours
                  before the first dose of lenalidomide AND thalidomide. FCBP must either commit to
                  continued abstinence from heterosexual intercourse or begin TWO acceptable
                  methods of birth control, one highly effective method and one additional
                  effective method AT THE SAME TIME, at least 28 days before she starts taking
                  lenalidomide and/or thalidomide. Females of reproductive potential must adhere to
                  the scheduled pregnancy testing as required in the Revlimid REMS program . Men
                  must agree to use a latex condom during sexual contact with a FCBP even if they
                  have had a successful vasectomy. All patients must be counseled at a minimum of
                  every 28 days about pregnancy precautions and risks of fetal exposure.

                  12. Able to take aspirin 81 or 325 mg daily as prophylactic anticoagulation,
                  unless already on therapeutic anticoagulation. Patients intolerant to ASA may use
                  coumadin or low molecular weight heparin.

             Exclusion criteria:

               1. Any serious medical condition, laboratory abnormality, or psychiatric illness
                  that would prevent the subject from providing informed consent.

               2. Any condition, including the presence of laboratory abnormalities, which places
                  the subject at unacceptable risk if he/she were to participate in the study or
                  confounds the ability to interpret data from the study.

               3. Evidence of laboratory TLS by Cairo-Bishop Definition of Tumor Lysis Syndrome.
                  Subjects may be enrolled upon correction of electrolyte abnormalities.

               4. Concurrent use of other anti-cancer agents or treatments.

               5. Prior treatment with thalidomide or lenalidomide.

               6. Active serious infection not controlled with antibiotics.

               7. Autoimmune hemolytic anemia or thrombocytopenia requiring treatment.

               8. Known positive for HIV

               9. Active infection with hepatitis B, defined by being positive for HepBsAg or Hep B
                  DNA by PCR, or hepatitis C

              10. Pre-existing peripheral neuropathy greater than grade 2

              11. Pregnant or breast feeding females. (Lactating females must agree not to breast
                  feed while taking lenalidomide and/or thalidomide).