Anti-CD3 & Anti-CD7 Ricin A Immunotoxin-Combination for Acute Graft Versus Host Disease

Study Overview
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Brief Summary
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In this study, a combination of two T-cell directed antibodies both conjugated to a cell-killing toxin will be evaluated. Previous in vitro studies have demonstrated that this so-called immunotoxin-combination (IT-combination) acts synergistically in eliminating T cells. In a subsequent clinical pilot-study, the IT-combination has generated encouraging results when applied as third line therapy. Extensive biological and clinical responses could be noted in the absence of severe acute toxicities. Building on this experience, the current study aims at evaluating the characteristics of the IT-combination when administered in an earlier phase of the disease, i.e. as second line instead of as third line therapy.

Detailed Description
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The experimental design is a non-controlled multicentric fixed-dose Phase I/II study. A total of 12 evaluable patients will be enrolled in 4 transplant centers throughout the Netherlands, in a 9 to 12 months period. The treatment consists of a standard dose of 4 infusions IT-combination (4 mg/m2), given 48-hours apart over a 4-hour period. The intended follow-up period is 12 months. The patient will also be asked to participate in additional research aiming at determining the presence and evolution of biomarkers suggestive for the extent to which the IT-combination 'resets the T-cell compartment, induces clinical tolerance, and/or enhances the risk of over-immunosuppression.

Official Title
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A Phase I/II Multicentric Study to Determine the Safety and Efficacy of a Combination of Anti-CD3 & Anti-CD7 Ricin A Immunotoxins for the Treatment of Steroid-Resistant Acute Graft-Versus-Host Disease

Conditions
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Acute Graft Versus Host Disease

Intervention / Treatment
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* Biological: IT-Combination


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients suffering from severe acute GVHD (Grade II-IV) progressing after 3 days, or non-improving after 5 days, of prednisolone at 2 mg/kg a day. Age ≥ 18 years. Patients or their guardians should have given written informed consent using forms approved by the Institutional Review Board. Exclusion Criteria: Patients receiving concomitant investigational therapeutics/prophylaxis for acute GVHD at the time of enrollment. Patients with histological signs/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 20 g/l or less. Patients having uncontrolled bacterial, viral or fungal infections at the start of therapy. Patients with current evidence of active intrapulmonary disease. Patients with known hypersensitivity to any of the components of the study drug (murine mAb or RTA). Patients who are pregnant, breast feeding, or, if sexually active, unwilling to use effective birth control for the duration of the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Treatment arm | Biological: IT-Combination<br>* The treatment consists of a standard dose of 4 infusions of IT-combination (4 mg/m2), given 48-hours apart over a 4-hour period. The IT-combination is a combination of two immunotoxins. One immunotoxin is a mAb anti-CD3 conjugated to recombinant ricin A chain and the other immunotoxin is a mAb anti-CD7 conjugated to recombinant ricin A chain.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The acute GVHD response rate on study Day 29 |  | Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The safety and tolerability of the IT-combination, as determined by the number and intensity of adverse and serious adverse events during 12 months |  | 12 months | 
| The acute GVHD relapse rate |  | 12 months | 
| The incidence of chronic GVHD during 12 months |  | 12 months | 
| The overall survival and progression free survival during 12 months |  | 12 months | 
| The kinetics of treatment-induced T cell and Natural Killer (NK) cell depletion |  | 12 months | 
| The pharmacokinetic profile of the IT-combination |  | day 9 | 
| The occurrence and extent of humoral responses against the IT-combination |  | 12 months | 
| The occurrence of any treatment-induced cytokine release |  | day 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute GVHD, immunotoxin, anti-CD3, anti-CD7, Ricin A