T-Guard as Treatment for Steroid Refractory Acute GVHD (BMT CTN 1802)

Study Overview
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Brief Summary
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The study is designed as an open-label, single arm Phase III, multicenter trial to evaluate the efficacy and safety of T-Guard treatment in patients with Steroid-Refractory acute Graft versus Host Disease (SR-aGVHD).

Detailed Description
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Allogeneic Hematopoietic Cell Transplantation (allo-HSCT) is a potent immunotherapy with curative potential for several hematological disorders. Improvements in survival following allo-HSCT have led to its increasing use, but the leading cause of non-relapse mortality (NRM) remains graft-versus-host-disease (GVHD. Despite recent advances in the understanding of transplantation immune tolerance, aGVHD is a frequent and major complication of allo-HSCT involving activation of donor T-lymphocytes, which ultimately causes host tissue damage. T-Guard has a rapid onset, preferential killing of activated T cells, and short half-life, leading to depletion of allo-reactive T cells and quick post-treatment reconstitution of the immune system.

Official Title
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An Open-Label, Single-Arm, Multicenter Study, of Combination Anti-CD3/CD7 Immunotoxin (T-Guard) for Steroid-Refractory Acute Graft-versus-Host Disease)

Conditions
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Steroid-Refractory Acute Graft Versus Host Disease

Intervention / Treatment
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* Drug: T-Guard


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must be at least 12.0 years of age at the time of consent. Patient has undergone first allo-HSCT from any donor source using bone marrow, peripheral blood stem cells, or cord blood. Recipients of nonmyeloablative, reduced intensity, and myeloablative conditioning regimens are eligible. Patients diagnosed with SR-aGVHD after allo-HSCT. SR is defined as aGVHD that: Progressed after 3 days of primary treatment with prednisone (or equivalent) of greater than or equal to 2mg/kg/day No improvement after 7 days of primary treatment with prednisone (or equivalent) of greater than or equal to 2mg/kg/day. Patients with visceral (GI and/or liver) plus skin aGVHD at prednisone (or equivalent) initiation with improvement in skin GVHD without any improvement in visceral GVHD after 7 days of primary treatment with prednisone (or equivalent) of greater than or equal to 2mg/kg/day Previously was treated with prednisone (or equivalent) of greater than or equal to 1mg/kg/day and aGVHD has developed in a previously uninvolved organ system Progression and no improvement are defined in the protocol. Improvement or progression in organs is determined by comparing current organ staging to staging at initiation of prednisone (or equivalent) treatment. Staging is performed per MAGIC criteria. Evidence of myeloid engraftment (e.g., absolute neutrophil count greater than or equal to 0.5 × 10^9/L for 3 consecutive days if ablative therapy was previously used). Use of growth factor supplementation is allowed. Patients or an impartial witness (in case the patient is capable of providing verbal consent but not capable of signing the informed consent form (ICF)) should have given written informed consent. For patients less than 18 years of age, a written informed consent of the parents or guardian and written assent of the patient will be obtained, per the local requirements. Exclusion Criteria: Patients who have been diagnosed with overlap syndrome, that is, with any concurrent features of cGVHD. Patients requiring any of the following: mechanical ventilation, vasopressor support, or hemodialysis. Patients who have received any systemic treatment, besides steroids, as upfront treatment of aGVHD OR as treatment for SR-aGVHD. Patients who have severe hypoalbuminemia, with an albumin of less than or equal to 1 g/dl. Patients who have a CK level of greater than 5 times the upper limit of normal. Patients with uncontrolled infections. Infections are considered controlled if appropriate therapy has been instituted and, at the time of enrollment, no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection. Patients with evidence of relapsed, progressing or persistent malignancy. Patients with evidence of minimal residual disease requiring withdrawal of systemic immune suppression Patients with known hypersensitivity to any of the components murine monoclonal antibodies (mAb) or Recombinant Ricin Toxin A-chain (RTA). Patients who have received more than one allo-HSCT. Patients with known human immunodeficiency virus infection. Female patients who are pregnant, breast feeding, or, if sexually active and of childbearing potential, unwilling to use effective birth control from start of treatment until 30 days after the last infusion of T-Guard. Male patients who are, if sexually active and with a female partner of childbearing potential, unwilling to use effective birth control from start of treatment until 65 days after the last infusion of T-Guard. Patients with any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the patient; or interfere with interpretation of study data. Patients whose decision to participate might be unduly influenced by perceived expectation of gain or harm by participation, such as patients in detention due to official or legal order.

Ages Eligible for Study
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Minimum Age: 12 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
Intervention Model: Single Group Assignment
Interventional Model Description: A single group of patients will receive T-Guard for treatment of steroid-refractory acute GVHD.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: T-Guard Treatment<br>Patients will receive T-Guard for treatment of steroid-refractory acute GVHD. | Drug: T-Guard<br>* Patients will receive 4 doses of T-Guard treatment, administered intravenously as four 4-hour infusions at least two calendar days (no less than 40 hours) apart. Each dose consists of 4 mg/m^2 Body Surface Area (BSA).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) | Complete Response at Day 28 is defined as a score of 0 for the GVHD staging in all evaluable organs at the Day 28 visit along with freedom from additional systemic therapy for treatment of acute GVHD. | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Complete Response (DoCR) | Evaluate the duration of complete response (DoCR) Early Trial Closure. | Through Day 180 | 
| Overall Survival (OS) | Estimate the overall survival (OS) at Day 30. | Day 30 | 
| Overall Response Rate (CR or Partial Response (PR)) | Estimate the overall response rate (CR or partial response (PR)) at Days 14, 28, and 56. | Days 14, 28, and 56 | 
| Proportions of CR, PR, Mixed Response (MR), no Response (NR) and Progression | Describe proportions of CR, PR, mixed response (MR), no response (NR), and progression of aGVHD at Days 7, 14, 28, and 56. | Days 7, 14, 28, and 56 | 
| Non-Relapse Mortality (NRM) | Estimate the cumulative incidence of non-relapse mortality (NRM) at Days 100 and 180. | Days 100 and 180 | 
| Relapse-free Survival | Estimate relapse-free survival at Day 180. | Days 180 | 
| GVHD-free Survival | Estimate GVHD-free survival at Days 90 and 180 | Days 90 and 180 | 
| Cumulative Incidence of Chronic GVHD | Estimate the cumulative incidence of chronic GVHD (cGVHD) at Day 180 | Day 180 | 
| Cumulative Incidence of Disease Relapse/Progression | Estimate the cumulative incidence of disease relapse/progression at Day 180 | Day 180 | 
| Incidence of Systemic Infections | Describe the incidence of systemic infections | initiation of T-Guard to 28 days post-last dose | 
| Incidence of Toxicities | Describe the incidence of CTCAE v5 Grade 3-5 toxicities | initiation of T-Guard to 28 days post-last dose | 
| Pharmacokinetics of T-Guard - Cinf | Observed and model-predicted concentration of T-Guard at the end of infusion | Before each infusion & at the following post-infusion timepoints: 4, 5, 6, 8 & 24 hours for the 1st infusion; 4, 6 & 24 hours for the 2nd & 3rd infusions; 4, 6, 24 & 48 hours for the 4th infusion (infusions occur within the time frame of Day 0 to Day 14) | 
| Pharmacokinetics of T-Guard - CL | Systemic clearance of T-Guard | Before each infusion & at the following post-infusion timepoints: 4, 5, 6, 8 & 24 hours for the 1st infusion; 4, 6 & 24 hours for the 2nd & 3rd infusions; 4, 6, 24 & 48 hours for the 4th infusion (infusions occur within the time frame of Day 0 to Day 14) | 
| Pharmacokinetics of T-Guard - AUC | Model-predicted area under the curve from the start of the current infusion until the next infusion or until 48 hours following for the last infusion | Before each infusion & at the following post-infusion timepoints: 4, 5, 6, 8 & 24 hours for the 1st infusion; 4, 6 & 24 hours for the 2nd & 3rd infusions; 4, 6, 24 & 48 hours for the 4th infusion (infusions occur within the time frame of Day 0 to Day 14) | 
| Pharmacokinetics of T-Guard - t1/2 | Model-predicted terminal half-life of T-Guard | Before each infusion & at the following post-infusion timepoints: 4, 5, 6, 8 & 24 hours for the 1st infusion; 4, 6 & 24 hours for the 2nd & 3rd infusions; 4, 6, 24 & 48 hours for the 4th infusion (infusions occur within the time frame of Day 0 to Day 14) | 
| Pharmacokinetics of T-Guard - Vc | Volume of the central compartment | Before each infusion & at the following post-infusion timepoints: 4, 5, 6, 8 & 24 hours for the 1st infusion; 4, 6 & 24 hours for the 2nd & 3rd infusions; 4, 6, 24 & 48 hours for the 4th infusion (infusions occur within the time frame of Day 0 to Day 14) | 
| Immunogenicity | Assess the immunogenicity of T-Guard via ADA responses in the form of human anti-SPV-T3a-RTA and anti-WT1-RTA -antibodies evaluated in serum samples | Baseline, Days 7, 14, 28, 90, and 180 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Steroid-refractory acute GVHD, Acute GVHD, GVHD treatment