Evaluating Safety and Efficacy of TOL101 Induction Versus Anti-Thymocyte Globulin to Prevent Kidney Transplant Rejection

A Two Part, Phase 1/2, Safety, PK and PD Study of TOL101, an Anti-TCR Monoclonal Antibody for Prophylaxis of Acute Organ Rejection in Patients Receiving Renal Transplantation

Induction therapy with antibodies is administered during transplant surgery and for a short period of time following transplant surgery in an effort to render the immune system less able to mount an initial rejection response. In general, induction therapy is associated with better outcomes compared to the absence of induction therapy. However, currently used induction agents, some of which are not labeled or indicated for induction therapy in transplantation, have drawbacks related to long-term immune system suppression increasing susceptibility to opportunistic infections or malignancies, and other immune-mediated side effects.

An unmet medical need exists for a more specific approach to prevent acute organ rejection, without unnecessarily exposing the patient to non-specific or open-ended immune suppression, which may exacerbate the risks of infections and malignancies. TOL101 is a novel antibody that targets a very specific immune cell type that is critical in the acute organ rejection response. In this two-part study, TOL101 will be evaluated for the prophylaxis of acute organ rejection when used as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus in first time kidney transplant recipients.

This study will test the hypothesis that a more specific approach (with TOL101) to prevention of acute organ rejection may provide similar or better efficacy than the currently used induction antibodies (such as Anti-Thymocyte Globulin or Thymoglobulin) while carrying fewer risks in terms of opportunistic infections, malignancies and adverse effects.

Study Overview

• Status: Unknown
• Conditions: End Stage Renal Disease; Renal Transplant
• Intervention / Treatment: Drug: Anti-Thymocyte Globulin; Drug: Steroids; Drug: Tacrolimus; Drug: Mycophenolate mofetil (MMF); Drug: TOL101; Drug: TOL101

• Study Type: Interventional
• Enrollment (Anticipated): 85
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • St Barnabas Medical Center
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • Buffalo, New York, United States, 14203
      • Buffalo General Hospital
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Fort Worth, Texas, United States, 76104
      • Baylor All Saints
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Recipient of a primary renal transplant from a living or standard criteria cadaveric donor
• Male or female 18-60 years of age
• Recipient with a PRA < 20%

Exclusion Criteria:

• Previous solid organ transplant
• Recipient of HLA-identical kidney allograft transplant
• Recipient of an ABO incompatible donor kidney
• Known HIV infection or other major infection
• History of malignancy within 3 years (excluding treated basal cell or squamous cell carcinoma of the skin) prior to enrollment
• History of tuberculosis
• Recipient with cardiovascular disease
• Treatment with immunosuppressive medications within 1 month prior to enrollment
• Known or suspected allergy to mice
• Pregnant or lactating
• Unable or unwilling to participate in all required study activities for the duration of the study (6 months)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Anti-Thymocyte Globulin; Anti-Thymocyte Globulin induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.	Drug: Anti-Thymocyte Globulin; 1.5mg/kg IV on Day of Transplant and 1.0-1.5 mg/kg IV once daily for a minimum of 4.5mg/kg and a maximum of 7.5mg/kg total cumulative dose; Other Names: Thymoglobulin; Drug: Steroids; IV methylprednisolone prior to first 3 doses of study drug; oral prednisone tapered to 5-10 mg over 6 months; Drug: Tacrolimus; Oral administration started by 6 days post-transplantation and continued for 6 months; Drug: Mycophenolate mofetil (MMF); Oral administration started by Day 1 post-transplantation and continued for 6 months
Experimental: TOL101 (Dose A); TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.	Drug: Steroids; IV methylprednisolone prior to first 3 doses of study drug; oral prednisone tapered to 5-10 mg over 6 months; Drug: Tacrolimus; Oral administration started by 6 days post-transplantation and continued for 6 months; Drug: Mycophenolate mofetil (MMF); Oral administration started by Day 1 post-transplantation and continued for 6 months; Drug: TOL101; Potential Therapeutic Dose (PTD)-A (0.28-56 mg to be determined in Phase 1/Part A ) IV once daily x 6-10 doses starting on Day of Transplant; Drug: TOL101; Potential Therapeutic Dose (PTD)-B (0.28-56 mg to be determined in Phase 1/Part A ) IV once daily x 6-10 doses starting on Day of Transplant
Experimental: TOL101 (Dose B); TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.	Drug: Steroids; IV methylprednisolone prior to first 3 doses of study drug; oral prednisone tapered to 5-10 mg over 6 months; Drug: Tacrolimus; Oral administration started by 6 days post-transplantation and continued for 6 months; Drug: Mycophenolate mofetil (MMF); Oral administration started by Day 1 post-transplantation and continued for 6 months; Drug: TOL101; Potential Therapeutic Dose (PTD)-A (0.28-56 mg to be determined in Phase 1/Part A ) IV once daily x 6-10 doses starting on Day of Transplant; Drug: TOL101; Potential Therapeutic Dose (PTD)-B (0.28-56 mg to be determined in Phase 1/Part A ) IV once daily x 6-10 doses starting on Day of Transplant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the safety and tolerability of ascending doses of TOL101 and the effectiveness of TOL101 to target and downregulate T cells in patients undergoing first renal transplantation	The following safety parameters will be monitored: Adverse events, standard laboratory safety evaluations (hematology and serum chemistries), symptom constellation indicating cytokine release syndrome, serum concentrations of cytokines and nitric oxide, malignancies, CMV viremia, BKV viremia, EBV viremia and other infections	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Graft survival	6 months
Patient survival	6 months
The effects of ascending doses of TOL101 on CD3+ T lymphocyte numbers and other immune cell subsets	14 days post-transplant (Part A); 6 months (Part B)
The pharmacokinetic (PK) profile of TOL101 in renal transplant recipients and the exposure-response (PK parameter to CD3+ T lymphocyte numbers) relationship over time	14 days post-transplant
Biopsy-proven acute organ rejection	6 months
Renal function by measured GFR at 6 months post-transplant and urine protein to creatinine ratio at 3 and 6 months post-transplant	6 months
Delayed graft function	first 7 days post-transplant
Immunogenicity of TOL101 by measurement of anti-TOL101 antibodies	at 14 and 28 days post-transplant
The presence of Donor Specific Antibody at 3 months (Part B only) and 6 months post-transplant	6 months

Collaborators and Investigators

• Sponsor: Tolera Therapeutics, Inc
• Investigators: Principal Investigator: Stuart Flechner, MD, The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Anticipated): June 1, 2013
• Study Completion (Anticipated): June 1, 2013

Study Registration Dates

• First Submitted: June 26, 2010
• First Submitted That Met QC Criteria: June 28, 2010
• First Posted (Estimate): June 30, 2010

Study Record Updates

• Last Update Posted (Estimate): June 11, 2013
• Last Update Submitted That Met QC Criteria: June 10, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Keywords: Immunosuppression; Antibody; Transplant; Kidney; Kidney Failure; T cell; Kidney Transplant; Renal; Induction; Monoclonal; Anti-rejection
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Tacrolimus; Mycophenolic Acid; Thymoglobulin; Antilymphocyte Serum
• Other Study ID Numbers: TTI-121