Unavailability of investigational product

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.

"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."

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.