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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Anti-Thymocyte Globulin | Active Comparator | Anti-Thymocyte Globulin induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus. |
|
| TOL101 (Dose A) | Experimental | TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus. |
|
| TOL101 (Dose B) | Experimental | TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Anti-Thymocyte Globulin | Drug | 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 |
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Stuart Flechner, MD | The Cleveland Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Colorado Denver | Aurora | Colorado | 80045 | United States | ||
| University of Kentucky |
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|
| TOL101 | Drug | 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 |
|
| TOL101 | Drug | 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 |
|
| Steroids | Drug | IV methylprednisolone prior to first 3 doses of study drug; oral prednisone tapered to 5-10 mg over 6 months |
|
| Tacrolimus | Drug | Oral administration started by 6 days post-transplantation and continued for 6 months |
|
| Mycophenolate mofetil (MMF) | Drug | Oral administration started by Day 1 post-transplantation and continued for 6 months |
|
| 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 |
| Lexington |
| Kentucky |
| 40536 |
| United States |
| University of Michigan | Ann Arbor | Michigan | 48109 | United States |
| St Barnabas Medical Center | Livingston | New Jersey | 07039 | United States |
| Buffalo General Hospital | Buffalo | New York | 14203 | United States |
| Montefiore Medical Center | The Bronx | New York | 10467 | United States |
| Cleveland Clinic Foundation | Cleveland | Ohio | 44195 | United States |
| Medical University of South Carolina | Charleston | South Carolina | 29425 | United States |
| Baylor University Medical Center | Dallas | Texas | 75246 | United States |
| Baylor All Saints | Fort Worth | Texas | 76104 | United States |
| University of Utah | Salt Lake City | Utah | 84132 | United States |
| University of Virginia Health System | Charlottesville | Virginia | 22908 | United States |
| ID | Term |
|---|---|
| D007676 | Kidney Failure, Chronic |
| D051437 | Renal Insufficiency |
| ID | Term |
|---|---|
| D051436 | Renal Insufficiency, Chronic |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000961 | Antilymphocyte Serum |
| C512542 | thymoglobulin |
| C000594305 | TOL-101 |
| D013256 | Steroids |
| D016559 | Tacrolimus |
| D009173 | Mycophenolic Acid |
| ID | Term |
|---|---|
| D007106 | Immune Sera |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D001688 | Biological Products |
| D045424 | Complex Mixtures |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D002208 | Caproates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D005227 | Fatty Acids |
| D008055 | Lipids |
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