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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Hematologic Neoplasms

Intervention / Treatment
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* Drug: AMD3100
* Procedure: Leukopheresis
* Procedure: Stem cell transplant


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 - Donor<br>Day 1 AMD3100 320 ug/kg IV Leukopheresis Day 2 (if peripheral blood stem cell (PBSC) collected is not sufficient) AMD3100 320 ug/kg IV Leukopheresis | Drug: AMD3100<br> <br> * Other names: Plerixafor;Procedure: Leukopheresis<br> <br> |
| Experimental: Arm 2 - Recipient<br>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<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 |