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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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End Stage Renal Disease, Renal Transplant

Intervention / Treatment
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* Drug: Anti-Thymocyte Globulin
* Drug: TOL101
* Drug: TOL101
* Drug: Steroids
* Drug: Tacrolimus
* Drug: Mycophenolate mofetil (MMF)


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Anti-Thymocyte Globulin<br>Anti-Thymocyte Globulin induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus. | Drug: Anti-Thymocyte Globulin<br>* 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<br>* Other names: Thymoglobulin;Drug: Steroids<br>* IV methylprednisolone prior to first 3 doses of study drug; oral prednisone tapered to 5-10 mg over 6 months<br>Drug: Tacrolimus<br>* Oral administration started by 6 days post-transplantation and continued for 6 months<br>Drug: Mycophenolate mofetil (MMF)<br>* Oral administration started by Day 1 post-transplantation and continued for 6 months<br>|
| Experimental: TOL101 (Dose A)<br>TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus. | Drug: TOL101<br>* 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<br>Drug: Steroids<br>* IV methylprednisolone prior to first 3 doses of study drug; oral prednisone tapered to 5-10 mg over 6 months<br>Drug: Tacrolimus<br>* Oral administration started by 6 days post-transplantation and continued for 6 months<br>Drug: Mycophenolate mofetil (MMF)<br>* Oral administration started by Day 1 post-transplantation and continued for 6 months<br>|
| Experimental: TOL101 (Dose B)<br>TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus. | Drug: TOL101<br>* 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<br>Drug: Steroids<br>* IV methylprednisolone prior to first 3 doses of study drug; oral prednisone tapered to 5-10 mg over 6 months<br>Drug: Tacrolimus<br>* Oral administration started by 6 days post-transplantation and continued for 6 months<br>Drug: Mycophenolate mofetil (MMF)<br>* Oral administration started by Day 1 post-transplantation and continued for 6 months<br>|

What is the study measuring?
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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 | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Graft survival |  | 6 months | 
| Patient survival |  | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney, Renal, Transplant, Kidney Transplant, Kidney Failure, Induction, Monoclonal, Antibody, T cell, Anti-rejection, Immunosuppression