A Study to Compare T-Guard vs Ruxolitinib for Treatment of Steroid-Refractory Acute Graft-vs-Host Disease (BMT CTN 2002)
18 Years and older, Male and Female
BMT CTN 2002 (primary)
NCI-2021-14060
2021-000343-53
5U24HL138660-02
XEN-TG-005
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.
Objectives
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.
Eligibility
- Inclusion Criteria:
To be eligible to participate in this study, patients must meet the following:
1. Patients must be at least 18.0 years of age at the time of consent.
2. Patient has undergone first allo-HSCT from any donor source or graft source.
Recipients of nonmyeloablative, reduced intensity, and myeloablative conditioning
regimens are eligible.
3. 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.
4. 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.
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.
Exclusion Criteria:
Patients will be excluded from study entry if they meet any of the following exclusion
criteria:
1. 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.
2. 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
3. Patients who have previously received treatment with eculizumab.
4. Patients who have previously received checkpoint inhibitors (either before or after
allo-HCT).
5. Patients who have been diagnosed with overlap syndrome, that is, with any concurrent
features of cGVHD.
6. Patients requiring mechanical ventilation or vasopressor support.
7. 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.
8. Patients who have severe hypoalbuminemia, with an albumin of less than or equal to 1
g/dl.
9. Patients who have a creatine kinase (CK) level of greater than 5 times the upper
limit of normal.
10. 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.
11. 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.
12. Patients with evidence of minimal residual disease requiring withdrawal of systemic
immune suppression.
13. Patients with unresolved serious toxicity or complications (other than aGVHD) due to
previous transplant.
14. History of sinusoidal obstruction syndrome (SOS)/veno-occlusive disease (VOD).
15. Patients with known hypersensitivity to any of the components murine mAb or
Recombinant Ricin Toxin A-chain (RTA).
16. 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.
17. Patients who have received more than one allo-HSCT.
18. Patients with known human immunodeficiency virus infection.
19. Patients who have a BMI greater than or equal to 35 kg/m2.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
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