In-vivo Regulatory T Cell Enhancement With Cyclophosphamide and Sirolimus With or Without Vidaza (Azacitidine) for Steroid-refractory Acute Graft-versus-host Disease (T-REG)
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Purpose
In this study the investigators are proposing to treat patients with steroid-refractory Graft-versus-host Disease (GVHD) in a manner designed to promote CD4+CD25+FoxP3+ Tregs. The profound immune suppression which follows the most common salvage treatment for GVHD have unfortunately lead to very poor outcomes because of high infection rates. A more targeted approach based on the promotion and stabilization of Tregs is hoped to allow GVHD control without the profound immunosuppression usually seen. High-dose cyclophosphamide and sirolimus have been successfully used for the prevention of 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.
| Condition | Intervention | Phase |
|---|---|---|
|
Graft Versus Host Disease |
Drug: Cyclophospahmide and Sirolimus Drug: Low dose IL-2, Cyclophosphamide and Sirolimus Drug: Low dose IL-2, low dose Vidaza, cyclophosphamide & Sirolimus |
Phase 1 Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | 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 |
- The primary objective of this study is to determine the response rate of patients treated steroid-refractory GVHD using cyclophospahmide and sirolimus combined with 3 variations of low-dose IL 2 and low-dose Vidaza. [ Time Frame: 28 days to 100 days post transplant ] [ Designated as safety issue: No ]
| Enrollment: | 3 |
| Study Start Date: | August 2011 |
| Study Completion Date: | July 2012 |
| Primary Completion Date: | March 2012 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Cyclophosphamide and Sirolimus
Patients will be treated in sequential cohorts of 5. In cohort A, the first 5 enrolled patients will be receive cyclophosphamide and sirolimus only
|
Drug: Cyclophospahmide and Sirolimus
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. Other Name: Cytoxan
|
| Experimental: Low dose IL-2 with Cytoxan + Sirolimus |
Drug: Low dose IL-2, Cyclophosphamide and Sirolimus
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. Other Names:
|
| Experimental: Low dose IL-2, Vidaza, Cytoxan & Sirolimus |
Drug: Low dose IL-2, low dose Vidaza, cyclophosphamide & Sirolimus
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. Other Names:
|
Eligibility| Ages Eligible for Study: | 18 Years to 70 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Patients must have a documented clinical diagnosis of grade II-IV acute graft-versus- host disease defined as 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 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.
Contacts and Locations| United States, New Jersey | |
| John Theurer Cancer Center at Hackensack University Medical Center | |
| Hackensack, New Jersey, United States, 07601 | |
| Principal Investigator: | Michele Donato, MD | Hackensack University Medical Center |
More Information
No publications provided
| Responsible Party: | Hackensack University Medical Center |
| ClinicalTrials.gov Identifier: | NCT01453140 History of Changes |
| Other Study ID Numbers: | TREG - Pro2219 |
| Study First Received: | October 13, 2011 |
| Last Updated: | May 8, 2013 |
| Health Authority: | United States: Institutional Review Board |
Additional relevant MeSH terms:
|
Graft vs Host Disease Immune System Diseases Azacitidine Cyclophosphamide Interleukin-2 Sirolimus Everolimus Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Antineoplastic Agents Therapeutic Uses Enzyme Inhibitors Immunosuppressive Agents |
Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Myeloablative Agonists Analgesics, Non-Narcotic Analgesics Sensory System Agents Peripheral Nervous System Agents Central Nervous System Agents Antibiotics, Antineoplastic Antifungal Agents Anti-Infective Agents Anti-Bacterial Agents |
ClinicalTrials.gov processed this record on May 16, 2013