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

Hematologic Neoplasms Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00914849
• Other study ID #: 09-0713 / 201103429
• Status: Completed
• Phase: Phase 2
• First received: June 1, 2009
• Last updated: July 22, 2013
• Start date: August 2009
• Est. completion date: February 2012

Study information

• Verified date: July 2013
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Description:

• To reduce the number of donors treated with 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 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 GVHD and chronic GVHD in patients who receive IV AMD3100 mobilized peripheral blood stem cells.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 68
• Est. completion date: February 2012
• Est. primary completion date: January 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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 FDA licensed test.

• Donor must have an 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-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 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 Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hematologic Neoplasms

Intervention

Drug:
• AMD3100

Procedure:
• Leukopheresis

Locations

Country	Name	City	State
United States	Washington University School of Medicine	St. Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

References & Publications (9)

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

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. — View Citation

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. — View Citation

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. Erratum in: Biol Blood Marrow Transplant. 2007 Jun;13(6):747. Craft, Timothy C [corrected to Craft, Timothy P]. — View Citation

Lévesque 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. — View Citation

Liles WC, Broxmeyer HE, Rodger E, Hubel K, Cooper S, Hangoc G, Bridger GJ, Henson GW, Calandra G, Dale D. Leucocytosis and mobilization of pluripotent hematopoietic progenitor cells in healthy volunteers induced by single dose administration of AMD-3100, a CXCR4 antagonist. Blood. 2001;96:3071a

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To reduce the number of donors treated with IV AMD3100 who require a second collection to obtain the minimum CD34/kg (2 X 106) necessary for allogeneic stem cell transplant when compared to our historic group who received 240ug SC AMD3100.		1 year	Yes
Secondary	To estimate with 95% confidence intervals the proportion of donors who experience grade 3-4 infusional toxicity & the proportion from whom = 2.0 x 10e6 CD34+ cells/kg recipient weight are safely mobilized following 1 or 2 intravenous infusions.		Day of infusion	Yes
Secondary	To determine the kinetics of mobilization using IV AMD3100 and to determine if stem cell products collected after mobilization with IV AMD3100 can be used safely for transplant in HLA-matched recipients as measured by neutrophil engraftment by day +21.		21 days	Yes
Secondary	To determine the pharmacokinetics and pharmacodynamics of IV AMD3100 on stem cell and T-cell phenotyping and on immune reconstitution after transplantation.		Day 1 and Day 2	No
Secondary	To determine the rate of acute GVHD and chronic GVHD in patients who receive IV AMD3100 mobilized peripheral blood stem cells.		Day 0-Day 100 (acute), Day 101-Year 1 (chronic)	Yes
Secondary	Rate of neutrophil engraftment for recipients		Day 21	No
Secondary	Rate of platelet engraftment for recipients		Day 30	No
Secondary	Transplant related mortality rate for recipients		Day 100	Yes
Secondary	Grades and rates of grade 3-4 toxicity for recipients		1 year	Yes

External Links

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