Skip to main content

Sitagliptin Phosphate to Improve Engraftment After Umbilical Cord Blood Transplant in Patients with Hematologic Malignancies

Trial Status: Complete

The main purpose of this trial is to learn if blocking a protein called “DPP-IV” with the drug sitagliptin will speed up engraftment after umbilical cord transplant. Umbilical cord blood (UCB) is increasingly used as a source of stem cells for patients with blood cancers who need an allogeneic stem cell transplant (a transplant with stem cells from another person) but who have no suitably matched donors. However, the relatively small stem cell dose in UCB is a major limitation for transplantation in adults, and engraftment can be delayed. This study is investigating whether the drug sitagliptin can be used to increase and speed up engraftment in adults receiving UCB transplantation, overcoming the limitation of small stem cell doses associated with umbilical cord blood.

Inclusion Criteria

  • Patients must have one of the following disease types: * Acute myeloid leukemia (AML) with any of the following: ** In first complete remission (CR1) with high-risk features defined by any of the following: *** Presence of any of the cytogenetics abnormalities: -5/5q-, -7/7q-, t(9:22), t(6;9), inv(3), 9q, 11q23 abnormalities, or complex karyotype with 3 or more abnormalities per clone *** Need for 2 cycles of induction therapy to achieve CR1 *** Preceding history of myelodysplasia or the prior administration of chemotherapy for a non-myeloid malignancy (i.e., secondary AML) ** Patients in second or subsequent complete remission (CR2, CR3, etc.) ** Primary refractory or relapsed AML with peripheral blood blasts < 2.0x10^9/l or with extramedullary disease (excluding active disease of the central nervous system) * Acute lymphoblastic leukemia (ALL) with any of the following: ** In CR1 with high-risk features defined by any of the following cytogenetic abnormalities, including Ph+, t(4;11), 11q23 abnormalities, or t(1;9) ** Patients in second or subsequent complete remission (CR2, CR3, etc.) ** Primary refractory or relapsed ALL with peripheral blood blasts < 2.0x10^9/l or with extramedullary disease (excluding active disease of the central nervous system) * Myelodysplasia with any of the following features: ** Refractory anemia with excess blasts with 11-20% blasts in the bone marrow (RAEB II) ** Refractory anemia with excess blasts with 5-10% blasts (RAEB I) and poor risk cytogenetics (i.e., chromosome 7 abnormalities or complex karyotype with at least 3 abnormalities per clone) ** 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) * Chronic myelogenous leukemia (CML) with one of the following criteria: ** Accelerated phase, defined by any of the following: *** Blasts 10-19% of peripheral blood white cells or bone marrow cells *** Peripheral blood basophils at least 20% *** Persistent thrombocytopenia (< 100 x 10^9/l) unrelated to therapy, or persistent thrombocytosis (> 1000 x 10^9/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) *** Resistance to tyrosine kinase inhibitors (e.g., imatinib, dasatinib, nilotinib) defined as no complete cytogenetic response even if the above criteria are not met ** First 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 in addition to imatinib 400 mg daily at least one of the following options: a) imatinib 600-800 mg daily, b) nilotinib, or c) dasatinib ** Second or subsequent chronic phase provided a complete hematologic remission was not achieved by 3 months or a major cytogenetic remission (< 35 % Philadelphia chromosome + metaphases) by 6 months and the patient had received in addition to imatinib 400 mg daily at least one of the following options: a) imatinib 600-800 mg daily, b) nilotinib, or c) dasatinib * 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: ** Failure to achieve complete remission to primary induction therapy ** Relapsed and refractory to at least one line of salvage systemic therapy
  • At least 35 days following start of preceding leukemia induction cytotoxic chemotherapy
  • Karnofsky performance status >= 70%
  • For patients in remission, there should be no readily available consenting human leukocyte antigen (HLA)-matched related donor who is either matched fully matched or mismatched at only one locus of HLA-A, -B, and DRB1; patients who have active leukemia (refractory or relapsed) may be transplanted on this protocol regardless of availability of a related donor since these patients would not typically be transplanted on standard of care treatment plans
  • No availability of a readily available HLA-matched volunteer unrelated donor (8 of 8 allele match at HLA-A, -B, -C and -DRB1); patients with unstable disease who are in danger of significant disease progression while waiting to procure volunteer donor cells will be eligible to be treated on this protocol, even if a matched donor is available
  • Patients must have a matched or partially matched UCB unit with >= 2.5 x10^7 nucleated cells/kg of recipient weight at the time of cryopreservation
  • No current uncontrolled bacterial, viral or fungal infection (defined as currently taking medication and progression of clinical symptoms)
  • No human immunodeficiency virus (HIV) disease; patients with immune dysfunction are at a significantly higher risk of infection from intensive immunosuppressive therapies
  • Non pregnant and non-nursing; treatment under this protocol would expose a fetus to significant risks; women of childbearing potential should have a negative pregnancy test prior to study entry; women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial; appropriate methods of birth control include oral contraceptives, implantable hormonal contraceptives (Norplant), or double barrier method (diaphragm plus condom)
  • Left ventricular ejection fraction (LVEF) >= 45% corrected
  • Diffusing capacity of the lung for carbon monoxide (DLCO) >= 50% of predicted value (corrected for hemoglobin)
  • Serum creatinine * Male: =< 1.7 mg/dl * Female: =< 1.5 mg/dl * Or estimated creatinine clearance of >= 60 ml/min
  • Bilirubin =< 2 x upper limit of normal value
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2 x upper limit of normal value (unless elevation is determined by the treating physician to be related to involvement by underlying cancer)
  • 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
  • Patients who are taking other insulin secretagogues and/or insulin

Exclusion Criteria

  • Symptomatic uncontrolled coronary artery disease or congestive heart failure
  • Severe hypoxemia with room air pulmonary arterial oxygen tension (PaO2) < 70, supplemental oxygen dependence, or DLCO < 50% predicted
  • Patients with central nervous system (CNS) involvement refractory to intrathecal chemotherapy
  • Prior allogeneic or autologous hematopoietic stem cell transplant in the last 6 months
  • Patients who have hypersensitivity to sitagliptin
  • Patients with a history of pancreatitis, cholelithiasis, alcoholism, or fasting hypertriglyceridemia (> 2 x ULN)

Florida

Tampa
Moffitt Cancer Center
Status: APPROVED
Contact: Brian C. Betts
Phone: 800-456-7121

Indiana

Indianapolis
Indiana University / Melvin and Bren Simon Cancer Center
Status: COMPLETED
Contact: Sherif Shafik Farag
Phone: 317-278-0460

New York

New York
Mount Sinai Hospital
Status: APPROVED
Contact: Luis Manuel Isola
Phone: 212-824-7320
Valhalla
New York Medical College
Status: COMPLETED
Contact: Mitchell S. Cairo
Phone: 914-594-3794

Ohio

Cleveland
Case Western Reserve University
Status: APPROVED
Contact: Hillard Michael Lazarus
Phone: 800-641-2422

PRIMARY OBJECTIVES:

I. Evaluate the efficacy of cluster of differentiation 26 (CD26)/dipeptidyl-peptidase 4 (DPP-IV) inhibition in increasing the proportion of adult patients with hematological malignancies engrafting by day +30 following transplantation of umbilical cord blood (UCB) by 20%.

SECONDARY OBJECTIVES:

I. Define the median times to neutrophil and platelet engraftment.

II. Describe rate of engraftment failure by day +100.

III. Describe the incidence of grade 3 and 4 non-hematological toxicity.

IV. Describe the incidence and severity of acute graft-versus-host disease (GvHD) at day +100 and chronic GvHD at 1 year.

V. Transplant-related mortality at 6 month.

VI. Describe relapse rate and survival.

VII. Describe the pharmacokinetics and pharmacodynamic effects of sitagliptin (sitagliptin phosphate) in the setting of high-dose chemotherapy and UCB transplantation.

OUTLINE: Patients receive 1 of 2 preparative regimens according to institutional preferences.

TOTAL BODY IRRADIATION BASED REGIMEN: Patients receive allopurinol orally (PO) daily on day -8 to -1, undergo total-body irradiation (TBI) twice daily (BID) on days -7 to -4, receive fludarabine phosphate intravenously (IV) over 30 minutes on days -5 to -3, and cyclophosphamide IV over 2 hours on days -3 and -2.

CHEMOTHERAPY ONLY BASED REGIMEN: Patients receive allopurinol PO daily on days -9 to -1, melphalan IV over 20 minutes on day -8, thiotepa IV over 30 minutes every 12 hours on day 7, fludarabine phosphate IV over 30 minutes on days -6 to -3, and anti-thymocyte globulin IV over 6 hours on days -3 to -1.

All patients receive sitagliptin phosphate PO every 12 hours on days -1 to 3 and undergo umbilical cord blood transplant on day 0.

GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus IV continuously and sirolimus PO beginning on day -3 to day 100 with a taper to day 180.

After completion of study treatment, patients are followed up every 3 months for 1 year.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Indiana University / Melvin and Bren Simon Cancer Center

Principal Investigator
Sherif Shafik Farag

  • Primary ID HL112669
  • Secondary IDs NCI-2012-02174
  • Clinicaltrials.gov ID NCT01720264