Steroid-Refractory Acute Graft Versus Host Disease
Conditions
Keywords
Steroid-refractory acute GVHD, Acute GVHD, GVHD 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.
Interventions
DRUGT-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).
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Xenikos
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A single group of patients will receive T-Guard for treatment of steroid-refractory acute GVHD.
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Non-Relapse Mortality (NRM) | Days 100 and 180 | Estimate the cumulative incidence of non-relapse mortality (NRM) at Days 100 and 180. |
| 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 |
| 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 - 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 - 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 |
| 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 |
| 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 |
| Duration of Complete Response (DoCR) | Through Day 180 | Evaluate the duration of complete response (DoCR) Early Trial Closure. |
| 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. |
| Relapse-free Survival | Days 180 | Estimate relapse-free survival at Day 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Discontinuation of Systemic Steroids | Day 180 | Describe discontinuation of systemic steroids by Day 180 post initiation of T-Guard therapy |
| Incidence of CMV Reactivation | Day 180 | Estimate the incidence of CMV reactivation requiring therapy by Day 180 post initiation of T-Guard Therapy |
| Incidence of EBV-associated Lymphoproliferative Disorder or EBV Reactivation | Day 180 | 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 |
| Incidence of IMP-related SAEs | Through Day 180 | Describe the incidence of Investigational Medicinal Product (IMP) related SAEs |
| T-cell Subsets and NK Cells | Baseline and Days 0, 2, 4, 6, 14, 28, 56, 180 | 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. |
| Acute GVHD Biomarkers | Baseline and Days 7, 14, 28 | 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. |
| Patient-reported Outcomes Using a Subset of the PROMIS Measures | Baseline and Days 28, 56, 180 | 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 |
| Corticosteroid Dose | Baseline, Days 28 and 56 | Corticosteroid-dose (measured in prednisone-equivalent) at baseline, Days 28 and 56 post initiation of T- Guard therapy. |
| Rate of Near-CR | Days 28 and 56 | 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 |
Countries
United States
Participant flow
Recruitment details
Participants from 2 transplant centers willing to participate signed an Institutional Review Board approved Informed Consent Form and had eligibility for enrollment evaluated. If a participant's eligibility was confirmed they were enrolled into the study. The first participant was enrolled in December 2019, and the last participant was enrolled in January 2020.
Participants by arm
| Arm | Count |
|---|---|
| T-Guard Treatment Patients will receive T-Guard for treatment of steroid-refractory acute GVHD.
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). | 3 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 3 |
Baseline characteristics
| Characteristic | T-Guard Treatment |
|---|---|
| Age, Continuous | 36.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 3 |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 3 / 3 |
Outcome results
Primary
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.
Time frame: Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T-Guard Treatment | Complete Response (CR) | 0 Participants |
Secondary
Cumulative Incidence of Chronic GVHD
Estimate the cumulative incidence of chronic GVHD (cGVHD) at Day 180
Time frame: Day 180
Population: Study stopped as safety stopping guideline was met.
Secondary
Cumulative Incidence of Disease Relapse/Progression
Estimate the cumulative incidence of disease relapse/progression at Day 180
Time frame: Day 180
Population: Study stopped as safety stopping guideline was met.
Secondary
Duration of Complete Response (DoCR)
Evaluate the duration of complete response (DoCR) Early Trial Closure.
Time frame: Through Day 180
Population: Study stopped as safety stopping guideline was met.
Secondary
GVHD-free Survival
Estimate GVHD-free survival at Days 90 and 180
Time frame: Days 90 and 180
Population: Study stopped as safety stopping guideline was met.
Secondary
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
Time frame: Baseline, Days 7, 14, 28, 90, and 180
Population: Study stopped as safety stopping guideline was met.
Secondary
Incidence of Systemic Infections
Describe the incidence of systemic infections
Time frame: initiation of T-Guard to 28 days post-last dose
Population: Study stopped as safety stopping guideline was met.
Secondary
Incidence of Toxicities
Describe the incidence of CTCAE v5 Grade 3-5 toxicities
Time frame: initiation of T-Guard to 28 days post-last dose
Population: Study stopped as safety stopping guideline was met.
Secondary
Non-Relapse Mortality (NRM)
Estimate the cumulative incidence of non-relapse mortality (NRM) at Days 100 and 180.
Time frame: Days 100 and 180
Population: Study stopped as safety stopping guideline was met.
Secondary
Overall Response Rate (CR or Partial Response (PR))
Estimate the overall response rate (CR or partial response (PR)) at Days 14, 28, and 56.
Time frame: Days 14, 28, and 56
Population: Study stopped as safety stopping guideline was met.
Secondary
Overall Survival (OS)
Estimate the overall survival (OS) at Day 30.
Time frame: Day 30
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T-Guard Treatment | Overall Survival (OS) | 3 Participants |
Secondary
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
Time frame: 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)
Population: Study stopped as safety stopping guideline was met.
Secondary
Pharmacokinetics of T-Guard - Cinf
Observed and model-predicted concentration of T-Guard at the end of infusion
Time frame: 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)
Population: Study stopped as safety stopping guideline was met.
Secondary
Pharmacokinetics of T-Guard - CL
Systemic clearance of T-Guard
Time frame: 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)
Population: Study stopped as safety stopping guideline was met.
Secondary
Pharmacokinetics of T-Guard - t1/2
Model-predicted terminal half-life of T-Guard
Time frame: 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)
Population: Study stopped as safety stopping guideline was met.
Secondary
Pharmacokinetics of T-Guard - Vc
Volume of the central compartment
Time frame: 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)
Population: Study stopped as safety stopping guideline was met.
Secondary
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.
Time frame: Days 7, 14, 28, and 56
Population: Study stopped as safety stopping guideline was met.
Secondary
Relapse-free Survival
Estimate relapse-free survival at Day 180.
Time frame: Days 180
Population: Study stopped as safety stopping guideline was met.
Other Pre-specified
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.
Time frame: Baseline and Days 7, 14, 28
Population: Study stopped as safety stopping guideline was met.
Other Pre-specified
Corticosteroid Dose
Corticosteroid-dose (measured in prednisone-equivalent) at baseline, Days 28 and 56 post initiation of T- Guard therapy.
Time frame: Baseline, Days 28 and 56
Population: Study stopped as safety stopping guideline was met.
Other Pre-specified
Discontinuation of Systemic Steroids
Describe discontinuation of systemic steroids by Day 180 post initiation of T-Guard therapy
Time frame: Day 180
Population: Study stopped as safety stopping guideline was met.
Other Pre-specified
Incidence of CMV Reactivation
Estimate the incidence of CMV reactivation requiring therapy by Day 180 post initiation of T-Guard Therapy
Time frame: Day 180
Population: Study stopped as safety stopping guideline was met.
Other Pre-specified
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
Time frame: Day 180
Population: Study stopped as safety stopping guideline was met.
Other Pre-specified
Incidence of IMP-related SAEs
Describe the incidence of Investigational Medicinal Product (IMP) related SAEs
Time frame: Through Day 180
Population: Study stopped as safety stopping guideline was met.
Other Pre-specified
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
Time frame: Baseline and Days 28, 56, 180
Population: Study stopped as safety stopping guideline was met.
Other Pre-specified
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
Time frame: Days 28 and 56
Population: Study stopped as safety stopping guideline was met.
Other Pre-specified
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.
Time frame: Baseline and Days 0, 2, 4, 6, 14, 28, 56, 180
Population: Study stopped as safety stopping guideline was met.