Autologous Hematopoietic Stem Cell Transplantation for Allogeneic Organ Transplant Tolerance

NCT02549586 | Completed Phase 2 DMC

• 1 other identifier: Tol 001
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 2

Brief Summary

This open-label, proof-of-principle two center cohort study will evaluate the ability of autologous hematopoietic stem cell transplantation to induce tolerance in recipients of deceased or live donor liver transplants (ASCOTT). A maximum of 10 participants will be entered at a minimum of 3 months post liver transplant. The participants will undergo autologous hematopoietic stem cell transplants (HSCT) to "re-educate" their immune systems to accept the graft without the need for long term immunosuppression (tolerance).

Conditions

Complication of Transplanted Organ, Nos

Keywords

solid organ transplant; immune tolerance; autologous stem cell transplant; blood and marrow transplant; autoimmune disease

Outcome Measures

Primary Outcomes (1)

• Number of patients who develop tolerance post autologous HSCT

  Number of patients who develop tolerance at 24 months post HSCT as defined clinically and histologically in the absence of any immunosuppression in liver transplant recipients.

  24 months post HSCT

Secondary Outcomes (3)

• HSCT mortality

  2 years post HSCT

• HSCT related morbidity

  at 2 years post HSCT

• Rate of immune reconstitution

  at 2 years post HSCT

Study Arms (1)

Autologous HSCT

EXPERIMENTAL

Eligible participants will undergo an Autologous Hematopoietic Stem Cell Transplant (HSCT) as a two-step intervention.

Drug: Autologous Hematopoietic Stem Cell Transplant

Interventions

Autologous Hematopoietic Stem Cell Transplant DRUG

Step 1: Participants will receive intravenous chemotherapy and cytokine-based treatment for mobilization of hematopoietic stem cells (HSC) into the circulation, followed by collection using peripheral vein leukopheresis. The HSC graft product will undergo ex vivo purification with CD34 selection using Miltenyil CliniMACS and cryopreserved. Step 2: Intravenous busulphan, cyclophosphamide and anti-thymocyte globulin will be administered to participants to achieve immune ablation prior to the infusion of the participants' own thawed HSC graft product (HSC transplant). Routine supportive measures will be employed during the recovery from the chemotherapy and HSCT. Participants' immune suppression will be stopped at the time of immunoablative therapy and will be switched to everolimus which will be discontinued at 6 months post HSCT.

Also known as: HSCT

Autologous HSCT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must be 18 years of age or older.
• Participants must be a minimum of 6 months post-transplant;
• Participants are recipients of a hepatic allograft for alcohol induced liver disease; or a genetic form of liver disease such as hemochromatosis or Wilson's disease; or an autoimmune liver disease including sclerosing cholangitis, autoimmune hepatitis, and/or primary biliary cirrhosis.

You may not qualify if:

• Participants \< 18 yr.
• Participants with cardiac, renal, pulmonary, hepatic, or other organ impairment that would limit their ability to receive dose intensive chemotherapy;
• Participants with any active or chronic infection. Participants with previous reactivation of Epstein-Barr virus, cytomegalovirus , BK, human herpesvirus 6 or varicella-zoster virus would be considered eligible if the virus has returned to a latent state;
• Participants who are seropositive for HIV1, HIV2, Hepatitis B Surface Antigen, and Hepatitis C;
• Participants with a previous history of a malignancy other than squamous or basal cell carcinoma of the skin, or post-transplant lymphoproliferative disease (PTLD);
• Participants whose life expectancy is severely limited by another co-morbid illness;
• Participants with evidence of myelodysplasia, other non-autoimmune cytopenia, or an inherited immunodeficiency state;
• Pregnancy or Participants who are unwilling to practice two active forms of contraception during the time of chemotherapy administration. Participants must be willing to commit to not becoming pregnant from enrollment in the study until 2 years following their HSCT.
• Participants unable to comply with the medical treatment specified in the protocol;
• Participants unable to give written informed consent in accordance with research ethics board guidelines.

Sponsors & Collaborators

• Gary A Levy, O. Ont. MD. FRCP AGAF: lead
• Ottawa Hospital Research Institute: collaborator

Study Sites (2)

The Ottawa Hopital

Ottawa, Ontario, K1H 8L6, Canada

Location

Multi-Organ Transplant Program, Toronto General Hospital

Toronto, Ontario, M5G 2N2, Canada

Location

Related Publications (10)

• Sykes M, Levy G. Advances in transplantation. Semin Immunol. 2011 Aug;23(4):222-3. doi: 10.1016/j.smim.2011.08.013. Epub 2011 Sep 22. No abstract available.

  PMID: 21943504 BACKGROUND

• Sayegh MH, Carpenter CB. Transplantation 50 years later--progress, challenges, and promises. N Engl J Med. 2004 Dec 23;351(26):2761-6. doi: 10.1056/NEJMon043418. No abstract available.

  PMID: 15616214 BACKGROUND

• Azzi JR, Sayegh MH, Mallat SG. Calcineurin inhibitors: 40 years later, can't live without .. J Immunol. 2013 Dec 15;191(12):5785-91. doi: 10.4049/jimmunol.1390055.

  PMID: 24319282 BACKGROUND

• Selzner N, Grant DR, Shalev I, Levy GA. The immunosuppressive pipeline: meeting unmet needs in liver transplantation. Liver Transpl. 2010 Dec;16(12):1359-72. doi: 10.1002/lt.22193.

  PMID: 21117245 BACKGROUND

• Kaplan B, Qazi Y, Wellen JR. Strategies for the management of adverse events associated with mTOR inhibitors. Transplant Rev (Orlando). 2014 Jul;28(3):126-33. doi: 10.1016/j.trre.2014.03.002. Epub 2014 Mar 12.

  PMID: 24685370 BACKGROUND

• Gotthardt DN, Bruns H, Weiss KH, Schemmer P. Current strategies for immunosuppression following liver transplantation. Langenbecks Arch Surg. 2014 Dec;399(8):981-8. doi: 10.1007/s00423-014-1191-9. Epub 2014 Apr 20.

  PMID: 24748543 BACKGROUND

• Sachs DH, Kawai T, Sykes M. Induction of tolerance through mixed chimerism. Cold Spring Harb Perspect Med. 2014 Jan 1;4(1):a015529. doi: 10.1101/cshperspect.a015529.

  PMID: 24384815 BACKGROUND

• Kawai T, Sachs DH, Sykes M, Cosimi AB; Immune Tolerance Network. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med. 2013 May 9;368(19):1850-2. doi: 10.1056/NEJMc1213779. No abstract available.

  PMID: 23656665 BACKGROUND

• Xie L, Ichimaru N, Morita M, Chen J, Zhu P, Wang J, Urbanellis P, Shalev I, Nagao S, Sugioka A, Zhong L, Nonomura N, Takahara S, Levy GA, Li XK. Identification of a novel biomarker gene set with sensitivity and specificity for distinguishing between allograft rejection and tolerance. Liver Transpl. 2012 Apr;18(4):444-54. doi: 10.1002/lt.22480.

  PMID: 22162188 BACKGROUND

• Chruscinski A, Juvet S, Moshkelgosha S, Renner E, Lilly L, Selzner N, Bredeson C, Grant D, Adeyi O, Fischer S, Demetris AJ, Zhang J, Epstein M, Macarthur M, Clement AM, Khalili K, Allan D, Altouri S, Bence-Bruckler I, Cattral M, Fulcher J, Galvin Z, Ghanekar A, Greig P, Huebsch L, Humar A, Kew A, Kekre N, Kim TK, McDiarmid S, Martin L, McGilvray I, Sabloff M, Sapisochin G, Selzner M, Smith R, Tinckam K, Yi TJ, Levy G, Atkins H. Autologous Hematopoietic Stem Cell Transplantation for Liver Transplant Recipients With Recurrent Primary Sclerosing Cholangitis: A Pilot Study. Transplantation. 2022 Mar 1;106(3):562-574. doi: 10.1097/TP.0000000000003829.

  PMID: 34049362 DERIVED

MeSH Terms

Conditions

Pyloric Stenosis, Hypertrophic; Autoimmune Diseases

Condition Hierarchy (Ancestors)

Pyloric Stenosis; Gastric Outlet Obstruction; Stomach Diseases; Gastrointestinal Diseases; Digestive System Diseases; Immune System Diseases

Study Officials

• Gary A Levy, MD FRCP AGAF

  University of Toronto Transplant Institute - Multi Organ Transplant Program

  PRINCIPAL INVESTIGATOR

• Harold L Atkins, MD FRCP(C)

  Ottawa Hospital Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Gary A Levy, O. Ont. MD. FRCP AGAF

Model Details: Pt are receiving everolimus in combination with autologous stem cell transplant to induce tolerance

Study Record Dates

• First Submitted: September 1, 2015
• First Posted: September 15, 2015
• Study Start: December 1, 2015
• Primary Completion: April 30, 2020
• Study Completion: April 30, 2020
• Last Updated: April 28, 2021

Record last verified: 2021-04

Locations

CA (2)