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

• ClinicalTrials.gov Identifier: NCT00640497
• Recruitment Status: Withdrawn
• First Posted: March 21, 2008
• Last Update Posted: April 29, 2009
• Sponsor: Henogen
• Information provided by: Henogen

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 (Clinical Trial)
• Estimated 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: January 2010
• Estimated Primary Completion Date: January 2012
• Estimated Study Completion Date: January 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.

Outcome Measures

Primary Outcome Measures :

1. The acute GVHD response rate on study Day 29 [ Time Frame: Day 29 ]

Secondary Outcome Measures :

1. 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 ]
2. The acute GVHD relapse rate [ Time Frame: 12 months ]
3. The incidence of chronic GVHD during 12 months [ Time Frame: 12 months ]
4. The overall survival and progression free survival during 12 months [ Time Frame: 12 months ]
5. The kinetics of treatment-induced T cell and Natural Killer (NK) cell depletion [ Time Frame: 12 months ]
6. The pharmacokinetic profile of the IT-combination [ Time Frame: day 9 ]
7. The occurrence and extent of humoral responses against the IT-combination [ Time Frame: 12 months ]
8. The occurrence of any treatment-induced cytokine release [ Time Frame: day 7 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

Netherlands

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

Sponsors and Collaborators

Henogen

Investigators

• Principal Investigator: Anton V Schattenberg,, MD, PhD,; Department of Hematology Radboud University Nijmegen (RUN) Medical Centre

More Information

Publications:

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.

• Responsible Party: Sophie Houard CSO, Henogen
• ClinicalTrials.gov Identifier: NCT00640497
• Other Study ID Numbers: HN019/ITC-001
• First Posted: March 21, 2008
• Last Update Posted: April 29, 2009
• Last Verified: April 2009

Keywords provided by Henogen:

acute GVHD; immunotoxin; anti-CD3; anti-CD7; Ricin A

Additional relevant MeSH terms:

Graft vs Host Disease; Immune System Diseases