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Sirolimus Prophylaxis for aGVHD in TME SCID

Primary Purpose

Severe Combined Immunodeficiency, Transplacental Maternal Engraftment, Stem Cell Transplant

Status
Withdrawn
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Sirolimus
Sponsored by
University of California, San Francisco
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Severe Combined Immunodeficiency focused on measuring SCID, severe combined immunodeficiency, maternal engraftment, aGVHD prophylaxis, sirolimus

Eligibility Criteria

1 Day - 1 Year (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Infants diagnosed with SCID on CA newborn screen
  • Evidence of Maternal Engraftment
  • Unconditioned haploidentical hematopoeitic stem cell transplant

Exclusion Criteria:

  • Evidence of acute graft vs. host disease

Sites / Locations

  • Benioff Children's Hospital at UCSF Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Sirolimus

Arm Description

Sirolimus (0.05 mg/kg/day) day -5 for aGVHD prophylaxis through day +100 or until T-regulatory cells >9% of CD4 effector cells; whichever comes first.

Outcomes

Primary Outcome Measures

Incidence of aGVHD
Incidence of aGVHD (dermatitis, hepatitis, enteritis) as defined by UCSF SOP CL 221.06 by Day +100.

Secondary Outcome Measures

T-regulatory cell enumeration
T-regulatory cell enumeration studies by blood draw prior to prophylaxis and at day +30, day+60, day+100.
Sirolimus therapeutic drug monitoring
Sirolimus therapeutic drug monitoring will be done via blood draws(after initial 4th dose; thereafter every 4th dose with adjustment; once stable it will be measured weekly). We will determine the average dose in milligrams per kilograms that would be needed to reach therapeutic trough levels of 5-8 ng/mL.

Full Information

First Posted
June 19, 2014
Last Updated
December 1, 2015
Sponsor
University of California, San Francisco
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1. Study Identification

Unique Protocol Identification Number
NCT02177760
Brief Title
Sirolimus Prophylaxis for aGVHD in TME SCID
Official Title
Sirolimus in Prevention of aGVHD in Maternally Engrafted (TME) Severe Combined Immunodeficiency (SCID) Infants Receiving Unconditioned Hematopoietic Stem Cell Transplant (HSCT)
Study Type
Interventional

2. Study Status

Record Verification Date
December 2015
Overall Recruitment Status
Withdrawn
Why Stopped
Preliminary data suggested a better approach available
Study Start Date
July 2014 (undefined)
Primary Completion Date
November 2015 (Actual)
Study Completion Date
November 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of California, San Francisco

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Study Design: SCID infants receiving an unconditioned haploidentical transplant will be started on Sirolimus (0.05 mg/kg/day) day -5 for Acute Graft-Versus-Host Disease (aGVHD) prophylaxis. Sirolimus levels will be monitored with goal sirolimus trough level of 5-8 ng/mL. Patients will be monitored for signs of aGVHD as defined by UCSF SOP CL 221.06 through day +100. Sirolimus will be tapered once T-regulatory cell to CD4 effector cell ratio is > or = 9%. Setting: Inpatient BMT Unit Benioff Children's Hospital at UCSF Medical Center Study Subjects: 15 infants with diagnosis of maternally engrafted T cells SCID by CA Newborn screen receiving unconditioned haploidentical HSCT Main Outcome Measures: Incidence of aGVHD (dermatitis, hepatitis, enteritis) as defined by SOP CL 221.06 by Day +100. Hypothesis 1. Patients placed on sirolimus prophylaxis will have lower incidence of aGVHD compared to historical controls. Hypothesis 2. Lower doses of sirolimus milligram per kilogram will be required to maintain goal troughs of 5-8 ng/mL.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Severe Combined Immunodeficiency, Transplacental Maternal Engraftment, Stem Cell Transplant
Keywords
SCID, severe combined immunodeficiency, maternal engraftment, aGVHD prophylaxis, sirolimus

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sirolimus
Arm Type
Experimental
Arm Description
Sirolimus (0.05 mg/kg/day) day -5 for aGVHD prophylaxis through day +100 or until T-regulatory cells >9% of CD4 effector cells; whichever comes first.
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
Rapamune
Primary Outcome Measure Information:
Title
Incidence of aGVHD
Description
Incidence of aGVHD (dermatitis, hepatitis, enteritis) as defined by UCSF SOP CL 221.06 by Day +100.
Time Frame
105 days
Secondary Outcome Measure Information:
Title
T-regulatory cell enumeration
Description
T-regulatory cell enumeration studies by blood draw prior to prophylaxis and at day +30, day+60, day+100.
Time Frame
105 days
Title
Sirolimus therapeutic drug monitoring
Description
Sirolimus therapeutic drug monitoring will be done via blood draws(after initial 4th dose; thereafter every 4th dose with adjustment; once stable it will be measured weekly). We will determine the average dose in milligrams per kilograms that would be needed to reach therapeutic trough levels of 5-8 ng/mL.
Time Frame
105 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Day
Maximum Age & Unit of Time
1 Year
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Infants diagnosed with SCID on CA newborn screen Evidence of Maternal Engraftment Unconditioned haploidentical hematopoeitic stem cell transplant Exclusion Criteria: Evidence of acute graft vs. host disease
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Chris Dvorak, MD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
Benioff Children's Hospital at UCSF Medical Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
10021471
Citation
Buckley RH, Schiff SE, Schiff RI, Markert L, Williams LW, Roberts JL, Myers LA, Ward FE. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med. 1999 Feb 18;340(7):508-16. doi: 10.1056/NEJM199902183400703.
Results Reference
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PubMed Identifier
17968328
Citation
Dvorak CC, Cowan MJ. Hematopoietic stem cell transplantation for primary immunodeficiency disease. Bone Marrow Transplant. 2008 Jan;41(2):119-26. doi: 10.1038/sj.bmt.1705890. Epub 2007 Oct 29.
Results Reference
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PubMed Identifier
11535520
Citation
Muller SM, Ege M, Pottharst A, Schulz AS, Schwarz K, Friedrich W. Transplacentally acquired maternal T lymphocytes in severe combined immunodeficiency: a study of 121 patients. Blood. 2001 Sep 15;98(6):1847-51. doi: 10.1182/blood.v98.6.1847.
Results Reference
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PubMed Identifier
19744131
Citation
Pulsipher MA, Wall DA, Grimley M, Goyal RK, Boucher KM, Hankins P, Grupp SA, Bunin N. A phase I/II study of the safety and efficacy of the addition of sirolimus to tacrolimus/methotrexate graft versus host disease prophylaxis after allogeneic haematopoietic cell transplantation in paediatric acute lymphoblastic leukaemia (ALL). Br J Haematol. 2009 Dec;147(5):691-9. doi: 10.1111/j.1365-2141.2009.07889.x. Epub 2009 Sep 10.
Results Reference
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PubMed Identifier
20717025
Citation
Cutler C, Antin JH. Sirolimus immunosuppression for graft-versus-host disease prophylaxis and therapy: an update. Curr Opin Hematol. 2010 Nov;17(6):500-4. doi: 10.1097/MOH.0b013e32833e5b2e.
Results Reference
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PubMed Identifier
24497539
Citation
Pulsipher MA, Langholz B, Wall DA, Schultz KR, Bunin N, Carroll WL, Raetz E, Gardner S, Gastier-Foster JM, Howrie D, Goyal RK, Douglas JG, Borowitz M, Barnes Y, Teachey DT, Taylor C, Grupp SA. The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children's Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial. Blood. 2014 Mar 27;123(13):2017-25. doi: 10.1182/blood-2013-10-534297. Epub 2014 Feb 4.
Results Reference
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PubMed Identifier
18481161
Citation
Yong PL, Russo P, Sullivan KE. Use of sirolimus in IPEX and IPEX-like children. J Clin Immunol. 2008 Sep;28(5):581-7. doi: 10.1007/s10875-008-9196-1. Epub 2008 May 15.
Results Reference
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PubMed Identifier
19543393
Citation
Strauss L, Czystowska M, Szajnik M, Mandapathil M, Whiteside TL. Differential responses of human regulatory T cells (Treg) and effector T cells to rapamycin. PLoS One. 2009 Jun 22;4(6):e5994. doi: 10.1371/journal.pone.0005994.
Results Reference
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PubMed Identifier
23165499
Citation
Fujioka T, Tamaki H, Ikegame K, Yoshihara S, Taniguchi K, Kaida K, Kato R, Inoue T, Nakata J, Ishii S, Soma T, Okada M, Ogawa H. Frequency of CD4(+)FOXP3(+) regulatory T-cells at early stages after HLA-mismatched allogeneic hematopoietic SCT predicts the incidence of acute GVHD. Bone Marrow Transplant. 2013 Jun;48(6):859-64. doi: 10.1038/bmt.2012.232. Epub 2012 Nov 19.
Results Reference
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Sirolimus Prophylaxis for aGVHD in TME SCID

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