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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Acute Graft Versus Host Disease
• Intervention / Treatment: Biological: IT-Combination

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 Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 6525 GA
    • Department of Hematology Radboud University Nijmegen (RUN)
  • Rotterdam, Netherlands, 3153075 EA
    • Department of Hematology Erasmus MC/Daniel den Hoed Cancer CenterGroene Hilledijk
  • Utrecht, Netherlands, 1003584 CX
    • L.F. , Department of HematologyUMC Utrecht

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The acute GVHD response rate on study Day 29	Day 29

Secondary Outcome Measures

Outcome Measure	Time Frame
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

Collaborators and Investigators

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

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2010
• Primary Completion (Anticipated): January 1, 2012
• Study Completion (Anticipated): January 1, 2012

Study Registration Dates

• First Submitted: March 4, 2008
• First Submitted That Met QC Criteria: March 18, 2008
• First Posted (Estimate): March 21, 2008

Study Record Updates

• Last Update Posted (Estimate): April 29, 2009
• Last Update Submitted That Met QC Criteria: April 28, 2009
• Last Verified: April 1, 2009

More Information

Terms related to this study

• Keywords: acute GVHD; immunotoxin; anti-CD3; anti-CD7; Ricin A
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease
• Other Study ID Numbers: HN019/ITC-001