T-REG: In-vivo Regulatory T Cell Enhancement With Cyclophosphamide and Sirolimus

Sponsor
Hackensack Meridian Health (Other)
Overall Status
Terminated
CT.gov ID
NCT01453140
Collaborator
(none)
3
Enrollment
1
Location
3
Arms
11
Duration (Months)
0.3
Patients Per Site Per Month

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 DiseaseIntervention/TreatmentPhase
  • 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
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

Study Type:
Interventional
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 :
Aug 1, 2011
Actual Primary Completion Date :
Mar 1, 2012
Actual Study Completion Date :
Jul 1, 2012

Arms and Interventions

ArmIntervention/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:
  • Cytoxan
  • Drug: Cyclophosphamide and Sirolimus
    Day 1: Cyclophosphamide Day 2: Sirolimus
    Other Names:
  • Other names: Cytoxan
  • 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:
  • Interleukin-2
  • Cytoxan
  • 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:
  • Other names:
  • Interleukin-2
  • Cytoxan
  • 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:
  • Interleukin-2
  • Azactidine
  • Cytoxan
  • Drug: Low dose IL-2, Vidaza, Cytoxan & Sirolimus
    Vidaza will be initiated between day 27 and 32 following the cyclophosphamide.
    Other Names:
  • Other names:
  • Interleukin-2
  • Azactidine
  • Cytoxan
  • Outcome Measures

    Primary Outcome Measures

    1. 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

    Ages Eligible for Study:
    18 Years to 70 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    SiteCityStateCountryPostal Code
    1John Theurer Cancer Center at Hackensack University Medical CenterHackensackNew JerseyUnited States07601

    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.
    Responsible Party:
    Hackensack Meridian Health
    ClinicalTrials.gov Identifier:
    NCT01453140
    Other Study ID Numbers:
    • TREG - Pro2219
    First Posted:
    Oct 17, 2011
    Last Update Posted:
    Mar 2, 2022
    Last Verified:
    Feb 1, 2022

    Study Results

    Participant Flow

    Recruitment Details4/11/2011 - 5/1/2013 - recruitment at Hackensack University Medical Center
    Pre-assignment DetailPts.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 TitleCyclophosphamide and Sirolimus Only
    Arm/Group DescriptionCyclophosphamide = 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
    STARTED3
    COMPLETED0
    NOT COMPLETED3

    Baseline Characteristics

    Arm/Group TitleCyclophosphamide and Sirolimus
    Arm/Group DescriptionPatients will be treated in sequential cohorts of 5. In cohort A, the first 5 enrolled patients will be receive cyclophosphamide and sirolimus only
    Overall Participants3
    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

    1. Primary Outcome
    TitleResponse 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.
    DescriptionThe 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 Frame28 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 TitleCyclophosphamide and SirolimusLow Dose IL-2 With Cytoxan + SirolimusLow Dose IL-2, Vidaza, Cytoxan & Sirolimus
    Arm/Group DescriptionPatients will be treated in sequential cohorts of 5. In cohort A, the first 5 enrolled patients will be receive cyclophosphamide and sirolimus onlyPatients 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 Participants300
    Number [Participants]
    0
    0%

    Adverse Events

    Time FrameSAE 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 TitleCyclophosphamide and SirolimusLow Dose IL-2 With Cytoxan + SirolimusLow Dose IL-2, Vidaza, Cytoxan & Sirolimus
    Arm/Group DescriptionCyclophosphamide 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 onlyLow 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 & SirolimusLow 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 SirolimusLow Dose IL-2 With Cytoxan + SirolimusLow Dose IL-2, Vidaza, Cytoxan & Sirolimus
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total/ (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Cyclophosphamide and SirolimusLow Dose IL-2 With Cytoxan + SirolimusLow Dose IL-2, Vidaza, Cytoxan & Sirolimus
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total3/3 (100%) 0/0 (NaN) 0/0 (NaN)
    Blood and lymphatic system disorders
    SAE 5379 - Anemia1/3 (33.3%) 10/0 (NaN) 00/0 (NaN) 0
    Hepatobiliary disorders
    SAE 5878- Graft Versus Host Disease (GVHD)1/3 (33.3%) 10/0 (NaN) 00/0 (NaN) 0
    Immune system disorders
    SAE 6031- Post-transplant lymphoproliferative disorder (PTLD)1/3 (33.3%) 10/0 (NaN) 00/0 (NaN) 0
    Infections and infestations
    SAE 5063 - C. difficile Infection1/3 (33.3%) 10/0 (NaN) 00/0 (NaN) 0
    Deep Vein Thrombosis, Cytomegalovirus infection and Graft Versus Host Disease Complications1/3 (33.3%) 10/0 (NaN) 00/0 (NaN) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    SAE 5856-brain1/3 (33.3%) 10/0 (NaN) 00/0 (NaN) 0
    SAE 5055- Deep vein thrombosis (DVT)1/3 (33.3%) 10/0 (NaN) 00/0 (NaN) 0
    Nervous system disorders
    SAE 5917-neurological1/3 (33.3%) 10/0 (NaN) 00/0 (NaN) 0
    Other (Not Including Serious) Adverse Events
    Cyclophosphamide and SirolimusLow Dose IL-2 With Cytoxan + SirolimusLow Dose IL-2, Vidaza, Cytoxan & Sirolimus
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/3 (0%) 0/0 (NaN) 0/0 (NaN)

    Limitations/Caveats

    3 patients enrolled - all 3 had grade 4 (possibly treatment related) limiting toxicities. All three patients have since passed away. Study was closed after being on hold as per stopping rules.

    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/TitleDr. Michele Donato, MD
    OrganizationHackensack University Medical Center
    Phone551-996-2000 ext 3524
    EmailMDonato@hackensackumc.org
    Responsible Party:
    Hackensack Meridian Health
    ClinicalTrials.gov Identifier:
    NCT01453140
    Other Study ID Numbers:
    • TREG - Pro2219
    First Posted:
    Oct 17, 2011
    Last Update Posted:
    Mar 2, 2022
    Last Verified:
    Feb 1, 2022