Sitagliptin for Prevention of Acute Graft Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation
- Conditions
- Graft vs Host DiseaseHematopoietic Stem Cell Transplantation
- Interventions
- Registration Number
- NCT02683525
- Lead Sponsor
- Sherif S. Farag
- 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.).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 37
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Sitagliptin Sitagliptin 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.
- Primary Outcome Measures
Name Time Method Percentage of Patients With Grade II-IV Acute GvHD by Day +100 Following Transplant up to 100 days Percent of patients and the 95% Confidence interval who did not have Grade II-IV Acute GvHD by 100 days following transplant. Since the study completed the two-phase design, proper inference was used to generate the confidence interval (Koyama and Chen). Only patients who were on the study for at least 100 days post transplant were included in the analysis.
- Secondary Outcome Measures
Name Time Method Percentage of Patients With Grade II-IV Acute GvHD at Day +100 100 days from transplant Kaplan-Meier methods will be used to conduct a competing risk analysis. Time until grade II-IV acute GvHD will be calculated from transplant until grade II-IV acute GvHD or death from GvHD. Patients who relapsed or died from causes other than GvHD will be considered a competing risk and calculated from time of transplant until relapse or death. Otherwise, patients will be censored and calculated from transplant until the last known alive date. The cumulative incidence percentage of grade II-IV acute GvHD at day +100 was calculated along with a 95% confidence interval.
Number of Patients With Treatment Related Adverse Events Grade 3 or Higher for Non-hematological Toxicity up to 2 months Number of unique patients who had a treatment related (possible, probable or definite) non-hematological adverse event that was graded 3 or greater.
Percentage of Patients With Grade III-IV Acute GvHD at Day +100 100 days from transplant Kaplan-Meier methods will be used to conduct a competing risk analysis. Time until grade III-IV acute GvHD will be calculated from transplant until grade III-IV acute GvHD or death from GvHD. Patients who relapsed or died from causes other than GvHD will be considered a competing risk and calculated from time of transplant until relapse or death. Otherwise, patients will be censored and calculated from transplant until the last known alive date. The cumulative incidence percentage of grade II-IV acute GvHD at day +100 was calculated along with a 95% confidence interval.
Median Time to Engraftment of Neutrophils up to 1 month Time to neutrophil engraftment will be analyzed by the Kaplan-Meier method. The time to engraftment of neutrophils is defined as the time from day 0 to the date of the first of three consecutive days after transplantation during which the absolute neutrophils count (ANC) is at least 0.5 x109/l. Patients who did not have neutrophil engraftment before death will be censored at the date of death. The median and 95% confidence intervals were calculated.
Median Time to Engraftment of Platelets up to 4 months Time to platelet engraftment will be analyzed by the Kaplan-Meier method. The time to engraftment of platelets is defined as the time from day 0 to the first of seven consecutive Complete Blood Counts (CBCs) obtained on different days after transplantation during which the platelet count is at least 20 x109/l. The CBCs obtained should be at least seven days after the most recent platelet transfusion. The median and 95% confidence intervals were calculated.
Number of Unique Patients With Infections by Day +100 100 days from transplant Number of unique patients who had each type of infection (i.e., viral, bacterial, fungal, etc.) during the 100 days post transplant. A patient could have more than one type of infection.
Percentage of Patients With Non-relapse Mortality (NRM) at +1 Year 1 year from transplant Kaplan-Meier methods will be used to conduct a competing risk analysis. Time until non-relapse death will be calculated from transplant until death. Patients who died from relapse will be considered a competing risk and calculated from time of transplant until death. Otherwise, patients will be censored and calculated from transplant until the last known alive date. The cumulative incidence percentage of non-relapse mortality at day +365 was calculated along with a 95% confidence interval.
Percentage of Patients Surviving at +1 Year 1 year from transplant Duration of time from the start of treatment to time of death due to any causes. Patients who do not die will be censored on their last known alive date. Kaplan-Meier methods will be used and the median and 95% confidence intervals will be calculated. The cumulative incidence percentage of survival at day +365 was calculated along with a 95% confidence interval.
Percentage of Patients Diagnosed With Chronic GvHD at 1 Year 1 year from transplant 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 as a competing risk. Kaplan-Meier methods will be used to conduct a competing risk analysis. Time until chronic GvHD will be calculated from transplant until chronic GvHD or death from GvHD. Patients who relapsed or died from causes other than GvHD will be considered a competing risk and calculated from time of transplant until relapse or death. Otherwise, patients will be censored and calculated from transplant until the last known alive date. The cumulative incidence percentage at 1 year will calculated along with a 95% confidence interval.
Percentage of Patients With Relapse of the Primary Hematological Malignancy at 1 Year 1 year from transplant Kaplan-Meier methods will be used to conduct a competing risk analysis. Time until relapse will be calculated from transplant until relapse or death from relapse. Patients who died from causes other than relapse will be considered a competing risk and calculated from time of transplant until death. Otherwise, patients will be censored and calculated from transplant until the last known alive date. The cumulative incidence percentage of relapse at day +365 was calculated along with a 95% confidence interval.
Trial Locations
- Locations (2)
Indiana University Health Hospital
🇺🇸Indianapolis, Indiana, United States
Indiana University Health Melvin and Bren Simon Cancer Center
🇺🇸Indianapolis, Indiana, United States