Clinical trial NCT03653247: A Study to Assess the Safety, Tolerability, and Efficacy of BIVV003 for Autologous Hematopoietic Stem Cell Transplantation in Patients With Severe Sickle Cell Disease
Official title: A Phase 1/2, Open-Label, Multicenter, Single-Arm Study to Assess the Safety, Tolerability, and Efficacy of BIVV003 for Autologous Hematopoietic Stem Cell Transplantation in Patients With Severe Sickle Cell Disease
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Sickle Cell Disease
Keywords: Intervention: Genetic: BIVV003
Drug: Busulfan
Biological: Plerixafor
Phase: Phase 1/2
Lead sponsor: Sangamo Therapeutics
Sponsor class: INDUSTRY
First posted: 2018-08-31
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants who are Alive at Post-transplantation Day 100
timeFrame: Day 100
measure: Percentage of Participants who are Alive at Post-transplantation Week 52
timeFrame: Week 52
measure: Percentage of Participants who are Alive at Post-transplantation Week 104
timeFrame: Week 104
measure: Percentage of Participants With Successful Engraftment
timeFrame: Up to Day 42
measure: Number of Participants With Adverse Events (AEs)
timeFrame: Up to Week 104
measure: Number of Participants With Serious Adverse Events (SAEs)
timeFrame: Up to Week 104
Secondary outcomes:
measure: CD34 + HSPC Yield from Plerixafor Stem Cell Mobilization
timeFrame: Approximately 12 weeks
measure: Proportion of Participants with Sufficient Stem Cell Mobilization for Rescue Aliquot and BIVV003 Production
timeFrame: Approximately 12 weeks
measure: Yield of Zinc Finger Nuclease (ZFN)-edited Investigational Product
timeFrame: Approximately 12 weeks
measure: Time to Initial Neutrophil Recovery Following BIVV003 Infusion
timeFrame: Up to Week 104
measure: Time to Platelet Recovery Following BIVV003 Infusion
timeFrame: Up to Week 104
measure: Percentage of Participants With Maintenance of Absolute Neutrophil Count (ANC) of >=500/mcL to last Participant Visit
timeFrame: Up to Week 104
measure: Percentage of Participants With Maintenance of Platelet count of >=50,000/mcL to last Participant Visit
timeFrame: Up to Week 104
measure: Change From Baseline in Peripheral Blood Fetal Hemoglobin (HbF) Levels
timeFrame: Baseline up to Week 104
measure: Change From Baseline in Peripheral Blood Percent (%)F cells
timeFrame: Baseline up to Week 104
measure: Change From Baseline in Peripheral Blood Sickle Hemoglobin (HbS) Levels
timeFrame: Baseline up to Week 104
measure: Change From Baseline in Peripheral blood total hemoglobin (Hb) concentration
timeFrame: Baseline up to Week 104
measure: Change From Baseline in Reticulocyte Count
timeFrame: Baseline up to Week 104
measure: Change From Baseline in Lactate Dehydrogenase (LDH) Levels
timeFrame: Baseline up to Week 104
measure: Change From Baseline in Haptoglobin Levels
timeFrame: Baseline up to Week 104
measure: Change From Baseline in Serum Bilirubin Levels
timeFrame: Baseline up to Week 104
measure: Change From Baseline in Patient-Reported Outcomes Measurement Information System 57 (PROMIS-57) Scale Score
timeFrame: Baseline up to Week 104
measure: Number of Participants With Sickle Cell Disease (SCD)-related Clinical Events
timeFrame: Baseline up to Week 104
measure: Number of SCD Related Clinical Events by Severity
timeFrame: Baseline up to Week 104
measure: Participants lymphocyte Counts
timeFrame: At Weeks 13 and 52
measure: Participants Immunoglobulin levels
timeFrame: At Weeks 13 and 52
measure: Number of Red Blood Cell (RBC) Transfusions Received During the Post-transplantation Study Period
timeFrame: Up to Week 104
measure: Total Volume of RBC Transfused
timeFrame: Up to Week 104
Other outcomes:
Locations:
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center
state: California
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Bethesda
country: United States
facility: Investigational Site Number 101
state: Maryland
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
Study officials:
affiliation: Sangamo Therapeutics
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: Brusson M, Miccio A. Genome editing approaches to beta-hemoglobinopathies. Prog Mol Biol Transl Sci. 2021;182:153-183. doi: 10.1016/bs.pmbts.2021.01.025. Epub 2021 Mar 1.