Sitagliptin for Prevention of Acute Graft Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation

This is an open label phase II study in patients undergoing allogeneic hematopoietic stem
cell transplantation and receiving standard sirolimus and tacrolimus GvHD prophylaxis.
Although the myeloablative preparative regimen is not prescribed, it is anticipated that most
patients will receive total body irradiation (TBI) plus etoposide (TBI/VP16), or high-dose
thiotepa plus cyclophosphamide according to institutional standards. Regardless of the
preparative regimen, all patients will receive the following regimen for GvHD prophylaxis,
which includes the study drug sitagliptin:

Day -3: Tacrolimus is initiated on day -3 with a suggested starting dose of 0.01 mg/kg/day IV
as a continuous infusion and them modified to target a serum level of 5-10 ng/ml. Serum
levels should be monitored at least twice weekly until discharge, then at times of outpatient
clinic visits according to institutional practice. Tacrolimus may be switched to PO dosing
when the patient is able to tolerate oral intake satisfactorily. Note that concurrent use of
agents such as itraconazole, voriconazole or fluconazole (at doses > 200 mg) may inhibit the
metabolism of tacrolimus, and thus increase tacrolimus levels. Initial dosing may be
decreased in order to account for increased levels related to use of 'azole' agents. In
addition, it is recommended to check tacrolimus levels twice weekly when these agents are
initiated concurrently.

Sirolimus is started on day -3 with a suggested loading dose of 1 mg PO, then 0.5 mg/day PO
single dose from day -2 to maintain a target serum level of 5-10 ng/ml. Serum levels should
be monitored twice weekly until discharge, then at times of outpatient clinic visits
according to institutional practice. Initial dosing may be decreased in order to account for
increased levels related to use of 'azole' agents.

Day -1: Sitagliptin 600 mg q 12 hours PO starting on Day -1 to be administered between 8:00
am and 10:00 am then given every 12 hours (total 32 doses) through day +14.

In the absence of acute GvHD, begin tapering of both tacrolimus and sirolimus on Day +100 as
tolerated with a goal of stopping by Day +180. The rate of taper may be adjusted for presence
of signs and symptoms of GvHD. Mycophenolate mofetil may be substituted for tacrolimus or
sirolimus if any toxicity related to these drugs arises (e.g., renal failure, hemolytic
microangiopathy, allergic rash, etc.).

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)