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

Steroid-Refractory Acute Graft Versus Host Disease Clinical Trial

— 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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04128319
• Other study ID #: BMTCTN1802
• Secondary ID: 2U10HL069294-115
• Status: Terminated
• Phase: Phase 3
• Start date: November 21, 2019
• Est. completion date: February 17, 2020

Study information

• Verified date: December 2021
• Source: Xenikos
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Terminated
• Enrollment: 3
• Est. completion date: February 17, 2020
• Est. primary completion date: February 17, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Graft vs Host Disease
• Steroid-Refractory Acute Graft Versus Host Disease

Intervention

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).

Locations

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

Sponsors (5)

Lead Sponsor	Collaborator
Xenikos	Blood and Marrow Transplant Clinical Trials Network, National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI), National Marrow Donor Program

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	Discontinuation of Systemic Steroids	Describe discontinuation of systemic steroids by Day 180 post initiation of T-Guard therapy	Day 180
Other	Incidence of CMV Reactivation	Estimate the incidence of CMV reactivation requiring therapy by Day 180 post initiation of T-Guard Therapy	Day 180
Other	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
Other	Incidence of IMP-related SAEs	Describe the incidence of Investigational Medicinal Product (IMP) related SAEs	Through Day 180
Other	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
Other	Acute GVHD Biomarkers	Serum ST2 and Regenerating Family Member 3 Alpha (REG3a) 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
Other	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
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.	Day 28
Secondary	Duration of Complete Response (DoCR)	Evaluate the duration of complete response (DoCR) Early Trial Closure.	Through Day 180
Secondary	Overall Survival (OS)	Estimate the overall survival (OS) at Day 30.	Day 30
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.	Days 14, 28, and 56
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.	Days 7, 14, 28, and 56
Secondary	Non-Relapse Mortality (NRM)	Estimate the cumulative incidence of non-relapse mortality (NRM) at Days 100 and 180.	Days 100 and 180
Secondary	Relapse-free Survival	Estimate relapse-free survival at Day 180.	Days 180
Secondary	GVHD-free Survival	Estimate GVHD-free survival at Days 90 and 180	Days 90 and 180
Secondary	Cumulative Incidence of Chronic GVHD	Estimate the cumulative incidence of chronic GVHD (cGVHD) at Day 180	Day 180
Secondary	Cumulative Incidence of Disease Relapse/Progression	Estimate the cumulative incidence of disease relapse/progression at Day 180	Day 180
Secondary	Incidence of Systemic Infections	Describe the incidence of systemic infections	initiation of T-Guard to 28 days post-last dose
Secondary	Incidence of Toxicities	Describe the incidence of CTCAE v5 Grade 3-5 toxicities	initiation of T-Guard to 28 days post-last dose
Secondary	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)
Secondary	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)
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	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)
Secondary	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)
Secondary	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)
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	Baseline, Days 7, 14, 28, 90, and 180

External Links

•   Blood and Marrow Transplant Clinical Trials Network Website