• To further assess the safety and tolerability profile of AMD3100 when administered in escalating higher doses (240 microgram/kg dose, 320 microgram/kg dose 400 microgram/kg dose 480 microgram/kg dose) in humans.
  

• To determine the peak CD34+ cell mobilization kinetics of AMD3100 in successive cohorts of healthy subjects receiving two different doses of AMD3100.
  

Drug: AMD3100
N/A

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.