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Donor-Alloantigen-Reactive Regulatory T Cell Therapy in Liver

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Donor-Alloantigen-Reactive Regulatory T Cell Therapy in Liver Confidential Page 1 of 80 Donor-Alloantigen-Reactive Regulatory T Cell Therapy in Liver Transplantation Version 7.0/ August 1, 2018 IND# 15479 Study Sponsor(s): The National Institute of Allergy and Infectious Diseases (NIAID) Grant #: R34AI095135 and U01AI110658-01 Study Drug Manufacturer/Provider: Sanofi US PRINCIPAL INVESTIGATOR CO- PRINCIPAL INVESTIGATOR CO- PRINCIPAL INVESTIGATOR SANDY FENG, MD, PHD JEFFREY BLUESTONE, PHD SANG-MO KANG, MD, FACS Professor of Surgery Executive Vice Chancellor and Provost Associate Professor Director, Abdominal Transplant A.W. Clausen Distinguished Professor University of California, San Surgery Fellowship in Medicine Francisco University of California, San University of California, San Francisco 513 Parnassus Ave. Francisco 513 Parnassus Ave. Box 0780, HSE-520 505 Parnassus Ave. Box 0400, HSW-1128 San Francisco, CA 94143-0780 Box 0780, M-896 San Francisco, CA 94143-0780 Phone: (415) 353-1888 San Francisco, CA 94143-0780 Phone: (415) 476-4451 E-mail: Sang- Phone: (415) 353-8725 Fax: (415) 476-9634 [email protected] Fax: (415) 353-8709 E-mail: [email protected] E-mail: [email protected] CO- PRINCIPAL INVESTIGATOR BIOSTATISTICIAN MEDICAL OFFICER QIZHI TANG, PHD DAVID IKLÉ, PHD NANCY BRIDGES, MD Associate Professor Senior Statistical Scientist Chief, Transplantation Branch Director, UCSF Transplantation Rho, Inc. Division of Allergy, Immunology, Research Lab 6330 Quadrangle Drive and Transplantation University of California, San Chapel Hill, NC 27517 NIAID Francisco Phone: (910) 558-6678 5601 Fishers Ln, 6B31 513 Parnassus Ave. Fax: (919) 408-0999 Bethesda, MD 20892 Box 0780, HSE-520 E-mail: [email protected] Phone: (301) 480-6316 San Francisco, CA 94143-0780 E-mail: [email protected] Phone: (415) 476-1739 Fax: (415) 502-8326 E-mail: [email protected] PROGRAM OFFICER REGULATORY OFFICER PROJECT MANAGER DEBORAH HAYES, MS JULIA GOLDSTEIN, MD TINA SLEDGE, RN Transplantation Branch Office of Regulatory Affairs Transplantation Branch Division of Allergy, Immunology and Division of Allergy, Immunology, and Division of Allergy, Immunology, Transplantation Transplantation and Transplantation NIAID NIAID NIAID 5601 Fishers Ln, 6B35 5601 Fishers Ln, 7B29 5601 Fishers Ln, 6B28 Bethesda, Maryland 20892 Bethesda, MD 20892 Bethesda, MD 20892 Phone: (240) 627-3496 Phone: (240) 627-3509 Phone: (240) 627-3561 E-mail: [email protected] Email: [email protected] Email: [email protected] Confidentiality Statement The information contained within this document is not to be disclosed in any way without the prior permission of the Protocol Chair, or the Division of Allergy, Immunology and Transplantation, NIAID of the National Institutes of Health. Tregs in Liver Transplantation (RTB-002) Version 7.0/ August 1, 2018 Confidential Page 2 of 80 INVESTIGATOR SIGNATURE PAGE Protocol: Version/Date: Tregs in Liver Transplantation 7.0 / August 1, 2018 Site Principal Investigator: Title: Donor-Alloantigen-Reactive Regulatory T Cell Therapy in Liver Transplantation Study Sponsor: The National Institute of Allergy and Infectious Diseases (NIAID) INSTRUCTIONS: The site Principal Investigator should print, sign, and date at the indicated location below. A copy should be kept for your records and the original signature page sent. After signature, please return the original of this form by surface mail to: DAIT Regulatory Management Center PPD, Inc. 3900 Paramount Parkway Morrisville, NC 27560 Phone: (919) 456-4229 I confirm that I have read the above protocol in the latest version. I understand it, and I will work according to the principles of Good Clinical Practice as described in the United States Code of Federal Regulations (CFR) – 45 CFR part 46 and 21 CFR parts 50, 56, and 312, and in the International Conference on Harmonization (ICH) document Guidance for Industry: E6 Good Clinical Practice: Consolidated Guidance dated April 1996. Further, I will conduct the study in keeping with local legal and regulatory requirements. As the site Principal Investigator, I agree to carry out the study by the criteria written in the protocol and understand that no changes can be made to this protocol without the written permission of the IRB and NIAID. ____________________________________ Site Principal Investigator (Print) ____________________________________ _________________ Site Principal Investigator (Signature) Date Tregs in Liver Transplantation (RTB-002) Version 7.0/ August 1, 2018 Confidential Page 3 of 80 Protocol Synopsis Title Donor-Alloantigen-Reactive Regulatory T Cell (darTreg) Therapy in Liver Transplantation Short Title darTregs in Liver Transplantation (deLTa) Protocol Number RTB-002 ClinicalTrials.gov NCT02188719 Identifier Clinical Phase Phase I Safety Objective This study will evaluate the safety, tolerability, and dose limiting toxicities (DLTs) of a Treg-supportive Immunosuppression (IS) regimen and darTreg infusion for adult, de novo, liver transplant recipients. Mechanistic This study will evaluate 1) the effects of a Treg-supportive IS regimen and Treg infusion on Objectives immunological profiles of liver transplant recipients, and 2) explore the hypothesis that ex vivo- expanded darTregs will be biologically active. Study Design A multi-center, open-label, dose escalation, pilot trial with four cohorts (Treg-supportive IS only group + three darTreg dosing groups) conducted in a phased schema. Safety Outcome The safety, tolerability, and dose-limiting toxicities (DLTs) of darTreg therapy given within the context of a Treg-supportive IS regimen will be evaluated with the rate of the following events within 40 weeks of transplantation. Clinical outcomes that will be described are: 1. Incidence and severity of biopsy proven acute rejection (AR) and/or chronic rejection (CR) 2. Incidence of ≥ Grade 3 infections as defined in Section 14.3.1 3. Incidence of wound complications (≥ CTCAE Version 4.0, Grade 3) 4. Incidence of anemia, neutropenia, and/or thrombocytopenia (according to study defined reporting requirements, Section 14.3.1 Grading Criteria) 5. Incidence of adverse events (AEs) attributable to the darTreg infusion including infusion reaction / cytokine release syndrome (CRS) (≥ CTCAE Grade 3), and malignant cellular transformation. Mechanistic 1. Treg frequency in peripheral blood using Treg TruCount assay Outcomes 2. Persistence of infused darTregs in blood and biopsies using deuterium labeling and T cell repertoire analysis 3. darTreg and darTconv frequency in peripheral blood using an in vitro allofrequency assay 4. Multicolor flow cytometry (MFC) to assess effect on immune profiles 5. Functional assessment of Treg in peripheral blood using a mixed lymphocyte reaction (MLR) suppression assay 6. Histology and immunophenotype of liver biopsies Accrual Objective 18 - 24 subjects: • Cohort 1: 3 subjects from Center 1 (Cohort 1a) + 3 subjects from Center 2 (Cohort 1b) • Cohort 2: At least 3, and up to 6 subjects (Dose A) • Cohort 3: At least 3, and up to 6 subjects from either Center (Dose B) • Cohort 4: 6 subjects from either Center (Dose C). Study Duration 4 year accrual period, 40 weeks of follow-up after transplantation Tregs in Liver Transplantation (RTB-002) Version 7.0/ August 1, 2018 Confidential Page 4 of 80 Treatment Treg-supportive IS regimen: Description • Rabbit anti-thymocyte globulin (Thymoglobulin®) induction (3-4.5 mg/kg started by day 3) • Corticosteroids (500 mg intra-operatively, taper to off by week 5) • Mycophenolate mofetil (1000 mg total daily dose) • TAC, with target trough level of 6-8 µg/dL Between 30 and 44 days following transplant: Subjects who are not eliminated by Exclusion Criteria C1 (Section 4.3.3) will proceed in the study and receive either TAC-based or EVR-based IS, based on eligibility Criteria C2 (Section 4.3.4) • TAC-based IS: reduce TAC trough level to 3-8 µg/dL; continue MMF • EVR-based IS: reduce TAC trough level to 3-5 µg/dL; EVR target trough level of 6-8 µg/dL; decrease then discontinue MMF Escalating darTregs therapy: Eligible and consented patients in Cohorts 2, 3, or 4 will have peripheral blood mononuclear cells (PBMCs) collected, which will be cryopreserved for subsequent induction, purification, and expansion of darTregs. At the time of transplant and after verification of the participant’s ongoing eligibility, donor cells will be collected and banked for production of stimulated donor B cells. Donor B cells will be used to generate darTregs for infusion at 11-20 weeks after transplant. Cohort 1 – Treg-supportive IS only Cohort 2 – darTreg infusion, 50 million (range 25 to 60 million) Cohort 3 – darTreg infusion, 200 million (range 100-240 million) Cohort 4 – darTreg infusion, 800 million (range 400-960 million) Inclusion Criteria Subjects who meet all of the following criteria are eligible for enrollment as study participants: 1. Able to understand and provide informed consent 2. End-stage liver disease and listed for deceased-donor primary solitary liver transplant 3. Between 21 and 70 years of age at the time of study entry/consent 4. Have a calculated MELD score ≤ 25 at the time of study entry/consent 5. Female and male subjects with reproductive potential must agree to use effective methods of birth control for the duration of the study 6. If history of HCV, have completed or in current treatment for HCV AND have no detectable HCV RNA 7. Subjects with HCC meeting Milan criteria Tregs in Liver Transplantation (RTB-002) Version 7.0/ August 1, 2018 Confidential Page 5 of 80 Exclusion Criteria Exclusion
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