AMD 3100 (Mozobil Plerixafor) to Mobilize Stem Cells for Donation

• ClinicalTrials.gov Identifier: NCT00075335
• Recruitment Status: Completed
• First Posted: January 9, 2004
• Results First Posted: February 7, 2018
• Last Update Posted: February 7, 2018
• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Richard Childs, M.D., National Institutes of Health Clinical Center (CC)

Tracking Information

• First Submitted Date: January 8, 2004
• First Posted Date: January 9, 2004
• Results First Submitted Date: April 1, 2014
• Results First Posted Date: February 7, 2018
• Last Update Posted Date: February 7, 2018
• Study Start Date: January 2004
• Actual Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 5, 2018)

• Change in Cytokine Gene Expression Profiles (84 Genes) in T Cells Following G-CSF Administration [ Time Frame: 1 Day ]
  Examine G-CSF mobilization effect on cytokine polarization of T-cells. Analyze cytokine gene expression profiles using a Th1-Th2-Th3 RT-PCR plate in CD3+ T cells collected form subjects mobilized with 5 injections of G-CSF. 84 cytokine genes were analyzed for significant alteration in their profiles.
• Change in Cytokine Gene Expression Profiles (84 Genes) in T Cells Following Plerixafor Administration [ Time Frame: 1 Day ]
  Examine plerixafor mobilization effect on cytokine polarization of T-cells. Analyze cytokine gene expression profiles using a Th1-Th2-Th3 RT-PCR plate in CD3+ T cells collected form subjects mobilized with a single injection of plerixafor. 84 cytokine genes were analyzed for significant alteration in their profiles.

• Original Primary Outcome Measures: Not Provided
• Change History: Complete list of historical versions of study NCT00075335 on ClinicalTrials.gov Archive Site
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: AMD 3100 (Mozobil Plerixafor) to Mobilize Stem Cells for Donation
• Official Title: Peripheral Blood Hematopoietic Progenitor Cell Mobilization With AMD 3100 (Mozobil) in Healthy Volunteers Previously Mobilized With G-CSF

Brief Summary

Peripheral blood progenitor cells (PBPC) have become the preferred source of hematopoetic 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 peripheral blood stem cell graft. Although regimens using G-CSF usually succeed in collecting adequate numbers of PBPC from healthy donors, 5%-10% will mobilize stem cells poorly and may require multiple large volume apheresis or bone marrow harvesting. Although G-CSF is generally well tolerated in healthy donors, it may be associated with bone pain, headache, myalgia and rarely life threatening side effects like stroke, myocardial infarction and splenic rupture.

AMD3100, is a bicyclam compound that inhibits the binding of stromal cell derived factor-1 (SDF-1) to its cognate receptor CXC- chemokine receptor 4 (CXCR4). CXCR4 is present on cluster of differentiation 34 (CD34)+ hematopoetic progenitor cells and its interaction with stromal cell derived factor 1 (SDF-1) plays a pivotal role in the homing of CD34+ cells in the bone marrow. Inhibition of the CXCR4-SDF1 axis by AMD3100 releases CD34+ cells into the circulation, which can then be collected easily by apheresis.

Recently, a published report demonstrated that large numbers of CD34+ cells were rapidly mobilized in healthy volunteers following a single subcutaneous injection of AMD3100. Remarkably, the number of CD34+ cells collected by apheresis following a single injection of AMD3100 was comparable to the number of CD34+ cells collected from historical controls receiving 5 days of G-CSF prior to stem cell mobilization.

In this study we will collect PBPCs following a single subcutaneous injection of AMD3100 from healthy donors who have previously had PBPC collected using standard G-CSF mobilization. The AMD3100 mobilized cells, G-CSF mobilized cells, and circulating cells prior to both AMD3100 and G-CSF mobilization will be analyzed in terms of cellular content and function of lymphocytes, natural killer (NK) cells, and antigen presenting cells. AMD3100 mobilized PBPC will be collected for the purpose of research studies and will not be used for therapeutic purposes.

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 peripheral blood stem cell graft. Although regimens using G-CSF usually succeed in collecting adequate numbers of PBPC from healthy donors, 5%-10% will mobilize stem cells poorly and may require multiple large volume apheresis or bone marrow harvesting. Although G-CSF is generally well tolerated in healthy donors, it may be associated with bone pain, headache, myalgia and rarely life threatening side effects like stroke, myocardial infarction and splenic rupture.

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-SDF1 axis by AMD3100 releases CD34+ cells into the circulation, which can then be collected easily by apheresis. Recently, a published report demonstrated that large numbers of CD34+ cells were rapidly mobilized in healthy volunteers following a single subcutaneous injection of AMD3100. Remarkably, the number of CD34+ cells collected by apheresis following a single injection of AMD3100 was comparable to the number of CD34+ cells collected from historical controls receiving 5 days of G-CSF prior to stem cell mobilization. Although the study population is relatively small, side-effects to this agent have been mild and transient with no serious complications having been reported. The ability to collect a large quantity of PBPC with a single injection of this drug makes this an attractive agent for mobilizing donors of allogeneic PBPC. However, the immunologic profiles of AMD3100 mobilized cells, in terms of lymphocyte content (T cell, B cell, NK cell, immuno-regulatory T cell), T cell polarization status (TH1 versus TH2), status of antigen presenting cells (DC1 versus DC2), alloreactive potential, and preservation of reactivity to infectious agents [e.g. Epstein Barr Virus (EBV), Cytomegalovirus (CMV)] are unknown. Consequently, whether AMD3100 mobilized PBPC would be suitable for use as an allograft is uncertain. In this study we will collect PBPCs following a single subcutaneous injection of AMD3100 from healthy donors who have previously had PBPC collected using standard G-CSF mobilization. The AMD3100 mobilized cells, G-CSF mobilized cells, and circulating cells prior to both AMD3100 and G-CSF mobilization will be analyzed in terms of cellular content and function of lymphocytes, NK cells, and antigen presenting cells. AMD3100 mobilized PBPC will be collected for the purpose of research studies and will not be used for therapeutic purposes.

The primary objective is to characterize the immunological properties of AMD3100 mobilized (cytokine gene expression profiles) T-cells compared to G-CSF mobilized T-cells.

Secondary endpoints include the cellular content and other immune properties of AMD3100 mobilized cells yields of hematopoietic progenitor cells, immune cells, and other cellular subsets collected by apheresis in subjects undergoing G-CSF and AMD3100 mobilization and the safety profile of AMD3100.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Healthy

Intervention

Drug: AMD3100 (Mozobil plerixafor)

AMD 3100 (Mozobil plerixafor)mobilized peripheral blood hematopoietic progenitor cells from healthy volunteers will be characterized by cellular content and immunological properties.

Other Name: Mozobil plerixafor

Study Arms

Experimental: AMD 3100 (Mozobil plerixafor)

AMD 3100 (Mozobil plerixafor)mobilized peripheral blood hematopoietic progenitor cells from healthy volunteers will be characterized by cellular content and immunological properties.

Intervention: Drug: AMD3100 (Mozobil plerixafor)

Publications *

• Möhle R, Murea S, Kirsch M, Haas R. Differential expression of L-selectin, VLA-4, and LFA-1 on CD34+ progenitor cells from bone marrow and peripheral blood during G-CSF-enhanced recovery. Exp Hematol. 1995 Dec;23(14):1535-42.
• Möhle R, Haas R, Hunstein W. Expression of adhesion molecules and c-kit on CD34+ hematopoietic progenitor cells: comparison of cytokine-mobilized blood stem cells with normal bone marrow and peripheral blood. J Hematother. 1993 Winter;2(4):483-9.
• Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L, Ponomaryov T, Taichman RS, Arenzana-Seisdedos F, Fujii N, Sandbank J, Zipori D, Lapidot T. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol. 2002 Jul;3(7):687-94. Epub 2002 Jun 17. Erratum in: Nat Immunol 2002 Aug;3(8):787.
• Lundqvist A, Smith AL, Takahashi Y, Wong S, Bahceci E, Cook L, Ramos C, Tawab A, McCoy JP Jr, Read EJ, Khuu HM, Bolan CD, Joo J, Geller N, Leitman SF, Calandra G, Dunbar C, Kurlander R, Childs RW. Differences in the phenotype, cytokine gene expression profiles, and in vivo alloreactivity of T cells mobilized with plerixafor compared with G-CSF. J Immunol. 2013 Dec 15;191(12):6241-9. doi: 10.4049/jimmunol.1301148. Epub 2013 Nov 15.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 22, 2012): 8
• Original Enrollment (submitted: June 23, 2005): 25
• Actual Study Completion Date: August 2012
• Actual Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

• INCLUSION CRITERIA:

  1. Mobilization and collection of PBPC using G-CSF at least 60 days prior to protocol enrollment (stem cell donors enrolled on Branch transplant protocols or healthy volunteers enrolled on 96-H-0049: Use of granulocyte colony stimulating factor mobilized leukapheresis collections from healthy volunteers).
  2. Ages greater than or equal to 18 years and less than or equal to 80 years.
  3. Normal renal function: creatinine less than 1.5 mg/dl.
  4. Normal liver function: total bilirubin less than 1.5mg/dl, alanine aminotransferase (ALT) 6 -41 U/L, aspartate aminotransferase (AST) 9-34 U/L.

  5. Normal blood count: white blood cell (WBC) 3000-10000/mm(3)

     granulocytes greater than 1500/mm(3)

     platelets greater than 150,000/mm(3)

     hemoglobin (females greater than 11.1 g/dl, males greater than 12.7 g/dl).

  6. Subject must be eligible for normal blood donation and fit to undergo apheresis procedure (antecubital veins must be adequate for peripheral access during apheresis).
  7. Ability to comprehend the investigational nature of the study and provide informed consent.

EXCLUSION CRITERIA: Any of the Following

1. Active infection or history of recurrent infection- hepatitis B and C (HBsAg, Anti-HBc, Anti-HCV), HIV and human T- lymphocytic virus (HTLV-1).
2. History of autoimmune disease such as rheumatoid arthritis, systemic lupus erythematous.
3. History of cancer within the past 5 years excluding basal cell or squamous cell carcinoma of the skin.
4. History of any hematologic disorders including thromboembolic disease.
5. 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 coronary heart disease (CHD) risk.
6. History of cerebrovascular disease, transient ischemic attack, or stroke.
7. Pregnant or lactating.
8. Severe psychiatric illness: mental deficiency sufficiently severe as to make informed consent impossible

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00075335
• Other Study ID Numbers: 040078; 04-H-0078 ( Other Identifier: NIH NHLBI )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Richard Childs, M.D., National Institutes of Health Clinical Center (CC)
• Study Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Collaborators: Not Provided

Investigators

• Principal Investigator: Richard W Childs, M.D.; National Heart, Lung, and Blood Institute (NHLBI)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: February 2018