Azacitidine, Lenalidomide and DLI as Salvage Therapy for MDS, CMML and sAML Relapsing After Allo-HSCT
Condition: Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes
Study type: Interventional
Phase: Phase 2

Summary: 
      This is a prospective, open-label, single-arm multi-center phase II study aiming to evaluate
      the safety and feasibility of the addition of Lenalidomide (investigational drug) to the
      standard therapy of Azacitidine and DLI (standard of care) as first salvage therapy for
      relapse of MDS, CMML and AML with MDS-related changes (sAML, with 20%-30% bone marrow blasts,
      formerly RAEB-T) after allo-SCT. The starting dose of Lenalidomid is 2.5 mg per day for 21
      days with a 7 day rest. The study incorporates 2 interim safety analyses after 10 and 20
      patients in order to find the optimal and safe dose of Lenalidomide.
    

Detailed description: 
      This is a prospective, open-label, single-arm multi-center phase II study aiming to evaluate
      the safety and feasibility of the addition of Lenalidomide (investigational drug) to the
      standard therapy of Azacitidine and DLI (standard of care) as first salvage therapy for
      relapse of MDS, CMML and AML with MDS-related changes (sAML, with 20%-30% bone marrow blasts,
      formerly RAEB-T) after allo-SCT.

      Study Design:

        -  prospective, open-label, single arm, multicenter phase-II trial

        -  total patients sample size: 50 patients

        -  number of trial sites: 6 all located in Germany and members of the EBMT Patients will be
           included at the time of relapse after first allo-SCT. Starting on day 1 all patients
           will receive Azacitidine 75 mg/m2/d for 7 days every 28 days for up to 8 cycles. DLIs
           will be given after cycle 4, 6 and 8. Lenalidomide will be also started on day 1 for 21
           days every 28 days for a maximum of 8 cycles. The concomitant administration of Aza and
           Lenalidomide will be used since safety and efficacy of this schedule has been
           demonstrated.

      Azacitidine and DLI represent a standard of care in this setting and are therefore not
      considered as investigational. As 5-Azacytidine is given in-label, treatment may be continued
      beyond 8 cycles. Additional DLIs may be given according to the investigators choice. However,
      to avoid severe GvHD it is recommended to give at least one more cycle 5-Azacytidine after
      additional DLIs.

      The study incorporates a dose escalating schedule for Lenalidomide and two safety interim
      analyses. A first interim analysis will be performed as soon as 10 patients have been treated
      with Lenalidomide at a dose of 2.5mg/day If no dose limiting toxicity is observed in this
      cohort the next cohort of 10 patients will be treated with 5 mg per day for 21 days starting
      on day 1. If dose limiting toxicity occurs the study will be closed. A second interim
      analysis will be performed as soon as 10 patients have been treated with Lenalidomide at a
      dose of 5mg/day and the 10th patient of this cohort has either completed 4 cycles or has
      discontinued treatment whichever occurs first. If no dose limiting toxicity is observed in
      this cohort, the dose of 5 mg per day for 21 days starting on day 1 will be chosen and the
      remaining patients will be treated with this dose of Lenalidomide. If dose limiting toxicity
      occurs in patients treated with 5mg per day the remaining patients will be treated with
      Lenalidomide at a dose of 2.5mg/day. A total number of 50 patients will be treated.

      Independent of the dose level, Lenalidomide will be stopped individually in the case of GvHD
      ≥ grade II.
    

Intervention name(s): Lenalidomide; Azacitidine; Donor Lymphocyte Infusions
Intervention type(s): Drug; Drug; Biological
Intervention description(s): Lenalidomide (investigational drug) will be added to standard of care (Aza and DLI) starting from day 1 for 21 days every 28 days for a maximum of 8 cycles. Starting dose of Lenalidomide 2.5 mg per day for the first 10 patients. If no dose limiting toxicity is identified in a first interim analysis, the next 10 patients will be treated with 5 mg per day. In case of no DLT after a second interim analysis, the remaining 30 patients are envisaged to be treated with 5 mg per day.; Starting on day 1 all patients will receive Azacitidine (standard of care) 75 mg/m2/d for 7 days every 28 days for up to 8 cycles.; DLIs will be given after cycle 4, 6 and 8 at a dose of 0.5-1x10^6 CD3/kg (1st DLI), 1-5x10^6 CD3/kg (2nd DLI) and 5-15x10^6 CD3/kg (3rd DLI).
Other intervention name(s): Revlimid; Vidaza; DLI
Intervention MeSH terms: Lenalidomide; Azacitidine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: relapse after allogeneic transplantation; MDS; AML; CMML; DLI; Azacitidine; Lenalidomide; C04.557.337.539.275; C15.378.190.625; C04.557.337.539.522