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

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

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).

Study Overview

• Status: Terminated
• Conditions: Steroid-Refractory Acute Graft Versus Host Disease
• Intervention / Treatment: Drug: T-Guard

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Kansas
    • Westwood, Kansas, United States, 66205
      • University of Kansas
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins University
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Minnesota
    • Minneapolis, Minnesota, United States, 55414
      • University of Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University in St. Louis
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University Of Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patient must be at least 12.0 years of age at the time of consent.
2. 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.

3. 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.

4. 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.
5. 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:

1. Patients who have been diagnosed with overlap syndrome, that is, with any concurrent features of cGVHD.
2. Patients requiring any of the following: mechanical ventilation, vasopressor support, or hemodialysis.
3. Patients who have received any systemic treatment, besides steroids, as upfront treatment of aGVHD OR as treatment for SR-aGVHD.
4. Patients who have severe hypoalbuminemia, with an albumin of less than or equal to 1 g/dl.
5. Patients who have a CK level of greater than 5 times the upper limit of normal.
6. 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.
7. Patients with evidence of relapsed, progressing or persistent malignancy.
8. Patients with evidence of minimal residual disease requiring withdrawal of systemic immune suppression
9. Patients with known hypersensitivity to any of the components murine monoclonal antibodies (mAb) or Recombinant Ricin Toxin A-chain (RTA).
10. Patients who have received more than one allo-HSCT.
11. Patients with known human immunodeficiency virus infection.
12. 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.
13. 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.
14. 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.
15. 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: T-Guard Treatment; Patients will receive T-Guard for treatment of steroid-refractory acute GVHD.	Drug: T-Guard; 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).

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Corticosteroid Dose	Corticosteroid-dose (measured in prednisone-equivalent) at baseline, Days 28 and 56 post initiation of T- Guard therapy.	Baseline, Days 28 and 56
Rate of Near-CR	Estimate the rate of near-CR (i.e. CR in GI and Liver with only Stage 1 Skin) at Days 28 and 56 post initiation of T- Guard therapy	Days 28 and 56
Discontinuation of Systemic Steroids	Describe discontinuation of systemic steroids by Day 180 post initiation of T-Guard therapy	Day 180
Incidence of CMV Reactivation	Estimate the incidence of CMV reactivation requiring therapy by Day 180 post initiation of T-Guard Therapy	Day 180
Incidence of EBV-associated Lymphoproliferative Disorder or EBV Reactivation	Estimate the incidence of Epstein-Barr Virus (EBV)- associate lymphoproliferative disorder or EBV reactivation requiring therapy with rituximab by Day 180 post initiation of T-Guard therapy	Day 180
Incidence of IMP-related SAEs	Describe the incidence of Investigational Medicinal Product (IMP) related SAEs	Through Day 180
T-cell Subsets and NK Cells	The evolution of specific cell populations over the 180 day follow-up period and, in particular, T-Guard's effect in depleting targeted T cell and NK cell subsets as well as its impact on relevant non-target populations (B cells, monocytes and dendritic cells), will be evaluated.	Baseline and Days 0, 2, 4, 6, 14, 28, 56, 180
Acute GVHD Biomarkers	Serum ST2 and Regenerating Family Member 3 Alpha (REG3α) concentrations and urine 3- Indoxyl Sulfate (3-IS) concentrations will be used to estimate the probability of NRM at Day 180 post-assessment for each patient. The proportion of patients with high risk biomarker status (defined as estimated NRM greater than 0.29) will be described at each time point.	Baseline and Days 7, 14, 28
Patient-reported Outcomes Using a Subset of the PROMIS Measures	Describe changes in patient-reported outcomes (PROs) using a subset of the PROMIS measures from baseline to Days 28, 56, and 180 post initiation of T- Guard therapy	Baseline and Days 28, 56, 180

Collaborators and Investigators

• Sponsor: Xenikos
• Collaborators: National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); National Marrow Donor Program; Blood and Marrow Transplant Clinical Trials Network
• Investigators: Study Chair: John Levine, MD, Icahn School of Medicine at Mount Sinai; Study Chair: Gabrielle Meyers, MD, Oregon Health and Science University

Publications and helpful links

General Publications

• Meyers G, Hamadani M, Martens M, Ali H, Choe H, Dawson P, Harris AC, van Hooren E, Klaassen W, Leifer E, MacMillan ML, van Oosterhout Y, Perez L, Pusic I, Vo P, Levine JE. Lessons learned from early closure of a clinical trial for steroid-refractory acute GVHD. Bone Marrow Transplant. 2022 Feb;57(2):302-303. doi: 10.1038/s41409-021-01529-x. Epub 2021 Nov 23.

Helpful Links

• Blood and Marrow Transplant Clinical Trials Network Website

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2019
• Primary Completion (Actual): February 17, 2020
• Study Completion (Actual): February 17, 2020

Study Registration Dates

• First Submitted: September 27, 2019
• First Submitted That Met QC Criteria: October 14, 2019
• First Posted (Actual): October 16, 2019

Study Record Updates

• Last Update Posted (Actual): December 16, 2021
• Last Update Submitted That Met QC Criteria: December 7, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Steroid-refractory acute GVHD; Acute GVHD; GVHD treatment
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease
• Other Study ID Numbers: BMTCTN1802; 2U10HL069294-11 (U.S. NIH Grant/Contract); 5U24HL138660 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No