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

Sponsor

Xenikos (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04934670

Collaborator

National Heart, Lung, and Blood Institute (NHLBI) (NIH), Blood and Marrow Transplant Clinical Trials Network (Other), National Cancer Institute (NCI) (NIH), National Marrow Donor Program (Other)

246

Enrollment

Locations

Arms

47.5

Anticipated Duration (Months)

4.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Steroid-Refractory Acute Graft Versus Host Disease	Drug: T-Guard Drug: Ruxolitinib	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

246 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Participants will be randomized at a ratio of 1:1 between the treatment armsParticipants will be randomized at a ratio of 1:1 between the treatment arms

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Actual Study Start Date :

Jun 16, 2022

Anticipated Primary Completion Date :

Jun 1, 2025

Anticipated Study Completion Date :

Jun 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: T-Guard Participants will be administered four doses of T-Guard intravenously for a 4-hour period every other day	Drug: T-Guard 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).
Active Comparator: Ruxolitinib Participants will take ruxolitinib twice daily for continuous daily dosing	Drug: Ruxolitinib 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. Other Names: Jakafi Jakavi

Arm

Intervention/Treatment

Experimental: T-Guard

Participants will be administered four doses of T-Guard intravenously for a 4-hour period every other day

Drug: T-Guard

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).

Active Comparator: Ruxolitinib

Participants will take ruxolitinib twice daily for continuous daily dosing

Drug: Ruxolitinib

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.

Other Names:

Jakafi

Jakavi

Outcome Measures

Primary Outcome Measures

Complete Response (CR) [Day 28]
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.

Secondary Outcome Measures

Overall Survival (OS) [Days 60, 90, and 180]
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.
Duration of Complete Response (DoCR) [Day 28]
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.
Time to Complete Response (CR) [Days 28 and 56]
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.
Overall Response Rate (ORR) [Days 14, 28, and 56]
Overall response is defined as either a complete or partial response (CR+PR). The ORR will be estimated for each treatment arm.
Proportion of Response [Days 6, 14, 28, and 56]
The proportion of participants in each aGVHD response category will be described for each treatment arm.
Non-relapse Mortality (NRM) [Days 90 and 180]
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.
Relapse-free Survival (RFS) [Day 180]
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.
GVHD-free Survival [Days 90 and 180]
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.
Chronic GVHD (cGVHD) [Day 180]
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.
Relapse/Progression of Underlying Malignancy [Day 180]
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.
Incidence of Infections [Day 90]
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.
Incidence of Toxicities [Day 56]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama	Birmingham	Alabama	United States	35294
2	City of Hope National Medical Center	Duarte	California	United States	91010
3	H. Lee Moffitt Cancer Center	Tampa	Florida	United States	33612
4	Emory University	Atlanta	Georgia	United States	30322
5	Loyola University Medical Center	Maywood	Illinois	United States	60153
6	Indiana University	Indianapolis	Indiana	United States	46202
7	University of Maryland Medical Center	Baltimore	Maryland	United States	21201
8	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905
9	Washington University St. Louis	Saint Louis	Missouri	United States	63110
10	Roswell Park Cancer Institute	Buffalo	New York	United States	14203
11	Mount Sinai Medical Center	New York	New York	United States	10029
12	Duke University Medical Center	Durham	North Carolina	United States	27710
13	Wake Forest University	Winston-Salem	North Carolina	United States	27109
14	Ohio State University	Columbus	Ohio	United States	43210
15	Oregon Health & Science University	Portland	Oregon	United States	97239
16	Penn State Hershey Medical Center	Hershey	Pennsylvania	United States	17033
17	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
18	Medical University of South Carolina	Charleston	South Carolina	United States	29425
19	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
20	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
21	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
22	Baylor College of Medicine	Houston	Texas	United States	77030
23	University of Utah	Salt Lake City	Utah	United States	84112
24	University of Virginia	Charlottesville	Virginia	United States	22903
25	University of Wisconsin	Madison	Wisconsin	United States	53705
26	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
27	Site BE300	Bruxelles		Belgium
28	Site BE305	Leuven		Belgium
29	Site BE302	Liège		Belgium
30	Site BE303	Yvoir		Belgium
31	Site HR320	Zagreb		Croatia
32	Site FR341	Angers		France
33	Site FR345	Créteil		France
34	SiteFR354	Nantes		France
35	SiteFR342	Paris		France
36	SiteFR348	Paris		France
37	Site FR356	Pierre-Bénite		France
38	Site FR351	Saint-Priest-en-Jarez		France
39	Site FR352	Toulouse		France
40	Site DE367	Dresden		Germany
41	Site DE364	Essen		Germany
42	Site DE360	Leipzig		Germany
43	Site DE362	Mainz		Germany
44	Site DE361	Muenster		Germany
45	Site NL461	Groningen		Netherlands
46	Site NL460	Maastricht		Netherlands
47	Site NL463	Nijmegen		Netherlands
48	Site ES447	Barcelona		Spain
49	Site ES446	Madrid		Spain
50	Site ES451	Santander		Spain
51	Site ES452	Sevilla		Spain