Conditions: Graft vs Host Disease Hematopoietic Stem Cell Transplantation
Keywords: Allogeneic Sitagliptin
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 37
Healthy volunteers: no

Brief 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.

Detailed description:
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.).

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

Interventions: intervention 1: Sitagliptin
Intervention descriptions: intervention 1: 600 mg ever 12 hours by mouth will be given starting the day before transplant through day +14 after transplant

Protocol document:
Prot_SAP_000.pdf: 
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1
Phase II Trial of Inhibition of Dipeptidyl Peptidase (DPP)-4 with Sitagliptin for the 
Prevention of Acute Graft-versus-Host Disease Following Allogeneic 
Hematopoietic Stem Cell Transplantation 
IUSCC-0522 
Principal Investigator 
 Sherif S. Farag MD, PhD 
 Indiana University Simon Cancer Center 
 980 W. Walnut Street 
 Indianapolis, IN 46202 
 Ph: (317) 278-0460 
 
E-mail: ssfarag@iu.edu
Co-Investigators 
Rafat Abonour, MD  
Robert Nelson, MD 
Mike Robertson, MD 
Jennifer Schwartz, MD 
Faculty Statistician 
Susan Perkins, PhD 
Research Nurse 
Carol Huntley, RN 
Support Provided By 
National Institutes of Health and Indiana University Simon 
Cancer Center 
Version 
December 4, 2017 
IND 
126833 
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Table of Contents 
1.0 Background ............................................................................................................................. 4 
1.1 
Dipeptidyl peptidase (DPP)-4 ......................................................................................... 4 
1.2 
Sitagliptin: a specific DPP-4 inhibitor approved for clinical use ...................................... 5 
1.3 
Clinical results of DPP-4 inhibition using high-dose sitagliptin ....................................... 7 
1.4 
Preclinical results for DPP-4 as a target for GvHD ......................................................... 9 
1.5 
Rationale for a current clinical trial of sitagliptin for prevention of acute GvHD ............ 10 
2.0 Objectives ............................................................................................................................. 10 
2.1 
Primary Objective ......................................................................................................... 10 
2.2 
Secondary Objectives ................................................................................................... 11 
2.3 
Exploratory Objectives .................................................................................................. 11 
3.0 Eligibility Criteria ................................................................................................................... 11 
3.1 
Inclusion Criteria ........................................................................................................... 11 
3.2 
Exclusion Criteria .......................................................................................................... 13 
4.0 Registration Procedures and Informed consent .................................................................... 14 
4.1 
Registration Procedures ............................................................................................... 14 
4.2 
Informed Consent ......................................................................................................... 14 
5.0 Treatment Plan ..................................................................................................................... 14 
6.0 Dose Adjustment ................................................................................................................... 15 
7.0 Ancillary Therapy .................................................................................................................. 15 
7.1 
Full supportive care. ..................................................................................................... 15 
7.2 
Use of Palifermin. ......................................................................................................... 15 
7.3 
Pneumocystis carinii prophylaxis. ................................................................................. 16 
7.4 
Herpes Zoster prophylaxis. ........................................................................................... 16 
7.5 
Cytomegalovirus (CMV) prophylaxis. ........................................................................... 16 
7.6 
Fungal prophylaxis. ...................................................................................................... 16 
8.0 Study Schedule ..................................................................................................................... 16 
8.1 
Guidelines for Pre-Study Testing .................................................................................. 16 
8.2 
Screening / Pre-Transplant and Treatment Schedule .................................................. 18 
9.0 Definitions and Assessment of Primary Endpoint: Acute GvHD ........................................... 19 
9.1 
Evaluation of acute GvHD ............................................................................................ 19 
9.2 
Grading of acute GvHD ................................................................................................ 19 
10.0 Definitions of Secondary Endpoints .................................................................................... 19 
10.1 
Time to engraftment of neutrophils ........................................................................... 19 
10.2 
Time to engraftment of platelets ............................................................................... 19 
10.3 
Chronic Graft versus Host Disease ........................................................................... 19 
10.4 
Hematological and Non-Hematological toxicity ......................................................... 20 
10.5 
Long-term follow-up .................................................................................................. 21 
11.0 Drug Formulation, Availability, and Preparation .................................................................. 21 
11.1 
Sitagliptin (JanuviaTM) ............................................................................................... 21 
11.2 
Tacrolimus (Prograf®) ............................................................................................... 23 
11.3 
Sirolimus (Rapamycin; Rapamune) ....................................................................... 24 
12.0 Criteria For Response, Progression, And Relapse ............................................................. 26 
12.1 
Response criteria for patients with AML and ALL ..................................................... 26 
12.2 
Response criteria for patients with myelodysplasia .................................................. 26 
12.3 
Response criteria for patients with CML ................................................................... 27 
12.4 
Response criteria for patients with Hodgkin’s or non-Hodgkin’s Lymphoma ............ 27 
13.0 Correlative Studies and Sample Submission ...................................................................... 29 
13.1 
Laboratory Correlative Studies ................................................................................. 29 
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14.0 Adverse Events and Reporting Guidelines ......................................................................... 31 
14.1 
Definitions of Adverse Events ................................................................................... 31 
14.2 
Adverse Event (AE) Reporting Requirements: ......................................................... 33 
15.0 Data and Safety Monitoring Plan ........................................................................................ 35 
15.1 
Study Auditing and Monitoring .................................................................................. 35 
15.2 
Early Study Closure .................................................................................................. 35 
15.3 
Study Accrual Oversight ........................................................................................... 35 
15.4 
Protocol Deviations ................................................................................................... 36 
16.0 Statistical Considerations .................................................................................................... 36 
16.1 
General Considerations ............................................................................................ 36 
16.2 
Study Design ............................................................................................................. 36 
16.3 
Sample Size .............................................................................................................. 36 
16.4 
Patient Characteristics and Significant Protocol Violations ....................................... 37 
16.5 
Analysis Plan ............................................................................................................ 37 
16.6 
Stopping Criteria ....................................................................................................... 38 
17.0 References .......................................................................................................................... 39 
APPENDIX I ................................................................................................................................ 42 
APPENDIX II ............................................................................................................................... 44 
 
 
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1.0 BACKGROUND 
Acute graft-versus-host disease (GvHD) remains one of the most significant causes of morbidity 
and mortality following allogeneic hematopoietic stem cell transplantation (HSCT) for 
hematological malignancies. Using standard GvHD prophylaxis regimens, the incidence of 
grade II-IV acute GvHD ranges from 35-50% with human leukocyte antigen (HLA)-matched 
related donors, and 40-70% with unrelated donors.1-3 While acute GvHD can be eliminated 
through the use of in vivo or ex-vivo depletion of T cells, relapse increased. However, using T 
cell-replete grafts, the effect of acute GvHD on the competing risks of transplant-related 
mortality (TRM) and relapse incidence has been clarified to a significant extent by a large 
analysis of 4,174 patients undergoing HLA-matched sibling transplants.4 In this large study, 
although GvHD was protective against relapse, patients developing severe (grades II-IV) GvHD 
had a net inferior survival to patients without acute GvHD or developing only grade I (mild) acute 
GvHD,4 indicating that the effect of severe GvHD more than mitigated the protective effects on 
relapse. Therefore, novel strategies preventing grades II-IV acute GvHD are likely to improve 
overall outcome of patients undergoing allogeneic HSCT. 
1.1 
Dipeptidyl peptidase (DPP)-4 
DPP-4 is a homodimeric type II transmembrane glycoprotein identical to leucocyte surface 
antigen CD26, and is also present in a soluble enzymatically active for form in plasma. 
CD26/DPP-4 has dipeptidylpeptidase activity that selectively removes the N-terminal dipeptide 
from peptides with proline or alanine at the penultimate position. DPP-IV is involved in a broad 
range of biological processes, including modulation of insulin release and metabolism,5 
modulating stromal-derived factor (SDF)-1 important in homing and engraftment of stem cells,6 
hematopoietic cytokines,6 and T immune functions.7,8 Specific DPP-4 inhibitors (e.g., sitagliptin) 
are now clinically available and approved for type 2 diabetes mellitus. We are investigating the 
clinical efficacy of sitagliptin to enhance engraftment of umbilical cord blood (UCB) 
transplantation.9  
In the immune system, CD26/DPP-4 is expressed on a specific population of CD4+CD45RO+ 
memory T cells, and is upregulated after T cell activation.10-12 CD26 is also associated with T 
cell signal transduction processes as a co-stimulatory molecule (Figure 1).7 Crosslinking of 
CD26 and CD3 with solid phase immobilized monoclonal antibodies (but not CD3 alone) 
enhances T cell co-stimulation, proliferation, and IL-2 production.12,13 Further studies 
demonstrated that recombinant soluble CD26 (rsCD26) enhances proliferative responses of 
peripheral blood lymphocytes to stimulation with soluble antigen, and that this effect requires 
DPP-4 enzymatic activity.8 Subsequently it was shown that the target cells of rsCD26 were 
CD14+ monocytes, and rsCD26 up-regulates CD86 on monocytes.  
The function of CD26/DPP-4 in T cell activation is shown in Figure 1. The ligand for CD26/DPP-
4 is caveolin-1, an integral membrane protein, expressed on a wide variety of cells, including 
antigen-presenting cells (APC).8,14 In APC, loaded antigens are trafficked in the cell through 
caveolae (vesicular invaginations of the membrane), and caveolin-1 is transported along with 
the peptide-MHC complex to the cell surface where it is expressed for interaction with cognate T 
cells.8,15 Upon binding CD26/DPP-4 on T cells, caveolin-1 is phosphorylated, which leads to the 
up-regulation of CD86 and enhanced co-stimulation of T cells, as described in Figure 1.16,17 
CD26-medated T-cell signaling, therefore, provides a positive co-stimulatory loop for action of 
CD28.17 Within T cells, CD26/DPP-4-caveolin-1 leads to T cell proliferation and IL-2 production 
(Figure 1).  
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CD26+ lymphocytes are 
reported to be increased in 
blood of acute GvHD patients, 
and infiltrate tissues involved 
by acute GvHD.18 In mouse 
models, depleting monoclonal 
antibodies against CD26 
prevent GvHD.18 However, as 
DPP-4 enzymatic activity of 
CD26 is required for 
interaction with caveolin-1, 
and in turn APC/T-cell 
signaling, we hypothesize that 
inhibition of DPP-4 enzymatic 
activity may be a novel 
therapeutic approach for 
preventing acute GvHD.  
1.2 
Sitagliptin: a specific 
DPP-4 inhibitor approved 
for clinical use  
Sitagliptin is an approved DPP-4 inhibitor for clinical use. It is available in an oral formulation 
only and has been approved by the Food and Drug Administration (FDA) for treatment of type 2 
diabetes mellitus.19 As antihyperglycemic agents, DPP-4 inhibitors increase active levels of 
incretin peptides, including glucagon-like peptide (GLIP)-1 and glucose-dependent insulinotropic 
peptide (GIP). The beneficial effects of GLIP-1 and GIP on glucose homeostasis are limited by 
the short half-life of these peptides due to rapid inactivation by DPP-4. Sitagliptin has been 
found to be highly selective for DPP-4, and demonstrates at least a 2600-fold margin over its 
activity against the closely related enzymes DPP-8 and DPP-9.20 This is important as in animal 
studies inhibition of DPP-8 or 9 by selective inhibitors or by non-selective DPP-4 inhibitors was 
associated with multiorgan toxicity.21  
Pharmacology of sitagliptin:  Sitagliptin phosphate is chemically described as 7-[(3R)-3-
amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3 (trifluoromethyl)-1,2,4-
triazolo[4,3-a] pyrazine phosphate (1:1) monohydrate. Sitagliptin enhances the effects of the 
incretin hormones GIP and GLIP-1, which are secreted in in response to food and have a role in 
regulating glucose homeostasis.22 Activation of GIP and GLIP-1 receptors on pancreatic β-cells 
leads to increased levels of cyclic AMP and intracellular calcium with subsequent glucose 
dependent insulin secretion. Also, sustained receptor activation leads stimulation of β-cell 
proliferation and resistance to apoptosis. GIP and GLIP-1 are rapidly inactivated by DPP-4, and 
following administration of sitagliptin, post-prandial levels of active GLIP-1 are increased and 
activity is prolonged.  While the effect on glucose homeostasis has been the clinical driving 
force for developing sitagliptin in Type 2 diabetes mellitus, DPP-4 also modulates other 
biological activities. In addition to and independent of its enzymatic activity in plasma, DPP-IV is 
a membrane-spanning peptidase that is widely distributed in numerous tissues and T-cells, B-
cells, and natural killer cells.  
Sitagliptin is a potent, reversible inhibitor of DPP-4/CD26. In vitro studies show that sitagliptin 
has high selectivity for DPP-4 (IC50, 18 nM). Affinity for other proline-specific peptidases, DPP-8 
(IC50, 48,000 nM) and DPP-9 (IC50, >100,000 nM), is low.20 Low affinity for these peptidases is 
of particular importance since in preclinical studies, inhibition of DPP-8 and DPP-9 has been 
associated with severe toxicities, including alopecia, blood dyscrasias, multi-organ 
Figure 1. Co-stimulatory function of CD26/DPP-IV in T cell activation. After antigen
uptake, a portion of caveolin-1 is exposed on the outer cell surface and aggregates in
the APC-T cell contact area in lipid rafts. Aggregated caveolin-1 then binds its specific
ligand, CD26, resulting in caveolin-1 phosphorylation. Phospho-caveolin-1 transduces a
signal into the APCs, leading to dissociation of IRAK-1 and Tollip, followed by activation
of NF-kB, and finally resulting in CD86 upregulation and T cell costimulation. In T cells,
binding
by
specific
MHC-peptide
complexes
leads
to
TCR
signal
transduction.
Additionally, caveolin-1 on the APC ligates CD26 dimers on the T cell surface, resulting
in the recruitment of lipid rafts in the plasma membrane and the recruitment of CARMA1
to the cytosolic portion of CD26. Ultimately, these steps lead to the activation of NF-kB,
to T cell proliferation, and to IL-2 production. Enzymatic DPP-IV activity is required for
these functions. (Adapted from Trends in Immunology 2008, 29: 295-301).
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histopathologic changes, and mortality in rats; and gastrointestinal toxicity in dogs.21 Likewise, 
whereas other nonselective DPP-4 inhibitors have been associated with the development of 
necrotic skin lesions in preclinical studies involving monkeys, no treatment-related skin toxicity 
was observed in a 3-month study in monkeys treated with sitagliptin.   
Pharmacokinetics and pharmacodynamic studies in normal volunteers and patients with 
diabetes mellitus: Sitagliptin has been tested extensively in healthy volunteers and in patients 
with type 2 diabetes mellitus and found to be safe and well tolerated.19,23-25 Importantly, as 
incretin stimulation of insulin release is glucose dependent, the risk of hypoglycemia is minimal 
and has not been observed in healthy volunteers given high doses (600 mg/day) of sitagliptin.24 
Hypoglycemia, however, may occur when sitagliptin is administered in combination with an 
insulin secretagogue (e.g., sulfonylureas) or insulin therapy, indicating the need for close 
monitoring 26  
The pharmacokinetics of sitagliptin in healthy subjects has been reported to be comparable with 
those observed in patients with type 2 diabetes.24,25 Key pharmacokinetic parameters in healthy 
subjects provided by the manufacturer are summarized in Table 1. The sitagliptin plasma area 
under the curve (AUC) is increased in a dose-dependent manner following both single dose 
(1.5-600 mg)25 and multidose (25-600 mg QD and 300 mg BID)23 in healthy volunteers. 
Absorption is not appreciably affected by food, and sitagliptin may be dosed without regard to 
meals.   
Sitagliptin does not appear to undergo 
extensive metabolism. Studies of 
metabolism and excretion of [14C]-
sitagliptin in healthy subjects indicated 
that the parent drug comprised the 
majority of plasma (78-90%) and urinary 
(84-88%) radioactivity.27 Six metabolites 
were detected in small amounts, but 
have been found to have several 
hundred-fold less activity against DPP-4 
and are not, therefore, believed to 
contribute to the pharmacologic activity 
of sitagliptin.27 Approximately 80% of the 
dose is cleared by the kidneys, and renal 
clearance is independent of dose.23,25 
Moderate hepatic impairment has 
minimal effect on sitagliptin 
pharmacokinetics.28 
In clinical studies involving healthy 
volunteers, treatment with sitagliptin was 
associated with dose-dependent 
inhibition of DPP-IV activity.23,25 Furthermore, in rodent models of diabetes, near maximal 
glucose lowering effects have been observed with 80% or greater inhibition of plasma DPP-4 
activity.29 In a study of 70 healthy normal volunteers receiving multiple oral doses (up to 600 mg 
per day) of sitagliptin for up to 10 days have shown that although the terminal half-life of the 
drug ranged from 11.8 to 14.4 hours, sustained inhibition of plasma DPP-4 enzyme activity for 
at least 24 hours after each dose was observed only at higher doses.23 Sitagliptin produced a 
dose-dependent inhibition of plasma DPP-4 enzyme activity, with greater than 90% inhibition 
seen at the highest dose of 600 mg/day. 23  
Table 1. Pharmacokinetic parameters in 
healthy subjects 
Parameter 
Value 
Bioavailability 
87% 
Volume of 
distribution 
~198 L 
Protein binding 
38% 
Tmax 
1-4 hours 
Metabolism 
Minimal hepatic metabolism 
Elimination 
87% urine (~79% 
unchanged);  
13% feces 
Apparent terminal 
t1/2 
~12.4 hours 
Renal clearance 
~350 ml/min 
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Reported adverse events of sitagliptin in patients with diabetes mellitus: Reported clinical 
evaluation of sitagliptin has been essentially restricted to patients with type 2 diabetes mellitus. 
In all large clinical trials reported, sitagliptin has been very well tolerated. In a phase II, 
randomized, double blind, placebo and active-controlled parallel group study, where treatment 
was for 12 weeks, there was no difference in the incidence of adverse events between the 
sitagliptin (up 100 mg per day) and placebo groups.30 In a phase III trial comparing sitagliptin 
100 mg/day, sitagliptin 200 mg/day, or placebo for 24 weeks, the incidence of drug-related 
adverse events were slightly higher in the sitagliptin treated patients and were reported in 9.7%, 
10.8%, and 7.5%, respectively.31 The adverse events occurring at a frequency of 2% or more 
and with a higher incidence in one or both of the sitagliptin groups compared to placebo, 
included constipation, nasopharyngitis, pharyngitis, pharyngolaryngeal pain, urinary tract 
infection, myalgia, arthralgia, hypertension, and dizziness.31 A slight increase (4.2% and 4.7%) 
in white blood cell count was reported in the sitagliptin arms, but was not considered clinically 
significant. Similar mild biochemical changes, including a 3-4% increase in creatinine kinase 
(CK) and a 3-4 IU/ml decrease in alkaline phosphatase were also observed in patients treated 
with sitagliptin, but were not of any clinical significance.31 In a second Phase III double-blind, 
placebo controlled trial comparing sitagliptin at doses of 100 mg/day, 200 mg/day, and placebo 
for 18 weeks, drug-related clinical adverse events were slightly higher in the placebo treated 
group (10.2%, 8.3% and 17.3%, respectively).32 No serious adverse events were reported 
during the study. There was no significant difference in the incidence of hypoglycemia between 
groups. Adverse events occurring at a higher frequency in the sitagliptin groups compared with 
placebo were nasopharyngitis, back pain, osteoarthritis, and pain in extremities.32 Clinically 
insignificant changes in white blood cell count (increase of 5-10% from baseline), alkaline 
phosphatase (decrease of 5-10% from baseline), and in uric acid (increase of ~12 μmol/l) were 
observed in patients treated with sitagliptin.   
In the post-marketing experience, reports of acute pancreatitis, acute renal failure, 
hypoglycemia (when sitagliptin has been used concurrently with insulin secretagogues or 
insulin), and allergic and hypersensitivity reactions have been reported (Januvia Prescribing 
Information, Merck Sharp & Dohme Corp.). While case reports have documented acute 
pancreatitis in patients receiving sitagliptin, a large analysis of pooled clinical trials failed to 
confirm that the incidence of this adverse event occurs more commonly among diabetic patients 
treated with sitagliptin.33 
1.3 
Clinical results of DPP-4 inhibition using high-dose sitagliptin  
We have studied the clinical effect of DPP-4 inhibition using high doses of the specific inhibitor 
sitagliptin for enhancing the engraftment of umbilical cord blood (UCB) transplants. In a pilot 
trial, we recently reported the safety of high-dose sitagliptin (600 mg per day) in the setting of 
myeloablative chemoradiotherapy and allogeneic transplantation using UCB.9 Pharmacokinetics 
(PK) and pharmacodynamic studies associated with this trial showed that while the PK 
parameters of sitagliptin appeared to be similar to those previously reported in patients with 
diabetes mellitus and normal volunteers,23 the dose of 600 mg per day used did not result in 
sustained inhibition of plasma DPP-4 as was expected.23 Further, the kinetics of engraftment 
was significantly associated with the extent of plasma DPP-4 inhibition,9 suggesting that plasma 
DPP-4 inhibition may be a good surrogate for the efficacy of sitagliptin in this context. 
Pharmacokinetic-pharmacodynamic modeling indicated that improved inhibition of DPP-IV could 
be better achieved using multiple daily dosing.34  
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Based on the 
pharmacodynamic 
data from the pilot trial, 
a dose-escalation 
study was 
subsequently 
performed, testing 
sitagliptin doses of 600 
mg every 12 hours, 
and 600 mg every 8 
hours. While sitagliptin 
dosing of 600 mg 
every 12 hours was 
well tolerated, grade 5 
dose-limiting toxicity 
(capillary leak 
syndrome and 
multiorgan failure) was 
observed at 600 mg 
every 8 hours.35 More sustained inhibition of plasma DPP-IV activity was observed with twice 
daily dosing of sitagliptin (Figure 2).35 Based on these studies, we have initiated a phase II 
clinical trial of in vivo DPP-4 inhibition using sitagliptin at 600 mg every 12 hours starting Day -1 
through Day +3 (total 10 doses) in adult patients with hematological malignancies undergoing 
UCB transplantation, with the engraftment as the primary endpoint (ClinicalTrials.gov identifier: 
NCT01720264). The results from the first 8 patients treated at the higher dose have confirmed 
the safety of 600 mg every 12 hours dosing of sitagliptin, with no toxicity related to sitagliptin 
observed. 
While not the primary endpoint of the pilot study, an important observation was the very low 
incidence of acute GvHD.9 Of 17 patients receiving one and two antigen mismatched UCB 
transplants, and treated with the specific DPP-IV inhibitor sitagliptin, only 1 (6%) patient 
developed acute grade II GvHD on day +259 while tapering immunosuppression after a median 
follow-up of 259 (range, 84-736) days at time of reporting.9 This low incidence of severe acute 
GvHD is significantly lower than previously reported for patients receiving UCB transplants, 
even when anti-thymocyte globulin (ATG) has been used as part of the preparative regimen.36-38 
The remarkably low incidence of severe GvHD observed in this trial has prompted us to take our 
clinical observations back to the bench to further study DPP-4 as a potential target for 
prevention of acute GvHD.   
Figure 2. Plasma DPP-4 activity (mean values ± standard error) as a 
percentage of baseline following different sitagliptin dosing schedules. 
Inhibition of DPP-4 activity was not sustained using 600 q 24 hours. In a 
dose-escalation study, sitagliptin given q 12 or q 8 hours resulted in greater 
inhibition of DPP-4 activity.  
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I U S C C-0 5 2 2  
V er si o n 1 2/ 0 4/ 2 0 1 7  
 
 
9  
1. 4  
Pr e cli ni c al r e s ult s f or D P P -4 
a s a t ar g et f or G v H D  
Sit a gli pti n i n hi bit s T c ell a cti v ati o n 
i n r e s p o n s e t o all o g e n ei c 
sti m ul ati o n. W e a s s e s s e d t h e 
pr olif er ati o n of T c ell s i n mi x e d 
l y m p h o c yt e r e a cti o n s u si n g 
m o n o c yt e s a s sti m ul at or c ell s, b ot h 
o bt ai n e d fr o m r a n d o m d o n or b uff y 
c o at s o bt ai n e d fr o m t h e I n di a n a 
Bl o o d C e nt er. Fr e s hl y (i m m u n o -
m a g n eti c all y) p urifi e d C D 3
+  T c ell s 
w er e tr e at e d diff er e nt c o n c e ntr ati o n 
( 1 5 0-1 5 0 0 n g/ ml; c o n c e ntr ati o n s w e 
h a v e e a sil y a n d s af el y a c hi e v e d i n 
vi v o  i n all o g e n ei c tr a n s pl a nt p ati e nt s 9 ) wit h sit a gli pti n f or 3 0 mi n ut e s, w a s h e d, a n d t h e n c o-
c ult ur e d wit h all o g e n ei c irr a di at e d p eri p h er al bl o o d m o n o n u cl e ar c ell s ( P B M C) f or 4 d a y s. 
Pr olif er ati o n i n T c ell s w a s a s s e s s e d b y H 3 -t h y mi di n e u pt a k e ( a d d e d t o l a st 2 4 h o ur s of c ult ur e). 
A s s h o w n i n Fi g ur e 3, t h er e w a s a d o s e -d e p e n d e nt i n hi biti o n of T c ell pr olif er ati o n wit h 
sit a gli pti n.  Tr e at m e nt of P B M C sti m ul at or c ell s, a s o p p o s e d t o T c ell s, wit h sit a gli pti n h a d n o 
eff e ct o n pr olif er ati o n ( n ot s h o w n).  
D o n or T c ell s fr o m C D 2 6 -/- 
k n o c k o ut mi c e i n d u c e l e s s 
G v H D i n tr a n s pl a nt e d mi c e.  
I n a w ell-e st a b li s h e d M H C-
mi s m at c h e d ( B L 6 B A L B/ c) 
m o u s e tr a n s pl a nt m o d el, 
B A L B/ c r e ci pi e nt mi c e w er e 
l et h all y irr a di at e d ( 8 0 0 c G y) 
a n d tr a n s pl a nt e d wit h 2 x 1 0 6  
b o n e m arr o w ( B M) c ell s fr o m 
d o n or wil d t y p e ( W T) or C D 2 6 -
/- B L 6 mi c e, wit h or wit h o ut 
5 x 1 0 6  p urifi e d C D 3 +  s pl e e n 
c ell s ( n = 1 0 p er gr o u p). A s 
s h o w n i n Fi g ur e 4 , B L A B/ c 
mi c e r e c ei vi n g B L 6 C D 2 6
-/- 
B M al o n e r e m ai n e d h e alt h y 
a n d fr e e of G v H D. W hil e all 
B A L B/ c mi c e w h o r e c ei v e d 
B M + C D 3 +  s pl e e n fr o m W T d o n or s r a pi dl y di e d fr o m G v H D wit hi n 2 0 d a y s, t h er e w a s 
si g nifi c a ntl y pr ot e cti o n fr o m G v H D i n B A L B/ c mi c e r e c ei vi n g B M + C D 3 +  s pl e e n c ell s fr o m 
C D 2 6 -/- B L 6 mi c e, s u g g e sti n g t h at C D 2 6 o n d o n or T c ell s pl a y s a si g nifi c a nt r ol e i n m e di ati n g 
a c ut e G v H D. U nli k e i n h u m a n r e ci pi e nt s, 9  sit a gli pti n ( a n d ot h er  D P P -4 i n hi bit or s s u c h a s 
Di pr oti n A) bl o c k D P P -4 e n z y m ati c a cti vit y f or o nl y 2 -3 h o ur s (i. e., si g nifi c a ntl y l e s s s u st ai n e d 
e n z y m ati c bl o c k a d e) i n t hi s m o u s e m o d el r e q uiri n g fr e q u e nt d ail y d o si n g b y g a v a g e m a ki n g 
s u c h i n vi v o pr e cli ni c al t e sti n g n ot f e a si bl e.  N o n et h el e s s, t h e a g gr e g at e of o ur cli ni c al, e x -vi v o 
M L R st u di e s, a n d i n vi v o r e s ult s i n C D 2 6 -/- m o u s e tr a n s pl a nt st u di e s, s h o w n a b o v e, str o n gl y 
s u g g e st t h at bl o c ki n g C D 2 6/ D P P -4 a cti vit y will li k el y al s o pr ot e ct fr o m G v H D . 
Fi g ur e 3 . Sit a gli pti n i n hi bit s all or e a cti v e T c ell pr olif er ati o n i n 
mi x e d  l y m p h o c yt e  r e a cti o n s  i n  a  d o s e -d e p e n d e nt  m a n n er 
( s e e t e xt).  
Fi g ur e 4.  C D 2 6  k n o c k o ut ( C D 2 6 -/-)
 
B L 6 d o n or C D 3 c ell s c a u s e 
si g nifi c a ntl y  l e s s  G v H D  a n d  i m pr o v e d  s ur vi v al  c o m p ar e d  wit h 
W T  B L 6  C D 3  c ell s  i n  B L 6 B A L B/ c  m o u s e  tr a n s pl a nt  m o d el  
( P < 0. 0 1) ( s e e t e xt) 
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1.5 
Rationale for a current clinical trial of sitagliptin for prevention of acute GvHD 
The combination of sirolimus and tacrolimus is an accepted standard regimen for prevention of 
acute GvHD in patients undergoing allogeneic hematopoietic cell transplantation,39,40 and has 
been the institutional standard regimen at Indiana University since 2007 for patients undergoing 
myeloablative transplants for hematological malignancies. A randomized phase III trial 
comparing sirolimus and tacrolimus with tacrolimus and methotrexate showed the regimens to 
be equivalent for prevention of acute grades II-IV GvHD, although the sirolimus containing 
regimen was associated with less of the most severe (grades III-IV) acute GvHD,39 with no 
increase in relapse. A recent meta-analysis has also confirmed the potential of the sirolimus and 
tacrolimus regimen to reduce the incidence of severe acute GvHD.40 The reported frequency of 
grades II-IV acute GvHD by day 100 after transplantation following sirolimus and tacrolimus 
prophylaxis has varied in different series and trials (up to 43%), with the efficacy of the regimen 
being similar in both matched related and well-matched unrelated donor transplants.40 
Therefore, the development of a novel regimen with a potential to reduce the incidence of 
grades II-IV acute GvHD to less than 20% to be a significant advance and be worthy of further 
study in future comparative studies. 
Most of what is known about the pathophysiology of GvHD has been gained largely from mouse 
models. Acute GvHD is initiated by infused donor T cells that recognize alloantigen expressed 
by recipient antigen presenting cells (APCs).41-43 This recognition results in the activation, 
differentiation, and expansion of donor T cells in the secondary lymphoid tissues and 
subsequent migration to target organs to cause profound tissue damage.42,44-47 Therefore, it is 
expected that this event occurs quite early after transplant when host APCs are still present, 
before they are replaced by donor-derived cells. Indeed, several studies have shown that 
activation of alloreactive T cells that induce acute GvHD begins quite early post-transplantation 
following radiation or high-dose chemotherapy,48 with highest levels of expansion of donor 
dendritic cells (DCs), known to play a key role in inducing acute GvHD, occurring by day +3, 
and highest levels of inflammatory cytokines (interleukin-2, interferon-γ, and tumor necrosis 
factor-α) occurring at day +5.48  Further, the number of DCs recovered to normal by day +21.  
While the expansion and activation kinetics of immune cells in human acute GvHD development 
are not known, an early occurrence of activation of alloreactive T cells is consistent with our 
clinical observation in UCB transplants where short term sitagliptin administration appeared to 
reduce the incidence of acute GvHD.9 Therefore, in the absence of definitive kinetics data in the 
human, and based on data derived from mouse models, we propose to continue sitagliptin 
dosing in this trial until day +14 after transplantation.  
As noted above, there is strong rationale from our pre-clinical data and clinical observation in 
UCB transplantation to study sitagliptin for prevention of GvHD. We have shown that high-dose 
sitagliptin at a dose of 600 mg every 12 hours is safe and well-tolerated in the setting of 
myeloablative conditioning, and produces acceptable inhibition of DPP-4 activity in vivo (as 
performed under IND 114587).  Therefore, in this trial we propose to test short-term sitagliptin in 
combination with standard sirolimus and tacrolimus for prevention of severe acute GvHD. 
2.0 OBJECTIVES 
2.1 
Primary Objective 
Evaluate the efficacy of sitagliptin in reducing the incidence of grade II-IV acute GvHD by day 
+100 post-transplant in patients undergoing allogeneic hematopoietic stem cell transplantation 
and receiving standard sirolimus and tacrolimus GvHD prophylaxis. We will test the null 
hypothesis H0: p0≥0.30 versus the alternative H1: p1<0.15, where p is the probability of grades 
II-IV acute GvHD by day +100. 
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2.2 
Secondary Objectives 
The following descriptive secondary objectives will be studied: 
 
Describe the tolerability and potential toxicity of sitagliptin. 
 
Describe the cumulative incidence of grades II-IV acute GvHD by day +100. 
 
Describe the cumulative incidence of grades III-IV acute GvHD. 
 
Describe the engraftment kinetics of absolute neutrophil count and platelets. 
 
Describe the incidence of infections occurring during the 100 days post-transplant.  
 
Describe non-relapse mortality (NRM) at day +30, +100, and 1 year post-transplant. 
 
Describe overall survival. 
 
Describe the incidence of chronic GvHD.  
 
Describe the cumulative incidence of relapse of the primary hematological 
malignancy. 
2.3 
Exploratory Objectives 
The following exploratory studies will be conducted (see Section 13.0): 
 
Describe immune cell reconstitution 
 
Describe changes in plasma soluble CD26 antigen (sCD26) and plasma DPP-4 activity 
from baseline in patients undergoing allogeneic transplantation, as a possible 
biomarker for development of GvHD 
 
Explore for any association between inhibition of plasma DPP-4 activity following 
sitagliptin administration and development of acute GvHD by comparing activities in 
patients who develop GvHD with those who do not.   
3.0 ELIGIBILITY CRITERIA 
3.1 
Inclusion Criteria 
3.1.1  Patients with any of the following hematologic malignancies: 
 
Acute myeloid leukemia (AML) with any of the following: 
 In first remission (CR1) with intermediate risk or high-risk cytogenetic and/or 
molecular features. 
 Patients in second or subsequent complete remission (CR2, CR3, etc.). 
 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% 
 
Acute lymphoblastic leukemia (ALL) with any of the following: 
 In CR1 or subsequent complete remission (CR2, CR3, etc.) 
 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 
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• 
Bone marrow blasts >25% at time of enrollment 
• 
Age >40 years 
 
Myelodysplasia with a Revised International Prognostic System Score (IPSS-R) 
of greater than 3 at the time of evaluation for transplantation (see Table below). 
 
 
IPSS-R cytogenetics prognostic grouping to assign sub-score: 
• 
Very Good: -Y, del(11q) 
• 
Good: normal karyotype, del(5q), del(12p), del(20q) 
• 
Intermediate: del(7q) as single abnormality, +8,  +19, any other 
abnormality not in other categories 
• 
Poor: -7, inv(3), double abnormality including -7/del(7q), complex with 3 
abnormalities per clone 
 
Very Poor: complex karyotype with more than 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% 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) 
 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. 
 
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 
 Failed stem cell collection 
 
Patients with Hodgkin’s lymphoma meeting one of the following criteria: 
 Primary refractory (failure to achieve complete remission to primary induction 
therapy)  
 Relapsed and refractory to at least one line of salvage systemic therapy  
 Failed stem cell collection  
3.1.2 Patient age ≥ 18 to ≤ 60 years 
Variable
0
0.5
1
1.5
2
3
4
Cytogenetics
Very good
Good
Intermediate
Poor
Very poor
BM blasts(%)
≤ 2
>2 to <5
5 to 10
>10
Hb (g/dl)
≥ 10
8 to <10
<8
PLTS (x109/l)
≥100
50 to <100
<50
Neutrophils
(x109/l)
≥0.8
<0.8
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3.1.3 Karnofsky Performance status ≥ 70% 
3.1.4 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). 
3.1.5 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).  
 
3.1.6 No uncontrolled bacterial, viral or fungal infection at time of enrollment defined as 
currently taking medication and progression of clinical symptoms 
3.1.7 No HIV disease (Patients with immune dysfunction are at a significantly higher 
risk of infection from intensive immunosuppressive therapies.) 
3.1.8 Non-pregnant and non-nursing  
3.1.9 Required baseline values within 60 days prior to admission: 
 
LVEF ≥ 45%  
 
DLCO ≥ 50% of predicted (corrected for hemoglobin) 
3.1.10 Required baseline laboratory values within 16 days prior to admission: 
 
Estimated creatinine clearance ≥60 ml/min 
 
Serum total bilirubin ≤ 2 x upper limit of normal value (ULN) 
 
AST and ALT ≤ 2 x ULN (unless determined by treating physician to be related to 
underlying malignancy) 
3.1.11 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.) 
3.1.12 Patients must otherwise fulfill institutional criteria for eligibility to undergo 
myeloablative allogeneic stem cell transplantation 
3.2 
Exclusion Criteria 
3.2.1 Symptomatic uncontrolled coronary artery disease or congestive heart failure 
3.2.2 Severe hypoxemia with room air PaO2 < 70, supplemental oxygen dependence, 
or DLCO < 50% predicted 
3.2.3 Patients with active central nervous system involvement  
3.2.4 Prior allogeneic or autologous hematopoietic stem cell transplant in past 12 
months  
3.2.5 Patients with diabetes mellitus requiring insulin secretagogues and/or insulin 
3.2.6 Patients with hypertriglyceridemia with serum triglyceride level ≥500 mg/d (lipid 
lowering drugs may be used to control level). 
3.2.7 Patients who have hypersensitivity to sitagliptin 
3.2.8 Patients with a history of pancreatitis 
3.2.9 Patients with symptomatic cholelithiasis 
3.2.10 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) 
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4.0 REGISTRATION PROCEDURES AND INFORMED CONSENT 
4.1 
Registration Procedures   
Patients who appear to be eligible for this trial will undergo the Informed Consent Process and 
be screened for eligibility utilizing the Eligibility Criteria. The original signed IRB approved 
Informed Consent Document and completed eligibility checklist will be forwarded to the Clinical 
Trials Office designee for eligibility verification and registration in the OnCore® database. 
Notification will be sent to the principal investigator, treating physician and research nurse when 
registration is complete to confirm registration and inform them of patient ID number. 
4.2 
Informed Consent 
The patient must be aware of the neoplastic nature of his/her disease and willingly consent after 
being informed of the procedure to be followed, the experimental nature of the therapy, 
alternatives, potential benefits, side effects, risks, and discomforts as objectively as possible. 
Consent will be obtained using the IRB approved consent.  
Written informed consent will be obtained from all subjects before initiation of any study-specific 
procedures. Procedures performed as part of the subject’s routine clinical management and 
obtained prior to signing informed consent may be utilized for screening or baseline purposes 
provided the procedure was performed within the timeframe specified in the protocol. 
5.0 TREATMENT PLAN 
This is an open label phase II study. 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 tacrolimus and 
sirolimus for GvHD prophylaxis, which includes the study drug sitagliptin: 
Day -3: 
Tacrolimus is initiated on day -3. Tacrolimus may be given according to 
institutional practice at the investigator’s discretion. However, it is recommended 
that tacrolimus be given at a starting dose of 0.02 mg/kg/day IV as a continuous 
infusion, and then modified to target serum levels of 5-10 ng/ml. Serum levels 
should be monitored according to institutional practice (typically at least three 
times weekly until discharge, then at times of outpatient clinic visits). 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. Sirolimus may be given according to institutional 
practice at the investigator’s discretion. However, it is recommended that 
sirolimus be given at a starting dose of 4 mg PO, and then modified to target 
serum levels of 5-10 ng/ml. Serum levels should be monitored according to 
institutional practice (typically at least three times weekly until discharge, then at 
times of outpatient clinic visits). Initial dosing may be decreased in order to 
account for increased levels related to use of ‘azole’ agents. 
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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.).  
6.0 DOSE ADJUSTMENT 
The dose of sitagliptin should be adjusted for altered renal dysfunction according to the 
creatinine clearance as calculated by the Cockcroft-Gault formula:  
Creatinine Clearance (CrCl) = 
 
where Age is in years, Serum Creatinine (Se Cr) in mg/dl, and Weight in in kilograms (kg).  For 
females multiply result by 0.85. 
Adjustment: 
 
CrCl ≥ 50 ml/min, no dose adjustment 
CrCl ≥ 30 to < 50 ml/min, reduce by 50% (300 mg every 12 hours) 
CrCl < 30 ml/min (including dialysis), reduce by 75% (150 mg every 12 hours) 
The dose of sitagliptin will not be adjusted for liver dysfunction. 
Discontinuation of sitagliptin 
Sitagliptin will be discontinued if the patient develops any of the following: 
• 
Pancreatitis 
• 
Hypersensitivity reaction to sitagliptin 
• 
Any grade 3-4 organ toxicity thought to be related or possibly related to sitaglipin  
7.0 ANCILLARY THERAPY 
7.1 
Full supportive care.  
Patients should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, antiemetics, etc., when appropriate according to institutional 
standards.  
7.2 
Use of Palifermin.  
Palifermin may be used for prevention of severe mucositis according to institutional 
preferences (usually for TBI containing regimens). If used, palifermin will be 
administered according to the following schedule: 
Palifermin 60 mcg/kg/day IV bolus on the three consecutive days prior* to the 
preparative regimen (i.e., days -8, -9, -10 if TBI-based regimen is used; OR days -9, -10, 
-11 if chemotherapy only regimen used) AND again for three days after infusion of 
peripheral blood stem cell (PBSC) (i.e., on days 0 to +2). 
*MUST have a minimum of 24 hours between LAST dose of Palifermin and FIRST dose 
of either preparative regimen. 
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7.3 
Pneumocystis carinii prophylaxis.  
Prophylaxis against pneumocystis infection will be according to institutional 
standards. (An acceptable regimen includes, but is not restricted to cotrimoxazole one 
DS tablet once daily on Mondays, Wednesdays and Fridays. Patients allergic/intolerant 
to cotrimoxazole may receive dapsone or inhaled pentamidine instead). Prophylaxis will 
commence on engraftment (defined as achievement of ANC ≥ 0.5x109/l for three 
consecutive days) and continue until at least day +180 post-transplant. This may be 
continued beyond Day +180 at the discretion of the treating physician. For patients who 
develop chronic GvHD (after Day +180), it is recommended that pneumocystis 
prophylaxis be continued for an extended period at the discretion of the treating 
physician. 
7.4 
Herpes Zoster prophylaxis.   
All patients will receive acyclovir (or equivalent) for day +1 until day +180 following 
transplantation according to institutional standards.  
7.5 
Cytomegalovirus (CMV) prophylaxis.  
Prophylaxis against CMV infection will be according to institutional standards. Either 
prophylaxis using drug therapy or monitoring for CMV reactivation and pre-emptive 
therapy upon activation may be used. It is recommended that patients will be monitored 
weekly for reactivation of CMV using a sensitive assay (e.g., quantitative PCR, ppp65 
antigenemia, or hybrid capture assay) until day +100 (see Section 10.5 for 
recommended frequency of monitoring after day 100). Acceptable pre-emptive therapy 
includes Foscarnet (90 mg/kg BID), ganciclovir (10 mg/kg/day), or valganciclovir until 
resolution. Doses of drugs are adjusted for renal function and myelosuppression.    
7.6 
Fungal prophylaxis.  
Patients will receive prophylaxis to cover yeasts and mold infections according to 
institutional standards and at the investigator’s discretion.  The recommended 
regimen is fluconazole 400 mg PO QD from day +1 to day +100. Acceptable alternatives 
are voriconazole, micafungin, caspofungin, lipid preparations of amphotericin B. 
8.0 STUDY SCHEDULE 
8.1 
Guidelines for Pre-Study Testing  
To be completed within 60 DAYS before day of admission: 
• 
MUGA scan or ECHO 
• 
Pulmonary function tests 
• 
HIV, HTLV, hepatitis B and C serology 
• 
Bone marrow aspirate (only for patients with leukemia or MDS to document remission-
if patient is known to be in relapse, bone marrow aspirate will not be done) 
To be completed within 16 DAYS before day of admission: 
• 
Liver profile to document total bilirubin, AST and ALT levels ≤ 2 x upper limits of 
normal values (unless determined by the treating physician to be related to the 
underlying cancer).  
• 
Estimated creatinine clearance (CrCl) to document ≥ 60 ml/min 
• 
Pregnancy test (serum or urine β-hCG) for all women of childbearing potential 
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8.2 
Screening / Pre-Transplant and Treatment Schedule 
 
Prior to 
start of 
Preparati
ve 
Regimen 
Time points peritransplant 
Follow-
up 
Days -1 to 
+14 
+30 
days 
(±3) 
+100 
days 
(±7) 
+180 
days 
(±7) 
+270 
days 
(±7) 
+365 
days 
(±7) 
+5 
years7 
Sitagliptin 
treatment 
 
X1 
 
 
 
 
 
 
Patient Evaluation 
H&P** 
CBC** 
CMP** 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
GvHD evaluation 
 
X2 
X2 
X2 
X2 
X2 
X2 
X 
Soluble (s) CD26 
antigen 
X 
X3 
X 
X 
X 
X 
X 
 
Plasma DPP-4 
activity (PD) 
X 
X4 
X 
X 
X 
X 
X 
 
Plasma sitagliptin 
(PK) 
 
X5 
 
 
 
 
 
 
Immune cell 
analysis 
 
X (day +14) 
X 
X 
X 
X 
X 
 
BAFF 
 
X (day +14) 
X 
X 
X 
X 
X 
 
AE assessment6 
X 
X 
X 
X 
 
 
 
 
1Sitagliptin is administered 600 mg every 12 hours from day -1 to day +14. 
2Highest grade of acute or severity of acute GvHD and/or chronic GvHD is recorded (see 
Section 9.0). 
3sCD26 is measured at baseline (prior to start of preparative regimen), day -1, day 0, day 7, day 
14 during this period, and thereafter as indicated. 
4DPP-4 activity is measured at baseline (prior to start of preparative regimen); day -1 pre-dose 
of sitagliptin, then 2, 4, and 6 hours after first dose; thereafter activity is measured 30 minutes 
before each morning dose and 2 hours post-morning dose through last dose on day +14. 
5Plasma sitagliptin levels are measured at baseline (day -1 pre-dose of sitagliptin), then 2, 4, 
and 6 hours after first dose; thereafter activity is measured 30 minutes before each morning 
doseand 2 hours post-morning dose through last dose on day +14. 
6Refer to Section 10.4 for a complete list of AEs that will be captured until day +100. 
7Patients will be followed annually per institutional standards beginning year 2 through year 5 for 
development and severity of chronic GvHD, late-onset acute GvHD, relapse or progression of 
primary malignancy, and survival. 
** Patients will be evaluated clinically by history and physical examination (H&P) and laboratory 
testing for safety and toxicity during routine standard of care assessments.  These will occur at 
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minimum frequencies of daily during preparative regimen until discharge from hospital, then 
weekly until day +30, every two weeks until day +100, and then monthly thereafter until day 
+365. CBC, complete blood count; CMP, complete metabolic panel.  
9.0 DEFINITIONS AND ASSESSMENT OF PRIMARY ENDPOINT: ACUTE GVHD 
The primary endpoint of the study will be the development of acute GvHD in the first 100 days 
post- transplant. Patients will be monitored for the development of acute GvHD at least every 
second day until day +28 or discharge, then at each subsequent clinic visit as outpatient. 
Beyond day +100, patients will be followed at their routine clinic visits for the development of 
chronic GvHD (a secondary endpoint). 
9.1 
Evaluation of acute GvHD 
GvHD must be documented by biopsy of at least one of the organs involved (skin, gut, or liver). 
Each organ will be staged using standard criteria, as outlined below (see Section 8.2). The 
character and extent of skin involvement will be determined by examination. The rules of nine 
will be used to estimate skin surface area involved. Staging is also based on the extent and 
character of the skin; for example, the presence or absence of bullae. Gastrointestinal GvHD 
requires 24-hour stool volume for staging. In addition, a history will be performed to document 
the absence or presence of abdominal pain, nausea, and vomiting. Patients will also be 
evaluated for the presence of ileus. Hepatic staging will be determined by elevation of serum 
total bilirubin. The grade of acute GvHD used for evaluation of the therapy will be the maximum 
grade developed during the entire period of evaluation. 
 
9.2 
Grading of acute GvHD 
Acute GvHD should be graded according to standard clinical criteria as outlined in 
Appendix II. 
10.0 DEFINITIONS OF SECONDARY ENDPOINTS 
10.1 
Time to engraftment of neutrophils 
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 
(NEUTROPHILS + BANDS) is at least 0.5 x109/l.  Patients surviving at least 14 days after 
transplant will be evaluable for this endpoint. 
10.2 
Time to engraftment of platelets 
The time to engraftment of platelets is defined as the time day 0 to the date of the first of 7 
consecutive days of an unsupported (i.e., sustained for at least 7 days without transfusion) 
platelet count of at least 20 x109/l post-transplant (i.e., Day 0). The date of the first of 7 
consecutive days of an unsupported platelet count of at least 50 x109/l will also be noted.  
10.3 
Chronic Graft versus Host Disease 
Assessment of chronic GvHD will be according to the National Institutes of Health (NIH) scoring 
system.50,51 Briefly, a clinical categorical system (0-3) is used for scoring of individual organs 
that describes the severity for each affected organ taking functional impact into account. Eight 
organs (skin, mouth, eyes, gastrointestinal [GI] tract, liver, lungs, joints, and female genital tract) 
are assessed. In general, a score of 0 means no manifestations/symptoms, a score of 1 
indicates no significant impairment of function or activities of daily living (ADL), a score of 2 
reflects significant impairment of ADL but no major disability, and a score of 3 indicates 
significant impairment of ADL with major disability. The scoring is clinical and the only mandated 
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laboratory tests for its completion are liver function tests, although pulmonary function tests will 
be performed only when indicated by symptoms. Global severity (mild, moderate, severe) is 
calculated from these scores according to the number and severity of organs reported:  
Mild:   
1 or 2 organs (except lung) with score 1.  
Moderate:  
≥3 organs with score 1, or lung score 1, or 1 or more organs with score 2.  
Severe:  
any organ with a score 3, or lung score 2.  
10.4 
Hematological and Non-Hematological toxicity 
Assessment of toxicity and adverse events will be based upon the descriptions and grading 
scales of the revised NCI Common Terminology Criteria for Adverse events (CTCAE) version 
4.0. A copy of the CTCAE version 4.0 is available from (http://ctep.info.nih.gov). 
For non-hematological toxicity, biochemical changes that are reversible with simple 
supplementation or treatment (e.g., electrolyte abnormalities, hyperglycemia, asymptomatic liver 
enzyme elevations, serum creatinine fluctuations related to hydration status, etc.) will not be 
captured. However, all cases of hypoglycemia will be recorded and their potential attribution to 
sitagliptin will be captured. The following major toxicities will be also recorded in the first 100 
days: 
 
Sinusoidal obstruction syndrome (SOS). The diagnosis of SOS is will be based 
on the McDonald criteria.52 Hepatic SOS is defined by the occurrence of 2 or more 
of the following criteria before day 30: (1) total bilirubin >2 mg/dl; (2) painful 
hepatomegaly; and (3) unexplained weight gain of >2% from baseline. No other 
reasonable explanation for these signs could be present at the time of diagnosis. 
Clinical grading of VOD will be according to Bearman criteria:53 
Mild: 
Self-limiting (resolving within day 100), no therapy required 
Moderate: 
Self-limiting (resolving within day 100) but requiring therapy, 
including diuretics for fluid retention, narcotic analgesia for painful 
hepatomegaly. 
Severe: 
VOD persisting to day 100 or causing hepatic failure or death. 
 
Interstitial pneumonitis. The incidence of grade 3-4 pulmonary toxicity, within the 
first 100 days post-transplantation, will be described. 
 
Pancreatitis 
 
Incidence of infections during first 100 days post-transplant. Infectious 
episodes will be documented as “proven” if an organism is isolated or confirmed by 
serological, molecular, or histological evidence, or “suspected” if there is 
documented fever and organ-related changes without isolated organism. The sites 
of infection will also be described. Infections to be reported include, but are not 
limited to, blood stream bacterial infections, pneumonia, all fungal infections, viral 
reactivation or infection (including CMV, EBV, HHV-6, BK, adenovirus, RSV, etc.), 
and any sepsis resulting in organ failure regardless of origin or organism isolation. 
Simple neutropenic fever will not be captured. 
 
Thrombotic microangiopathy (TMA).  TMA will be defined according to the Blood 
and Marrow Transplantation Clinical Trials Network (BMT-CTN) consensus criteria, 
and requires all of the following criteria for diagnosis57 
o Schistocytosis (≥2 schistocytes in high power field) on peripheral blood 
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o Increased LDH 
o Doubling of serum creatinine or ≥50% decrease in creatinine clearance from 
baseline 
o Negative direct and indirect Coomb’s test. 
All cases of grade 3-4 TMA will reported annually to the Food and Drug Administration 
(FDA) in the annual report. 
 
Transfusion requirements during first 100 days. It is expected that almost all 
patients undergoing myeloablative conditioning will develop grade 4 hematological 
toxicities. However, the number of units of red blood cells and platelets transfused in 
the first 100 days post-transplant (or longer if no engraftment has occurred) will be 
recorded and monitored. 
10.5 
Long-term follow-up 
Beyond day +100, patients will be followed up for development and severity of chronic GvHD, 
late-onset acute GvHD, relapse or progression of primary malignancy, and survival annually for 
up to 5 years (beginning year 2). Causes of death should be recorded as either related to 
relapse or progression of malignancy, acute or chronic GvHD, infection in the presence or 
absence of GvHD, other transplant-related complication, or unrelated to transplantation (i.e., 
incidental). 
11.0 DRUG FORMULATION, AVAILABILITY, AND PREPARATION 
11.1 
Sitagliptin (JanuviaTM) 
11.1.1 Availability 
Sitagliptin is a specific DPP-4 inhibitor that is approved by the FDA for the treatment of 
type 2 diabetes mellitus.  In this protocol, sitagliptin will be purchased commercially and 
provided by the study. 
11.1.2 Preparation 
Sitagliptin is commercially available as 25 mg, 50 mg, and 100 mg tablets. Sitagliptin will 
be supplied by the study and provided to patients free of charge.  
11.1.3 Storage and stability 
Sitagliptin tablets should be stored at 20-25°C (68-77°F), with excursions permitted to 
15-30°C (59-86°F). 
11.1.4 Administration 
Sitagliptin may be administered with or without food.   
11.1.5 Toxicity 
The most common toxicity that occurred in clinical trials of patients with type 2 diabetes 
mellitus and in healthy volunteers are as follow: 
Side effects occurring with a frequency of 1% to 10%: headache (5%), diarrhea (3%), 
upper respiratory tract infection (6%), and nasopharyngitis (5%). 
Side effects occurring with an incidence less than or equal to placebo: abdominal pain 
(2%), hypoglycemia (1%), nausea (1%), neutrophils increased, and elevation of serum 
creatinine. 
During controlled clinical trials in healthy subjects, single doses of up to 800 mg 
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sitagliptin were administered. Maximal mean increases in QTc of 8.0 msec were 
observed in one study at a dose of 800 mg sitagliptin, a mean effect that is not 
considered clinically important. There is no experience with doses above 800 mg in 
humans. 
There have been post-marketing reports of acute pancreatitis, including fatal and non-
fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly 
discontinue sitagliptin. 
There have been post-marketing reports of acute renal failure, sometimes requiring 
dialysis. Dosage adjustment is recommended in patients with moderate or severe renal 
insufficiency and in patients with ESRD. Assessment of renal function is recommended 
prior to initiating sitagliptin and periodically thereafter.  
There is an increased risk of hypoglycemia when sitagliptin is added to an insulin 
secretagogue (e.g., sulfonylurea) or insulin therapy. Consider lowering the dose of the 
sulfonylurea or insulin to reduce the risk of hypoglycemia.  
There have been post-marketing reports of serious allergic and hypersensitivity 
reactions in patients treated with sitagliptin such as anaphylaxis, angioedema, and 
exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these 
reactions occurred within the first 3 months after initiation of treatment with sitagliptin, 
with some reports occurring after the first dose. In such cases, promptly discontinue 
sitagliptin, assess for other potential causes and institute appropriate monitoring and 
treatment.  
11.1.6 Drug interactions 
In clinical studies in diabetic patients, sitagliptin did not meaningfully alter the 
pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral 
contraceptives, providing in vivo evidence of a low propensity for causing drug 
interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic 
transporter (OCT). 
Sitagliptin had a minimal effect on the pharmacokinetics of digoxin. Following 
administration of 0.25 mg digoxin concomitantly with 100 mg of sitagliptin daily for 10 
days, the plasma AUC of digoxin was increased by 11%, and the plasma Cmax by 18%. 
Effects of Other Drugs on Sitagliptin: Clinical data described below suggest that 
sitagliptin is not susceptible to clinically meaningful interactions by co-administered 
medications: 
Metformin: Co-administration of multiple twice-daily doses of metformin with sitagliptin 
did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 
diabetes. 
Cyclosporine: A study was conducted to assess the effect of cyclosporine, a potent 
inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a 
single 100 mg oral dose of sitagliptin and a single 600 mg oral dose of cyclosporine 
increased the AUC and Cmax of sitagliptin by approximately 29% and 68%, respectively. 
These modest changes in sitagliptin pharmacokinetics were not considered to be 
clinically meaningful. The renal clearance of sitagliptin was also not meaningfully altered. 
Therefore, meaningful interactions would not be expected with other p-glycoprotein 
inhibitors. 
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11.2 
Tacrolimus (Prograf®) 
11.2.1 Availability 
Tacrolimus is commercially available as an injection (5 mg/ml; 1 ml ampoules) and as 
oral capsules (1 mg and 5 mg). 
11.2.2 Preparation  
Tacrolimus injection must be diluted prior to IV infusion with 0.9% sodium chloride or 5% 
dextrose injection to a concentration of 4-20 µg/ml. Solutions should be prepared in non-
PVC plastic or glass. Tacrolimus injection and diluted solutions of the drug should be 
inspected visually for particulate matter and discoloration prior to administration 
whenever solution and container permit. 
11.2.3 Administration 
Oral therapy should be started as soon as possible as per protocol and 8 to 12 hours 
after stopping intravenous therapy. Oral doses will be administered twice a day. 
11.2.4 Storage and stability 
Tacrolimus capsules and injection should be stored at controlled room temperature, 15-
30°C (59-86°F). 
11.2.5 Toxicity 
In patients receiving tacrolimus, 5% to 47% experienced anemia, 8% to 32% 
experienced leukocytosis, and 14% to 24% experienced thrombocytopenia. Rare cases 
of microangiopathic hemolytic anemia have been reported. Chest pain was reported in 
19%. Mild to moderate hypertension is a common adverse effect associated with 
tacrolimus therapy. Antihypertensive therapy may be required. The most common 
adverse effects of tacrolimus have involved the central nervous system, and include 
headache (37% to 64%), tremors (48% to 56%), insomnia (32% to 64%), paresthesia 
(17% to 40%); and dizziness (19%). Tremor and headache may respond to a dosage 
reduction. Visual changes, agitation, anxiety, confusion, seizures, depression, 
hallucinations, myoclonus, neuropathy, psychosis, incoordination, and abnormal dreams 
have been reported in 3% to 15% of tacrolimus-treated patients. Hyperkalemia (13% to 
45%), hypokalemia (13% to 29%), hypophosphatemia (49%), and hypomagnesemia 
(16% to 48%) have been associated with tacrolimus therapy. Hyperuricemia has been 
reported in greater than 3% of tacrolimus-treated patients. Gastrointestinal adverse 
effects of tacrolimus have included nausea (32% to 46%), vomiting (14% to 29%), 
anorexia (7% to 34%), constipation (23% to 35%) and diarrhea (37% to 72%). 
Nephrotoxicity was reported in 38% and 52% of liver and kidney transplant patients, 
respectively. Overt nephrotoxicity is usually seen early after transplantation and is 
characterized by an increased serum creatinine and a decrease in urine output. 
Hematuria has been reported in greater than 3% of tacrolimus-treated patients. 
Abnormal liver function tests have been reported in 6% to 36% of patients; ascites was 
reported in 7% to 27% of these patients. 
Other miscellaneous effects that have occurred in clinical trials include pain (24% to 
63%), fever (19% to 48%), asthenia (11% to 52%), back pain (17% to 30%), and 
peripheral edema (12% to 36%). The incidence of hyperglycemia is 17% and may 
require therapy with insulin. Other less frequently occurring effects (greater than 3%) 
includes abscess, chills, peritonitis, and photosensitivity reactions. Anaphylaxis has been 
reported in a few patients receiving intravenous tacrolimus. Tacrolimus injection contains 
cremophor which in other drugs has been associated with anaphylaxis. Because 
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tacrolimus is an immunosuppressive, the risk of opportunistic infections is increased. 
11.2.6 Drug Interactions 
Tacrolimus is metabolized by cytochrome P450 3A4. Drugs that are inhibitors (e.g., 
itraconazole) or inducers (e.g., phenytoin) of 3A4 might be expected to increase or 
decrease tacrolimus concentrations, respectively. This could result in increased or 
decreased effect of tacrolimus. 
11.3 
Sirolimus (Rapamycin; Rapamune) 
11.3.1 Availability and preparation 
Sirolimus is commercially available as solution for oral use as 1 mg/ml (60 ml) 
(containing ethanol 1.5% to 2.5%; packaged with oral syringes and a carrying case), as 
1 mg and 2 mg tablets. 
11.3.2 Administration 
The oral solution should be mixed with at least 2 ounces of water or orange juice. No 
other liquids should be used for dilution. Patient should drink diluted solution 
immediately. The cup should then be refilled with an additional 4 ounces of water or 
orange juice, stirred vigorously, and the patient should drink the contents at once. 
Sirolimus should be taken 4 hours after cyclosporine oral solution, cyclosporine 
capsules, or tacrolimus capsules. 
11.3.3 Storage and stability 
Store Sirolimus capsules at controlled room temperature, 15-30°C (59-86°F). 
11.3.4 Toxicity 
The Incidence of many adverse effects is dose related. The following are reported 
adverse events associated with Sirolimus. 
Common 
Cardiovascular: Peripheral edema (54% to 64%), hypertension (39% to 49%), peripheral 
edema (54% to 64%), edema (16% to 24%), chest pain (16% to 24%) 
Central nervous system: Fever (23% to 34%), headache (23% to 34%), pain (24% to 
33%), insomnia (13% to 22%) 
Dermatologic: Acne (20% to 31%), rash (10% to 20%) 
Endocrine & metabolic: Hyperlipidemia (38% to 57%), hypercholesterolemia (38% to 
46%), hypophosphatemia (15% to 23%), hypokalemia (11% to 21%) 
Gastrointestinal: Diarrhea (25% to 42%), constipation (28% to 38%), abdominal pain 
(28% to 36%), nausea (25% to 36%), vomiting (19% to 25%), dyspepsia (17% to 25%), 
weight gain (8% to 21%) 
Genitourinary: Urinary tract infection (20% to 33%) 
Hematologic: Anemia (23% to 37%), thrombocytopenia (13% to 40%) 
Neuromuscular & skeletal: Weakness (22% to 40%), arthralgia (25% to 31%), tremor 
(21% to 31%), back pain (16% to 26%) 
Renal: Serum creatinine increased (35% to 40%) 
Respiratory: Dyspnea (22% to 30%), upper respiratory infection (20% to 26%), 
pharyngitis (16% to 21%) 
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Uncommon: 
Cardiovascular: Atrial fibrillation, CHF, facial edema, hypervolemia, hypotension, 
palpitation, peripheral vascular disorder, postural hypotension, syncope, tachycardia, 
thrombosis, vasodilation, venous thromboembolism 
Central nervous system: Chills, malaise, anxiety, confusion, depression, dizziness, 
emotional lability, hypoesthesia, hypotonia, neuropathy, somnolence 
Dermatologic: Dermatitis (fungal), hirsutism, pruritus, skin hypertrophy, dermal ulcer, 
ecchymosis, cellulitis, skin carcinoma 
Endocrine & metabolic: Cushing's syndrome, diabetes mellitus, glycosuria, acidosis, 
dehydration, hypercalcemia, hyperglycemia, hyperphosphatemia, hypocalcemia, 
hypoglycemia, hypomagnesemia, hyponatremia, hyperkalemia (12% to 17%) 
Gastrointestinal: Enlarged abdomen, anorexia, dysphagia, eructation, esophagitis, 
flatulence, gastritis, gastroenteritis, gingivitis, gingival hyperplasia, ileus, mouth 
ulceration, oral moniliasis, stomatitis, weight loss 
Genitourinary: Pelvic pain, scrotal edema, testis disorder, impotence 
Hematologic: Leukocytosis, polycythemia, TTP, hemolytic-uremic syndrome, 
hemorrhage, leukopenia (9% to 15%) 
Hepatic: Abnormal liver function tests, alkaline phosphatase increased, ascites, LDH 
increased, transaminases increased 
Local: Thrombophlebitis 
Neuromuscular & skeletal: Arthrosis, bone necrosis, CPK increased, leg cramps, 
myalgia, osteoporosis, tetany, hypertonia, paresthesia 
Ocular: Abnormal vision, cataract, conjunctivitis 
Otic: Ear pain, deafness, otitis media, tinnitus 
Renal: Albuminuria, bladder pain, BUN increased, dysuria, hematuria, hydronephrosis, 
kidney pain, tubular necrosis, nocturia, oliguria, pyelonephritis, pyuria, nephropathy 
(toxic), urinary frequency, urinary incontinence, urinary retention 
Respiratory: Asthma, atelectasis, bronchitis, cough, epistaxis, hypoxia, lung edema, 
pleural effusion, pneumonia, rhinitis, sinusitis 
Miscellaneous: Abscess, diaphoresis, facial edema, flu-like syndrome, herpes simplex, 
hernia, infection, lymphadenopathy, lymphocele, lymphoproliferative disease, peritonitis, 
sepsis, increase in serum lipids (cholesterol and triglycerides).  
11.3.5 Drug interactions 
Sirolimus is a substrate of CYP3A4, and weakly inhibits CYP3A4.  The following drugs 
have been found to interact with sirolimus: 
Antifungal agents, imidazoles (itraconazole, ketoconazole, voriconazole): May increase 
the levels/effects of sirolimus. Concurrent use is not recommended, or levels must be 
closely monitored. 
Calcineurin inhibitors (cyclosporine, tacrolimus): Concurrent therapy may increase the 
risk of HUS/TTP/TMA. Cyclosporine capsules (modified) or cyclosporine oral solution 
(modified) increase Cmax and AUC of sirolimus during concurrent therapy, and 
cyclosporine clearance may be reduced during concurrent therapy. Sirolimus should be 
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taken 4 hours after cyclosporine oral solution (modified) and/or cyclosporine capsules 
(modified). 
Clarithromycin: May increase serum concentrations of sirolimus. Concurrent use not 
recommended. 
CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of sirolimus. 
Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, 
phenobarbital, phenytoin, and rifamycins. Concurrent use is not recommended. 
CYP3A4 inhibitors: May increase the levels/effects of sirolimus. Example inhibitors 
include azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, 
isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, 
and verapamil. Concurrent use is not recommended. 
Calcium channel antagonists: Diltiazem may increase serum concentrations of sirolimus; 
monitor. Verapamil and nicardipine may share this effect. 
Erythromycin: May increase serum concentrations of sirolimus. Concurrent use is not 
recommended. 
Rifampin: May decrease serum concentrations of sirolimus. Concurrent use is not 
recommended. 
12.0 CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE 
Although not a primary endpoint of the study, formal evaluation of response and disease status 
will be performed on at Days +30 (if not in remission at time of transplant), +100, +180, +270 
and +365. After 1 year post transplant, disease evaluation will be according to institutional 
standards of care until progression and/or death until year 5. Patient may be assessed more 
frequently at the discretion of the treating physician. 
12.1 
Response criteria for patients with AML and ALL 
12.1.1 Complete Remission (CR): defined by the presence of all of the following: 
• 
Bone marrow cellularity > 20% with maturation of all cell lines, blasts ≤ 5% of 
total nucleated cells, and absence of Auer rods (for patients with AML). 
• 
No extramedullary leukemia (e.g., CNS or soft-tissue involvement) 
12.1.2 Treatment Failure: defined as failure to achieve CR. 
12.1.3 Relapse: defined by any of the following factors after being in CR: 
• 
Reappearance of circulating blast cell in the peripheral blood. 
• 
More than 5% blasts in the bone marrow, not attributable to another cause. 
• 
Development of extramedullary leukemia 
12.2 
Response criteria for patients with myelodysplasia 
12.2.1 Complete Remission (CR): defined by the presence of all of the following: 
• 
Bone marrow cellularity > 20% with maturation of all cell lines, blasts ≤ 5% of 
total nucleated cells and no morphological or cytogenetic evidence of dysplasia. 
12.2.2 Treatment Failure: defined as failure to achieve CR. 
12.2.3 Relapse: defined by any of the following factors after being in CR: 
• 
Reappearance of circulating blast cell in the peripheral blood. 
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• 
>5% blasts in the bone marrow not attributable to another cause and/or 
reappearance of any cytogenetic abnormality previously present. 
12.3 
Response criteria for patients with CML 
12.3.1 Complete hematological response (CHR): The complete disappearance of all 
signs and symptoms of the disease including palpable splenomegaly. The peripheral 
blood white cell (WBC) and platelet counts must be within institutional normal 
ranges. Bone marrow aspirate differential must have ≤ 5% blast cells. 
12.3.2 Partial Hematological Response (PHR): 
• 
A decrease in the WBC count by at least 50% and to < 20,000/µl. 
OR 
• 
The achievement of CHR except for 
a) Persistence of palpable splenomegaly; or 
b) Persistence of immature cells (>5% myelocytes, promyelocytes, or blasts) 
in peripheral blood; or 
c) Thrombocytosis (exceeding the upper limit of normal), which must have 
decreased by more than 50% of pretreatment levels. 
12.3.3 Cytogenetic response: Patients in CHR may be further classified in terms of 
cytogenetic response, as assessed from a bone marrow aspirate, as follows: 
• 
Complete cytogenetic response (CCyR): 100% normal metaphases. 
• 
Partial cytogenetic response (PCyr): > 65% normal metaphases (i.e., 1-34% 
Ph+ metaphases). 
• 
Major cytogenetic response (MCyR): Includes both complete and partial 
cytogenetic response (i.e., < 35% Ph+ metaphases). 
• 
Minor cytogenetic response (MiCyR): 1-65% normal metaphases (i.e., 35-99% 
Ph+ metaphases). 
In the rare typical CML patients who do not have a Ph+ chromosome demonstrated by 
classical cytogenetics, but have a demonstrable BCR/ABL translocation at diagnosis, 
the “cytogenetic” response will be assessed by fluorescent in-situ hybridization 
(FISH) analysis. In this case, responses are defined as: 
• 
Complete response by FISH: A 100% reduction in the cells positive for the 
translocation of BCR and ABL (i.e., 0% cells positive). 
• 
Partial response by FISH: A reduction greater than 50% but less than 100% of 
cells positive for the BCR/ABL translocation. 
12.3.4 Molecular response: Patients who have achieved a cytogenetic response will 
be evaluated for a molecular response by RT-PCR analysis for minimal residual disease. 
A complete molecular response is defined as no detectable BCR/ABL transcript. 
12.4 
Response criteria for patients with Hodgkin’s or non-Hodgkin’s Lymphoma 
12.4.1 Complete Response (CR): defined by the presence of all the following criteria 
• 
Complete disappearance of all detectable clinical and radiographic evidence of 
target lesions and disappearance of all disease-related symptoms if present prior 
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to therapy, as well as normalization of those biochemical abnormalities (e.g., 
LDH, etc.) definitely assignable to NHL. 
• 
All lymph nodes and nodal masses must have regressed to normal size (≤ 1.5 
cm in their greatest transverse diameter for nodes > 1.5 cm prior to therapy). 
Previously involved nodes that were 1.1 to 1.5 cm in their greatest transverse 
diameter prior to treatment must have decreased to ≤ 1 cm in their greatest 
transverse diameter after treatment, or by more than 75% in the sum of the 
products of their greatest transverse diameters (SPD). 
• 
The spleen, if considered to be enlarged before therapy on the basis of a CT 
scan, must have regressed in size and must not be palpable on physical 
examination. (No normal size can be specified, however, because of the 
difficulties in evaluating splenic and hepatic size.) Any macroscopic nodules in 
any organs detectable on imaging studies should no longer be present. Similarly, 
other organs considered to be enlarged prior to therapy due to involvement of 
lymphoma (i.e., kidneys, liver, etc.) must have decreased in size. 
• 
If the bone marrow was involved by lymphoma prior to treatment, the infiltrate 
must be cleared on repeat bone marrow aspirate and biopsy of same site. 
12.4.2 Complete Response Uncertain (CRu): Complete response/uncertain will 
include those patients who have met the criteria in Section 12.4.1 bullet points 1 and 3, 
but with one or more of the following: 
• 
A residual node > 1.5 cm in greatest transverse diameter that has regressed 
more than 75% in the SPD. Individual nodes that were previously confluent must 
have regressed more than 75% in their SPD compared with the size of the 
original mass. 
• 
Indeterminate bone marrow (increased number or size of aggregates without 
cytologic or architectural atypia). 
12.4.3 Partial Response (PR):  
• 
A decrease of ≥ 50% in the SPD of the six largest dominant nodes or nodal 
masses. These nodes or masses should be selected according to the following 
features: a) they should be clearly measurable in at least two perpendicular 
measurements; b) they should be from as disparate regions of the body as 
possible; and c) they should include mediastinal and retroperitoneal areas of 
disease whenever these sites are involved. 
• 
No increase in the size of other nodes, liver, or spleen. 
• 
Splenic and hepatic nodules must regress by at least 50% in SPD. 
• 
With the exception of splenic and hepatic nodules, involvement of other organs is 
considered assessable and not measurable disease. 
• 
Bone marrow assessment is irrelevant for determination of a PR because it is 
assessable and not measurable disease; however, if positive, the cell type 
should be specified in the report, e.g., large-cell lymphoma. 
• 
No new sites of disease. 
12.4.4 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as references the smallest sum LD since the treatment 
started. 
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12.4.5 Progressive Disease:  
• 
50% or more increase from nadir in the SPD of any previously identified 
abnormal node for PRs or non-responders. 
• 
Appearance of any new lesion during or at the end of therapy. 
13.0 CORRELATIVE STUDIES AND SAMPLE SUBMISSION 
13.1 
Laboratory Correlative Studies   
13.1.1 Pharmacokinetic studies of sitagliptin. Plasma levels of sitagliptin will be 
performed by Dr. David Jones’ Laboratory at the Clinical Pharmacology Analytical Core 
of the Indiana University Simon Cancer Center. Plasma sitagliptin levels will be assayed 
by high-turbulence liquid chromatography online extraction method,54 and detected by 
mass spectroscopy (API 4000, Applied Biosystems, Toronto, Canada) using selected 
reaction monitoring with turbo-ionspray interface in the positive ion mode, as adapted by 
Dr. Jones’ Laboratory (limit of assay 1.23 nmol/l). PK analysis will be performed both 
non-compartmentally, as well as by population pharmacokinetics-based approaches. 
Additional analyses will include the development of a pharmacokinetic-
pharmacodynamic model linking sitagliptin concentrations to DPP4 activity to 
subsequent development of grades 2-4 acute GvHD by day +100, and engraftment as 
measured by neutrophils post-transplant. To facilitate these analyses, additional 
variables from previously collected laboratory values will be extracted from the medical 
record from the period immediately preceding transplant to time of engraftment. Values 
to be extracted will include but are not limited to liver function tests, kidney function tests 
and CBC with differential.  
Timepoints of collection will be Day -1 before first dose of sitagliptin and then 2, 4 and 6 
hours after the FIRST dose. Thereafter, samples are to be collected 30 minutes 
BEFORE and 2 hours AFTER each morning dose (+/- 10 minutes for all timepoints Day -
1 thru Day +14). Samples will be processed and stored at the Research Laboratory at 
the Clinical Trials Office at IUSCC until transfer to Dr. Jones’ laboratory for analysis. 
Detailed information regarding collection and processing can be found in the laboratory 
manual for this study. 
13.1.2 Pharmacodynamic studies of plasma CD26/DPP-IV activity. We will use 
plasma CD26/DPP-IV activity as a surrogate to provide some level of confidence that 
biologically active levels of the drug are achieved using the dose and schedule 
administered by demonstrating target inhibition. However, to explore whether plasma 
CD26/DPP-IV inhibition will provide a good surrogate marker, we will correlate DPP-IV 
activity with plasma levels of sitagliptin and subsequent development of grades 2-4 
acute GvHD by day +100, and engraftment as measured by neutrophils post-transplant.   
Plasma DPP-IV activity will be assayed in Dr. Farag’s laboratory using a modification of 
the chromogenic assay we have previously used to assess DPP-IV activity on CD34+ 
UCB cells,55 and previously reported by others.23  Plasma DPP-IV activity will be 
assayed by incubating 4 µl of plasma with the chromogenic substrate Gly-Pro-p-
nitroanilide (400 µM) (Gly-Pro-pNA; Sigma, St. Louis, MO) at 37°C in 96-well microplates 
and determining the amount of nitroanilide (pNA) released in the supernatant by 
measuring absorbance at 390 nm over time. Absorbance will be measured at 390 nm on 
a microplate spectrofluorometer (SpectraMax 190; Molecular Devices, Menlo Park, CA). 
The change in absorbance between each 30 second interval will be averaged over 10 
minutes to calculate the slope for each sample. Enzyme activity is defined as the slope 
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(in mOD/min) from 4 to 14 minutes. The mean percentage inhibition of DPP-IV activity 
relative to baseline following sitagliptin administration will be plotted against time. 
Timepoints of collection will be at baseline (i.e., prior to the start of the preparative 
regimen), Day -1 before first dose of sitagliptin and then 2, 4 and 6 hours after the FIRST 
dose. Thereafter, samples are to be collected 30 minutes BEFORE and 2 hours AFTER 
each morning dose through Day +14 (+/- 10 minutes for all timepoints Day -1 thru Day 
+14). Then samples will be collected Day +30 (± 3 days), +100, +180, +270 and +365 (± 
7 days at all other timepoints). 
Samples will be processed and stored at the Research Laboratory at the Clinical Trials 
Office at IUSCC until transfer to Dr. Farag’s laboratory for analysis. Detailed information 
regarding collection and processing can be found in the laboratory manual for this study. 
13.1.3 Soluble CD26 (sCD26) antigen levels. There is currently no conclusive 
information about the behavior of antigen expression, sCD26 concentration, and 
enzymatic function under disease conditions, particularly in transplantation. Some 
studies have suggested that sCD26/DPP-IV activity may be a promising biomarker for 
monitoring the immune status in solid organ transplantation.56 There are no studies 
investigating the changes in sCD26 or DPP-IV activity in the setting of hematopoietic 
stem cell transplantation. Therefore, in addition to plasma DPP-IV activity, we will also 
explore the change in sCD26 antigen in the peri-transplant process. Plasma sCD26 will 
be assayed at defined points using the Human sCD26 Platinum ELISA kit from 
eBiosciences (San Diego, CA).  
Timepoints of collection will be prior to the start of the preparative regimen, Days -1, 0, +7, 
+14, and then Day +30 (± 3 days), +100, +180, +270 and +365 (± 7 days at all other 
timepoints). 
Samples will be processed and stored at the Research Laboratory at the Clinical Trials 
Office at IUSCC until transfer to Dr. Farag’s laboratory for analysis. Detailed information 
regarding collection and processing can be found in the laboratory manual for this study. 
13.1.4 Immune reconstitution studies. We will also investigate the effect of DPP-4 
inhibition by sitagliptin on immune cell reconstitution at defined time points after 
transplantation. The following lymphocyte subsets will be assessed by multiparameter 
flow-cytometry in Dr. Farag’s laboratory: 
 
CD3+T cells (CD3+CD4+, and CD3+CD8+) 
 
CD3+ T cells expressing CD26 (CD4+CD26+. And CD8+CD26+)  
 
Treg cells (CD3+CD4+CD25+FOXP3+)  
 
CD4+ T cell subsets (CD45RA+CD27+, CD45RA+CD27-CD62L+, CD45RA-
CD27+CD62L+, CD45RA-CD27+CD62L-, CD45RA-CD27-) 
 
CD8+ T cell subsets (CD45RA+CD27+, CD45RA+CD27-CD62L+, CD45RA-
CD27+CD62L+, CD45RA-CD27+CD62L-, CD45RA-CD27-) 
 
B cells (CD19)  
 
NK cells (CD3-CD56+) 
 
In addition, we will assess plasma BAFF (B cell activating factor from the tumor necrosis 
factor) as BAFF levels and BAFF/B cell ratio have been correlated with development of 
chronic GvHD. Plasma BAFF levels will be assayed at defined time points using the 
Human BAFF Instant ELISA kit from eBiosciences (San Diego, CA) in Dr. Farag’s 
laboratory.  
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Samples will be processed and stored at the Research Laboratory at the Clinical Trials 
Office at IUSCC until transfer to Dr. Farag’s laboratory for analysis. Detailed information 
regarding collection and processing can be found in the laboratory manual for this study. 
13.1.5 Microchimerism analysis. Chimerism will be assayed on unfractionated whole 
blood and in CD3 selected (T-cell) cells using polymerase chain reaction for 
amplification of short tandem repeat markers, as currently performed routinely for 
patients undergoing standard allogeneic stem cell transplantation.   
Timepoints of collection will be prior to starting study treatment, samples must be 
collected from the donor cells AND the patient for baseline analysis of short tandem 
repeats (STR). In addition, samples will also be collected from the patient on Day +30 (± 
3 days), +100, +180, +270 and +365 (± 7 days at all other timepoints). 
Microchimerism samples will be processed at the institution’s local laboratory according 
to standard practice (STR analysis is preferred).  
14.0 ADVERSE EVENTS AND REPORTING GUIDELINES 
14.1 
Definitions of Adverse Events 
14.1.1 Adverse Event (AE). An adverse event is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related. An adverse event (also referred to as an adverse experience) can be any 
unfavorable and unintended sign (e.g. an abnormal laboratory finding), symptom, or 
disease temporarily associated with the use of a drug, without any judgment about 
causality.  An adverse event can arise with any use of the drug (e.g., off-label use, use in 
combination with another drug) and with any route of administration, formulation, or 
dose, including an overdose. Adverse events will be graded according to the NCI 
Common Toxicity Criteria, Version 4.0. 
14.1.2 Suspected Adverse Reaction (SAR). Suspected adverse reaction is any 
adverse event for which there is a reasonable possibility that the drug caused the 
adverse event. For the purposes of IND safety reporting, ‘reasonable possibility’ means 
there is evidence to suggest a causal relationship between the drug and the adverse 
event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. Suspected 
adverse reactions are the subset of all adverse events for which there is a reasonable 
possibility that the drug caused the event. 
Examples of types of evidence that would suggest a causal relationship between the 
drug and the adverse event: 
• 
A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-
Johnson’s Syndrome). 
• 
One or more occurrences of an event that is not commonly associated with 
drug exposure, but is otherwise uncommon in the population exposed to the 
drug (e.g., tendon rupture). 
• 
An aggregate analysis of specific events observed in a clinical trial (such as 
known consequences of the underlying disease or condition under 
investigation or other events that commonly occur in the study population 
independent of drug therapy) that indicates those events occur more 
frequently in the drug treatment group than in a concurrent or historical control 
group. 
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14.1.3 Adverse Reaction (AR). An adverse reaction is any adverse event caused by a 
drug. Adverse reactions are a subset of all suspected adverse reactions where there is 
reason to conclude that the drug caused the event. 
14.1.4 Serious Adverse Event (SAE). An adverse event or suspected adverse reaction 
is considered “serious” if it results in any of the following outcomes: 
• 
Results in death  
• 
Is life-threatening. Life-threatening is defined as an adverse event or 
suspected adverse reaction that places the subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction 
that, had it occurred in a more severe form, might have caused death.  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
NOTE: Hospitalizations that are not considered SAEs are:  
 
Hospitalization planned prior to first administration of study drug 
 
Hospitalization for elective treatment of a pre-existing condition 
unrelated to the study medication 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based 
upon appropriate medical and scientific judgment, may jeopardize the patient 
or may require intervention (e.g., medical, surgical) to prevent one of the 
other serious outcomes listed in the definition above).  Examples of such 
events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or 
drug abuse. 
14.1.5 Unexpected Adverse Event. An adverse event or suspected adverse reaction is 
considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or, if an investigator brochure is not 
required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as amended. For example, 
under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) 
if the investigator brochure referred only to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by 
virtue of greater specificity) if the investigator brochure listed only cerebral vascular 
accidents. "Unexpected," as used in this definition, also refers to adverse events or 
suspected adverse reactions that are mentioned in the investigator brochure as 
occurring with a class of drugs or as anticipated from the pharmacological properties of 
the drug, but are not specifically mentioned as occurring with the particular drug under 
investigation.  
This definition relies entirely on the adverse events or suspected adverse reactions listed 
in the investigator brochure for the particular drug under investigation (or elsewhere in 
the general investigational plan if an investigator brochure is not required or available) as 
the basis for determining whether newly acquired information generated from clinical 
trials or reported from other sources is unexpected. This means that events not listed for 
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the particular drug under investigation in the investigator brochure are considered 
“unexpected” and those listed are considered “expected.” When new adverse event 
information is received, it is the sponsor’s responsibility to determine whether the event 
is “unexpected” for IND safety reporting purposes. In the clinical trial setting, there has 
been some confusion with the term “expected” as it has been used to mean “anticipated” 
for the disease being treated or population being studied rather than “listed in the 
investigator brochure.” For example, some adverse events can be anticipated to occur 
as a result of a disease or in an older population (e.g., cancer-related deaths in a cancer 
trial, strokes or acute myocardial infarctions in an older population). However, for 
reporting purposes, these anticipated events are not “expected” because they are not 
listed in the investigator brochure (i.e., the test drug is not suspected or known to cause 
them). 
Adverse events listed in the investigator brochure as occurring with members of the 
same class of drugs, or as anticipated from the pharmacological properties of the drug, 
would be considered unexpected until they have been observed with the drug under 
investigation. For example, although angioedema is anticipated to occur in some 
patients exposed to drugs in the angiotensin-converting enzyme (ACE) inhibitor class 
and angioedema would be described in the investigator brochure as a class effect, a 
case of angioedema observed with the drug under investigation should be considered 
unexpected for reporting purposes until it is included in the investigator brochure as 
occurring with the drug under investigation. 
14.1.6 Determining Attribution to the Investigational Agent(s) 
Attribution: An assessment of the relationship between the AE and the medical 
intervention. CTCAE does not define an AE as necessarily “caused by a therapeutic 
intervention”. After naming and grading the event, the clinical investigator must assign 
an attribution to the AE using the following attribution categories: 
Relationship 
Attribution 
Description 
Unrelated to 
investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related 
Unlikely 
The AE is doubtfully related 
Related to investigational 
agent/intervention 
Possible 
The AE may be related 
Probable 
The AE is likely related 
Definite 
The AE is clearly related 
14.2 
Adverse Event (AE) Reporting Requirements: 
Grade III/IV and all related adverse events (AEs) will be recorded from the time of first 
study drug administration and for at least 30 days after treatment discontinuation.  All 
AEs considered related to trial medication will be followed until resolution, return to 
baseline, or deemed clinically insignificant, even if this occurs post-trial. 
The following AEs are expected as part of the normal process of a high dose 
chemotherapy and radiotherapy containing preparative regimens for bone marrow 
transplant. They will not be collected or reported on source documents, regardless of 
grade: alopecia, nausea and vomiting, fatigue, thrombocytopenia, anemia and 
neutropenia. Further, non-hematological toxicity, biochemical changes that are 
reversible with simple supplementation or treatment (e.g., electrolyte abnormalities, 
hyperglycemia, asymptomatic liver enzyme elevations, serum creatinine fluctuations 
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related to hydration status, etc.) will not be collected or reported on source documents. 
However, time to engraftment of neutrophils and platelets and all cases of hypoglycemia, 
GVHD, SOS, interstitial pneumonitis, pancreatitis, incidence of infections, TMA, and 
transfusion requirements regardless of attribution and as described in Section 10.0 will 
be collected as endpoints for the secondary objectives of this study. If any of these 
events are deemed related to the study drug, they will be reported on source documents.   
14.2.1 Reporting to the FDA. Per CFR 312.32 (c), the investigator-sponsor of the IND 
must notify the Food and Drug Administration (FDA) and all participating investigators in 
a written IND safety report of any adverse experience.  There are two types of reports to 
the FDA: 7-day and 15-day reports. 
15-Day IND Reports:  
The investigator-sponsor of the IND must notify the Food and Drug Administration (FDA) 
and all participating investigators in a written IND safety report of any: 
• 
suspected adverse reaction that is both  
• 
serious and  
• 
unexpected   
Each written notification shall be made as soon as possible, and no later than 15 
calendar days after the investigator-sponsor’s initial receipt of the information.   
7-Day Reports: 
The investigator-sponsor must notify FDA and all participating investigators in a written 
IND safety report of any adverse experience: 
• 
fatal or life-threatening experience that is both 
• 
associated with use of the drug and 
• 
unexpected 
The FDA will be notified as soon as possible but no later than 7 calendar days after 
initial receipt of the information. 
Report Content: 
Each written notification may be submitted on FDA Form 3500A or in a narrative format 
and must bear prominent identification of its contents, i.e., “IND Safety Report”.  For 
purposes of this protocol, the MedWatch Report Form (FDA 3500A mandatory 
reporting), along with FDA Form 1571, and a cover letter submitted to the 
appropriate FDA division, will serve as the written IND safety report.  Follow-up 
information to a safety report should be submitted as soon as the relevant information is 
available. 
Submit: 
• 
MedWatch Report Form (FDA 3500A) 
• 
FDA Form 1571 
• 
Cover Letter 
The IUSCC Protocol Development Coordinator should be contacted to assist with all 
FDA submissions and will be provided with a copy of all events that are reported to the 
FDA.  All IND submissions will be maintained in a master file in the Clinical Trials Office 
of the IU Simon Cancer Center. 
14.2.2 Reporting to the IRB 
Unanticipated problems involving risks to subjects or others will be reported promptly to 
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the IRB if they:  
• 
unexpected; 
• 
related or possibly related to participation in the research; and 
• 
suggests that the research places subjects or others at a greater risk of harm 
than was previously known or recognized.   
If the serious adverse event does not meet all three (3) criteria listed above, the event 
does not have to be promptly reported to the Indiana University IRB.  However, it should 
be reported at the time of continuing review. 
Prompt reporting of unanticipated problems to the IRB is defined as within 5 days from 
becoming aware of the event. 
14.2.3 Reporting to the IUSCC Data Safety Monitoring Committee:  
Regardless of study sponsorship, the study team must enter all initial and follow-up SAE, 
expedited, and noncompliance reports into OnCore® for review by the DSMC chair 
and/or coordinator. Expedited reports may include IRB Prompt Report Forms, AdEERS 
reports, MedWatch, and additional SAE forms as required by the sponsor. When follow-
up information is received, a follow-up report should also be created in OnCore®. This 
DSMC reporting requirement is in addition to any other regulatory bodies to be notified 
(i.e. IRB, FDA, pharmaceutical company, etc.). The DSMC chair and/or coordinator will 
review all SAE, expedited, and noncompliance reports monthly.  
15.0 DATA AND SAFETY MONITORING PLAN  
Investigators will conduct continuous review of data and patient safety. Weekly review meetings 
for high-risk trials are required and will include the principle investigator, clinical research 
specialist and/or research nurse (other members per principle investigator’s discretion). Weekly 
meeting summaries should include review of data and patient safety by including the number of 
patients, significant toxicities as described in the protocol, dose adjustments and responses 
observed. Summaries are to be submitted to DSMC@iupui.edu weekly and reviewed monthly. A 
summary template can be found in Appendix I. 
15.1 
Study Auditing and Monitoring  
All trials conducted at the IUSCC are subject to auditing and/or monitoring. Reports will be 
reviewed by the full DSMC at the time of study review (Reference Risk Table in full DSMC 
Charter).  
15.2 
Early Study Closure  
At any time during the conduct of the trial, if it is the opinion of the investigators that the risks (or 
benefits) to the patient warrant early closure of the study, this recommendation should be made 
in writing to the Data Safety Monitoring Committee. Alternatively, the DSMC may initiate 
suspension or early closure of the study based on its review. 
The DSMC has streamlined the reporting process by utilizing reports from OnCore. This has 
allowed direct view of reports within the Clinical Trials Management System (CTMS); thus 
discontinuing paper reports. SAE reports are entered into OnCore and reviewed by the DSMC 
chair and/or coordinator monthly. Findings will be reported to the full DSMC at the time of study 
review.  
15.3 
Study Accrual Oversight  
Accrual data will be entered into the IU Simon Cancer Center OnCore system. The Protocol 
Progress Committee (PPC) reviews study accrual twice per year while the PPC coordinator 
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reviews accrual quarterly.  
15.4 
Protocol Deviations  
Protocol deviations are entered into OnCore and reviewed by the DSMC chair and/or 
coordinator monthly. Findings will be reported to the full DSMC at the time of study review.  
16.0 STATISTICAL CONSIDERATIONS  
16.1 
General Considerations 
Statistical analysis of this study will be the responsibility of Biostatistics and Data Management 
Core at IUSCC. Parameter estimates and relevant summary statistics will be reported where 
appropriate. For continuous variables, summary statistics will include number of patients, mean, 
median, standard deviation, minimum and maximum. Categorical endpoints will be summarized 
using number of patients, frequency, and percentages. Missing data will not be imputed. 
Additional exploratory analyses of the data will be conducted as deemed appropriate. Changes 
from this analysis plan will not require an amendment to the protocol unless it changes a 
significant feature of the protocol. 
16.2 
Study Design 
The trial is an open label Simon minimax two-stage Phase II trial of a fixed dose of oral 
sitagliptin to assess the safety and efficacy in preventing grades II-IV acute GvHD in patients 
undergoing matched related and unrelated allogeneic peripheral blood stem cell transplantation 
for hematological malignancies.  
CTCAE Version 4.0 will be used to summarize adverse events in the assessment of safety and 
tolerability of the combination therapy.  
16.3 
Sample Size 
The primary endpoint of this phase II study is the incidence of grade II-IV acute GvHD by day 
+100.  Patients who expire before day +100 from other causes and have not developed any 
GvHD will not be evaluable for the primary endpoint and will be replaced. However, such 
patients will be evaluable for other secondary endpoints (see below), and will be included in 
evaluation for the stopping rule of non-relapse mortality (see below).  
This study uses a Simon minimax two-stage design. The primary objective is to assess if DPP-4 
inhibition using sitagliptin will reduce the incidence of grade II-IV acute GvHD by day +100 from 
30% to 15% or less.  In effect, this is the same as inversing the proportion of patients without 
acute grade II-IV GvHD by day +100 from 70% to 85% or more.  In statistical terms, we are 
testing the null hypothesis H0: p0 ≤ 0.70 versus the alternative hypothesis H1: p1 ≥ 0.85, where p 
is the probability of being without acute grade II-IV GvHD by day +100.  We will use a minimax 
optimal stage design with a one-sided type I error set to 0.1, and a type II error rate set to 0.2. In 
the first stage, 23 evaluable patients will be entered.  If 6 or more develop acute grade II-IV 
GvHD by day +100 (i.e., 17 or fewer of these patients have no or only grade I acute GvHD by 
day +100), the study will be stopped in favor of the null hypothesis. On the other hand, if only 
less than 6 develop acute grade II-IV GvHD by day +100, an additional 13 evaluable patients 
will be accrued for a total of 36 evaluable patients. In the final analysis, if fewer than 8 of the 36 
evaluable patients develop acute grade II-IV GvHD by day +100, the null hypothesis will be 
rejected, and we will conclude that DPP-IV inhibition with sitagliptin for prevention of severe 
GvHD is worthy of further study.  
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With an expected non-relapse mortality rate of 10-15% in the first 100 days post transplantation, 
we expect to enroll approximately 40-43 patients to have 36 patients evaluable for the primary 
endpoint.  
16.4 
Patient Characteristics and Significant Protocol Violations 
16.4.1 Patient Characteristics 
Patient demographics and patient baseline characteristics will be listed and summarized 
for all patients enrolled, including age, gender, and race. For these baseline 
characteristics, counts, means, medians, standard deviation, minimum and maximum 
values will be presented as appropriate. 
16.4.2 Significant Protocol Violations 
The IUSCC will closely monitor the study to identify and evaluate any violation of good 
clinical practices (GCP) or clinically important protocol violations. Clinically important 
protocol violation will be defined as those deviations from the protocol that could affect 
patient safety, data integrity, or the conclusions drawn from the study. Important protocol 
violations and any actions to be taken regarding the exclusion of patients or affected 
data from specific analyses will be summarized and listed. 
16.4.3 Patient Disposition 
Patient disposition will be tabulated and will show the number of patients enrolled, and 
the number of patients completing each stage of the study. All reasons for 
discontinuation will be listed and summarized. 
16.4.4 Treatment Exposure/Compliance will be summarized using descriptive 
statistics for all enrolled patients. 
16.5 
Analysis Plan 
All patients who receive at least one dose of sitagliptin will be analyzed for the primary and 
secondary efficacy endpoints and for safety endpoints of toxicity, including mortality and 
stopping criteria (see Section 16.6). However, as noted below, patients who expire before day 
+100 of causes other than acute GvHD will not be considered evaluable for the primary 
endpoint, and will be replaced.  These patients, however, will still be analyzed for secondary 
endpoints, safety, and taken into account in the determining the stopping rule (see Section 
16.6). 
 
16.5.1 Safety and Tolerability 
To evaluate the safety and tolerability of sitagliptin, summaries of treatment related 
adverse events in the population will be tabulated. All adverse events (AEs) will be 
presented in incidence tables coded by CTCAE term. An adverse event will be 
considered treatment related if it occurred on or after date of first dose of sitagliptin, and 
was possibly, probably, or definitely related to treatment. All adverse events will be 
recorded until off study date. All deaths recorded in this study will be listed and 
summarized, and the cause documented. 
16.5.2 Analysis of Primary Objective 
The primary objective is to investigate if DPP-IV inhibition using sitagliptin can result in a 
20% decrease in the incidence of acute grade II-IV GvHD by day +100 following 
matched-related or well-matched unrelated allogeneic PBSC transplantation.  Patients 
who expire before day +100 of causes other than acute GvHD will not be considered 
evaluable for the primary endpoint, and will be replaced. Patients who develop acute 
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grades II-IV GvHD after day +100 (usually in the setting of tapering of immune 
suppressive drugs) will not be included in the estimate of the primary endpoint, but will 
de described separately.  
Two-sided 95% confidence intervals (calculated using the Jennison-Turnbull method) 
will be calculated to estimate the proportion of patients who develop acute grade II-IV 
acute GvHD. 
16.5.3 Analysis of Secondary and Exploratory Objectives 
For the secondary objectives, non-hematological toxicity (other than nausea, vomiting, 
non-GvHD related diarrhea, and electrolyte abnormalities) will be graded and described 
according to The National Cancer Institute Common Terminology Criteria for Adverse 
events (CTCAE) version 4.0 (http://ctep.cancer.gov), and will be described in terms of 
frequency.  Attribution to sitagliptin will also be described.  In addition, the incidence and 
types of infections (viral, bacterial, fungal, etc.) will be tabulated and described.  
In addition to the description of acute GvHD rate for the primary endpoint, the cumulative 
incidences of all grades of acute GvHD, grade II-IV acute GvHD, and grade III-IV acute 
GvHD by day +100 will be described using a competing risk analysis with deaths from 
causes other than GvHD considered as a competing risk.   
Patients surviving at least 100 days will be evaluable for chronic GvHD. The cumulative 
incidence of chronic GvHD (total, and mild, moderate, severe) will be described using 
deaths from causes other than chronic GvHD considered a competing risk 
The time to engraftment of neutrophils will be defined as the time from day 0 of 
transplant to the first of three consecutive days after transplantation during which the 
ANC is ≥ 0.5 x109/l. The time to engraftment of platelets will be defined as the time from 
day 0 to the first of seven consecutive days after transplantation during which the 
platelet count is ≥ 20 x109/l without transfusion. The cumulative incidence of engraftment 
of neutrophils and platelets will be described using competing risk analysis with death 
before engraftment as a competing risk. 
The cumulative incidence of non-relapse mortality will be described with death from 
relapse considered a competing risk (the same model will be used to describe the 
cumulative incidence of relapse). Overall survival will be described using the Kaplan-
Meier method. Actuarial survival at day +30, +100, +180, and 1 year with 95% 
confidence intervals will be estimated.  
For the exploratory objectives, the trajectories of immune cell reconstitution, plasma 
sCD26, and plasma DPP-4 activity for each patient will be plotted graphically over time, 
and inhibition of plasma DPP-4 activity will be explored as a predictor of a GHVD using 
the same approach, denoting in the plots for whom and when did a GHVD occur. 
16.6 
Stopping Criteria 
We wish to insure that patients being treated with this approach do not experience unacceptable 
levels of transplant-related mortality (assessed by non-relapse mortality) within 180 days of 
transplantation. The expected 180-day non-relapse mortality (NRM) for patients undergoing 
matched sibling and well-matched volunteer unrelated donor PBSC transplants is approximately 
30-35%.  Therefore, in this protocol, we wish to insure that the 180 day NRM is 35% or less. To 
do this, we will compute binomial probabilities after each five patients either, reaching 180 days 
post-transplant, or dying prior to 180 days post-transplant. If the lower 90% confidence interval 
of the proportion becomes greater than 35%, the trial will be suspended. The following table lists 
the number of patients dying of NRM within 180 days of transplant to require suspension for 
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unacceptable NRM. 
Number of patients treated evaluable for 
NRM at 180 days 
Suspend if the number of patients experience non-relapse 
mortality by day +180 
5 
4 
10 
6 
15 
8 
20 
11 
25 
13 
30 
15 
 
17.0 REFERENCES
 
1. 
Nash RA, Antin JH, Karanes C, et al: Phase 3 study comparing methotrexate and 
tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host 
disease after marrow transplantation from unrelated donors. Blood 96:2062-8, 2000 
 
2. 
Ratanatharathorn V, Nash RA, Przepiorka D, et al: Phase III study comparing 
methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-
versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood 
92:2303-14, 1998 
 
3. 
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APPENDIX I 
DSMC Meeting Summary Template 
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APPENDIX II 
IU Health Acute GvHD Assessment Tool  
1. 
 
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2. 
 
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