A Study to Compare T-Guard vs Ruxolitinib for Treatment of Steroid-Refractory Acute Graft-vs-Host Disease (BMT CTN 2002)

Study Overview
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Brief Summary
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This is an open-label, randomized, Phase 3, multicenter trial, which has been designed to compare the efficacy and safety of T-Guard to ruxolitinib in patients with Grade III or IV Steroid-Refractory acute Graft-Versus-Host Disease (SR-aGVHD). The primary hypothesis is that T-Guard treatment will improve the Day 28 complete response (CR) rate in patients with Grades III and IV SR-aGVHD compared to ruxolitinib.

Detailed Description
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Graft-vs-Host Disease (GVHD) is a complication that affects many hematopoietic stem cell transplant (HSCT) patients; it occurs when the new cells from a transplant attack the recipient's body. Acute GVHD (aGVHD) typically develops within the first three months after HSCT and is typically treated with steroid therapy. A significant fraction of the aGVHD population (10-50%) fail to respond to treatment and are deemed steroid-refractory (SR). Participants that develop Grade III or IV SR aGVHD will be randomized to receive T-Guard or ruxolitinib and will be followed for approximately 180 days. Participants will be stratified by center region (US vs. Europe) and age group (at least 55 years vs. under 55). Participants randomized to the T-Guard arm will receive 4 doses administered intravenously as four 4-hour infusions, and participants randomized to the ruxolitinib arm will receive one dose administered orally twice a day. The primary analysis will include all participants that are randomized.

Official Title
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A Phase 3, Randomized, Open-Label, Multicenter Study, to Compare T-Guard to Ruxolitinib for the Treatment of Patients With Grade III or IV Steroid-Refractory Acute Graft-Versus-Host Disease (SR-aGVHD) (BMT CTN 2002)

Conditions
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Steroid-Refractory Acute Graft Versus Host Disease

Intervention / Treatment
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* Drug: T-Guard
* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible to participate in this study, patients must meet the following: Patients must be at least 18.0 years of age at the time of consent. Patient has undergone first allo-HSCT from any donor source or graft source. Recipients of nonmyeloablative, reduced intensity, and myeloablative conditioning regimens are eligible. Patients diagnosed with Grade III/IV SR-aGVHD after allo-HSCT. SR includes aGVHD initially treated at a lower steroid dose, but must meet one of the following criteria: Progressed or new organ involvement after 3 days of treatment with methylprednisolone (or equivalent) of greater than or equal to 2 mg/kg/day No improvement after 7 days of primary treatment with methylprednisolone (or equivalent) of greater than or equal to 2mg/kg/day Patients with visceral (GI and/or liver) plus skin aGVHD at methylprednisolone (or equivalent) initiation with improvement in skin GVHD without any improvement in visceral GVHD after 7 days of primary treatment with methylprednisolone (or equivalent) of greater than or equal to 2mg/kg/day Patients who have skin GVHD alone and develop visceral aGVHD during treatment with methylprednisolone (or equivalent) of greater than or equal to 1mg/kg/day and do not improve after 3 days of greater than or equal to 2mg/kg/day Improvement or progression in organs is determined by comparing current organ staging to staging at initiation of methylprednisolone (or equivalent) treatment. Patients must have evidence of myeloid engraftment (e.g., absolute neutrophil count greater than or equal to 0.5 × 109/L for 3 consecutive days if ablative therapy was previously used). Use of growth factor supplementation is allowed. 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. Exclusion Criteria: Patients will be excluded from study entry if they meet any of the following exclusion criteria: Patients who have a creatinine greater than or equal to 2mg/dL or estimated creatinine clearance less than 40 mL/min or those requiring hemodialysis. Patients who have been diagnosed with active TMA, defined as meeting all the following criteria: Greater than 4% schistocytes in blood (or equivalent if semiquantitative scale is used e.g., 3+ or 4+ schistocytes on peripheral blood smear) De novo, prolonged or progressive thrombocytopenia (platelet count less than 50 x 109/L or 50% or greater reduction from previous counts) Sudden and persistent increase in lactate dehydrogenase concentration greater than 2x ULN Decrease in hemoglobin concentration or increased transfusion requirement attributed to Coombs-negative hemolysis Decrease in serum haptoglobin Patients who have previously received treatment with eculizumab. Patients who have previously received checkpoint inhibitors (either before or after allo-HCT). Patients who have been diagnosed with overlap syndrome, that is, with any concurrent features of cGVHD. Patients requiring mechanical ventilation or vasopressor support. Patients who have received any systemic treatment, besides steroids, as upfront treatment of aGVHD or as treatment for SR-aGVHD. Reinstitution of previously used GVHD prophylaxis agents (e.g., tacrolimus, cyclosporin, MTX, MMF) or substitutes in cases with previously documented intolerance will be permitted. Previous treatment with a JAK inhibitor as part of GVHD prophylaxis or treatment is not allowed. Patients who have severe hypoalbuminemia, with an albumin of less than or equal to 1 g/dl. Patients who have a creatine kinase (CK) level of greater than 5 times the upper limit of normal. 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. Persisting fever without other signs or symptoms will not be interpreted as progressing infection. Progression of infection is defined as: hemodynamic instability attributable to sepsis OR new symptoms attributable to infection OR worsening physical signs attributable to infection OR worsening radiographic findings attributable to infection Patients with radiographic findings attributable to infection within 4 weeks prior to enrollment must have a repeat radiographic exam within one week of enrollment that documents absence of worsening. Patients with evidence of relapsed, progressing, or persistent malignancy, or who have been treated for relapse after transplant, or who may require rapid immune suppression withdrawal as pre-emergent treatment of early malignancy relapse. Patients with evidence of minimal residual disease requiring withdrawal of systemic immune suppression. Patients with unresolved serious toxicity or complications (other than aGVHD) due to previous transplant. History of sinusoidal obstruction syndrome (SOS)/veno-occlusive disease (VOD). Patients with known hypersensitivity to any of the components murine mAb or Recombinant Ricin Toxin A-chain (RTA). Patients who have had treatment with any other investigational agent, device, or procedure within 21 days (or 5 half-lives, whichever is greater) prior to enrollment. An investigational agent is defined as medications without any known FDA or EMA approved indications. Patients who have received more than one allo-HSCT. Patients with known human immunodeficiency virus infection. Patients who have a BMI greater than or equal to 35 kg/m2. Patients who are taking sirolimus must discontinue prior to starting study treatment. The sirolimus blood level must be less than 2 ng/mL prior to starting study treatment. 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 study treatment. 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 study treatment. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized at a ratio of 1:1 between the treatment arms
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: T-Guard<br>Participants will be administered four doses of T-Guard intravenously for a 4-hour period every other day | Drug: T-Guard<br>* T-Guard will be administered intravenously inpatient over 4 hours every 2 calendar days on Days 0, 2, 4, and 6, at a dose of 4mg/m2 Body Surface Area (BSA).<br>|
| Active Comparator: Ruxolitinib<br>Participants will take ruxolitinib twice daily for continuous daily dosing | Drug: Ruxolitinib<br>* Ruxolitinib will be administered orally twice a day starting on Day 0 through Day 56, at a dose of 10mg. Ruxolitinib taper can be initiated starting on Day 56 for participants responding to treatment, tapering will be done according to institutional practices.<br>* Other names: Jakavi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) | The primary objective of this trial is to assess the rate of CR on Day 28 post-randomization in Grades III and IV SR-aGVHD patients treated with T-Guard treatment in comparison to ruxolitinib. | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as survival of death from any cause. The time from randomization until death from any cause will be described for each arm. | Days 60, 90, and 180 | 
| Duration of Complete Response (DoCR) | DoCR will be evaluated only in the set of participants who are in CR at Day 28 post-randomization. The primary definition of DoCR is the time from Day 28 until an aGVHD target organ worsens by at least 1 stage and requires a significant escalation in treatment, or death. | Day 28 | 
| Time to Complete Response (CR) | The time from randomization until first attaining a CR will be described for each treatment arm, with death and additional systemic treatment for aGVHD treated as competing risks. | Days 28 and 56 | 
| Overall Response Rate (ORR) | Overall response is defined as either a complete or partial response (CR+PR). The ORR will be estimated for each treatment arm. | Days 14, 28, and 56 | 
| Proportion of Response | The proportion of participants in each aGVHD response category will be described for each treatment arm. | Days 6, 14, 28, and 56 | 
| Non-relapse Mortality (NRM) | NRM is defined as death from any cause other than malignancy relapse/progression. The time from randomization until NRM will be described for each treatment arm. | Days 90 and 180 | 
| Relapse-free Survival (RFS) | RFS is defined as being alive and free of malignancy relapse/progression. The time from randomization until malignancy relapse/progression or death will be described for each arm. | Day 180 | 
| GVHD-free Survival | GVHD-free survival is defined as being alive, in CR, and free of cGVHD. The proportion of participants with GVHD-free survival post-randomization will be estimated for each treatment arm. | Days 90 and 180 | 
| Chronic GVHD (cGVHD) | The maximum severity of cGVHD post-randomization will be tabulated by arm. The time from randomization until onset of cGVHD of any severity (mild, moderate, or severe) will be described for each treatment arm. | Day 180 | 
| Relapse/Progression of Underlying Malignancy | The time from randomization until malignancy relapse/progression will be described for each treatment arm, with death prior to relapse/progression treated as a competing risk. | Day 180 | 
| Incidence of Infections | The frequency of Grade 2-3 infections occurring after randomization will be tabulated by infection site, date of onset, and severity. The cumulative incidence of Grade 2-3 infections will be described by treatment arm. | Day 90 | 
| Incidence of Toxicities | The frequency of Grade 3-5 toxicities per CTCAE version 5 occurring after randomization will be tabulated by organ system for each treatment arm. The maximum severity of reported toxicities during that period will also be summarized. | Day 56 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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T-Guard, Ruxolitinib, Steroid-Refractory, GVHD, Acute GVHD, aGVHD, Grade III, Grade IV, Complete Response (CR), Transplant, Hematopoietic Stem Cell Transplant (HSCT)