Clofarabine Followed By Lenalidomide for High-Risk Myelodysplastic Syndromes and Acute Myeloid Leukemia
Condition: Myeldysplastic Syndrome (MDS); Chronic Myelomonocytic Leukemia; Bone Marrow Diseases; Neutropenia; Acute Myeloid Leukemia (AML)
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Neutropenia; Bone Marrow Diseases; Syndrome
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

        -  Several types of blood cancer are associated with poor outcomes including high-risk
           myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute
           myelogenous leukemia (AML). Many people with MDS, CMML, and AML are not candidates for
           standard treatments. New types of treatment are needed for these cancers.

        -  Clofarabine and lenalidomide are anticancer drugs. The first damages cancer cells in the
           body. The second can alter blood supply to abnormal cells or affect how the immune
           system attacks these cells. These drugs have been previously tested as treatments for
           MDS and leukemia. However, they have not been tried as a combination for MDS, CMML, and
           AML. Researchers want to see if these drugs are safe and effective for these types of
           cancer.

      Objectives:

      - To test the safety and effectiveness of clofarabine and lenalidomide for people with
      high-risk MDS, CMML, and AML.

      Eligibility:

        -  Individuals at least 18 years of age who have high-risk MDS, CMML, and AML.

        -  Participants must not be candidates for standard treatments.

      Design:

        -  Participants will be screened with a physical exam and medical history. Blood and bone
           marrow samples will be collected.

        -  Participants will have 5 days of treatment with clofarabine. It will be given through a
           vein during an inpatient hospital stay. If there are no serious side effects after the
           infusion, participants will continue treatment as outpatients.

        -  After 28 days, participants will have a bone marrow biopsy to check their response to
           treatment.

        -  After the biopsy, participants will start lenalidomide treatment. Half of the
           participants will take the drug for 28 days (one treatment cycle). The other half will
           take it for 56 days (two cycles). More blood tests and biopsies will be used to monitor
           treatment.

        -  If there are no serious side effects and the disease does not become worse, participants
           may keep taking lenalidomide at lower doses for up to 12 more cycles.
    

Detailed description: 
      High risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute
      myelogenous leukemia (AML) are hetereogeneous myeloid malignancies that are associated with a
      poor prognosis. Due to advanced age and medical comorbidities, the majority of MDS, CMML, and
      AML patients are not candidates for potentially curative standard treatments such as
      allogeneic stem cell transplantation (SCT) or intensive chemotherapy (ICT). New therapeutic
      approaches that improve response rates, have lesser toxicity, and extend survival are clearly
      needed for high risk MDS and AML patients.

      Clofarabine is a myelosuppressive, second generation purine nucleoside analogue which has
      shown meaningful efficacy at variable dosing levels for high risk MDS and AML patients with a
      favorable toxicity profile compared to intensive chemotherapy. Lenalidomide is an oral
      structural analogue of thalidomide with a complex mechanism of action including
      immunomodulatory, anti-angiogenic, and direct cytotoxic effects which is a well-established
      treatment for MDS and has shown agent single efficacy at higher doses for AML. Lenalidomide s
      therapeutic benefit in AML has been the greatest in patients with low presenting total
      leukocyte and circulating blast counts. We hypothesize that the initial cytoreductive effects
      of clofarabine may augment the effectiveness of subsequent lenalidomide therapy and create a
      favorable immunologic milieu for patients eligible for lenalidomide maintenance therapy. This
      open-label, single institution phase I trial will evaluate a sequential combination of IV
      clofarabine with oral lenalidomide for the treatment of high risk MDS, CMML, and AML.
      Subjects will receive a single course of IV clofarabine (5 milligrams per metered square per
      day times 5) for cytoreduction. This will be followed by oral lenalidomide consolidation with
      dose escalation from 25 mg daily for 21/28 days for 1 cycle in the first cohort up to 50 mg
      daily for 28/28 days for 2 cycles in the fourth cohort. In the absence of dose limiting
      toxicity or disease progression, Subjects will receive lenalidomide maintenance, starting at
      a dose of 10 mg daily in 28 day cycles, with dose adjustments, for up to 12 cycles.

      The overall objective is to determine the safety of sequential therapy with clofarabine and
      lenalidomide in subjects with high risk MDS, CMML, and AML. The primary study endpoint will
      be the toxicity profile of this novel treatment combination in each cohort. Secondary
      endpoints will include characterization of response and duration, overall survival, and the
      feasibility of maintenance lenalidomide therapy for responding subjects.
    

Intervention name(s): Clofarabine; Lenalidomide
Intervention type(s): Drug; Drug
Intervention MeSH terms: Lenalidomide; Clofarabine
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Myelodysplastic Syndromes; Acute Myeloid Leukemia (AML); Chronic Myelomonocytic Leukemia (CMML)