T-REG: In-vivo Regulatory T Cell Enhancement With Cyclophosphamide and Sirolimus
Study Details
Study Description
Brief Summary
In this study the investigators are proposing to treat patients with steroid-refractory Graft-versus-host Disease (GVHD) stabilization using IL-2 and azacitidine
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cyclophosphamide and Sirolimus cyclophosphamide and sirolimus combo |
Drug: Cyclophosphamide 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 Names:
Drug: Cyclophosphamide and Sirolimus
Day 1: Cyclophosphamide Day 2: Sirolimus
Other Names:
|
| Experimental: Lowdose IL-2, Cytoxan + Sirolimus 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
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:
Drug: Low dose IL-2 with Cytoxan + Sirolimus
treatment arm B will be receiving low-dose IL-2 in conjunction with the cyclophosphamide and sirolimus
Other Names:
|
| Experimental: Lowdose IL-2, Vidaza, cyclophosphamide & Sirolimus 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
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:
Drug: Low dose IL-2, Vidaza, Cytoxan & Sirolimus
Vidaza will be initiated between day 27 and 32 following the cyclophosphamide.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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. [28 days to 100 days post transplant]
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.
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | John Theurer Cancer Center at Hackensack University Medical Center | Hackensack | New Jersey | United States | 07601 |
Sponsors and Collaborators
- Hackensack Meridian Health
Investigators
- Principal Investigator: Michele Donato, MD, Hackensack Meridian Health
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- TREG - Pro2219
Study Results
Participant Flow
| Recruitment Details | 4/11/2011 - 5/1/2013 - recruitment at Hackensack University Medical Center |
|---|---|
| Pre-assignment Detail | Pts.must have a documented clinical diagnosis of grade II-IV acute graft-versus- host disease defined as GVHD (graft versus host disease) within 100 days p transplantation. Patients must be steroid-refractory defined as progression after 3 days of corticosteroid therapy or no response after 5 days of same. see study details. |
| Arm/Group Title | Cyclophosphamide and Sirolimus Only |
|---|---|
| Arm/Group Description | Cyclophosphamide = 4g/m2 IV Sirolimus = 6 mg PO x 1; 2 mg PO No patients were enrolled in the Cyclophosphamide, Sirolimus, IL-2 arm or the Cyclophosphamide, Sirolimus, IL-2, azacitidine arm |
| Period Title: Overall Study | |
| STARTED | 3 |
| COMPLETED | 0 |
| NOT COMPLETED | 3 |
Baseline Characteristics
| Arm/Group Title | Cyclophosphamide and Sirolimus |
|---|---|
| Arm/Group Description | Patients will be treated in sequential cohorts of 5. In cohort A, the first 5 enrolled patients will be receive cyclophosphamide and sirolimus only |
| Overall Participants | 3 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
3
100%
|
| >=65 years |
0
0%
|
| Sex: Female, Male (Count of Participants) | |
| Female |
1
33.3%
|
| Male |
2
66.7%
|
Outcome Measures
| Title | 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. |
|---|---|
| Description | 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. |
| Time Frame | 28 days to 100 days post transplant |
Outcome Measure Data
| Analysis Population Description |
|---|
| No patients were enrolled in the Low dose IL-2 with Cytoxan + Sirolimus or Low dose IL-2, Vidaza, Cytoxan & Sirolimus arms |
| Arm/Group Title | Cyclophosphamide and Sirolimus | Low Dose IL-2 With Cytoxan + Sirolimus | Low Dose IL-2, Vidaza, Cytoxan & Sirolimus |
|---|---|---|---|
| Arm/Group Description | Patients will be treated in sequential cohorts of 5. In cohort A, the first 5 enrolled patients will be receive cyclophosphamide and sirolimus only | Patients in treatment arm B will be receiving low-dose IL-2 in conjunction with the cyclophosphamide and sirolimus. | Patients in treatment arm C will be receiving low-dose azacitidine (Vidaza) |
| Measure Participants | 3 | 0 | 0 |
| Number [Participants] |
0
0%
|
Adverse Events
| Time Frame | SAE data was collected over a period of 6 months for the three patients enrolled in the study | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Please see SAE # 5045 and 5063 SAE # 5633 and 5878 and SAE 5055 for h/o DVT, CMV+ -dated 10-18-11 SAE 5247 for diarrhea and fever - dated 12-13-11 SAE 5379 for severe anemia dated 1-10-12 SAE 5899 for new brain masses vs abscess dated 4-6-12 SAE 5917 for confusion,malaise weakness dated 4-23-12 | |||||
| Arm/Group Title | Cyclophosphamide and Sirolimus | Low Dose IL-2 With Cytoxan + Sirolimus | Low Dose IL-2, Vidaza, Cytoxan & Sirolimus | |||
| Arm/Group Description | 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 | Low dose IL-2 with Cyclophosphamide + Sirolimus - In cohort B, the next 5 patients will additionally receive cyclophosphamide and sirolimus & low-dose IL-2 Low dose IL-2, low dose Vidaza, Cyclophosphamide & Sirolimus | Low dose IL-2, Vidaza, Cytoxan & Sirolimus - In cohort C the next 5 enrolled patients will additionally receive cyclophosphamide and Sirolimus, low-dose IL-2 and low-dose Vidaza | |||
All Cause Mortality |
||||||
| Cyclophosphamide and Sirolimus | Low Dose IL-2 With Cytoxan + Sirolimus | Low Dose IL-2, Vidaza, Cytoxan & Sirolimus | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Cyclophosphamide and Sirolimus | Low Dose IL-2 With Cytoxan + Sirolimus | Low Dose IL-2, Vidaza, Cytoxan & Sirolimus | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/3 (100%) | 0/0 (NaN) | 0/0 (NaN) | |||
| Blood and lymphatic system disorders | ||||||
| SAE 5379 - Anemia | 1/3 (33.3%) | 1 | 0/0 (NaN) | 0 | 0/0 (NaN) | 0 |
| Hepatobiliary disorders | ||||||
| SAE 5878- Graft Versus Host Disease (GVHD) | 1/3 (33.3%) | 1 | 0/0 (NaN) | 0 | 0/0 (NaN) | 0 |
| Immune system disorders | ||||||
| SAE 6031- Post-transplant lymphoproliferative disorder (PTLD) | 1/3 (33.3%) | 1 | 0/0 (NaN) | 0 | 0/0 (NaN) | 0 |
| Infections and infestations | ||||||
| SAE 5063 - C. difficile Infection | 1/3 (33.3%) | 1 | 0/0 (NaN) | 0 | 0/0 (NaN) | 0 |
| Deep Vein Thrombosis, Cytomegalovirus infection and Graft Versus Host Disease Complications | 1/3 (33.3%) | 1 | 0/0 (NaN) | 0 | 0/0 (NaN) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| SAE 5856-brain | 1/3 (33.3%) | 1 | 0/0 (NaN) | 0 | 0/0 (NaN) | 0 |
| SAE 5055- Deep vein thrombosis (DVT) | 1/3 (33.3%) | 1 | 0/0 (NaN) | 0 | 0/0 (NaN) | 0 |
| Nervous system disorders | ||||||
| SAE 5917-neurological | 1/3 (33.3%) | 1 | 0/0 (NaN) | 0 | 0/0 (NaN) | 0 |
Other (Not Including Serious) Adverse Events |
||||||
| Cyclophosphamide and Sirolimus | Low Dose IL-2 With Cytoxan + Sirolimus | Low Dose IL-2, Vidaza, Cytoxan & Sirolimus | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/3 (0%) | 0/0 (NaN) | 0/0 (NaN) | |||
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. Michele Donato, MD |
|---|---|
| Organization | Hackensack University Medical Center |
| Phone | 551-996-2000 ext 3524 |
| MDonato@hackensackumc.org |
- TREG - Pro2219