| Conditions: |
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Stem Cell Mobilization |
| Purpose: |
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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.
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| Study Summary: |
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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.
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| Criteria: |
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- INCLUSION CRITERIA:
Ages greater than or equal to18 years and less than or equal to 50 years
Normal renal function: creatinine less than 1.5 mg/dl
Normal liver function: total bilirubin less than 1.5mg/dl, ALT and AST levels must be
below the laboratory's high normal value.
Normal blood count:
WBC 3000-10000/mm(3)
Granulocytes greater than 1500/mm(3)
Platelets greater than 150,000/mm(3), and
Hemoglobin (females greater than 11.1 g/dl, males greater than 12.7 g/dl)
Antecubital veins must be adequate for peripheral access for phlebotomy (subject must be
eligible for normal blood donation)
Ability to comprehend the investigational nature of the study and provide informed consent
EXCLUSION CRITERIA: ANY OF THE FOLLOWING:
Active infection or history of recurrent infection, hepatitis B and C (HBsAg, Anti-HCV),
HIV and/or HTLV-1
History of autoimmune disease such as rheumatoid arthritis, systemic lupus erythematous
History of cancer within the past 5 years excluding basal cell or squamous cell carcinoma
of the skin
History of any hematologic disorders including thromboembolic disease
History of cardiac disease such as uncontrolled hypertension, peripheral vascular disease,
myocardial infarction, cardiac arrhythmias or related symptoms such as tachycardia, chest
pain, shortness of breath which have required medical intervention or treatment or a
Framingham coronary disease risk prediction score of greater than 10% 10 year CHD risk
History of cerebrovascular disease, transient ischemic attack, or stroke
Pregnant or lactating
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| NCT ID: |
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NCT00322127 |
| Primary Contact: |
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Principal Investigator
Richard W Childs, M.D.
National Heart, Lung, and Blood Institute (NHLBI)
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| Backup Contact: |
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N/A |
| Location Contact: |
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Bethesda, Maryland 20892
United States
There is no listed contact information for this specific location.
Site Status: N/A |