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

Sponsor

Tolera Therapeutics, Inc (Industry)

Overall Status

Unknown status

CT.gov ID

NCT01154387

Collaborator

(none)

Enrollment

Locations

Arms

Duration (Months)

7.1

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
End Stage Renal Disease Renal Transplant	Drug: Anti-Thymocyte Globulin Drug: TOL101 Drug: TOL101 Drug: Steroids Drug: Tacrolimus Drug: Mycophenolate mofetil (MMF)	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

85 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jul 1, 2010

Anticipated Primary Completion Date :

Jun 1, 2013

Anticipated Study Completion Date :

Jun 1, 2013

Arms and Interventions

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: 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: 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 B) TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.	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 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

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: 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: 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 B)

TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.

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

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

Outcome Measures

Primary Outcome Measures

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 [6 months]
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

Secondary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Denver	Aurora	Colorado	United States	80045
2	University of Kentucky	Lexington	Kentucky	United States	40536
3	University of Michigan	Ann Arbor	Michigan	United States	48109
4	St Barnabas Medical Center	Livingston	New Jersey	United States	07039
5	Montefiore Medical Center	Bronx	New York	United States	10467
6	Buffalo General Hospital	Buffalo	New York	United States	14203
7	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
8	Medical University of South Carolina	Charleston	South Carolina	United States	29425
9	Baylor University Medical Center	Dallas	Texas	United States	75246
10	Baylor All Saints	Fort Worth	Texas	United States	76104
11	University of Utah	Salt Lake City	Utah	United States	84132
12	University of Virginia Health System	Charlottesville	Virginia	United States	22908