A Phase III, multicenter, randomized controlled study to compare safety and efficacy of a haploidentical HSCT and adjunctive treatment with ATIR101, a T-lymphocyte enriched leukocyte preparation depleted ex vivo of host alloreactive T-cells, versus a haploidentical HSCT with post-transplant cyclophosphamide in patients with a hematologic malignancy (HATCY studie)

For many patients with a hematologic malignancy, a hematopoetic stem cell
transplantation (HSCT) remains the only curative option. The use of a matched
(related or unrelated) donor is considered standard of care for patients who
are eligible for an HSCT. However, a significant number of patients do not
receive this potentially life-saving treatment, because a suitable matched
related or unrelated donor cannot be found in a timely manner or cannot be
found at all.

An alternative is the use of mismatched relatives who are partially matched to
the recipient, as a stem cell donor (haploidentical donor). However, an HSCT
from a haploidentical donor is not without risk for the patient. These risks
include infection, graft rejection, graft-versus-host-disease (GVHD), relapse
and adverse reactions to concomitant therapies (e.g., radiation, chemotherapy,
anti-viral drugs).
The haploidentical transplantation procedure has become feasible through the
use of methods to remove donor T-cells from the graft, in order to reduce the
risk of GVHD. Downside of this approach is that patients can remain severely
immune compromised for more than 1 year after the transplantation with a high
risk of life-threatening complications resulting in high transplant-related
mortality (TRM) rates and low overall survival (OS).

ATIR101 is a cell-based, personalized medicinal product manufactured for one
specific recipient using apheresis material from a donor. ATIR101 a
T-lymphocyte enriched leukocyte preparation depleted ex vivo of host
alloreactive T-cells. A haploidentical stem cell transplantation followed by
ATIR101 can offer patients in need of an HSCT, who lack a suitable HLA-matched
sibling or unrelated donor, a potentially life-saving treatment. Because
ATIR101 consists of a high dose of donor lymphocytes, which have been depleted
of host alloreactive T-cells, patients are expected to be protected from
life-threatening infections without increasing the risk of life-threatening
GVHD. Moreover, the possibility that the anti-tumor effects of T-cells in
ATIR101 have been preserved could provide another benefit to patients. This
potential graft versus leukemia effect could reduce the risk of relapse and
thereby further increase the probability of long-term survival.

In conclusion, the development of a therapy that allows early immune protection
and reconstitution following a haploidentical HSCT without increasing the risk
of life-threatening (acute) GVHD can significantly improve the clinical outcome
of patients by preventing TRM caused by acute GVHD and/or infections and
possibly relapse. In addition, the possibility to use mismatched
(haploidentical) family donors can provide a significant advantage for many
patients for whom a suitable matched donor is not available. Therefore,
participation in this study provides patients the prospect of direct benefit.

The objective of this study is to compare safety and efficacy of a
haploidentical T cell depleted HSCT and adjunctive treatment with ATIR101
versus a haploidentical T cell replete HSCT with post-transplant administration
of high dose cyclophosphamide (PTCy) in patients with a hematologic malignancy.
An additional objective of the study is to compare the effect of the two
treatments on quality of life.

Study CR-AIR-009 is a Phase III randomized controlled multicenter open-label
study comparing two parallel groups. After signing informed consent, a total of
about 250 patients will be randomized in a 1:1 fashion to receive either a TCD
HSCT (CD34 selection) from a related, haploidentical donor, followed by ATIR101
infusion, or a T cell replete HSCT, followed by a high dose of PTCy.
Randomization will use minimization to balance treatment groups with respect to
underlying disease (AML, ALL, or MDS), DRI (intermediate risk, high risk, or
very high risk) and center. A stochastic treatment allocation procedure will be
used so that the treatment assignment is random for all patients entered in the
study.
Patients randomized in the ATIR101 group will receive a single ATIR101 dose of
2×10E6 viable T-cells/kg between 28 and 32 days after the HSCT.
All patients will be followed up for at least 24 months post HSCT. Patient
follow-up beyond 24 months post HSCT will be discontinued when a total number
of 156 GRFS events has been reached.

Patients randomized in the ATIR101 group will receive a single ATIR101 dose of
2×10E6 viable T-cells/kg between 28 and 32 days on top of a T-cell depleted,
CD34 selected HSCT. Patients in the PtCY group will be treated with T-cell
replete HSCT and post-transplant high dose- cyclosphosphamide ("Baltimore
protocol").
All patients will be followed up for at least 24 months post HSCT.

The development of a therapy that allows early immune protection and
reconstitution following a haploidentical HSCT without increasing the risk of
life-threatening (acute) GVHD can significantly improve the clinical outcome of
patients by preventing TRM caused by acute GVHD and/or infections and possibly
relapse. In addition, the possibility to use mismatched (haploidentical) family
donors can provide a significant advantage for many patients for whom a
suitable matched donor is not available. Therefore, participation in this study
provides patients the prospect of direct benefit.