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

Phase 3

Terminated

Conditions: Steroid-Refractory Acute Graft Versus Host Disease

Interventions: Drug: T-Guard

Registration Number: NCT04128319

Lead Sponsor: Xenikos

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 3

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
T-Guard Treatment	T-Guard	Patients will receive T-Guard for treatment of steroid-refractory acute GVHD.

Primary Outcome Measures

Name	Time	Method
Complete Response (CR)	Day 28	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.

Secondary Outcome Measures

Name	Time	Method
Relapse-free Survival	Days 180	Estimate relapse-free survival at Day 180.
Overall Survival (OS)	Day 30	Estimate the overall survival (OS) at Day 30.
Overall Response Rate (CR or Partial Response (PR))	Days 14, 28, and 56	Estimate the overall response rate (CR or partial response (PR)) at Days 14, 28, and 56.
Proportions of CR, PR, Mixed Response (MR), no Response (NR) and Progression	Days 7, 14, 28, and 56	Describe proportions of CR, PR, mixed response (MR), no response (NR), and progression of aGVHD at Days 7, 14, 28, and 56.
Pharmacokinetics of T-Guard - CL	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)	Systemic clearance of T-Guard
Pharmacokinetics of T-Guard - t1/2	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)	Model-predicted terminal half-life of T-Guard
Duration of Complete Response (DoCR)	Through Day 180	Evaluate the duration of complete response (DoCR) Early Trial Closure.
Incidence of Toxicities	initiation of T-Guard to 28 days post-last dose	Describe the incidence of CTCAE v5 Grade 3-5 toxicities
Pharmacokinetics of T-Guard - Cinf	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)	Observed and model-predicted concentration of T-Guard at the end of infusion
Pharmacokinetics of T-Guard - AUC	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)	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
Cumulative Incidence of Disease Relapse/Progression	Day 180	Estimate the cumulative incidence of disease relapse/progression at Day 180
Incidence of Systemic Infections	initiation of T-Guard to 28 days post-last dose	Describe the incidence of systemic infections
Non-Relapse Mortality (NRM)	Days 100 and 180	Estimate the cumulative incidence of non-relapse mortality (NRM) at Days 100 and 180.
GVHD-free Survival	Days 90 and 180	Estimate GVHD-free survival at Days 90 and 180
Cumulative Incidence of Chronic GVHD	Day 180	Estimate the cumulative incidence of chronic GVHD (cGVHD) at Day 180
Pharmacokinetics of T-Guard - Vc	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)	Volume of the central compartment
Immunogenicity	Baseline, Days 7, 14, 28, 90, and 180	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

Trial Locations

Locations (24): Emory University
🇺🇸
Atlanta, Georgia, United States
Indiana University
🇺🇸
Indianapolis, Indiana, United States
University of Kansas
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Westwood, Kansas, United States
University of Maryland
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Baltimore, Maryland, United States
University of Minnesota
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Minneapolis, Minnesota, United States
University of Pennsylvania
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Philadelphia, Pennsylvania, United States
Johns Hopkins University
🇺🇸
Baltimore, Maryland, United States
Fred Hutchinson Cancer Research Center
🇺🇸
Seattle, Washington, United States
H. Lee Moffitt Cancer Center
🇺🇸
Tampa, Florida, United States
Mount Sinai Medical Center
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New York, New York, United States
Cincinnati Children's Hospital Medical Center
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Cincinnati, Ohio, United States
City of Hope National Medical Center
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Duarte, California, United States
Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States
Children's Hospital Los Angeles
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Los Angeles, California, United States
University of Michigan
🇺🇸
Ann Arbor, Michigan, United States
Washington University in St. Louis
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Saint Louis, Missouri, United States
Ohio State University
🇺🇸
Columbus, Ohio, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
University of Utah
🇺🇸
Salt Lake City, Utah, United States
Oregon Health & Science University
🇺🇸
Portland, Oregon, United States
Baylor College of Medicine
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Houston, Texas, United States
University of Wisconsin
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Madison, Wisconsin, United States
Medical College of Wisconsin
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Milwaukee, Wisconsin, United States
University of Nebraska
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Omaha, Nebraska, United States