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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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ClinicalTrials.gov Identifier: NCT01453140
Recruitment Status : Completed
First Posted : October 17, 2011
Last Update Posted : July 18, 2013
Sponsor:
Information provided by (Responsible Party):
Hackensack Meridian Health

Brief Summary:
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 or disease Intervention/treatment 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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (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
Study Start Date : August 2011
Actual Primary Completion Date : March 2012
Actual Study Completion Date : July 2012


Arm Intervention/treatment
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:
  • Interleukin-2
  • Cytoxan

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:
  • Interleukin-2
  • Azactidine
  • Cytoxan




Primary Outcome Measures :
  1. 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 ]


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01453140


Locations
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United States, New Jersey
John Theurer Cancer Center at Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
Sponsors and Collaborators
Hackensack Meridian Health
Investigators
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Principal Investigator: Michele Donato, MD Hackensack Meridian Health
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Responsible Party: Hackensack Meridian Health
ClinicalTrials.gov Identifier: NCT01453140    
Other Study ID Numbers: TREG - Pro2219
First Posted: October 17, 2011    Key Record Dates
Last Update Posted: July 18, 2013
Last Verified: July 2013
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Sirolimus
Cyclophosphamide
Interleukin-2
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents