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T-Guard as Treatment for Steroid Refractory Acute GVHD (1802)

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ClinicalTrials.gov Identifier: NCT04128319
Recruitment Status : Not yet recruiting
First Posted : October 16, 2019
Last Update Posted : October 16, 2019
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Information provided by (Responsible Party):
Xenikos

Brief Summary:
The study is designed as an open-label, single arm Phase III, multicenter trial to evaluate the efficacy and safety of T-Guard treatment in patients with Steroid-Refractory acute Graft versus Host Disease (SR-aGVHD).

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

Detailed Description:
Allogeneic Hematopoietic Cell Transplantation (allo-HSCT) is a potent immunotherapy with curative potential for several hematological disorders. Improvements in survival following allo-HSCT have led to its increasing use, but the leading cause of non-relapse mortality (NRM) remains graft-versus-host-disease (GVHD. Despite recent advances in the understanding of transplantation immune tolerance, aGVHD is a frequent and major complication of allo-HSCT involving activation of donor T-lymphocytes, which ultimately causes host tissue damage. T-Guard has a rapid onset, preferential killing of activated T cells, and short half-life, leading to depletion of allo-reactive T cells and quick post-treatment reconstitution of the immune system.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 47 participants
Intervention Model: Single Group Assignment
Intervention Model Description: A single group of patients will receive T-Guard for treatment of steroid-refractory acute GVHD.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Single-Arm, Multicenter Study, of Combination Anti-CD3/CD7 Immunotoxin (T-Guard) for Steroid-Refractory Acute Graft-versus-Host Disease.
Estimated Study Start Date : October 2019
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : September 2021


Arm Intervention/treatment
Experimental: T-Guard Treatment
Patients will receive T-Guard for treatment of steroid-refractory acute GVHD.
Drug: T-Guard
Patients will receive 4 doses of T-Guard treatment, administered intravenously as four 4-hour infusions at least two calendar days apart. Each dose consists of 4 mg/m2 Body Surface Area (BSA).




Primary Outcome Measures :
  1. Complete Response (CR) [ Time Frame: Day 28 ]
    To assess the rate of Day 28 complete response (CR) in SR-aGVHD patients treated with T-Guard therapy.


Secondary Outcome Measures :
  1. Duration of Complete Response (DoCR) [ Time Frame: Through Day 180 ]
    Evaluate the duration of complete response (DoCR)

  2. Overall Survival (OS) [ Time Frame: Days 90 and 180 ]
    Estimate the overall survival (OS) at Days 90 and 180.

  3. Overall response rate (CR or partial response (PR)) [ Time Frame: Days 14, 28, and 56 ]
    Estimate the overall response rate (CR or partial response (PR)) at Days 14, 28, and 56.

  4. Proportions of CR, PR, mixed response (MR), no response (NR) and progression [ Time Frame: Days 7, 14, 28, and 56 ]
    Describe proportions of CR, PR, mixed response (MR), no response (NR), and progression of aGVHD at Days 7, 14, 28, and 56.

  5. Non-Relapse Mortality (NRM) [ Time Frame: Days 100 and 180 ]
    Estimate the cumulative incidence of non-relapse mortality (NRM) at Days 100 and 180.

  6. Relapse-free survival [ Time Frame: Days 180 ]
    Estimate relapse-free survival at Day 180.

  7. GVHD-free survival [ Time Frame: Days 90 and 180 ]
    Estimate GVHD-free survival at Days 90 and 180

  8. Event-free survival [ Time Frame: Day 180 ]
    Estimate event-free survival (EFS) at Day 180

  9. Cumulative incidence of chronic GVHD [ Time Frame: Day 180 ]
    Estimate the cumulative incidence of chronic GVHD (cGVHD) at Day 180

  10. Cumulative incidence of disease relapse/progression [ Time Frame: Day 180 ]
    Estimate the cumulative incidence of disease relapse/progression at Day 180

  11. Incidence of systemic infections [ Time Frame: initiation of T-Guard to 28 days post-last dose ]
    Describe the incidence of systemic infections

  12. Incidence of toxicities [ Time Frame: initiation of T-Guard to 28 days post-last dose ]
    Describe the incidence of CTCAE v5 Grade 3-5 toxicities

  13. Pharmacokinetics of T-Guard - Cinf [ Time Frame: Before each infusion & at the following post-infusion timepoints: 4, 5, 6, 8 & 24 hours for the 1st infusion; 4, 6 & 24 hours for the 2nd & 3rd infusions; 4, 6, 24 & 48 hours for the 4th infusion (infusions occur within the time frame of Day 0 to Day 14) ]
    Observed and model-predicted concentration of T-Guard at the end of infusion

  14. Pharmacokinetics of T-Guard - CL [ Time Frame: Before each infusion & at the following post-infusion timepoints: 4, 5, 6, 8 & 24 hours for the 1st infusion; 4, 6 & 24 hours for the 2nd & 3rd infusions; 4, 6, 24 & 48 hours for the 4th infusion (infusions occur within the time frame of Day 0 to Day 14) ]
    Systemic clearance of T-Guard

  15. Pharmacokinetics of T-Guard - AUC [ Time Frame: Before each infusion & at the following post-infusion timepoints: 4, 5, 6, 8 & 24 hours for the 1st infusion; 4, 6 & 24 hours for the 2nd & 3rd infusions; 4, 6, 24 & 48 hours for the 4th infusion (infusions occur within the time frame of Day 0 to Day 14) ]
    Model-predicted area under the curve from the start of the current infusion until the next infusion or until 48 hours following for the last infusion

  16. Pharmacokinetics of T-Guard - t1/2 [ Time Frame: Before each infusion & at the following post-infusion timepoints: 4, 5, 6, 8 & 24 hours for the 1st infusion; 4, 6 & 24 hours for the 2nd & 3rd infusions; 4, 6, 24 & 48 hours for the 4th infusion (infusions occur within the time frame of Day 0 to Day 14) ]
    Model-predicted terminal half-life of T-Guard

  17. Pharmacokinetics of T-Guard - Vc [ Time Frame: Before each infusion & at the following post-infusion timepoints: 4, 5, 6, 8 & 24 hours for the 1st infusion; 4, 6 & 24 hours for the 2nd & 3rd infusions; 4, 6, 24 & 48 hours for the 4th infusion (infusions occur within the time frame of Day 0 to Day 14) ]
    Volume of the central compartment

  18. Immunogenicity [ Time Frame: Baseline, Days 7, 14, 28, 90, and 180 ]
    Assess the immunogenicity of T-Guard via ADA responses in the form of human anti-SPV-T3a-RTA and anti-WT1-RTA -antibodies evaluated in serum samples


Other Outcome Measures:
  1. Corticosteroid dose [ Time Frame: Baseline, Days 28 and 56 ]
    Corticosteroid-dose (measured in prednisone-equivalent) at baseline, Days 28 and 56 post initiation of T- Guard therapy.

  2. Rate of near-CR [ Time Frame: Days 28 and 56 ]
    Estimate the rate of near-CR (i.e. CR in GI and Liver with only Stage 1 Skin) at Days 28 and 56 post initiation of T- Guard therapy

  3. Discontinuation of systemic steroids [ Time Frame: Day 180 ]
    Describe discontinuation of systemic steroids by Day 180 post initiation of T-Guard therapy

  4. Incidence of CMV reactivation [ Time Frame: Day 180 ]
    Estimate the incidence of CMV reactivation requiring therapy by Day 180 post initiation of T-Guard Therapy

  5. Incidence of EBV-associated lymphoproliferative disorder or EBV reactivation [ Time Frame: Day 180 ]
    Estimate the incidence of Epstein-Barr Virus (EBV)- associate lymphoproliferative disorder or EBV reactivation requiring therapy with rituximab by Day 180 post initiation of T-Guard therapy

  6. Incidence of IMP-related SAEs [ Time Frame: Through Day 180 ]
    Describe the incidence of Investigational Medicinal Product (IMP) related SAEs

  7. T-cell subsets and NK cells [ Time Frame: Baseline and Days 0, 2, 4, 6, 14, 28, 56, 180 ]
    The evolution of specific cell populations over the 180 day follow-up period and, in particular, T-Guard's effect in depleting targeted T cell and NK cell subsets as well as its impact on relevant non-target populations (B cells, monocytes and dendritic cells), will be evaluated.

  8. Acute GVHD biomarkers [ Time Frame: Baseline and Days 7, 14, 28 ]
    Serum ST2 and Regenerating Family Member 3 Alpha (REG3α) concentrations and urine 3- Indoxyl Sulfate (3-IS) concentrations will be used to estimate the probability of NRM at Day 180 post-assessment for each patient. The proportion of patients with high risk biomarker status (defined as estimated NRM greater than 0.29) will be described at each time point.

  9. Patient-reported outcomes using a subset of the PROMIS measures [ Time Frame: Baseline and Days 28, 56, 180 ]
    Describe changes in patient-reported outcomes (PROs) using a subset of the PROMIS measures from baseline to Days 28, 56, and 180 post initiation of T- Guard therapy



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patient must be at least 12 years of age at the time of consent.
  2. Patient has undergone first allo-HSCT from any donor source using bone marrow, peripheral blood stem cells, or cord blood. Recipients of nonmyeloablative, reduced intensity, and myeloablative conditioning regimens are eligible.
  3. Patients diagnosed with SR-aGVHD after allo-HSCT. SR is defined as aGVHD that:

    • Progressed after 3 days of primary treatment with prednisone (or equivalent) of greater than or equal to 2mg/kg/day
    • No improvement after 7 days of primary treatment with prednisone (or equivalent) of greater than or equal to 2mg/kg/day.
    • Patients with visceral (GI and/or liver) plus skin aGVHD at prednisone (or equivalent) initiation with improvement in skin GVHD without any improvement in visceral GVHD after 7 days of primary treatment with prednisone (or equivalent) of greater than or equal to 2mg/kg/day
    • Previously was treated with prednisone (or equivalent) of greater than or equal to 1mg/kg/day and aGVHD has developed in a previously uninvolved organ system Progression and no improvement are defined in the protocol. Improvement or progression in organs is determined by comparing current organ staging to staging at initiation of prednisone (or equivalent) treatment. Staging is performed per MAGIC criteria.
  4. 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. For patients less than 18 years of age, a written informed consent of the parents or guardian and written assent of the patient will be obtained, per the local requirements.

Exclusion Criteria:

  1. Patients who have been diagnosed with overlap syndrome, that is, with any concurrent features of cGVHD.
  2. Patients requiring any of the following: mechanical ventilation, vasopressor support, or hemodialysis.
  3. Patients who have received any systemic treatment, besides steroids, as upfront treatment of aGVHD OR as treatment for SR-aGVHD.
  4. Patients who have severe hypoalbuminemia, with an albumin of less than or equal to 1 g/dl.
  5. Patients who have a CK level of greater than 5 times the upper limit of normal.
  6. 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. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
  7. Patients with evidence of relapsed, progressing or persistent malignancy.
  8. Patients with evidence of minimal residual disease requiring withdrawal of systemic immune suppression
  9. Patients with known hypersensitivity to any of the components murine monoclonal antibodies (mAb) or Recombinant Ricin Toxin A-chain (RTA).
  10. Patients who have received more than one allo-HSCT.
  11. Patients with known human immunodeficiency virus infection.
  12. 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 infusion of T-Guard.
  13. 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 infusion of T-Guard.
  14. 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.
  15. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04128319


Contacts
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Contact: Alyssa Ramirez 301-251-1161 ext 12744 aramirez@emmes.com
Contact: Kristin Peyton kpeyton@emmes.com

  Show 21 Study Locations
Sponsors and Collaborators
Xenikos
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Investigators
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Principal Investigator: Peter Dawson, PhD The Emmes Company, LLC
Study Chair: John Levine, MD Icahn School of Medicine at Mount Sinai
Study Chair: Gabrielle Meyers, MD Oregon Health and Science University
Study Director: Mary Horowitz, MD, MS Center for International Blood and Marrow Transplant Research

Additional Information:
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Responsible Party: Xenikos
ClinicalTrials.gov Identifier: NCT04128319     History of Changes
Other Study ID Numbers: BMT CTN 1802
2U10HL069294-11 ( U.S. NIH Grant/Contract )
First Posted: October 16, 2019    Key Record Dates
Last Update Posted: October 16, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Xenikos:
Steroid-refractory acute GVHD
Acute GVHD
GVHD treatment
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases