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

Graft vs Host Disease Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02027805
• Other study ID #: XEN/TG-001
• Secondary ID: 2013-000068-27
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: January 3, 2014
• Last updated: June 3, 2017
• Start date: March 5, 2014
• Est. completion date: November 3, 2016

Study information

• Verified date: June 2017
• Source: Xenikos
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: November 3, 2016
• Est. primary completion date: September 7, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Graft vs Host Disease

Intervention

Biological:
• T-Guard

Locations

Country	Name	City	State
Germany	University Hospital Münster	Münster	North Rhine-Westphalia
Netherlands	Radboudumc	Nijmegen	Gelderland

Sponsors (1)

Lead Sponsor	Collaborator
Xenikos

Countries where clinical trial is conducted

Germany,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Kinetics and specificity of treatment-induced T cell and natural killer cell (NK cell) depletion	Determined by the flow cytometric assessment of the number of T-, B- and NK-cells during the first 4 weeks after initiation of treatment	Up to Day 28
Other	Composition and evolution of T-, B- and NK-cell compartments	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.	Pre-treatment, Day 28, Day 90, and Day 180
Other	Composition and evolution of T-cell receptor (TCR) Vbeta repertoire		Pre-treatment, Day 28, Day 90, and Day 180
Other	The identification and evolution of host-reactive T-cell clones		Pre-treatment, Day 28, Day 90, and Day 180
Other	GVHD Biomarkers	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.	Pre-treatment, Day 14, Day 28, Day 90, and Day 180
Primary	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)	Day 28
Secondary	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.	During 6 months after initiation of treatment
Secondary	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).	Day 28
Secondary	Acute GVHD relapse rate		During 6 months after initiation of therapy
Secondary	Incidence of chronic GVHD		During 6 months after initiation of therapy
Secondary	Overall survival and progression free survival		During 6 months after initiation of treatment
Secondary	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).	Up to Day 9
Secondary	Anti-drug-antibodies	The occurrence and extent of humoral responses against T-Guard (anti-drug-antibodies, ADA).	Pre-treatment, Day 14, Day 28, Day 90, and Day 180
Secondary	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.	Day 1, 3, 5, and 7