| 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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