A Phase II Study Evaluating the Safety and Efficacy of Subcutaneous Plerixafor

Study Overview
=================
Brief Summary
-----------------
This is a Phase II, open-label, two strata, multicenter, prospective study of plerixafor-mobilized HLA-identical sibling allografts in recipients with hematological malignancies. This study will establish the safety and efficacy of subcutaneous plerixafor for this purpose.

Detailed Description
-----------------
The primary objective is to determine the proportion of donors whose cells can be successfully mobilized and collected with a sufficient CD34+ cell dose using plerixafor as the mobilizing agent, using an intention-to-treat analysis. Donor mobilization following plerixafor will be considered successful if ≥ 2.0x10e6 CD34+ cells/kg recipient weight are collected in no more than two leukapheresis collections. All donors receiving plerixafor will be included in the analysis of the primary objective based on the intention-to-treat principle.Recipients will be classified into one of the two strata, myeloablative or reduced intensity, according to his/her conditioning regimen. The target enrollment is 64 donor/recipient pairs, 32 pairs per stratum.

Official Title
-----------------
A Phase II Study Evaluating the Safety and Efficacy of Subcutaneous Plerixafor for the Mobilization and Transplantation of HLA-Matched Sibling Donor Hematopoietic Stem Cells in Recipients With Hematological Malignancies

Conditions
-----------------
Non-Hodgkin's Lymphoma, Related Donors Donating Peripheral Blood Stem Cells (PBSC) to a Family Member, Acute Myelogenous Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome, Chronic Myelogenous Leukemia, Hodgkin's Disease, Chronic Lymphocytic Leukemia

Intervention / Treatment
-----------------
* Drug: Plerixafor


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Donor: Donor eligibility will be determined according to applicable federal, state and local regulations and institutional standards 18-65 years of age 6/6 HLA-matched sibling Fulfill individual Transplant Center criteria to serve as a mobilized blood cell donor Serum creatinine <2.0mg/dl Recipient: 18 to 65 years of age 6/6 HLA antigen matched sibling willing to donate PBSC for transplant Fulfill individual Transplant Center Criteria for transplant One of the following diagnoses: Acute myelogenous leukemia (AML) in 1st remission or beyond with <5% marrow blasts and no circulating blasts. Marrow must be done within 30 days of the start of transplant conditioning regimen in alignment with other pre-transplant assessments. Acute lymphoblastic leukemia (ALL) in 1st remission or beyond with <5% marrow blasts and no circulating blasts Myelodysplastic syndrome, either intermediate-1,2, or high risk by International Prognostic Scoring System or transfusion dependent Chronic myelogenous leukemia (CML) failing or intolerant to tyrosine kinase inhibitor based therapy Non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) in 2nd or greater complete remission, partial remission, or in relapse (but with at least stable disease after most recent therapy) Chronic lymphocytic leukemia (CLL), relapsing after at least one prior regimen, or in remission with 17p deletion Serum creatinine must be <2.0mg/dl Total bilirubin and aspartate aminotransferase (AST) <3x normal Infectious disease marker (IDM) monitoring will be performed per institutional standards Karnofsky performance status of 70% or greater. Patients who have undergone a prior autologous transplantation are eligible for a reduced intensity transplant only Exclusion Criteria: Donor: Donor unwilling or unable to give informed consent, or unable to comply with the protocol including required follow-up and testing Donor already enrolled on another investigational agent study Pregnant or breast feeding females, or females not willing or able to use adequate contraception if sexually active Recipient: Patient unwilling or unable to give informed consent, or unable to comply with the protocol including required follow-up and testing Patients with active, uncontrolled infection at the time of the transplant preparative regimen Pregnant or breast feeding females, or females not willing or able to use adequate contraception if sexually active Patients with a history of previous central nervous system (CNS) tumor involvement showing active symptoms or signs along with documented disease on lumbar puncture and MRI of the brain within 30 days of start of conditioning A condition, which, in the opinion of the clinical investigator, would interfere with the evaluation of primary and secondary endpoints.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Related donors receiving plerixafor<br>Collection of sufficient CD34+ cells using plerixafor as the mobilizing agent. Eligible donors determined according to institutional standards 18-65 years of age 6/6 HLA-matched sibling Fulfill individual Transplant Center criteria to serve as a mobilized blood cell donor Serum creatinine <1.5 x institution upper limit of normal (ULN) or estimated creatinine clearance (CLCR) >50 mL/min Treatment Description: Receive subcutaneous plerixafor at 240 μg/kg and commence leukapheresis approximately 4 hours later. Leukapheresis will be performed up to two consecutive days. The target CD34+ cell dose is > 4.0 x 106/kg with a minimum of > 2.0 x 106/kg. | Drug: Plerixafor<br> <br> * Other names: AMD3000;|
| No Intervention: Recipients, myeloablative regimen<br>Patients undergoing conditioning under a myeloablative regimen Myeloablative (one of four general regimens): Busulfan (> 9 mg/kg po or iv total) with fludarabine Busulfan (> 9 mg/kg po or iv total) with cyclophosphamide Total body irradiation (> 1000 cGy) plus etoposide Total body irradiation (> 500 cGy) plus cyclophosphamide | |
| No Intervention: Recipients, reduced intensity conditioning regimen.<br>Patients undergoing conditioning using a reduced intensity conditioning regimen. Reduced Intensity (one of three general regimens): Busulfan (< 9 mg/kg po or iv total) plus fludarabine Melphalan (100-140 mg/m2 iv total) plus fludarabine Fludarabine plus cyclophosphamide (> 2000 mg/m2 total) | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Donors Whose Cells Were Successfully Mobilized and Collected With a Sufficient CD34+ Cell Dose Using Plerixafor as the Mobilizing Agent, Using an Intention-to-treat Analysis. | Donor mobilization following plerixafor was considered successful if ≥ 2.0x106 CD34+ cells/kg recipient weight was collected in no more than two leukapheresis collections. | donation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Severity of Acute Toxicities | Incidence and severity of acute toxicities before and during apheresis experienced by donors receiving plerixafor. Acute toxicities are graded according to the NCI Common Terminology Criteria for Adverse Events, version 4.0. This outcome measure is descriptive. Grade of maximum toxicity across all time points is reported. Higher grades denote worse outcomes. 0 = None, 1 = Mild, 2 = Moderate, 3 = severe. | baseline, Day 1, Day 2, Day 3 | 
| Adverse Effects | Adverse effects experienced by donors receiving plerixafor up to one year post donation. Number of participants with a maximum MTC >0 reported at each individual time point. Adverse effects are graded according to the NCI Common Terminology Criteria for Adverse Events, version 4.0. This outcome measure is descriptive. Participants can experience adverse effects at more than one time point evaluated. Higher grades denote worse outcomes. 0 = None, 1 = Mild, 2 = Moderate, 3 = severe. | 30 minutes, 60 minutes, 120 minutes, 240 minutes, 1 month, 6 months, 12 months post donation for each subject | 
| Incidence of and Kinetics of Neutrophil and Platelet Recovery After Transplantation of Hematopoietic Cells Mobilized With Plerixafor | Incidence of and kinetics of neutrophil and platelet recovery by day 100 in recipients after transplantation of hematopoietic cells mobilized with plerixafor. | Day +1 through neutrophil recovery or Day 21 (whichever is first) | 
| T-cell (CD3+) and Myeloid (CD33+) Chimerism After Transplantation of Hematopoietic Cells Mobilized With Plerixafor | T-cell (CD3+) and myeloid (CD33+) chimerism in recipients after transplantation of hematopoietic cells mobilized with plerixafor. This outcome measure is descriptive. | Chimerism was evaluated at serial timepoints post HCT in patients in both RIC and MAC strata. Chimerism was assessed at Day +28, +100, +180, and +365 | 
| Primary Graft Failure After Transplantation of Hematopoietic Cells Mobilized With Plerixafor | Incidence of primary graft failure in recipients after transplantation of hematopoietic cells mobilized with plerixafor. This outcome measure is descriptive. | Day 28 | 
| Incidence of Acute Graft-versus-host Disease (GVHD) | Incidence of acute graft-versus-host disease (GVHD) in recipients after transplantation of hematopoietic cells mobilized with plerixafor | Day 100 | 
| Immune Reconstitution | Rate and quality of immune reconstitution as evidenced by peripheral blood immunophenotype after transplantation of hematopoietic cells mobilized with plerixafor. | Day 28, 100, 180, 365 | 
| Incidence of Cytomegalovirus (CMV) Reactivation After Transplantation With Cells Mobilized With Plerixafor. | Percentage of recipients with prior CMV infection whose CMV was reactivated after transplantation with cell mobilized with plerixafor | day 365 | 
| Treatment-related Mortality and Disease Relapse/Progression | Incidence of treatment-related mortality and disease relapse/progression in recipients after transplantation of hematopoietic cells mobilized with plerixafor | Day 180, 365 | 
| Progression-free and Overall Survival | Probability of progression-free and overall survival after transplantation of hematopoietic cells mobilized with plerixafor | Day 180, 365 | 
| Cellular Composition of Allografts | Cellular composition of allografts mobilized with plerixafor (stem/progenitor cells, T/B/ (Natural killer) NK-cells) | donation | 
| Incidence of Chronic Graft-versus-host Disease (GVHD) | Incidence of chronic graft-versus-host disease (GVHD) in recipients after transplantation of hematopoietic cells mobilized with plerixafor | Day 365 | 
| Secondary Graft Failure After Transplantation of Hematopoietic Cells Mobilized With Plerixafor | Incidence of secondary graft failure in recipients after transplantation of hematopoietic cells mobilized with plerixafor. This outcome measure is descriptive. | Day 365 | 
| CD34+ Cell Count of Allografts | CD34+ cell count of allografts mobilized with plerixafor | donation |