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

Acute Graft Versus Host Disease Clinical Trial

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT00640497
• Other study ID #: HN019/ITC-001
• Status: Withdrawn
• Phase: Phase 1/Phase 2
• First received: March 4, 2008
• Last updated: April 28, 2009
• Start date: January 2010
• Est. completion date: January 2012

Study information

• Verified date: April 2009
• Source: Henogen
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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.

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."

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 12
• Est. completion date: January 2012
• Est. primary completion date: January 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Graft Versus Host Disease
• Graft vs Host Disease

Intervention

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.

Locations

Country	Name	City	State
Netherlands	Department of Hematology Radboud University Nijmegen (RUN)	Nijmegen
Netherlands	Department of Hematology Erasmus MC/Daniel den Hoed Cancer CenterGroene Hilledijk	Rotterdam
Netherlands	L.F. , Department of HematologyUMC Utrecht	Utrecht

Sponsors (1)

Lead Sponsor	Collaborator
Henogen

Country where clinical trial is conducted

Netherlands, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The acute GVHD response rate on study Day 29		Day 29	No
Secondary	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	Yes
Secondary	The acute GVHD relapse rate		12 months	No
Secondary	The incidence of chronic GVHD during 12 months		12 months	No
Secondary	The overall survival and progression free survival during 12 months		12 months	No
Secondary	The kinetics of treatment-induced T cell and Natural Killer (NK) cell depletion		12 months	No
Secondary	The pharmacokinetic profile of the IT-combination		day 9	No
Secondary	The occurrence and extent of humoral responses against the IT-combination		12 months	Yes
Secondary	The occurrence of any treatment-induced cytokine release		day 7	Yes