Sitagliptin for the Treatment of Grade 3-4 and Refractory Acute Graft-versus-host Disease

Study Overview
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Brief Summary
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The prognosis of severe (grade 3-4) and steroid refractory acute graft-versus-host disease (GVHD) continues to be dismal. Sitagliptin given as GVHD-prophylaxis has recently been shown to reduce the incidence of acute GVHD to less than 10% with an excellent safety profile. In this single center and single arm phase 2 study we aim to explore the safety and efficacy of sitagliptin in the treatment of severe and refractory acute GVHD. Patient with new onset grade 3-4 acute GVHD will receive standard treatment consisting CNI and methylprednisolone 1-2 mg/kg/day or an equivalent dose of prednisone. Patients with refractory grade 2-4 acute GVHD will continue their current treatment; however methylprednisolone dose will be reduced to ≤ 1 mg/kg/day or an equivalent dose of prednisone. Oral sitagliptin will be commenced at a dose of 100 mg BID. The dose will be increased by 100 mg every three days up to a maximal dose of 300 mg BID. In the case of significant drug related side effects or drug intolerance, the last tolerated dose will be resumed. Patients responding well to lower doses of sitagliptin, will not be given higher doses of the drug. Sitagliptin will be provided as long as deemed effective by the treating physician up to three months. The primary end point will be the proportion of patients achieving complete remission(CR), very good partial response (VGPR) or partial response (PR) by day 28.

Detailed Description
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The prognosis of severe (grade 3-4) and steroid refractory acute GVHD continues to be dismal. Sitagliptin given as GVHD-prophylaxis has recently been shown to reduce the incidence of acute GVHD to less than 10% with an excellent safety profile. In this single center and single arm phase 2 study we aim to explore the safety and efficacy of sitagliptin in the treatment of severe and refractory acute GVHD. Patient with new onset grade 3-4 acute GVHD will receive standard treatment consisting CNI and methylprednisolone 1-2 mg/kg/day or an equivalent dose of prednisone. Patients with refractory grade 2-4 acute GVHD will continue their current treatment; however methylprednisolone dose will be reduced to ≤ 1 mg/kg/day or an equivalent dose of prednisone. Oral sitagliptin will be commenced at a dose of 100 mg BID. The dose will be increased by 100 mg every three days up to a maximal dose of 300 mg BID. In the case of significant drug related side effects or drug intolerance, the last tolerated dose will be resumed. Patients responding well to lower doses of sitagliptin, will not be given higher doses of the drug. Sitagliptin will be provided as long as deemed effective by the treating physician up to three months. The primary end point will be the proportion of patients achieving CR, VGPR or PR by day 28. The secondary endpoints will be safety profile, proportion of patients achieving CR, VGPR or PR by day 56, 6-month duration of response (time from first response to GVHD progression or death), proportion of patients discontinuing immunosuppressive treatment by 3 and 6 months, proportion of patients developing chronic GVHD (limited and extensive) by 6 months, time to response, specific organ response, biomarker profile (ST2 and REG3a), Infection profile, OS at 6 months, GVHD free - disease free survival at 6 months.

Official Title
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Sitagliptin for the Treatment of Grade 3-4 and Refractory Acute Graft-versus-host Disease

Conditions
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Graft Vs Host Disease

Intervention / Treatment
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* Drug: Sitagliptin 100mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18-year old Grade 3-4 acute GVHD Refractory grade 2-4 acute GVHD Signed informed consent. Complete remission of the disease for which the patient was transplanted for. Exclusion Criteria: Patients with diabetes mellitus requiring therapy with oral hypoglycemic medications or Insulin on top of sitagliptin. Serious hypersensitivity reaction to sitagliptin such as angioedema or anaphylaxis.

Ages Eligible for Study
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Minimum Age: 17 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sitagliptin<br> | Drug: Sitagliptin 100mg<br>* Oral sitagliptin will be commenced at a dose of 100 mg BID. The dose will be increased by 100 mg every three days up to a maximal dose of 300 mg BID. In the case of significant drug related side effects or drug intolerance, the last tolerated dose will be resumed. Patients responding well to lower doses of sitagliptin, will not be given higher doses of the drug. Sitagliptin will be provided as long as deemed effective by the treating physician up to three months.<br>* Other names: JANUVIA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response | proportion of patients achieving complete remission (CR), very good partial response (VGPR) or partial response (PR) by day 28. | day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (safety and tolerability) | Incidence of treatment-emergent adverse events (safety and tolerability) | 3 months | 
| Response | Proportion of patients achieving CR, VGPR or PR by day 56. | day 56 | 
| Response | GVHD free - disease free survival at 6 months | 6 months | 
| Biomarker profile | ST2 and REG3a blood levels | By days 0, 14, 28, 42, 56, 70, 100 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SITAGLIPTIN