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

Sponsor

Henogen (Industry)

Overall Status

Withdrawn

CT.gov ID

NCT00640497

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Graft Versus Host Disease	Biological: IT-Combination	Phase 1/Phase 2

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."

Study Design

Study Type:

Interventional

Anticipated Enrollment :

12 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (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

Study Start Date :

Jan 1, 2010

Anticipated Primary Completion Date :

Jan 1, 2012

Anticipated Study Completion Date :

Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Treatment arm	Biological: IT-Combination 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.

Arm

Intervention/Treatment

Experimental: 1

Treatment arm

Biological: IT-Combination

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.

Outcome Measures

Primary Outcome Measures

The acute GVHD response rate on study Day 29 [Day 29]

Secondary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Department of Hematology Radboud University Nijmegen (RUN)	Nijmegen	Netherlands	6525 GA
2	Department of Hematology Erasmus MC/Daniel den Hoed Cancer CenterGroene Hilledijk	Rotterdam	Netherlands	3153075 EA
3	L.F. , Department of HematologyUMC Utrecht	Utrecht	Netherlands	1003584 CX