Sitagliptin Umbilical Cord Blood Transplant Study

Study Overview
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Brief Summary
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The main purpose of this trial is to study whether the drug sitagliptin can be given safely to patients undergoing umbilical cord blood transplantation to speed up engraftment (recovery of blood counts after transplant).

Detailed Description
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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. The advantages of UCB are that (1) it is associated with less risk of transmitting an infection from a donor, (2) it can be more safely given even if not completely matched compared to bone marrow or blood stem cells, and (3) it is much more quickly available than unrelated donor bone marrow or blood stem cells. While more commonly used for transplantation in children, UCB is increasingly being used in adults. However, because they are larger than children, the relatively smaller stem cell dose in UCB is 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. Sitagliptin is a drug given in tablet form that has been recently approved by the Food and Drug Administration (FDA) for the treatment of certain patients with diabetes mellitus (a disease that results in high blood sugar). Sitagliptin has been given to both normal healthy volunteers and diabetic patients and has been found to be safe and well-tolerated. The drug improves control of blood sugar in diabetics by inhibiting an enzyme called CD26/DPP-IV. Recent studies at Indiana University (and other centers) have shown that this same enzyme plays an important role in the way transplanted stem cells find their way to the bone marrow and engraft. Transplant studies in mice have found that inhibiting CD26/DPP-IV significantly increases the engraftment of stem cells. Based on these studies, it is believed that drugs that inhibit CD26/DPP-IV, such as sitagliptin, may also increase engraftment in patients who receive clinical stem cell transplants.

Official Title
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A Phase II Trial of Inhibition of CD26 Peptidase Using Sitagliptin to Enhance Engraftment After Umbilical Cord Blood Transplantation for Adults With Hematological Malignancies

Conditions
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Leukemia, Myeloid, Acute, Acute Lymphoblastic Leukemia, Myelodysplasia, Leukemia, Myelogenous, Chronic, Lymphoma, Non-Hodgkin

Intervention / Treatment
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* Drug: Sitagliptin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have one of the following disease types with disease-specific features as outlined in the protocol: Acute myeloid leukemia (AML) Acute lymphoblastic leukemia (ALL) Myelodysplasia Chronic myelogenous leukemia 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 Hodgkin's lymphoma Relapsed Multiple Myeloma At least 35 days following start of preceding leukemia induction cytotoxic chemotherapy Patient age 18-55 years Karnofsky Performance status ≥ 70% No availability of a consenting HLA-matched related donor who is either matched fully matched or mismatched at only one locus of HLA-A, -B, and DRB1. 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 greater than 1.8 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 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. Required baseline laboratory values as defined in the protocol Exclusion Criteria: Symptomatic uncontrolled coronary artery disease or congestive heart failure. Severe hypoxemia with room air PaO2 less than 70, supplemental oxygen dependence, or DLCO less than 50 percent 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 59 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sitagliptin once per day<br>600 mg sitagliptin once per day orally starting on Day -1 for a total of 4 doses | Drug: Sitagliptin<br>* 600 mg sitagliptin taken orally per the schedule listed in each of the three separate arms.<br>* Other names: Januvia;|
| Experimental: Sitagliptin twice per day<br>600 mg sitagliptin twice per day orally starting on Day -1 for a total of 8 doses | Drug: Sitagliptin<br>* 600 mg sitagliptin taken orally per the schedule listed in each of the three separate arms.<br>* Other names: Januvia;|
| Experimental: Sitagliptin three times per day<br>600 mg sitagliptin three times per day orally starting on Day -1 for a total of 12 doses | Drug: Sitagliptin<br>* 600 mg sitagliptin taken orally per the schedule listed in each of the three separate arms.<br>* Other names: Januvia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Incidence of Patients With Engraftment by Day +30 Following Transplant | Evaluate the efficacy of CD26/DPP-IV inhibition in increasing the cumulative incidence of adult patients with hematological malignancies engrafting by day +30 following transplantation of UCB by 30 percent. The cumulative incidence of patients achieving this will be reported. The value of the estimate will be from bootstrapping 1000 samples with replacement of the data and the 95% confidence interval will be calculated using the percentile method. | Transplant (Day 0) through Day +30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Neutrophil Engraftment | Time to neutrophil engraftment will be analyzed by the Kaplan-Meier method. The time to engraftment of neutrophils is defined as the time from day 0 to the date of the first of three consecutive days after transplantation during which the absolute neutrophils count (ANC) is at least 0.5 x109/l. Patients who did not have neutrophil engraftment before death will be censored at the date of death. The median and 95% confidence intervals will be provided. For the RCD group, all patients engrafted before day +30, except one patient who died at day 28 before engraftment. For the PD group, all patients engrafted before day +100, except one patient who died on day +103 before engraftment. For the 600 mg sitagliptin/12 hours group, two patients engrafted before day +100, and the other two patients died before day +100 before engraftment. The one patient on 600 mg sitagliptin/8 hours died on day +14 before engraftment. | Transplant (Day 0) up to 1 year | 
| Time to Platelet Engraftment | Time to platelet engraftment will be analyzed by the Kaplan-Meier method. The time to engraftment of platelets is defined as the time from day 0 to the first of seven consecutive days after transplantation during which the platelet count is at least 20 x109/l without transfusion support. Only patients who achieved engraftment of platelets will be included in the analysis. The median and 95% confidence intervals will be provided. | Transplant (Day 0) up to 1 year | 
| Treatment Related Adverse Events Grade 3 or Higher for Non-hematological Toxicity | Number of unique patients who had a treatment related (possible, probable or definite) non-hematological adverse event that was graded 3 or greater. | Transplant (Day 0) up to 3 years |