Efficacy and Safety of Lenalidomide in Combination With Cyclosporine A in Patients With Myelodysplastic Syndromes
Condition: Myelodysplastic Syndrome
MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome
Intervention: lenalidomide; cyclosporine A
Intervention description: Lenalidomide 10mg po daily; CSA 250mg orally twice daily
Intervention MeSH terms: Cyclosporine; Lenalidomide; Cyclosporins
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: stage (IPSS low and INT-1); RBC transfusion-dependent; non-del 5q MDS

Summary:

      Lenalidomide has shown significant efficacy in the treatment of anemia associated with both
      5q- and non 5q- MDS patients. The mechanism(s) of action of lenalidomide in MDS is still to
      be determined, but given the differences in response rates seen, it is probable that the
      mechanism is different for patients with 5q- disease compared to non 5q- patients. T-cell
      mediated activation of intramedullary apoptosis in patients with early MDS leading to
      impaired hematopoiesis has been well described. Immunomodulation with agents such as ATG,
      cyclosporine and thalidomide have demonstrated clear activity in some patients with MDS.
      Lenalidomide, among its many effects, is a potent immunomodulator, which may contribute to
      its ability to improve red blood cell counts in patients with MDS. It is possible that this
      effect could be augmented with the addition of cyclosporine A (CSA), in a similar manner to
      CSA effects in patients with other bone marrow failure syndromes such as aplastic anemia.

      Subjects will be treated with lenalidomide 10 mg PO daily days 1-28 of a 28-day cycle.
      Cyclosporine A will be started on day 1 of cycle 2 (day 29) at a dose of 5 mg/kg per day
      given orally in 2 divided doses. Cyclosporine A levels will be assessed weekly and doses will
      be adjusted to maintain a serum trough level between 100-450 mg/ml. Patients will continue on
      therapy for minimum of 16 weeks unless toxicity occurs which precludes continuation on
      therapy, disease progression and/or patient withdrawal of consent. Patients not achieving
      response after completing 16 weeks of therapy will discontinue treatment. Patients achieving
      response will continue therapy until disease progression, unacceptable toxicity or loss of
      response.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Understand and voluntarily sign an informed consent form.

          -  Age ≥ 18 years at the time of signing the informed consent form.

          -  Able to adhere to the study visit schedule and other protocol requirements.

          -  Diagnosis of low or intermediate-1 risk IPSS (MDS without an abnormality of chromosome
             5 involving a deletion between bands q31 and q33. Red blood cell (RBC)
             transfusion-dependent anemia as having received ≥ 2 units of RBCs within 8 weeks on
             the first day of study treatment.

          -  ECOG performance status of ≤ 2 at study entry

          -  Laboratory test results within the following ranges:

               -  Absolute neutrophil count (ANC) >500 x 109/L

               -  Platelet count ≥ 50 x 109/L

               -  Serum creatinine ≤ 2.0 mg/dL

               -  Total bilirubin ≤ 1.5 mg/dL

               -  AST (SGOT) and ALT (SGPT) ≤ 2 x ULN

          -  Disease free of prior malignancies for ≥ 5 years with exception of currently treated
             basal cell, squamous cell carcinoma of the skin, or carcinoma "insitu" of the cervix
             or breast.

          -  All study participants must be registered into the mandatory RevAssist® program, and
             be willing and able to comply with the requirements of RevAssist®.

          -  Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
             test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again
             within 24 hours of prescribing lenalidomide (prescriptions must be filled within 7
             days) and 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. FCBP must also agree to ongoing pregnancy testing. Men must also
             agree to use a latex condom during sexual contact with a FCBP even if they have had a
             successful vasectomy.

          -  Able to take asprin (81 or 325 mg) daily as a prophylactic anticoagulation (patients
             intolerant to ASA may use warfarin or low molecular weight heparin).

        Exclusion Criteria:

          -  Any serious medical condition, laboratory abnormality, or psychiatric illness that
             would prevent the subject from signing the informed consent form.

          -  Pregnant or breast feeding females. (Lactating females must agree not to breast feed
             while taking lenalidomide).

          -  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.

          -  Use of any other experimental drug or therapy within 28 days of baseline.

          -  Known hypersensitivity to thalidomide. Prior ≥ grade 3 NCI CTCAE (Version 3.0)
             allergic reaction/hypersensitivity.

          -  The development of erythema nodosum if characterized by a desquamating rash while
             taking thalidomide or similar drugs.

          -  Any prior use of lenalidomide.

          -  Concurrent use of other anti-cancer agents or treatments.

          -  Known positive for HIV or infectious hepatitis, type A, B, or C.

          -  Inability to aspirate bone marrow (dry tap).

          -  Proliferative (WBC ≥ 12,000/ul) CMML

          -  An abnormality of chromosome 5 involving a deletion between bands q31 and q 33.

          -  Any of the following lab abnormalities:

               -  Absolute neutrophil count (ANC) <500 cells/mm3 (0.5 x 109/L)

               -  Platelet count ≤ 50,000/mm3 (50 x 109/L)

               -  Serum creatinine ≥ 2.5 mg/dL (221µmol/L)

               -  Serum SGOT/AST or SGPT/ALT ≥ 2.0 x upper limit of normal (ULN)

               -  Serum direct bilirubin ≥ 2.0 mg/dL (34µmol/L)

          -  Clinically significant anemia due to factors such as iron, B12 or folate deficiencies,
             autoimmune or hereditary hemolysis or gastrointestinal bleeding (if a marrow aspirate
             is not evaluable for storage iron, transferring saturation must be ≥ 20% and serum
             ferritin not less than 50ng/mL).

          -  Use of hematopoietic growth factors within 7 days of the first day of study drug
             treatment.

          -  Chronic use (≥2 weeks) of greater than physiologic doses of a corticosteroid agent
             (dose equivalent to ≥ 10mg/day of prednisone) within 28 days of the first study drug
             treatment.

          -  Use of experimental or standard drug (i.e chemotherapeutic, immunosuppressive,
             cytoprotective agents) for the treatment of MDS within 28 days of the first day of
             study drug

          -  Prior history of malignancy other than MDS except basal cell or squamous cell
             carcinoma in situ of the cervix or breast, unless the patient has been free of disease
             for ≥ 5 year.

          -  Myocardial infarction within 6 months prior to enrollment, or NYHA (New York Hospital
             Association) Class III or IV heart failure disease. History of active angina,
             congestive heart disease, uncontrolled angina, severe uncontrolled ventricular
             arrhythmias, electrocardiographic evidence of uncontrolled ischemia and/or active
             conduction system abnormalities, or myocardial infarction within 6 months prior to
             enrollment, acute ischemia, or active conduction system abnormalities.

          -  Active viral or bacterial infections or any coexisting medical problem that would
             significantly increase the risks of this treatment program.

          -  History of thromboembolic event within the past 6 months prior to enrollment.

          -  Patients who have a hypersensitivity to Sandimmune® (cyclosporine).