Intravenous (IV) AMD3100 for Mobilization and Matched Related Transplant for Advanced Hematological Malignancies

A Phase II Study Evaluating the Safety and Efficacy of Intravenous AMD3100 for the Mobilization and Transplantation of HLA-Matched Sibling Donor Hematopoietic Stem Cells in Patients With Advanced Hematological Malignancies

To reduce the number of donors treated with IV AMD3100 who require a second collection to obtain the minimum cells necessary for allogeneic stem cell transplant.

Study Overview

• Status: Completed
• Conditions: Hematologic Neoplasms
• Intervention / Treatment: Procedure: Stem cell transplant; Drug: AMD3100; Procedure: Leukopheresis

Detailed Description

• To reduce the number of donors treated with intravenous (IV) AMD3100 who require a second collection to obtain the minimum CD34/kg (2 X 106) necessary for allogeneic stem cell transplantation when compared to our historic group who received 240ug SC AMD3100 from 33% (8 in 24) to 11% (3 in 27).
• To estimate with 95% confidence intervals the proportion of human leukocyte antigen (HLA)-identical sibling donors who experience grade 3-4 infusional toxicity and the proportion from whom ≥ 2.0 x 10e6 CD34+ cells/kg recipient weight are safely mobilized following one or two intravenous infusions.
• To determine the kinetics of stem cell and lymphocyte mobilization using IV AMD3100 and to determine if peripheral blood stem cell products collected after mobilization with IV AMD3100 can be used safely for hematopoietic cell transplantation in HLA-matched recipients as measured by neutrophil engraftment by day +21.
• To determine the pharmacokinetics and pharmacodynamics of IV AMD3100 on stem cell and T-cell phenotyping and on immune reconstitution after transplantation.
• To determine the rate of acute graft-versus-host disease (GVHD) and chronic GVHD in patients who receive IV AMD3100 mobilized peripheral blood stem cells.

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Donor Eligibility

• Donor is 18 to 70 years of age inclusive.
• If female and of child-bearing age: must be non-pregnant, not breast feeding and agree to use adequate contraception.
• Donor is a 6/6 HLA-matched sibling willing to donate PBSC for transplant.
• Donor must be willing to provide written informed consent.
• Adequate cardiac function with no history of congestive heart failure and no history of atrial fibrillation or ventricular tachyarrhythmia.
• Adequate renal function as defined by a calculated serum creatinine clearance of ≥75% of normal (Cockcroft-Gault equation).
• Adequate hepatic function as defined by a total bilirubin <2x normal or absence of hepatic fibrosis/cirrhosis.
• Adequate neurologic function as defined by NO evidence of a severe central or peripheral neurologic abnormality. No history of cerebrovascular accident or seizure disorder requiring anticonvulsant medication.
• Donor must be HIV-1&2 antibody and HTLV-I&II antibody sero-negative, by Food and Drug Administration (FDA) licensed test.
• Donor must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Donor must demonstrate ability to be compliant with study regimen.
• Donor must not have an active infection at the time of study entry.
• Donor does not have active alcohol or substance abuse within 6 months of study entry.
• Donor is not currently enrolled on another investigational agent study.
• Donor does not have any medical condition, which, in the opinion of the clinical investigator, would interfere with his/her evaluation.

Recipient Eligibility

• Recipient must have available the successful collection of an AMD3100 mobilized product. When an adequate collection cannot be obtained using G-CSF, some recipients may need to receive a combined product of mobilized cells with AMD3100 and g granulocyte-colony stimulating factor (G-CSF). Recipients who receive less than 2.0 X 106 CD34+ cells/kg/actual recipient weight after two days of IV AMD3100 will not be considered "eligible" but followed per protocol for safety purposes only.
• Patient is 18 to 65 years of age inclusive.
• Patient is willing and has a 6/6 HLA-matched sibling willing to donate PBSC for transplant.
• Patient must provide signed informed consent.
• If female and of child-bearing age: must be non-pregnant, not breast feeding, and uses adequate contraception.

• Patient must have one of the following diagnoses:

  • Acute myelogenous leukemia (AML) in 1st or subsequent remission or in relapse,
  • Acute lymphoblastic leukemia (ALL) in 1st or subsequent remission or in relapse,
  • Myelodysplastic syndrome either intermediate 1 or 2, or high risk by the International Prognostic Scoring System,
  • Chronic myelogenous leukemia (CML) in accelerated or second chronic phase,
  • Non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) in 2nd or greater complete remission, partial remission, or refractory relapse,
  • Chronic lymphocytic leukemia (CLL), Rai Stage 2-4, failing at least 2 prior regimens, OR
  • Multiple myeloma (MM), Stage 2-3.
• Adequate cardiac function with a left ventricular ejection fraction ≥ 40%.
• Adequate pulmonary function defined as NO severe or symptomatic restrictive or obstructive lung disease, and formal pulmonary function testing showing an FEV1 ≥50% of predicted and a DLCO ≥40% of predicted, corrected for hemoglobin.
• Adequate renal function as defined by a serum creatinine clearance of ≥75% of normal (Cockcroft-Gault equation).
• Adequate hepatic function as defined by a total bilirubin <2x normal or absence of hepatic fibrosis/cirrhosis.
• Adequate neurologic function as defined by NO evidence of a severe central or peripheral neurologic abnormality. Patients with a history of previous central nervous system (CNS) tumor involvement are eligible provided they are without symptoms or signs and the CNS is now free of disease on lumbar puncture and CT scan of the brain.
• No evidence of active infection at the time of the transplant preparative regimen or at time of transplantation.
• Patient must be HIV-1&2 antibody and HTLV-I & II antibody sero-negative, by FDA licensed test.
• Patient has an ECOG performance status of 0 or 1.
• Patient must demonstrate ability to be compliant with medical regimen.
• Patient must not have active alcohol or substance abuse within 6 months of study entry.
• Patient must not be enrolled on another investigational agent concurrently.
• Patient must not have any medical condition, which, in the opinion of the clinical investigator, would interfere with the evaluation of the patient.

Exclusion Criteria:

• See Inclusion criteria above

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1 - Donor; Day 1AMD3100 320 ug/kg IVLeukopheresis; Day 2 (if peripheral blood stem cell (PBSC) collected is not sufficient)AMD3100 320 ug/kg IVLeukopheresis	Drug: AMD3100; Other Names: Mozobil; Plerixafor; Procedure: Leukopheresis
Experimental: Arm 2 - Recipient; Standard of care and physician choice myeloablative or non-myeloablative chemotherapy with or without total body irradiation (permitted = cyclophosphamide and single dose total body irradiation (TBI) / fludarabine and busulfan / fractionated TBI and cyclophosphamide / fractionated TBI, etoposide, and cyclophosphamide / busulfan and cyclophosphamide / fludarabine, busulfan, and ATGAM Day 0 = Stem Cell Transplant	Procedure: Stem cell transplant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Donors Treated With IV AMD3100 Who Required a Second Collection to Obtain the Minimum CD34/kg (2 X 106) Necessary for Allogeneic Stem Cell Transplant	Completion of enrollment of all donors (17 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Donors Who Experience Grade 3-4 Infusional Toxicity		Up to Day 2
Number of Recipients Who Have Neutrophil Engraftment		Day 21
Pharmacokinetics of IV AMD3100 as Measured by the Mean Maximum Plasma Concentration (Cmax)	-Blood samples for pharmacokinetics were drawn on the following schedule: prior to IV infusion; 15 minutes after start of infusion; 30 minutes after start of infusion; 1 hour after start of infusion; 4 hours after start of infusion; 6 hours after start of infusion; 9 hours after start of infusion; 24 hours after start of infusion	Day 1 and Day 2
Pharmacokinetics of IV AMD3100 as Measured by Half Life	-Blood samples for pharmacokinetics were drawn on the following schedule: prior to IV infusion; 15 minutes after start of infusion; 30 minutes after start of infusion; 1 hour after start of infusion; 4 hours after start of infusion; 6 hours after start of infusion; 9 hours after start of infusion; 24 hours after start of infusion	Day 1 and Day 2
Pharmacokinetics of IV AMD3100 as Measured by Mean Area Under Curve (AUC)		Day 1 and Day 2
Rate of Acute GVHD (Grade II-IV) in Recipients		Day 0-Day 100 (acute)
Rate of Acute GVHD (Grade III-IV) in Recipients		Day 0-Day 100 (acute)
Time to Neutrophil Engraftment for Recipients	Measured by determine the first 3 consecutive measurement of neutrophil count = 500/ul following conditioning regimen induced nadir.	Up through Day 100
Time to Platelet Engraftment for Recipients	Measured by determining the first of 3 consecutive measurements of platelet count = 20,000/ul without platelet transfusion support for 7 days.	Up to Day 100
Transplant Related Mortality Rate for Recipients	Death that results from a transplant procedure related complication rather than from relapse of the underlying disease or unrelated cause.	Day 100
Grade 3-4 Toxicity for Recipients	Assessed and graded according to NCI Common Terminology for Adverse Events Version 3.0.	1 year
Rate of Chronic GVHD in Recipients		Day 101-1 year
Number of Donors Who Experience Grade 3-4 Mobilization Toxicity Due to Pheresis Procedure		Up to Day 2

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: John DiPersio, M.D., Ph.D., Washington University School of Medicine

Publications and helpful links

General Publications

• Levesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ. Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest. 2003 Jan;111(2):187-96. doi: 10.1172/JCI15994.
• Peled A, Petit I, Kollet O, Magid M, Ponomaryov T, Byk T, Nagler A, Ben-Hur H, Many A, Shultz L, Lider O, Alon R, Zipori D, Lapidot T. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science. 1999 Feb 5;283(5403):845-8. doi: 10.1126/science.283.5403.845.
• Broxmeyer HE, Hangoc G, Cooper S, Bridger G. Interference of the SDF-1/CXCR4 axis in mice with AMD3100 induces rapid high level mobilization of hematopoietic progenitor cells, and AMD3100 acts synergistically with G-CSF and MIP-1 alpha to mobilize progenitors. Blood. 2001;96:3371a
• Broxmeyer HE, Hangoc G, Cooper S, Li X, Bridger G, Clapp DW. AMD3100, an antagonist of CXCR4 and mobilizer of myeloid progenitor cells, is a potent mobilizer of competitive repopulating long term marrow self renewing stem cells in mice. Blood. 2002;98:2397a
• Liles WC, Broxmeyer HE, Rodger E, Wood B, Hubel K, Cooper S, Hangoc G, Bridger GJ, Henson GW, Calandra G, Dale DC. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood. 2003 Oct 15;102(8):2728-30. doi: 10.1182/blood-2003-02-0663. Epub 2003 Jul 10.
• Devine S, Adkins D, Khoury H, Vij R, Goodnough LT, Graubert T, Tomasson M, Blum W, DiPersio J, Brown R. Mobilization of donors with GM-CSF plus G-CSF or GM-CSF alone results in significantly different graft composition compared to G-CSF alone. Blood. 2002;100:825a
• Devine SM, Vij R, Rettig M, Todt L, McGlauchlen K, Fisher N, Devine H, Link DC, Calandra G, Bridger G, Westervelt P, Dipersio JF. Rapid mobilization of functional donor hematopoietic cells without G-CSF using AMD3100, an antagonist of the CXCR4/SDF-1 interaction. Blood. 2008 Aug 15;112(4):990-8. doi: 10.1182/blood-2007-12-130179. Epub 2008 Apr 21.
• Broxmeyer HE, Orschell CM, Clapp DW, Hangoc G, Cooper S, Plett PA, Liles WC, Li X, Graham-Evans B, Campbell TB, Calandra G, Bridger G, Dale DC, Srour EF. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med. 2005 Apr 18;201(8):1307-18. doi: 10.1084/jem.20041385.
• Hess DA, Bonde J, Craft TP, Wirthlin L, Hohm S, Lahey R, Todt LM, Dipersio JF, Devine SM, Nolta JA. Human progenitor cells rapidly mobilized by AMD3100 repopulate NOD/SCID mice with increased frequency in comparison to cells from the same donor mobilized by granulocyte colony stimulating factor. Biol Blood Marrow Transplant. 2007 Apr;13(4):398-411. doi: 10.1016/j.bbmt.2006.12.445. Erratum In: Biol Blood Marrow Transplant. 2007 Jun;13(6):747. Craft, Timothy C [corrected to Craft, Timothy P].
• Schroeder MA, Rettig MP, Lopez S, Christ S, Fiala M, Eades W, Mir FA, Shao J, McFarland K, Trinkaus K, Shannon W, Deych E, Yu J, Vij R, Stockerl-Goldstein K, Cashen AF, Uy GL, Abboud CN, Westervelt P, DiPersio JF. Mobilization of allogeneic peripheral blood stem cell donors with intravenous plerixafor mobilizes a unique graft. Blood. 2017 May 11;129(19):2680-2692. doi: 10.1182/blood-2016-09-739722. Epub 2017 Mar 14.

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (Actual): January 1, 2011
• Study Completion (Actual): February 1, 2012

Study Registration Dates

• First Submitted: June 1, 2009
• First Submitted That Met QC Criteria: June 4, 2009
• First Posted (Estimate): June 5, 2009

Study Record Updates

• Last Update Posted (Actual): May 17, 2017
• Last Update Submitted That Met QC Criteria: April 6, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Hematologic Diseases; Hematologic Neoplasms; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Plerixafor
• Other Study ID Numbers: 09-0713 / 201103429

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No