Clinical trial NCT04128319: T-Guard as Treatment for Steroid Refractory Acute GVHD (BMT CTN 1802)
Official title: An Open-Label, Single-Arm, Multicenter Study, of Combination Anti-CD3/CD7 Immunotoxin (T-Guard) for Steroid-Refractory Acute Graft-versus-Host Disease)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Steroid-Refractory Acute Graft Versus Host Disease
Keywords: Steroid-refractory acute GVHD
Acute GVHD
GVHD treatment
Lead sponsor: Xenikos
Sponsor class: INDUSTRY
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Blood and Marrow Transplant Clinical Trials Network
name: National Cancer Institute (NCI)
name: National Marrow Donor Program
First posted: 2019-10-16
Enrollment: 3
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: A single group of patients will receive T-Guard for treatment of steroid-refractory acute GVHD.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Complete Response (CR)
timeFrame: Day 28
Secondary outcomes:
measure: Duration of Complete Response (DoCR)
timeFrame: Through Day 180
measure: Overall Survival (OS)
timeFrame: Day 30
measure: Overall Response Rate (CR or Partial Response (PR))
timeFrame: Days 14, 28, and 56
measure: Proportions of CR, PR, Mixed Response (MR), no Response (NR) and Progression
timeFrame: Days 7, 14, 28, and 56
measure: Non-Relapse Mortality (NRM)
timeFrame: Days 100 and 180
measure: Relapse-free Survival
timeFrame: Days 180
measure: GVHD-free Survival
timeFrame: Days 90 and 180
measure: Cumulative Incidence of Chronic GVHD
timeFrame: Day 180
measure: Cumulative Incidence of Disease Relapse/Progression
timeFrame: Day 180
measure: Incidence of Systemic Infections
timeFrame: initiation of T-Guard to 28 days post-last dose
measure: Incidence of Toxicities
timeFrame: initiation of T-Guard to 28 days post-last dose
measure: Pharmacokinetics of T-Guard - Cinf
timeFrame: 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)
measure: Pharmacokinetics of T-Guard - CL
timeFrame: 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)
measure: Pharmacokinetics of T-Guard - AUC
timeFrame: 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)
measure: Pharmacokinetics of T-Guard - t1/2
timeFrame: 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)
measure: Pharmacokinetics of T-Guard - Vc
timeFrame: 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)
measure: Immunogenicity
timeFrame: Baseline, Days 7, 14, 28, 90, and 180
Other outcomes:
measure: Corticosteroid Dose
timeFrame: Baseline, Days 28 and 56
measure: Rate of Near-CR
timeFrame: Days 28 and 56
measure: Discontinuation of Systemic Steroids
timeFrame: Day 180
measure: Incidence of CMV Reactivation
timeFrame: Day 180
measure: Incidence of EBV-associated Lymphoproliferative Disorder or EBV Reactivation
timeFrame: Day 180
measure: Incidence of IMP-related SAEs
timeFrame: Through Day 180
measure: T-cell Subsets and NK Cells
timeFrame: Baseline and Days 0, 2, 4, 6, 14, 28, 56, 180
measure: Acute GVHD Biomarkers
timeFrame: Baseline and Days 7, 14, 28
measure: Patient-reported Outcomes Using a Subset of the PROMIS Measures
timeFrame: Baseline and Days 28, 56, 180
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Westwood
country: United States
facility: University of Kansas
state: Kansas
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University in St. Louis
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska
state: Nebraska
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Medical College of Wisconsin
name: Mehdi Hamadani, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Icahn School of Medicine at Mount Sinai
name: John Levine, MD
role: STUDY_CHAIR
affiliation: Oregon Health and Science University
name: Gabrielle Meyers, MD
role: STUDY_CHAIR
References:
citation: 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. No abstract available.