Anti-CD3 & Anti-CD7 Ricin A Immunotoxin-Combination for Acute Graft Versus Host Disease
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.
Acute Graft Versus Host Disease
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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 for the Treatment of Steroid-Resistant Acute Graft-Versus-Host Disease|
- The acute GVHD response rate on study Day 29 [ Time Frame: Day 29 ] [ Designated as safety issue: No ]
- The safety and tolerability of the IT-combination, as determined by the number and intensity of adverse and serious adverse events during 12 months [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
- The acute GVHD relapse rate [ Time Frame: 12 months ] [ Designated as safety issue: No ]
- The incidence of chronic GVHD during 12 months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
- The overall survival and progression free survival during 12 months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
- The kinetics of treatment-induced T cell and Natural Killer (NK) cell depletion [ Time Frame: 12 months ] [ Designated as safety issue: No ]
- The pharmacokinetic profile of the IT-combination [ Time Frame: day 9 ] [ Designated as safety issue: No ]
- The occurrence and extent of humoral responses against the IT-combination [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
- The occurrence of any treatment-induced cytokine release [ Time Frame: day 7 ] [ Designated as safety issue: Yes ]
|Study Start Date:||January 2010|
|Estimated Study Completion Date:||January 2012|
|Estimated Primary Completion Date:||January 2012 (Final data collection date for primary outcome measure)|
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.
"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."
|Department of Hematology Radboud University Nijmegen (RUN)|
|Nijmegen, Netherlands, 6525 GA|
|Department of Hematology Erasmus MC/Daniel den Hoed Cancer CenterGroene Hilledijk|
|Rotterdam, Netherlands, 3153075 EA|
|L.F. , Department of HematologyUMC Utrecht|
|Utrecht, Netherlands, 1003584 CX|
|Principal Investigator:||Anton V Schattenberg,, MD, PhD,||Department of Hematology Radboud University Nijmegen (RUN) Medical Centre|