Sitagliptin for Prevention of Acute Graft Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation
Condition: Graft vs Host Disease; Hematopoietic Stem Cell Transplantation
MeSH terms: Graft vs Host Disease
Intervention: Sitagliptin
Intervention description: 600 mg ever 12 hours by mouth will be given starting the day before transplant through day +14 after transplant
Intervention MeSH terms: Sitagliptin Phosphate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 37.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: Allogeneic; Sitagliptin

Summary:

      Primary Objective

      Evaluate the efficacy of sitagliptin in reducing the incidence of grade II-IV acute Graft
      Versus-Host Disease (GvHD) by day +100 post-transplant in patients undergoing allogeneic
      hematopoietic stem cell transplantation and receiving standard sirolimus and tacrolimus GvHD
      prophylaxis.

      Secondary Objectives

      The following descriptive secondary objectives will be studied:

        1. Describe the tolerability and potential toxicity of sitagliptin.

        2. Describe the cumulative incidence of grades II-IV acute GvHD by day +100.

        3. Describe the cumulative incidence of grades III-IV acute GvHD.

        4. Describe the engraftment kinetics of absolute neutrophil count and platelets.

        5. Describe the incidence of infections occurring during the 100 days post-transplant.

        6. Describe non-relapse mortality (NRM) at day +30, +100, and 1 year post-transplant.

        7. Describe overall survival.

        8. Describe the incidence of chronic GvHD.

        9. Describe the cumulative incidence of relapse of the primary hematological malignancy.
    

Eligibility criteria:

        INCLUSION CRITERIA:

        A. Patients with any of the following hematologic malignancies:

          1. Acute myeloid leukemia (AML) with any of the following:

               1. In first remission (CR1) with intermediate risk or high-risk cytogenetic and/or
                  molecular features.

               2. Patients in second or subsequent complete remission (CR2, CR3, etc.).

               3. Primary refractory or relapsed AML with no more than any one of the following
                  adverse additional features according to modified CIBMTR criteria:49

                    -  Duration of first CR < 6 months

                    -  Poor risk cytogenetics or molecular features (FLT-3 internal tandem
                       duplication (ITD); complex karyotype with ≥3 clonal abnormalities, 5q-/-5,
                       7q-/-7, 11q23 abnormalities, inv(3), monosomal karyotype)

                    -  Circulating peripheral blood blasts at time of enrollment

                    -  Karnofsky performance status <90%

          2. Acute lymphoblastic leukemia (ALL) with any of the following:

               1. In CR1 or subsequent complete remission (CR2, CR3, etc.)

               2. Primary refractory or relapsed ALL with no more than one of the following adverse
                  features according to modified CIBMTR criteria:49

                    -  Second or subsequent relapse

                    -  Bone marrow blasts >25% at time of enrollment

                    -  Age >40 years

          3. Myelodysplasia with any of the following features:

               1. Refractory anemia with excess blasts type I (5-10% blasts) or II (11-20% blasts)
                  in the bone marrow (RAEB I and II)

               2. Refractory cytopenia with multilineage dysplasia (RCMD) and poor risk
                  cytogenetics (i.e., chromosome 7 abnormalities or complex karyotype with at least
                  3 abnormalities per clone)

          4. Chronic myelogenous leukemia (CML) with one of the following criteria:

               1. Accelerated phase, defined by any of the following:

                    -  Blasts 10-19% in peripheral blood white cells or bone marrow

                    -  Peripheral blood basophils at least 20%

                    -  Persistent thrombocytopenia (<100 x 109/l) unrelated to therapy, or
                       persistent thrombocytosis (>1000 x 109/l) unresponsive to therapy

                    -  Increasing spleen size and increasing white blood cell (WBC) count
                       unresponsive to therapy

                    -  Cytogenetic evidence of clonal evolution (i.e., the appearance of an
                       additional genetic abnormality that was not present in the initial specimen
                       at the time of diagnosis of chronic phase)

               2. Chronic phase provided a complete hematologic remission was not achieved by 3
                  months or a complete cytogenetic remission by 18 months and the patient had
                  received at least 2 tyrosine kinase inhibitors

          5. Patients with aggressive non-Hodgkin's lymphoma (NHL), including diffuse large cell
             lymphoma, mediastinal B-cell lymphoma, transformed lymphoma, mantle cell lymphoma, and
             peripheral T cell lymphoma, who also have one of the following criteria:

               1. Failure to achieve complete remission to primary induction therapy

               2. Relapsed and refractory to at least one line of salvage systemic therapy

               3. Failed stem cell collection

          6. Patients with Hodgkin's lymphoma meeting one of the following criteria:

               1. Primary refractory (failure to achieve complete remission to primary induction
                  therapy)

               2. Relapsed and refractory to at least one line of salvage systemic therapy

               3. Failed stem cell collection

        B. Patient age ≥ 18 to ≤ 60 years

        C. Karnofsky Performance status ≥ 70%

        D. Patients must also receive a full myeloablative preparative regimen (Patients treated
        with either total body irradiation (TBI)-based or high-dose chemotherapy only regimens are
        eligible other than high-dose busulfan containing regimens or regimens that include
        anti-thymocyte globulin or other T cell depleting antibodies)

        E. Patients receiving allogeneic peripheral blood stem cell (PBSC) grafts from HLA-matched
        (5/6 and 6/6 matches) siblings or from well matched unrelated donors (9/10 or 10/10 matches
        at HLA-A, B, C, DRB1 and DQB1 by high resolution typing) are included. All grafts will be
        unmanipulated (i.e., no T cell depleted or CD34 selected grafts).

        F. No uncontrolled bacterial, viral or fungal infection at time of enrollment defined as
        currently taking medication and progression of clinical symptoms

        G. No HIV disease (Patients with immune dysfunction are at a significantly higher risk of
        infection from intensive immunosuppressive therapies)

        H. Non-pregnant and non-nursing

        I. Required baseline values within 60 days prior to admission:

          1. LVEF ≥ 45%

          2. DLCO ≥ 50% of predicted (corrected for hemoglobin)

        J. Required baseline laboratory values within 16 days prior to admission:

          1. Estimated creatinine clearance ≥60 ml/min

          2. Serum total bilirubin ≤ 2 x upper limit of normal value (ULN)

          3. AST and ALT ≤ 2 x ULN (unless determined by treating physician to be related to
             underlying malignancy)

        K. Signed written informed consent (Patient must be capable of understanding the
        investigational nature, potential risks and benefits of the study, and able to provide
        valid informed consent)

        L. Patients must otherwise fulfill institutional criteria for eligibility to undergo
        myeloablative allogeneic stem cell transplantation

        EXCLUSION CRITERIA:

        A. Symptomatic uncontrolled coronary artery disease or congestive heart failure

        B. Severe hypoxemia with room air PaO2 < 70, supplemental oxygen dependence, or DLCO < 50%
        predicted

        C. Patients with active central nervous system involvement

        D. Prior allogeneic or autologous hematopoietic stem cell transplant in past 12 months

        E. Patients with diabetes mellitus requiring insulin secretagogues and/or insulin

        F. Patients with hypertriglyceridemia with serum triglyceride level ≥500 mg/d (lipid
        lowering drugs may be used to control level)

        G. Patients with a history of pancreatitis

        H. Patients with symptomatic cholelithiasis

        I. Patients with a current dependence on alcohol (characterized by a physical addiction to
        alcohol that interferes with physical or mental health, and social, family or job
        responsibilities)