Steroid-Refractory Acute Graft Versus Host Disease Clinical Trial
— 1802Official title:
An Open-Label, Single-Arm, Multicenter Study, of Combination Anti-CD3/CD7 Immunotoxin (T-Guard) for Steroid-Refractory Acute Graft-versus-Host Disease)
| Verified date | December 2021 |
| Source | Xenikos |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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).
| 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. |
| 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 |
| 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 |
United States,
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
| 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 |
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Terminated |
NCT04934670 -
A Study to Compare T-Guard vs Ruxolitinib for Treatment of Steroid-Refractory Acute Graft-vs-Host Disease (BMT CTN 2002)
|
Phase 3 |