A Phase I/II study to determine the safety and efficacy of a combination of anti-CD3 & anti-CD7 ricin A immunotoxins for treating steroid-resistant acute graft-versus-host disease.

Acute GVHD is a feared and often life-threatening complication of allogeneic
hematopoietic stem cell transplantation. Acute GVHD is caused by donor-derived
T-cells that are co-transplanted with the graft and that recognize tissues of
their new host as *foreign*. Moreover, acute GVHD may also occur in patients
that are given post-transplant donor lymphocyte infusions (DLI) to
prevent/treat the recurrence of the underlying malignant disease. In vivo
elimination of the mature (mostly donor-derived) T cells in the patient can be
used as treatment of the disease, and allows the restoration of the T-cell
compartment with newly formed T cells. As these will now grow up in their new
environment, the recipient is likely to be accepted as *self* (*resetting* of
the T-cell compartment).

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.

PRIMARY
• To determine the efficacy on study Day 28 of the IT-combination in inducing a
clinical response in patients with severe acute GVHD refractory to first line
therapy with intermediate dose corticosteroids.

SECONDARY
• To evaluate the overall safety and efficacy during the first 12 months after
initiation of therapy.

• To determine the pharmacokinetic profile of the IT-combination.

• To determine the immunogenicity of the IT-combination.

ADDITIONAL RESEARCH
• The patient will 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 tolerance,
and/or enhances the risk of over-immunosuppression.

• The experimental design is a non-controlled multicentric fixed-dose Phase
I/II study.

• The treatment consists of a standard dose of 4 infusions IT-combination (4
mg/m2), given 48-hours apart over a 4-hour period.

• In case Dose Limiting Toxicities (DLT) are encountered, a downward dose
modification scheme based on the conventional *3+3 design* will be applied
(Paragraph 6.6 study protocol). The maximal tolerable dose (MTD) is defined as
the highest dose at which DLT occur in less than 33% of the patients.

• For the second and subsequent patients to be treated at this standard dose
level, it is required that the previous patient have been observed for at least
48 hours after the last infusion, and the maximal tolerable dose has not been
reached.

• A total of 12 evaluable patients will be enrolled in 4 transplant centers
throughout the Netherlands, in a 9 to 12 months period.

• The intended follow-up period is 12 months.

A treatment course consists of four doses of IT-combination, given 48-hours
apart as a 100 ml intravenous infusion over a 4-hour period.

The main dose limiting toxicities associated with similar products have been
vascular leak syndrome and myalgia associated with elevated serum creatine
kinase (CK) levels. Administration of xenogeneic proteins in general may lead
to anaphylactic reactions. The systemic administration of anti-CD3 antibodies,
as also present in the IT-combination, may result in the activation of T-cells
leading to serious cytokine release syndrome. The elimination of T-cells and
NK-cells as such (being the effector mechanism of the IT-combination), may
render patients more vulnerable to infections and secondary malignancies (e.g.
post-transplant lymphoproliferative disorder PTLD).

The observation that the IT-combination, when applied as third-line therapy,
generated clear biological and clinical responses without inducing severe acute
toxicities, justifies the expectation that patients with less advance disease
will also benefit from this agent. Presumably, the immune system and vital
organs of such patients will not yet be irreversibly damaged by the aGHVD and
immunosuppressive treatment at time of inclusion. Hence, it might be expected
that this Phase I/II study generates a significant fraction of responders,
hopefully with good long-term prognosis.