An Evaluation of Safety and Efficacy of Escalating Doses of AMD3100 to Mobilize CD34+ Cells in Healthy Volunteers
Condition: Healthy Volunteers
Study type: Interventional
Phase: Phase 1

Summary: 
      This study will determine how safely and well people can tolerate AMD3100 at larger than
      normal doses to mobilize CD34+ cells, (stem cells). AMD3100 is a new drug designed to
      mobilize stem cells for transplantation in cancer patients. It pushes those cells into the
      circulation, making it easier to collect them, and it temporarily increases the number of
      stem cells in a person's blood.

      Patients ages 18 to 50 in good health and who are not pregnant or breastfeeding may be
      eligible for this study. They will undergo the following tests and procedures:

        -  History and physical examination

        -  Review of medications, including those prescribed and over-the-counter, as well as
           nutritional supplements

        -  Blood tests for liver, kidneys, and other functions; and for infections including
           hepatitis and AIDS

        -  Pregnancy test

        -  Electrocardiogram

      On the day they receive AMD3100, patients will be admitted to the Clinical Center. They will
      receive two doses, injected under the skin, at intervals separated by 14 to 90 days. Dose
      levels are 240 and 320 micrograms/kg and 400 and 480 micrograms/kg. For 24 hours following
      the first AMD3100 administration, blood will be collected periodically through a plastic tube
      at amounts dependent on doses of AMD3100 given. If patients receive one of the two highest
      doses, their heart rhythm will be monitored continuously during the hospital stay. From 7 to
      10 days following administration of AMD3100, patients will give blood samples to monitor the
      effects. The second dose of AMD3100 will be given 14 to 90 days after the first one. Patients
      will return to the Clinical Center for the same procedures as done previously, but the dose
      of the drug will be higher.

      Risks involve side effects of AMD3100. In previous studies, patients who received the drug
      experienced a temporary increase in white blood cell counts. Serious side effects have
      included abnormally low platelet clot, abnormal heart rhythm, and low blood pressure.
      Patients will be carefully monitored for such effects.
    

Detailed description: 
      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.
    

Intervention name(s): AMD3100
Intervention type(s): Drug
Intervention description(s): a 2 mL clear glass vial containing 1.7 mL of a sterile isotonic solution.
Intervention MeSH terms: Plerixafor
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hematopoietic Stem Cells; Mobilization; CXCR4; SDF-1; Mozobil; Healthy Volunteer; HV