In-vivo Regulatory T Cell Enhancement With Cyclophosphamide and Sirolimus

Study Overview
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Brief Summary
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In this study the investigators are proposing to treat patients with steroid-refractory Graft-versus-host Disease (GVHD) stabilization using IL-2 and azacitidine

Detailed Description
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High-dose cyclophosphamide and sirolimus have been successfully used for the prevention of Graft-versus-host Disease (GVHD) and have shown to enhance the Tregs subpopulation. The addition of low dose IL-2 and a demethylating agent such as azacitidine will also be studied in an attempt to promote and stabilize the FoxP3 expression of Tregs.

Official Title
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Phase I- II Study of in Vivo Regulatory T Cell Enhancement With Cyclophosphamide and Sirolimus With or Without Vidaza (Azacitidine) for the Treatment of Steroid-refractory Acute Graft-versus-host Disease

Conditions
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Graft Versus Host Disease

Intervention / Treatment
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* Drug: Cyclophosphamide and Sirolimus
* Drug: Low dose IL-2 with Cytoxan + Sirolimus
* Drug: Low dose IL-2, low dose Vidaza, cyclophosphamide & Sirolimus
* Drug: Cyclophosphamide and Sirolimus
* Drug: Low dose IL-2 with Cytoxan + Sirolimus
* Drug: Low dose IL-2, Vidaza, Cytoxan & Sirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a documented clinical diagnosis of grade II-IV acute graft-versus- host disease defined as graft versus host disease (GVHD) occurring within the first 100 days of transplantation Patients must be steroid-refractory defines as progression after 3 days of corticosteroid therapy or no response after 5 days of corticosteroid therapy. Progression is defined as up-grading No response is defined as no down-grading Progression after 3 days requires patients to have received at least 2 mg/mg/day for a total of 6 mg/kg of methylprednisolone or its equivalent. No response after 5 days requires patient to have received at least 2 mg/kg/d for a total of 10 mg/kg of methylprednisolone or its equivalent. Patients with exacerbation of GVHD during steroid taper will require re-treatment with 2mg/kg/d of corticosteroids and will need to meet the criteria Age 18-70 Patients must have received an allogeneic hematopoietic stem cell transplant within 100 days of study enrollment. Serum creatinine < 2 mg/dL Exclusion Criteria: Patients cannot have active central nervous system (CNS) disease. Patients must not have received cyclophosphamide for GVHD prophylaxis Patients must not have pneumonia requiring oxygen supplementation Unable or unwilling to sign informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cyclophosphamide and Sirolimus<br>cyclophosphamide and sirolimus combo | Drug: Cyclophosphamide and Sirolimus<br>* On the first day of treatment, cyclophosphamide will be administered at a dose of 4g/m2 IV x 1 dose. Patients who are >40% above ideal weight will be dosed based on adjusted weight and adjusted BSA. One day after the administration of cyclophosphamide, patients will receive sirolimus 6 mg PO x 1 and on the following day will start sirolimus at a dose of 2 mg PO daily.<br>* Other names: Cytoxan;Drug: Cyclophosphamide and Sirolimus<br>* Day 1: Cyclophosphamide Day 2: Sirolimus<br>* Other names: Other names: Cytoxan;|
| Experimental: Lowdose IL-2, Cytoxan + Sirolimus<br>Low dose IL-2 with Cytoxan + Sirolimus Patients in treatment arm B will be receiving low-dose IL-2 in conjunction with the cyclophosphamide and sirolimus. | Drug: Low dose IL-2 with Cytoxan + Sirolimus<br>* Patients in treatment arm B will be receiving low-dose IL-2 in conjunction with the cyclophosphamide and sirolimus. IL-2 will be administered at a dose of 0.5E6 IU/m2 SQ daily x 8 weeks followed by 4 weeks off, starting 14 days after the cyclophosphamide.<br>* Other names: Cytoxan;Drug: Low dose IL-2 with Cytoxan + Sirolimus<br>* treatment arm B will be receiving low-dose IL-2 in conjunction with the cyclophosphamide and sirolimus<br>* Other names: Cytoxan;|
| Experimental: Lowdose IL-2, Vidaza, cyclophosphamide & Sirolimus<br>Lowdose IL-2, Vidaza, cyclophosphamide (Cytoxan) & Sirolimus Patients in treatment arm C will be receiving low-dose azacitidine (Vidaza). | Drug: Low dose IL-2, low dose Vidaza, cyclophosphamide & Sirolimus<br>* Patients in treatment arm C will be receiving low-dose azacitidine (Vidaza). The Vidaza will be initiated between day 27 and 32 following the cyclophosphamide. The dose administered will be 10 mg SQ daily for 5 days followed by 3 weeks off.<br>* Other names: Cytoxan;Drug: Low dose IL-2, Vidaza, Cytoxan & Sirolimus<br>* Vidaza will be initiated between day 27 and 32 following the cyclophosphamide.<br>* Other names: Cytoxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate of Patients With Steroid-refractory Graft-versus-host Disease (GVHD) Using Cyclophospahmide and Sirolimus Combined With 3 Variations of Low-dose IL 2 and Low-dose Vidaza. | The primary objective of this study is to determine the response rate of patients treated steroid-refractory graft-versus-host disease (GVHD) using cyclophospahmide and sirolimus combined with 3 variations of low-dose IL 2 and low-dose Vidaza with an outcome goal of promoting CD4+CD25+FoxP3+ Tregs. | 28 days to 100 days post transplant |