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Safety and Efficacy Study of T-Guard to Treat Steroid-resistant Acute GVHD

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ClinicalTrials.gov Identifier: NCT02027805
Recruitment Status : Completed
First Posted : January 6, 2014
Last Update Posted : June 6, 2017
Sponsor:
Information provided by (Responsible Party):
Xenikos

Brief Summary:
In this study, a combination of two antibodies both conjugated to a cell-killing toxin (so-called immunotoxins) will be evaluated. The antibodies are directed against T-cell antigens 'cluster of differentiation 3 antigen' (CD3) and CD7. Previous in vitro studies have demonstrated that this particular immunotoxin-combination, named T-Guard, acts synergistically in eliminating T cells with a preference for killing activated T-cells. In a subsequent clinical pilot-study, T-Guard has generated encouraging results when applied as third-line therapy for patients suffering form steroid-resistant acute Graft-versus-Host Disease (GVHD). Extensive biological and clinical responses could be noted in the absence of severe acute toxicities. Building on these results, the current study aims at evaluating the safety and efficacy of T-Guard for treating steroid-resistant GVHD when administered in an earlier phase of the disease process, i.e. as second-line instead of as third-line therapy.

Condition or disease Intervention/treatment Phase
Graft vs Host Disease Biological: T-Guard Phase 1 Phase 2

Detailed Description:

The experimental design is a bicentric non-controlled fixed-dose Phase I/II study. A total of 20 adult patients with acute steroid-resistant GVHD will be enrolled in a 12 months period. The treatment consists of a standard dose of 4 infusions T-Guard (4 mg/m2), given 48-hours apart over a 4-hour period. The intended follow-up period is 6 months.

The primary objective is to determine the efficacy of T-Guard, 4 weeks after the first infusion (Day 28), in inducing an objective clinical response in patients with acute GVHD refractory to standard first line corticosteroid therapy.

Secondary objectives are:

  • To evaluate the overall safety and efficacy of T-Guard during the first 6 months after imitation of therapy;
  • To determine the pharmacokinetic profile of T-Guard;
  • To determine the immunogenicity of T-Guard.

Exploratory objectives are:

  • To study the specificity and kinetics of the treatment-induced depletion and subsequent repopulation of lymphocyte subsets;
  • To evaluate diagnostic and predictive GVHD biomarkers relative to treatment outcomes.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Multicentric Study to Determine the Safety and Efficacy of a Combination of Anti-CD3 & Anti-CD7 Ricin A Immunotoxins (T-Guard) for the Treatment of Steroid-resistant Acute Graft-versus-Host Disease.
Actual Study Start Date : March 5, 2014
Actual Primary Completion Date : September 7, 2016
Actual Study Completion Date : November 3, 2016


Arm Intervention/treatment
Experimental: T-Guard
Four doses of T-Guard (4 mg/m2), administered at 48-hour intervals as 4 hour infusions.
Biological: T-Guard
Other Name: Combination of SPV-T3a-RTA and WT1-RTA (equal parts, w/w)




Primary Outcome Measures :
  1. Acute GVHD response rate [ Time Frame: Day 28 ]
    The acute GVHD response rate at 4 weeks after the first injection of T-Guard (Day 28), being defined as as the fraction of patients showing a complete or partial response (CR or PR)


Secondary Outcome Measures :
  1. Safety and tolerability of T-Guard [ Time Frame: During 6 months after initiation of treatment ]
    The safety and tolerability of T-Guard as assessed by evaluating Dose Limiting Toxicities (DLT's), adverse and serious adverse events reported during 6 months after initiation of treatment.

  2. Very good partial response rate [ Time Frame: Day 28 ]
    The proportion of patients achieving a very good partial response rate (VGPR) of their acute GVHD at 4 weeks after the first infusion (Day 28).

  3. Acute GVHD relapse rate [ Time Frame: During 6 months after initiation of therapy ]
  4. Incidence of chronic GVHD [ Time Frame: During 6 months after initiation of therapy ]
  5. Overall survival and progression free survival [ Time Frame: During 6 months after initiation of treatment ]
  6. Pharmacokinetic profile of T-Guard [ Time Frame: Up to Day 9 ]
    • Areas under the time-concentration curves (AUC);
    • Peak concentration (Cmax);
    • Time to peak concentration (Tmax);
    • Terminal-phase elimination half-life (t1/2);
    • Apparent Clearance (CL/F);
    • Steady-state volume of distribution (Vss/F).

  7. Anti-drug-antibodies [ Time Frame: Pre-treatment, Day 14, Day 28, Day 90, and Day 180 ]
    The occurrence and extent of humoral responses against T-Guard (anti-drug-antibodies, ADA).

  8. The occurrence of treatment-induced cytokine release [ Time Frame: Day 1, 3, 5, and 7 ]
    The occurrence of treatment-induced cytokine release, as determined by measurement of interleukin-2 (IL-2), IL-4, IL-5, IL-6, IL-8, IL-10, tumor necrosis factor-alpha (TNF-a), and interferon-gamma (IFN-g) serum levels at t = 0 (pre-dose), 1 and 4 hours after starting of each infusion.


Other Outcome Measures:
  1. Kinetics and specificity of treatment-induced T cell and natural killer cell (NK cell) depletion [ Time Frame: Up to Day 28 ]
    Determined by the flow cytometric assessment of the number of T-, B- and NK-cells during the first 4 weeks after initiation of treatment

  2. Composition and evolution of T-, B- and NK-cell compartments [ Time Frame: Pre-treatment, Day 28, Day 90, and Day 180 ]
    The flow cytometric phenotyping of lymphocyte subsets for determine the composition and evolution of the T-, B-, and NK-cells compartments at pretreatment and at 4 weeks, 3 and 6 months after the first infusion.

  3. Composition and evolution of T-cell receptor (TCR) Vbeta repertoire [ Time Frame: Pre-treatment, Day 28, Day 90, and Day 180 ]
  4. The identification and evolution of host-reactive T-cell clones [ Time Frame: Pre-treatment, Day 28, Day 90, and Day 180 ]
  5. GVHD Biomarkers [ Time Frame: Pre-treatment, Day 14, Day 28, Day 90, and Day 180 ]
    Measurement of diagnostic and predictive GVHD biomarkers relative to treatment outcomes, including citrulline, C reactive protein (CRP), elafin, IL-8, tumor necrosis factor receptor 1 (TNFR1), interleukin 2 receptor-alpha (IL-2Ralpha), hepatocyte growth factor (HGF), and Reg3alpha.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients suffering from acute GVHD which is staged Grade II-IV according to the modified Glucksberg Criteria and progressing after 3 days, or not improving after 7 days, of methylprednisolone at a dose of 2 mg/kg per day.
  • Age ≥18 years.
  • 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.

Exclusion Criteria:

  • Patients receiving concomitant investigational therapeutics for acute GVHD, including investigational agents used for GVHD prophylaxis, at the time of enrollment.
  • Patients with signs or symptoms suggestive of chronic GVHD.
  • Patients requiring mechanical ventilation, requiring vasopressor support, requiring hemodialysis, having serum creatinine > 266 µmol/l (> 3 mg/dl), or having a serum albumin level of 15 g/l or less.
  • Patients having uncontrolled bacterial, viral or fungal infections, at the discretion of the investigator, at the start of therapy.
  • Patients with current signs or symptoms of active intrapulmonary disease.
  • Patients with known hypersensitivity to any of the components of the study drug.
  • Female patients who are pregnant, breast feeding, or, if sexually active, unwilling to use effective birth control for the duration of the study.
  • Male patients who are, if sexually active, unwilling to use effective birth control for 30 days after the last infusion.
  • Patients participating in a clinical trial with another investigational product within 30 days prior to providing informed consent.
  • 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): NCT02027805


Locations
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Germany
University Hospital Münster
Münster, North Rhine-Westphalia, Germany, 48149
Netherlands
Radboudumc
Nijmegen, Gelderland, Netherlands, 6525 GA
Sponsors and Collaborators
Xenikos
Investigators
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Principal Investigator: Walter Van der Velden, MD, PhD Radboudumc, Nijmegen (Netherlands)
Principal Investigator: Matthias Stelljes, MD, PhD Unversity Hospital Münster, Münster (Germany)

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Responsible Party: Xenikos
ClinicalTrials.gov Identifier: NCT02027805     History of Changes
Other Study ID Numbers: XEN/TG-001
2013-000068-27 ( EudraCT Number )
First Posted: January 6, 2014    Key Record Dates
Last Update Posted: June 6, 2017
Last Verified: June 2017
Keywords provided by Xenikos:
Steroid-resistant
Graft vs Host Disease
Refractory acute Graft vs Host Disease
Hematopoietic Stem Cell Transplantation
Stem Cell Transplantation
Allogeneic Stem Cell Transplantation
Immune System Diseases
Antibodies, monoclonal
Immunotoxins
Immunosuppressive agents
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Immunotoxins
Immunologic Factors
Physiological Effects of Drugs