Back to resultsSafety and Efficacy Study of T-Guard to Treat Steroid-resistant Acute GVHD
Primary Purpose
Graft vs Host Disease
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
T-Guard
Sponsored by
About this trial
This is an interventional treatment trial for Graft vs Host Disease focused on measuring 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
Eligibility 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.
Sites / Locations
- University Hospital Münster
- Radboudumc
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
T-Guard
Arm Description
Four doses of T-Guard (4 mg/m2), administered at 48-hour intervals as 4 hour infusions.
Outcomes
Primary Outcome Measures
Acute GVHD response rate
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
Safety and tolerability of T-Guard
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.
Very good partial response rate
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).
Acute GVHD relapse rate
Incidence of chronic GVHD
Overall survival and progression free survival
Pharmacokinetic profile of T-Guard
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).
Anti-drug-antibodies
The occurrence and extent of humoral responses against T-Guard (anti-drug-antibodies, ADA).
The occurrence of treatment-induced cytokine release
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02027805
Brief Title
Safety and Efficacy Study of T-Guard to Treat Steroid-resistant Acute GVHD
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.
Study Type
Interventional
2. Study Status
Record Verification Date
June 2017
Overall Recruitment Status
Completed
Study Start Date
March 5, 2014 (Actual)
Primary Completion Date
September 7, 2016 (Actual)
Study Completion Date
November 3, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Xenikos
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graft vs Host Disease
Keywords
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
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Actual)
8. Arms, Groups, and Interventions
Arm Title
T-Guard
Arm Type
Experimental
Arm Description
Four doses of T-Guard (4 mg/m2), administered at 48-hour intervals as 4 hour infusions.
Intervention Type
Biological
Intervention Name(s)
T-Guard
Other Intervention Name(s)
Combination of SPV-T3a-RTA and WT1-RTA (equal parts, w/w)
Primary Outcome Measure Information:
Title
Acute GVHD response rate
Description
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)
Time Frame
Day 28
Secondary Outcome Measure Information:
Title
Safety and tolerability of T-Guard
Description
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.
Time Frame
During 6 months after initiation of treatment
Title
Very good partial response rate
Description
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).
Time Frame
Day 28
Title
Acute GVHD relapse rate
Time Frame
During 6 months after initiation of therapy
Title
Incidence of chronic GVHD
Time Frame
During 6 months after initiation of therapy
Title
Overall survival and progression free survival
Time Frame
During 6 months after initiation of treatment
Title
Pharmacokinetic profile of T-Guard
Description
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).
Time Frame
Up to Day 9
Title
Anti-drug-antibodies
Description
The occurrence and extent of humoral responses against T-Guard (anti-drug-antibodies, ADA).
Time Frame
Pre-treatment, Day 14, Day 28, Day 90, and Day 180
Title
The occurrence of treatment-induced cytokine release
Description
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.
Time Frame
Day 1, 3, 5, and 7
Other Pre-specified Outcome Measures:
Title
Kinetics and specificity of treatment-induced T cell and natural killer cell (NK cell) depletion
Description
Determined by the flow cytometric assessment of the number of T-, B- and NK-cells during the first 4 weeks after initiation of treatment
Time Frame
Up to Day 28
Title
Composition and evolution of T-, B- and NK-cell compartments
Description
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.
Time Frame
Pre-treatment, Day 28, Day 90, and Day 180
Title
Composition and evolution of T-cell receptor (TCR) Vbeta repertoire
Time Frame
Pre-treatment, Day 28, Day 90, and Day 180
Title
The identification and evolution of host-reactive T-cell clones
Time Frame
Pre-treatment, Day 28, Day 90, and Day 180
Title
GVHD Biomarkers
Description
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.
Time Frame
Pre-treatment, Day 14, Day 28, Day 90, and Day 180
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Walter Van der Velden, MD, PhD
Organizational Affiliation
Radboudumc, Nijmegen (Netherlands)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Matthias Stelljes, MD, PhD
Organizational Affiliation
Unversity Hospital Münster, Münster (Germany)
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Münster
City
Münster
State/Province
North Rhine-Westphalia
ZIP/Postal Code
48149
Country
Germany
Facility Name
Radboudumc
City
Nijmegen
State/Province
Gelderland
ZIP/Postal Code
6525 GA
Country
Netherlands
12. IPD Sharing Statement
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Safety and Efficacy Study of T-Guard to Treat Steroid-resistant Acute GVHD
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