Trial Information

A Prospective, Phase I/II Trial Determining the Efficacy and Safety of Allogeneic Hematopoietic Stem Cell Transplantation Using Banked Unrelated Umbilical Cord Blood Supplemented With Related, Haplo-Identical T-Cell Depleted Stem Cells in Subjects With High Risk Malignancies

Over the past decade, umbilical cord blood transplantation has been shown to be a viable
alternative donor stem cell source for hematopoietic cell transplantation in subjects with
catastrophic diseases treatable with transplantation therapy. UCB cells can cross partially
mismatched HLA barriers without intolerable acute or chronic Graft-versus-Host
Disease(GVHD). Thus, many subjects lacking a sufficiently matched, living related or
unrelated bone marrow or adult stem cell donor, can use partially HLA-matched UCB cells for
stem cell rescue after myeloablative irradiation and/or chemotherapy. UCB Cell dose,
expressed per kilogram of recipient body weight, is the best predictor of outcomes after UCB
transplantation. Cell dose thresholds strongly correlating with outcomes have been
identified.

In subjects receiving lower cell doses, while durable engraftment will ultimately occur,
there are significant delays in myeloid and platelet engraftment which, at best, result in
longer hospitalization and significant increases in resource utilization and in the worst
cases, result in increased early deaths from infection and regimen-related toxicity.

In infants and children weighing <40kg, it is possible to find a sufficiently matched UCB
unit that will deliver a dose of cells critical for successful engraftment (defined as 5 x
10e7 nucleated cells/kg) within a reasonable time frame in >90% of subjects. In teenagers
and adults weighing >40kg, this is not always possible. Because UCB units contain a
relatively fixed number of total nucleated cells, units delivering optimal cell dosing for
subjects weighing >70kg will only be identified <10% of the time. Attempts to increase the
dose of cells available for UCBT have included ex vivo expansion and combined unit
transplantation. While expansion of UCB cells ex vivo is possible, infusion of these
expanded cells have not resulted in shortening of engraftment times. Likewise, combinations
of up to 5 UCB units for a single myeloablative transplant have not shortened time to
neutrophil or platelet engraftment.

In this study, we take an alternative approach to facilitating early myeloid engraftment in
subjects undergoing UCB transplantation therapy. In subjects who cannot only identify a
donor delivering a cell dose >2 x 10e7 nucleated cells/kg, we will augment the UCBT with a
lower dose of haplo-identical, T-cell depleted stem cells from a related adult donor to
facilitate early, short-term engraftment with the primary goal of minimizing early
infections and other non-relapse mortality while the UCB cells engraft as the durable and
permanent graft. As the immunocompetent UCB cells engraft, we expect that they will reject
the immunologically incompetent haplo-identical adult stem cells. Thus, after approximately
100-180 days post transplant, the subject should convert to 100% donor chimerism with the
UCB donor graft.

In this study, we will investigate the use of unrelated UCB obtained from the umbilical cord
blood banks supplements with related, haplo-identical, T-cell depleted stem cells in
subjects with high risk refractory malignancies, myelodysplasia or severe aplastic anemia
amenable to stem cell transplantation therapy but lacking conventional related or unrelated
donors.

OBJECTIVES:

1. To determine the safety of co-transplantation of unrelated umbilical cord blood
supplemented with related, haplo-identical, T-cell depleted stem cells in subjects with
high risk malignancies.

2. To describe the rates of neutrophil and platelet engraftment and immune reconstitution
in these subjects.

3. To determine whether short and long term lymphohematopoietic engraftment is derived
from one or both donor sources.

The primary endpoint of the study is number of days to ANC of 500/uL

The secondary endpoints of the study are:

1. 180 day survival

2. Non-relapse mortality in the first 180 days post transplant

3. Number of days to untransfused platelet count of 50K/uL

4. Incidence of primary and secondary graft failure

5. Incidence and severity of acute and chronic graft-versus-host disease (GVHD)

6. Pace and quality of immune reconstitution

7. Rates of leukemic relapse

8. Donor chimerism