Ignite Creation Date:
2024-05-06 @ 9:27 AM
Last Modification Date:
2024-10-26 @ 12:14 PM
Study NCT ID:
NCT02989701
Status:
COMPLETED
Last Update Posted:
2018-01-25
First Post:
2016-12-08
Brief Title:
Pilot and Feasibility Trial of Plerixafor for Hematopoietic Stem Cell HSC Mobilization in Patients With Sickle Cell Disease Pilot and Feasibility Trial of Plerixafor for Hematopoietic Stem Cell HSC Mobilization in Patients With Sickle Cell Disease
Sponsor:
Alessandra Biffi
Organization:
Boston Childrens Hospital
Study Overview
Official Title:
Pilot and Feasibility Trial of Plerixafor for Hematopoietic Stem Cell HSC Mobilization in Patients With Sickle Cell Disease
Status:
COMPLETED
Status Verified Date:
2018-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Sickle cell disease SCD is one of the most common genetic diseases in the world In North America an estimated 2600 babies are born with SCD each year1 and approximately 70000 to 100000 individuals of all ages are affected in the United States2 The clinical manifestations of SCD include acute events such as recurrent debilitating painful crises as well as life-threatening pulmonary cardiovascular renal and neurologic complications The only established curative treatment for SCD patients is allogeneic hematopoietic stem cell transplant HSCT Unfortunately access to this intervention is limited by availability of suitable matched donors and HSCT is associated with significant morbidity and mortality For patients who cannot undergo HSCT treatment of SCD has been limited to one FDA-approved medication hydroxyurea and supportive symptomatic care After decades with very few novel therapeutic options for SCD patients autologous cell-based genetic therapies including lentiviral-based gene therapy as well as gene editing now offer the possibility of innovative curative approaches for patients lacking a matched donor for hematopoietic stem cell transplantation
Gene therapy for sickle cell disease is increasingly promising and there are currently open clinical trials at several centers that employ a gene addition strategy
Options for autologous HSC collection include bone marrow harvest or peripheral blood HSC mobilization Bone marrow BM harvest is an invasive procedure requiring anesthesia which is associated with sickle cell-related morbidities and may not achieve goal CD34 cell dose necessitating repeated procedures scheduled over multiple months In most gene therapy trials HSCs are obtained through peripheral collection after mobilization with granulocyte colony-stimulating factor G-CSF followed by peripheral blood PB apheresis However this approach is contraindicated in SCD because G-CSF has been reported to cause severe adverse effects in sickle cell patients Even with doses sometimes smaller than standard G-CSF has been shown to result in vaso-occlusive crises severe acute chest syndrome and in one report massive splenomegaly and death Alternative options for mobilization are needed
Plerixafor has been compared to G-CSF in a sickle cell mouse model and results showed effective mobilization of HSC subsets without neutrophil or endothelial activation and with lower total WBC and neutrophil counts compared to G-CSF-treated mice Plerixafor use has not yet been documented in sickle cell patients One other trial is currently open to test plerixafor in SCD patients NCT02193191 but no results have yet been reported Based on pre-clinical data the mechanism of action of plerixafor as well strategies the investigator will employ to mitigate risk the investigator anticipates that it will be well-tolerated in the SCD patient population
Gene therapy for sickle cell disease is increasingly promising and there are currently open clinical trials at several centers that employ a gene addition strategy
Options for autologous HSC collection include bone marrow harvest or peripheral blood HSC mobilization Bone marrow BM harvest is an invasive procedure requiring anesthesia which is associated with sickle cell-related morbidities and may not achieve goal CD34 cell dose necessitating repeated procedures scheduled over multiple months In most gene therapy trials HSCs are obtained through peripheral collection after mobilization with granulocyte colony-stimulating factor G-CSF followed by peripheral blood PB apheresis However this approach is contraindicated in SCD because G-CSF has been reported to cause severe adverse effects in sickle cell patients Even with doses sometimes smaller than standard G-CSF has been shown to result in vaso-occlusive crises severe acute chest syndrome and in one report massive splenomegaly and death Alternative options for mobilization are needed
Plerixafor has been compared to G-CSF in a sickle cell mouse model and results showed effective mobilization of HSC subsets without neutrophil or endothelial activation and with lower total WBC and neutrophil counts compared to G-CSF-treated mice Plerixafor use has not yet been documented in sickle cell patients One other trial is currently open to test plerixafor in SCD patients NCT02193191 but no results have yet been reported Based on pre-clinical data the mechanism of action of plerixafor as well strategies the investigator will employ to mitigate risk the investigator anticipates that it will be well-tolerated in the SCD patient population
Detailed Description:
This is a non-randomized pilot safety and feasibility single-center study which will treat subjects with SCD with plerixafor followed by collection of peripheral HSPCs by apheresis Accrual is a sample of up to 6 patients with at least three patients treated with a plerixafor dose of 180 mcgkg and potential for escalation to a dose of 240 mcgkg according to safety and tolerability of the lower dose Three patients will be treated at the lower dose of 180 mcgkg If none of these patients experience a dose limiting toxicity DLT the next three patients will be treated with the higher dose of 240 mcgkg If one or more of the patients treated at 240 mcgkg has a DLT then 180 mcgkg will be selected as the safe dose level If no patients at the 240 mcgkg have a DLT then 240 mcgkg will be selected as the safe dose level
Within 30 days prior to plerixafor administration subject will undergo laboratory testing history and physical exam In order to retain the possibility for the subject to use hisher autologous cells for a future therapeutic indication infectious disease testing and suitability for autologous transplant will be assessed per autologous transplant routine procedure
If the subject is taking hydroxyurea the medication will be stopped 14 days prior to the planned apheresis
Between Days -7 and -2 prior to apheresis the subject will undergo an exchange transfusion This transfusion will be timed in accordance with the patients existing chronic transfusion regimen An exchange transfusion will be performed with post-transfusion hemoglobin electrophoresis confirming a HbS of 30
After the exchange transfusion a bone marrow aspirate will be performed under local anesthesia or conscious sedation The reason for performing the pre-plerixafor bone marrow is that in addition to our primary objective of assessing safety and feasibility of plerixafor in SCD patients the investigator also aim to increase knowledge of HSPCs and their bone marrow niche in SCD patients - this will be relevant for better understanding basic disease pathophysiology but also for the possible future use of BM HSPCs obtained in basal conditions or after plerixafor administration for gene therapy or gene editing therapies It will be important to compare these phenotypic features in BM-derived cells versus plerixafor-derived cells Additionally however in order to also understand whether the HSPCs from SCD patients differ substantially from healthy donors having a pre-plerixafor baseline sample of HSPCs from the same SCD subjects will provide important biological information as well
On Day -1 the subject will be admitted to the Hematology service at Boston Childrens Hospital Confirmation of available compatible units of packed red blood cells will be confirmed prior to administration of plerixafor for use in case of an unexpected acute clinical need for transfusion Labs will be drawn including CBC differential hemoglobin electrophoresis type and screen and peripheral CD34 cell count The subject will receive a single dose of subcutaneous plerixafor
On Day 0 prior to apheresis labs will be drawn including CBC differential and peripheral CD34 count Starting 6 hours after plerixafor dose apheresis will be performed to collect 3-5x blood volumes If the subject does not already have central venous access access for apheresis will be obtained peripherally using 2 large bore 16g needles and blood will be processed in the cell separator Blood within the instrument will receive acid citrate dextrose formula A ACD-A 3 at a rate of 1 mLminL of total blood volume which is the standard apheresis dose 2 grams of calcium gluconate is infused over the course of the procedure to prevent hypocalcemia associated with citrate administration A CBC is drawn at the end of the procedure Vital signs are monitored every 15 minutes while on the instrument A second bone marrow aspirate will be performed before apheresis The subject will remain admitted to the Hematology service overnight
If excess cellular material is collected a portion of the collected apheresis product a minimum of 1 x 106 and a maximum of 3 x 106 unmanipulated CD34 cellskg will be stored in clinically compliant conditions for any possible future use for the patient
On Day 1 after apheresis labs will be drawn again including CBC differential and peripheral CD34 count The subject will be discharged from the Hematology service unless the subject does not meet standard clinical discharge criteria On Day 2 after apheresis the study team will communicate with the subject via phone to inquire about any symptoms experienced On Days 3 7 14 the subject will return for outpatient visit and labs
Within 30 days prior to plerixafor administration subject will undergo laboratory testing history and physical exam In order to retain the possibility for the subject to use hisher autologous cells for a future therapeutic indication infectious disease testing and suitability for autologous transplant will be assessed per autologous transplant routine procedure
If the subject is taking hydroxyurea the medication will be stopped 14 days prior to the planned apheresis
Between Days -7 and -2 prior to apheresis the subject will undergo an exchange transfusion This transfusion will be timed in accordance with the patients existing chronic transfusion regimen An exchange transfusion will be performed with post-transfusion hemoglobin electrophoresis confirming a HbS of 30
After the exchange transfusion a bone marrow aspirate will be performed under local anesthesia or conscious sedation The reason for performing the pre-plerixafor bone marrow is that in addition to our primary objective of assessing safety and feasibility of plerixafor in SCD patients the investigator also aim to increase knowledge of HSPCs and their bone marrow niche in SCD patients - this will be relevant for better understanding basic disease pathophysiology but also for the possible future use of BM HSPCs obtained in basal conditions or after plerixafor administration for gene therapy or gene editing therapies It will be important to compare these phenotypic features in BM-derived cells versus plerixafor-derived cells Additionally however in order to also understand whether the HSPCs from SCD patients differ substantially from healthy donors having a pre-plerixafor baseline sample of HSPCs from the same SCD subjects will provide important biological information as well
On Day -1 the subject will be admitted to the Hematology service at Boston Childrens Hospital Confirmation of available compatible units of packed red blood cells will be confirmed prior to administration of plerixafor for use in case of an unexpected acute clinical need for transfusion Labs will be drawn including CBC differential hemoglobin electrophoresis type and screen and peripheral CD34 cell count The subject will receive a single dose of subcutaneous plerixafor
On Day 0 prior to apheresis labs will be drawn including CBC differential and peripheral CD34 count Starting 6 hours after plerixafor dose apheresis will be performed to collect 3-5x blood volumes If the subject does not already have central venous access access for apheresis will be obtained peripherally using 2 large bore 16g needles and blood will be processed in the cell separator Blood within the instrument will receive acid citrate dextrose formula A ACD-A 3 at a rate of 1 mLminL of total blood volume which is the standard apheresis dose 2 grams of calcium gluconate is infused over the course of the procedure to prevent hypocalcemia associated with citrate administration A CBC is drawn at the end of the procedure Vital signs are monitored every 15 minutes while on the instrument A second bone marrow aspirate will be performed before apheresis The subject will remain admitted to the Hematology service overnight
If excess cellular material is collected a portion of the collected apheresis product a minimum of 1 x 106 and a maximum of 3 x 106 unmanipulated CD34 cellskg will be stored in clinically compliant conditions for any possible future use for the patient
On Day 1 after apheresis labs will be drawn again including CBC differential and peripheral CD34 count The subject will be discharged from the Hematology service unless the subject does not meet standard clinical discharge criteria On Day 2 after apheresis the study team will communicate with the subject via phone to inquire about any symptoms experienced On Days 3 7 14 the subject will return for outpatient visit and labs
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None