A Study to Assess the Safety, Tolerability, and Efficacy of BIVV003 for Autologous Hematopoietic Stem Cell Transplantation in Patients With Severe Sickle Cell Disease

Sangamo Therapeutics7 enrolled

Overview

This is an open label, multicenter, Phase 1/2 study in approximately eight adults with severe Sickle Cell Disease (SCD). The study will evaluate the safety, tolerability, and efficacy of autologous hematopoietic stem cell transplantation using BIVV003.

Subject participation in this study will be approximately 136 weeks. Enrolled subjects will be asked to participate in a separate long-term follow-up study to monitor the safety and efficacy of BIVV003 treatment for a total of 15 years post-transplant.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Sickle Cell Disease

Interventions

PlerixaforBIOLOGICAL

Plerixafor subcutaneous injection will be administered prior to apheresis.

BusulfanDRUG

Busulfan IV infusion will be administered as myeloablative conditioning therapy.

BIVV003GENETIC

BIVV003 will be administered as an IV infusion following myeloablative conditioning with busulfan.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 40 Years

Medical Language ↔ Plain English

Inclusion Criteria * Ages 18 to 40 * Confirmation of sickle cell disease (SCD) diagnosis (HbSS or HbS\[beta\]0 genotype) * Severe SCD, defined as having 1 or more of the following manifestations: Clinically significant neurologic event (example \[e.g.\], stroke) or any neurological deficit lasting more than 24 hours; History of 2 or more episodes or Acute Chest Syndrome (ACS) in 2 years prior to informed consent (despite adequate supportive therapies such as asthma therapy); Six or more pain crises per year in 2 years prior to informed consent (requiring intravenous \[IV\] pain management in the outpatient or inpatient hospital setting); History of 2 or more cases or priapism with participant seeking medical care in the 2-years prior to informed consent; Regular RBC transfusion therapy in the year prior to informed consent (having received 8 or more transfusions to prevent vaso-occlusive clinical complications); and Echocardiographic finding of tricuspid valve regurgitant jet (TRJ) velocity of greater than or equal to 2.5 meter per second (m/s) * Clinically stable to undergo stem cell mobilization and myeloablative hematopoietic stem cell transplantation (HSCT) * Adequate physiological function, defined as the following: Karnofsky/Lansky Performance of greater than or equal to 60; Acceptable cardiac function as defined in protocol; Acceptable pulmonary function as defined in protocol; Acceptable renal function as defined in protocol; and Acceptable hepatic function as defined in protocol * Ability to understand purpose and risks of study, provide Informed Consent Form (ICF) and authorization to use protected health information * Completion of age-appropriate cancer screening * Willingness to use double-barrier method of contraception through entire study period (for participants of childbearing potential) * Willingness to receive blood transfusions * Willingness to discontinue hydroxyurea (HU) at least 30 days prior to stem cell mobilization through Day 100 post-transplantation Exclusion Criteria: * Previous receipt of an autologous or allogeneic HSCT or solid organ transplantation * Previous treatment with gene therapy * Current enrollment in an interventional study or having received an investigational drug within 30 days of study enrollment * Pregnant or breastfeeding female * Female or male who plans to become pregnant or impregnate a partner, respectively, during the anticipated study period * Contraindication to plerixafor, apheresis, or busulfan * Treatment with prohibited medication in previous 30 days * Known allergy or hypersensitivity to plerixafor, busulfan, or investigational product excipients * History of active malignancy within past 5 years, any history of hematologic malignancy, or a family history of a cancer predisposition syndrome (without negative result of candidate) * Current diagnosis of uncontrolled seizures * History of significant bleeding disorder * Clinically significant infection * Any major organ dysfunction involving brain, kidney, liver, lung, or heart (e.g., congestive heart failure, pulmonary hypertension) * Corrected QT interval of more than 500 millisecond (ms) based on screening electrocardiogram (ECG) * Positive for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) * Known to have a gamma-globin variant associated with altered oxygen affinity * Hereditary persistence of fetal hemoglobin (HPFH) or HbF concentration of more than or equal to 20 percent (%) at screening * Absolute Neutrophil Count (ANC) of less than or equal to 1,000 per microliter * Platelet count of less than 100,000 per microliter * History of platelet alloimmunization (precluding ability to provide transfusion support) * Extensive Red Blood Cell (RBC) alloimmunization (precluding ability to provide transfusion support) * Judged unsuitable for participation by investigator and/or sponsor

Locations (5)

UCSF Benioff Children's Hospital

Oakland, California, United States

University of California Davis Comprehensive Cancer Center

Sacramento, California, United States

Children's Healthcare of Atlanta

Atlanta, Georgia, United States

Investigational Site Number 101

Bethesda, Maryland, United States

Outcomes

Primary Outcomes

Percentage of Participants who are Alive at Post-transplantation Day 100

The percentage of participants who are alive at post-transplantation Day 100 will be calculated using the Kaplan-Meier estimate.

Time frame: Day 100

Percentage of Participants who are Alive at Post-transplantation Week 52

The percentage of participants who are alive at post-transplantation Week 52 will be calculated using the Kaplan-Meier estimate.

Time frame: Week 52

Percentage of Participants who are Alive at Post-transplantation Week 104

The percentage of participants who are alive at post-transplantation Week 104 will be calculated using the Kaplan-Meier estimate.

Time frame: Week 104

Percentage of Participants With Successful Engraftment

Successful engraftment is defined by absolute neutrophil count (ANC) greater than or equal to \>=500 cells/microliter (mL) for 3 consecutive days.

Time frame: Up to Day 42

Number of Participants With Adverse Events (AEs)

An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Time frame: Up to Week 104

Number of Participants With Serious Adverse Events (SAEs)

An SAE is any untoward medical occurrence that at any dose: Results in death, in the view of the Investigator, places the participant at immediate risk of death (a life-threatening event); however, this does not include an event that, had it occurred in a more severe form, might have caused death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect or is a medically important event.

Data from ClinicalTrials.gov

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Secondary Outcomes

CD34 + HSPC Yield from Plerixafor Stem Cell Mobilization

Time frame: Approximately 12 weeks

Proportion of Participants with Sufficient Stem Cell Mobilization for Rescue Aliquot and BIVV003 Production

Time frame: Approximately 12 weeks

Yield of Zinc Finger Nuclease (ZFN)-edited Investigational Product

Time frame: Approximately 12 weeks

Time to Initial Neutrophil Recovery Following BIVV003 Infusion

Time frame: Up to Week 104

Time to Platelet Recovery Following BIVV003 Infusion

Time frame: Up to Week 104

Percentage of Participants With Maintenance of Absolute Neutrophil Count (ANC) of >=500/mcL to last Participant Visit

Percentage of participants maintaining ANC of \>=500/mcL to last Participant Visit (Week 104) will be calculated.

Time frame: Up to Week 104

Percentage of Participants With Maintenance of Platelet count of >=50,000/mcL to last Participant Visit

The percentage of participants attaining a post-transplant platelet count of \>=50,000/mcL and maintaining this level through last Participant Visit (Week 104) will be calculated.

Time frame: Up to Week 104

Change From Baseline in Peripheral Blood Fetal Hemoglobin (HbF) Levels

Change from baseline in HbF up to Week 104 will be assessed.