Sirolimus Prophylaxis for aGVHD in TME SCID

Severe Combined Immunodeficiency Clinical Trial

Official title:

Sirolimus in Prevention of aGVHD in Maternally Engrafted (TME) Severe Combined Immunodeficiency (SCID) Infants Receiving Unconditioned Hematopoietic Stem Cell Transplant (HSCT)

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT02177760
• Other study ID #: 14-13024
• Status: Withdrawn
• Phase: Phase 2
• First received: June 19, 2014
• Last updated: December 1, 2015
• Start date: July 2014
• Est. completion date: November 2015

Study information

• Verified date: December 2015
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: November 2015
• Est. primary completion date: November 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 1 Year

Eligibility

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Immunologic Deficiency Syndromes
• Severe Combined Immunodeficiency
• Stem Cell Transplant
• Transplacental Maternal Engraftment

Intervention

Drug:
• Sirolimus

Locations

Country	Name	City	State
United States	Benioff Children's Hospital at UCSF Medical Center	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
University of California, San Francisco

Country where clinical trial is conducted

United States, 

References & Publications (9)

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. — View 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. Review. — View Citation

Dvorak CC, Cowan MJ. Hematopoietic stem cell transplantation for primary immunodeficiency disease. Bone Marrow Transplant. 2008 Jan;41(2):119-26. Epub 2007 Oct 29. Review. — View 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. — View Citation

Müller 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. — View 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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of aGVHD	Incidence of aGVHD (dermatitis, hepatitis, enteritis) as defined by UCSF SOP CL 221.06 by Day +100.	105 days	No
Secondary	T-regulatory cell enumeration	T-regulatory cell enumeration studies by blood draw prior to prophylaxis and at day +30, day+60, day+100.	105 days	No
Secondary	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.	105 days	No