Trial Information

A Pilot Study of the Safety and Activity of Escalating Doses of AMD3100 to Mobilize CD34+ Cells in Healthy Volunteers

Peripheral blood progenitor cells (PBPC) have become the preferred source of hematopoietic
stem cells for allogeneic transplantation because of technical ease of collection and
shorter time required for engraftment. Traditionally, granulocyte-colony stimulating factor
(G-CSF) has been used to procure the PBPC graft. Although regimens using G-CSF usually
succeed in collecting adequate numbers of PBPC from healthy donors, 5%-10% of subjects will
mobilize progenitor cells poorly and may require multiple large volume apheresis or bone
marrow harvesting.

AMD3100 is a bicyclam compound that inhibits the binding of stromal cell derived factor-1
(SDF-1) to its cognate receptor CXCR4. CXCR4 is present on CD34+ hematopoietic progenitor
cells and its interaction with SDF-1 plays a pivotal role in the homing of CD34+ cells in
the bone marrow. Inhibition of the CXCR4-SDF-1 axis by AMD3100 releases CD34+ cells into the
circulation, which can then be collected easily by apheresis. Recently, several reports have
demonstrated that large numbers of progenitor CD34+ cells are rapidly mobilized in healthy
volunteers following a single subcutaneous injection of AMD3100. The ability to collect a
large quantity of PBPC's with a single injection of this drug makes this an attractive agent
for mobilizing both autologous and allogeneic donors for hematopoietic stem cell
transplantation.

A phase one dose escalating trial of AMD3100 in healthy donors done outside the NHLBI
suggested the peak CD34+ mobilizing effects of this agent occurred at the 240 microgram/kg
dose. Of note, no dose limiting toxicities were observed at the highest dose level of 320
mcg/kg. In two current trials at the NHLBI, AMD3100 has also proven to be well tolerated at
the 240 mcg/kg dose, however, the progenitor CD34+ cell yield following a matched volume
apheresis was lower compared to G-CSF mobilizations collected from the same healthy
volunteers. More importantly, the number of CD34+ cells collected following one dose of
AMD3100 has frequently been less than 3 x 10(6) CD34+ cells/kg, the previously defined
minimal dose of progenitor cells required to optimize allogeneic hematopoietic stem cell
transplantation outcomes. In addition, preliminary data from non-human primate studies
suggest that higher doses of AMD3100 may improve CD34+ cell yield in an apheresis
collection.

Based on these data, it is possible that inter-subject variability in CD34+ cell
mobilization may have led investigators (in the prior phase I study) to prematurely
terminate AMD3100 dose escalation based on the perception that CD34+ doses had peaked. We
therefore propose this dose escalating study, designed to evaluate the safety and activity
of AMD3100 when administered in escalating higher doses (240 microgram/kg dose, 320
microgram/kg dose 400 microgram/kg dose 480 microgram/kg dose). Activity will be evaluated
by measuring the most effective dose of AMD3100 in mobilizing progenitor CD34 + cells into
the circulation in healthy donors. To minimize inter-subject variability, we will administer
two different doses of AMD3100 to each subject, evaluating the peak CD34+ cell count
achieved after each dose. Separate cohorts of healthy volunteers will be evaluated for each
dose escalation. The short half life and rapid wash-out of AMD3100 allows for this method
of study.