Clinical trial NCT00640497: Anti-CD3 & Anti-CD7 Ricin A Immunotoxin-Combination for Acute Graft Versus Host Disease
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
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: Acute Graft Versus Host Disease
Keywords: acute GVHD
immunotoxin
anti-CD3
anti-CD7
Ricin A
Lead sponsor: Henogen
Sponsor class: INDUSTRY
First posted: 2008-03-21
Enrollment: 12
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 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: "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."

Eligibility criteria: 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.

Primary outcomes:
measure: The acute GVHD response rate on study Day 29
timeFrame: Day 29
Secondary outcomes:
measure: The safety and tolerability of the IT-combination, as determined by the number and intensity of adverse and serious adverse events during 12 months
timeFrame: 12 months
measure: The acute GVHD relapse rate
timeFrame: 12 months
measure: The incidence of chronic GVHD during 12 months
timeFrame: 12 months
measure: The overall survival and progression free survival during 12 months
timeFrame: 12 months
measure: The kinetics of treatment-induced T cell and Natural Killer (NK) cell depletion
timeFrame: 12 months
measure: The pharmacokinetic profile of the IT-combination
timeFrame: day 9
measure: The occurrence and extent of humoral responses against the IT-combination
timeFrame: 12 months
measure: The occurrence of any treatment-induced cytokine release
timeFrame: day 7
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Department of Hematology Radboud University Nijmegen (RUN)
city: Rotterdam
country: Netherlands
facility: Department of Hematology Erasmus MC/Daniel den Hoed Cancer CenterGroene Hilledijk
city: Utrecht
country: Netherlands
facility: L.F. , Department of HematologyUMC Utrecht
Study officials:
affiliation: Department of Hematology Radboud University Nijmegen (RUN) Medical Centre
name: Anton V Schattenberg,, MD, PhD,
role: PRINCIPAL_INVESTIGATOR
References:
citation: van Oosterhout YV, van Emst L, Schattenberg AV, Tax WJ, Ruiter DJ, Spits H, Nagengast FM, Masereeuw R, Evers S, de Witte T, Preijers FW. A combination of anti-CD3 and anti-CD7 ricin A-immunotoxins for the in vivo treatment of acute graft versus host disease. Blood. 2000 Jun 15;95(12):3693-701.