Plerixafor and Sargramostim (GM-CSF) for Mobilization of Allogeneic Sibling Donors

Study Overview
=================
Brief Summary
-----------------
This study will gather information about the combination the drugs plerixafor with sargramostim in donors of blood-forming cells (stem cells). These stem cells will be collected from the donor and transplanted into their sibling. The investigators believe that the two drugs together will provide enough stem cells for transplantation and may also reduce the risk of graft versus host disease.

Detailed Description
-----------------
The main purpose of this study is to gather information about the combination the drugs plerixafor with sargramostim in donors of blood-forming cells (stem cells). Stem cells can be taken from the bone marrow of the pelvic bones or from the blood following treatment with drugs called growth factors; sargramostim is such a drug. Once stem cells leave the bone marrow and circulate in the blood, they are called peripheral blood stem cells (PBSCs). These cells can be collected through a routine procedure called apheresis, which involves placing two IVs into the arm which are connected to an apheresis machine; the machine then takes blood from the body, removes the stem cells, and returns the blood to the body. Normally, a growth factor called filgrastim is given to donors in order to collect the stem cells used for transplantation. However, when stem cells collected using filgrastim are transplanted in patients, a possible unpredictable complication is graft versus host disease. It's thought that using a different growth factor such as sargramostim might reduce the occurrences of graft versus host disease in patients. However, sargramostim alone does not provide as many stem cells for transplantation as other growth factors. Plerixafor is another drug that can increase the number of PBSCs in a donor, but like with sargramostim, plerixafor alone does not always provide enough stem cells. This is why sargramostim and plerixafor are being combined in this study: the investigators believe that the two drugs together will provide enough stem cells for transplantation and may also reduce the risk of graft versus host disease.

Official Title
-----------------
A Phase II Trial Evaluating the Safety and Efficacy of Plerixafor and Sargramostim (GM-CSF) for the Mobilization of Peripheral Blood Stem Cells (PBSC) From Normal, HLA-Matched Allogeneic Sibling Donors

Conditions
-----------------
Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Lymphoma, Non-Hodgkin, Hodgkin Disease, Leukemia, Lymphocytic, Chronic, B-Cell, Multiple Myeloma

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Donor Eligibility Donor is 18 to 65 years of age inclusive. If female and of child-bearing age, donor must be non-pregnant, not breastfeeding, and agree to use adequate contraception. Donor is a 6/6 HLA-matched sibling willing to donate PBSC for transplant. Donor has adequate cardiac function with no history of congestive heart failure and no history of atrial fibrillation or ventricular tachyarrhythmia. Donor has adequate renal function as defined by a calculated serum creatinine clearance of ≥56 ml/min for females and ≥64 ml/min for males. Donor has adequate hepatic function as defined by a total bilirubin <2x normal or absence of hepatic fibrosis/cirrhosis. Donor has 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. Ability of the donor to understand and the willingness to sign a written informed consent document. Recipient Eligibility Recipient must have available the successful collection of a GM-CSF + plerixafor mobilized product. When an adequate collection cannot be obtained, G-CSF will be used and some recipients may need to receive a combined product of mobilized cells with plerixafor + GM-CSF and G-CSF mobilized cells. Recipients who receive less than 2.0 X 106 CD34+ cells/kg/actual recipient weight after six days of GM-CSF and two days of IV plerixafor will not be considered eligible but followed per protocol for safety purposes only. Recipient is 18 to 65 years of age inclusive. Recipient is willing and has a 6/6 HLA-matched sibling willing to donate PBSC for transplant. Recipient must provide signed informed consent. If female and of child-bearing age, recipient must be non-pregnant, not breastfeeding, and using adequate contraception. Recipient 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. Myeloproliferative disorder or neoplasm Recipient must have adequate cardiac function with a left ventricular ejection fraction ≥ 40%. Recipient must have 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. Recipient must have adequate renal function as defined by a serum creatinine clearance (Cockcroft-Gault equation)of ≥56 ml/min for females and ≥64 ml/min for males of normal Recipient must have adequate hepatic function as defined by a total bilirubin <2x normal or absence of hepatic fibrosis/cirrhosis. Recipient must have 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. Recipient must have no evidence of active infection at the time of the transplant preparative regimen or at time of transplantation. Recipient must be HIV-1&2 antibody and HTLV-I & II antibody sero-negative, by FDA licensed test. Recipient has an ECOG performance status of 0 or 1. Recipient must demonstrate ability to be compliant with medical regimen. Recipient must not have active alcohol or substance abuse within 6 months of study entry. Recipient must not be enrolled on another investigational agent concurrently. Recipient must not have any medical condition, which, in the opinion of the clinical investigator, would interfere with the evaluation of the patient. Recipient must have a life expectancy of greater than 4 weeks. Both men and women and members of all races and ethnic groups are eligible for this trial. Exclusion Criteria: Donor Exclusion Criteria in addition to that stated above Donor may not be receiving any other investigational agents. Donor may not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to plerixafor or GM-CSF, or known hypersensitivity to yeast-derived products or any component of the product.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 - Donor<br>Days 1-5: Mobilization with 5 mcg/kg/day GM-CSF (first 4 donors were mobilized with 10 mcg/kg GM-CSF then changed to 5 mcg/kg for remaining donors) Day 5: Mobilization with 320 mcg/kg plerixafor IV Day 5: Leukopheresis If PBSC collected are not adequate, then donor will be mobilized with GM-CSF and plerixafor IV on day 6 and have leukopheresis collection on day 6. | Drug: Sargramostim<br> <br> * Other names: GM-CSF, Leukine;Drug: Plerixafor<br> <br> * Other names: AMD3100, Mozobil;|
| No Intervention: Arm 2 - Recipient<br>Conditioning Regimens fludarabine and busulfan +/- thymoglobulin fractionated total body irradiation and cyclophosphamide busulfan and cyclophosphamide single dose total body irradiation and cyclophosphamide Day -2 = GvHD prophylaxis Day 0 or +1 = PBSC transplant Day +7 until neutrophil engraftment = G-CSF 5 ug/kg/day | |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Donors Requiring a Second Collection to Obtain a Minimum CD34/Kg (2 x 10^6) Necessary for Allogeneic Stem Cell Transplantation | The primary endpoint is to reduce the number of donors treated with GM-CSF who require a second collection to obtain a minimum CD34/Kg (2 x 106) necessary for allogeneic stem cell transplantation when compared to historic controls mobilized with GM-CSF or plerixafor alone. A reduction in failed first leukapheresis from 40% to less than 10% as seen with G-CSF alone would be considered clinically meaningful. | Up to 6 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Donors Who Experience Grade 3-4 Infusion Toxicity | Infusional toxicity will be evaluated by measuring the patient's blood pressure, heart rate, respirations and temperature one hour prior to the allograft infusion and then 15 minutes, 30 minutes, one hour, 2 hours, and 4 hours, and 6 hours post infusion. Donors will have vital signs collected at each time point. EKGs will be performed immediately prior to IV AMD3100 and one hour after infusion. | 30 days after completion of therapy (estimated to be 36 days) | 
| Number of Donors Who Mobilize ≥ 2x10^6 CD34+ Cells/Kg Recipient Weight Safely Following One or Two Aphereses | -The donor will undergo a leukapheresis procedure to process 20L of blood volume. After the procedure, the collection will be analyzed to look at CD34+ cell content. If it contains at least 2x10^6 CD34+ cells/kg, then the procedure will be considered successful. | Up to 6 days | 
| Percentage of Donors Who Reach 5x10^6 CD34+ Cells/Kg Recipient Weight in 1 or 2 Aphereses | -The donor will undergo a leukapheresis procedure to process 20L of blood volume. After the procedure, the collection will be analyzed to look at CD34+ cell content. The percentage of donors who reach at least 5x10^6 CD34+ cells/Kg recipient weight will be analyzed for this outcome measure. | 6 days | 
| Determine if Peripheral Blood Stem Cell Products Collected After Mobilization With IV Plerixafor Can be Used Safely for Hematopoietic Cell Transplantation in HLA-matched Recipients as Measured by Time to Neutrophil Engraftment (Recipient Only) | -Time to neutrophil engraftment is measured by determining the first of 3 consecutive measurements of neutrophil count ≥ 500/ul following conditioning regimen induced nadir. | Up to Day 21 | 
| Kinetics of Immune Reconstitution as Measured by Time to Neutrophil Engraftment (Recipient Only) | -Time to neutrophil engraftment is measured by determining the first of 3 consecutive measurements of neutrophil count ≥ 500/ul following conditioning regimen induced nadir. | Up to Day 100 | 
| Kinetics of Immune Reconstitution as Measured by Time to Platelet Engraftment (Recipient Only) | -Time to platelet engraftment is 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 180 | 
| Rate of Acute Graft vs. Host Disease (GvHD) (Recipient Only) | -Incidence and severity of acute GVHD will be assessed based on the Seattle criteria. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s). | Up through Day 100 | 
| Rate of Chronic Graft vs. Host Disease (GvHD) (Recipient Only) | Incidence and severity of chronic GVHD will be assessed based on the NIH consensus criteria and global severity scoring system. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s). | Day 100-1 year | 
| Transplant Related Mortality (Recipient Only) | Death that results from a transplant procedure related complication (e.g. infection, organ failure, hemorrhage, GVHD) rather than from relapse of the underlying disease or an unrelated cause. | 100 days | 
| Relapse and Disease Progression Rate | -A patient will be considered relapsed (disease progressed) when there is a recurrence of the original malignant disease after transplantation. | Up to 1 year | 
| Death of Any Cause (Recipients Only) |  | Up to 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Myelogenous, Chronic, BCR-ABL Positive