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Clinical Trial 21735

Cancer Type: Malignant Hematology
Study Type: Treatment
NCT#: NCT04934670

Phase: Phase III
Principal Investigator: Perez, Lia

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Overview

Study 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)

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.

Objective

Primary Objective: To assess the rate of complete response (CR) in Grades III and IV SR-aGVHD participants on Day 28 post-randomization. Secondary Objectives: 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.

Treatments

Therapies

Chemotherapy (NOS); Therapy (NOS)

Medications

Clemastine (); Diphenhydramine (); Jakafi (Ruxolitinib); Ruxolitinib (); T-Guard (); acetaminophen ()

Inclusion Criteria

Inclusion Criteria:

  • 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: (a) Progressed or new organ involvement after 3 days of treatment with methylprednisolone (or equivalent) of greater than or equal to 2 mg/kg/day (b)No improvement after 7 days of primary treatment with methylprednisolone (or equivalent) of greater than or equal to 2mg/kg/day (c) 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 (d) 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.
  • Other criteria may apply

  • Exclusion Criteria

    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 criteria listed in protocol.
  • 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
  • Other criteria may apply

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