| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Grade III or IV Steroid-Refractory Acute Graft-Versus-Host Disease (SR-aGVHD) |
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| E.1.1.1 | Medical condition in easily understood language |
| Acute Graft-versus-Host Disease that does not adequately respond on the regular treatment with corticosteroids. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068908 |
| E.1.2 | Term | AGVHD |
| E.1.2 | System Organ Class | 100000004870 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the rate of complete response (CR) in Grades III and IV SR-aGVHD participants on Day 28 post-randomization. |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives are the following:
1. Estimate the overall survival (OS) at Days 60, 90, and 180.
2. Evaluate the duration of complete response (DoCR).
3. Estimate the time to complete response (CR) from randomization.
4. Estimate the overall response rate (CR or partial response (PR)) at Days 14, 28, and 56.
5. Describe proportions of CR, PR, mixed response (MR), no response (NR), and progression of aGVHD at Days 6, 14, 28, and 56.
6. Estimate the cumulative incidence of non-relapse mortality (NRM) at Days 90 and 180.
7. Estimate relapse-free survival at Day 180.
8. Estimate GVHD-free survival at Days 90 and 180.
9. Estimate the cumulative incidence of chronic GVHD (cGVHD) at Day 180.
10. Estimate the cumulative incidence of underlying disease relapse/progression at Day 180.
11. Describe the incidence of infections.
12. Describe the incidence of toxicities.
13. Assess the pharmacokinetics (PK) of T-Guard.
14. Assess the immunogenicity of T-Guard.
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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.
3. Patients diagnosed with Grade III or 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
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 to provide verbal consent but not capable to sign the informed consent) should have given written informed consent.
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| E.4 | Principal 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 Thrombotic Microangiopathy (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, AND
• 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
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 acute GVHD) 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 monoclonal antibodies (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.
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 or everolimus must have it discontinued prior to starting study treatment.
21. Female patients who are pregnant, breast feeding, or, if sexually active and of childbearing potential (for definition refer to Appendix H), unwilling to use effective birth control (for definition refer to Appendix H) from start of treatment until 30 days after the last treatment dose.
22. Male patients who are, if sexually active and with a female partner of childbearing potential (for definition refer to Appendix H), unwilling to use effective birth control (for definition refer to Appendix H) from start of treatment until 65 days after the last treatment dose.
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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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the proportion of participants with a CR on Day 28 after randomization. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Overall Survival (OS) will be assessed at Days 60, 90 and 180 post-randomization.
Duration of Complete Response (DoCR): DoCR is defined as the time from Day 28 until an aGVHD target organ worsens by at least 1 stage and requires a significant escalation in treatment (defined below), or death.
Time to Complete Response: The time from randomization to first observation of CR will be evaluated.
Overall Response Rate (ORR): The ORR will be estimated at Days 14, 28, and 56 post-randomization.
Proportion of Response: Days 6, 14, 28 and 56 post-randomization.
Non-relapse Mortality (NRM): Days 90 and 180 post-randomization.
Relapse-free Survival (RFS): Day 180 post-randomization.
GVHD-free Survival: Days 90 and 180 post-randomization.
Chronic GVHD (cGVHD): Day 180 post-randomization
Relapse/Progression of Underlying Malignancy: Day 180 post-randomization
Incidence of Infections: from randomization to 90 days post-randomization
Incidence of Toxicities: from randomization to Day 56 post- randomization
Pharmacokinetics of T-Guard: before each infusion and at the following post-infusion timepoints: 4, 5, 6, 8, and 24 hours for the first infusion, 4, 6, and 24 hours for the second and third infusions, and 4, 6, 24 and 48 hours for the fourth infusion.
Immunogenicity of T-Guard: baseline and at Days 6, 14, 28, 90, and 180 after initiation of treatment in T-Guard treated participants only
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints are defined under E.5.2
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Croatia |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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