Clinical trial NCT02027805: 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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: 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
Lead sponsor: Xenikos
Sponsor class: INDUSTRY
First posted: 2014-01-06
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Acute GVHD response rate
timeFrame: Day 28
Secondary outcomes:
measure: Safety and tolerability of T-Guard
timeFrame: During 6 months after initiation of treatment
measure: Very good partial response rate
timeFrame: Day 28
measure: Acute GVHD relapse rate
timeFrame: During 6 months after initiation of therapy
measure: Incidence of chronic GVHD
timeFrame: During 6 months after initiation of therapy
measure: Overall survival and progression free survival
timeFrame: During 6 months after initiation of treatment
measure: Pharmacokinetic profile of T-Guard
timeFrame: Up to Day 9
measure: Anti-drug-antibodies
timeFrame: Pre-treatment, Day 14, Day 28, Day 90, and Day 180
measure: The occurrence of treatment-induced cytokine release
timeFrame: Day 1, 3, 5, and 7
Other outcomes:
measure: Kinetics and specificity of treatment-induced T cell and natural killer cell (NK cell) depletion
timeFrame: Up to Day 28
measure: Composition and evolution of T-, B- and NK-cell compartments
timeFrame: Pre-treatment, Day 28, Day 90, and Day 180
measure: Composition and evolution of T-cell receptor (TCR) Vbeta repertoire
timeFrame: Pre-treatment, Day 28, Day 90, and Day 180
measure: The identification and evolution of host-reactive T-cell clones
timeFrame: Pre-treatment, Day 28, Day 90, and Day 180
measure: GVHD Biomarkers
timeFrame: Pre-treatment, Day 14, Day 28, Day 90, and Day 180
Locations:
city: Münster
country: Germany
facility: University Hospital Münster
state: North Rhine-Westphalia
city: Nijmegen
country: Netherlands
facility: Radboudumc
state: Gelderland
Study officials:
affiliation: Radboudumc, Nijmegen (Netherlands)
name: Walter Van der Velden, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Unversity Hospital Münster, Münster (Germany)
name: Matthias Stelljes, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: