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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Biological: Plerixafor
* Drug: Busulfan
* Genetic: BIVV003


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIVV003<br>Participants will receive plerixafor as subcutaneous (SQ) administration followed by myeloablative conditioning therapy with intravenous (IV) busulfan. BIVV003 will then be administered as a 1-time IV infusion of autologous Cluster of Differentiation 34 + Hematopoietic Stem/Progenitor Cell (CD34+HSPC) transfected ex vivo with zinc finger nuclease (ZFN) messenger ribonucleic acid (mRNAs) targeting the B-cell lymphoma/leukemia 11A (BCL11A) locus. | Biological: Plerixafor<br>* Plerixafor subcutaneous injection will be administered prior to apheresis.<br>Drug: Busulfan<br>* Busulfan IV infusion will be administered as myeloablative conditioning therapy.<br>Genetic: BIVV003<br>* BIVV003 will be administered as an IV infusion following myeloablative conditioning with busulfan.<br>* Other names: Autologous CD34 + hematopoietic stem cells;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | Up to Week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD34 + HSPC Yield from Plerixafor Stem Cell Mobilization |  | Approximately 12 weeks | 
| Proportion of Participants with Sufficient Stem Cell Mobilization for Rescue Aliquot and BIVV003 Production |  | Approximately 12 weeks | 
| Yield of Zinc Finger Nuclease (ZFN)-edited Investigational Product |  | Approximately 12 weeks | 
| Time to Initial Neutrophil Recovery Following BIVV003 Infusion |  | Up to Week 104 | 
| Time to Platelet Recovery Following BIVV003 Infusion |  | 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. | 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. | 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. | Baseline up to Week 104 | 
| Change From Baseline in Peripheral Blood Percent (%)F cells | Change from baseline in %F cells up to Week 104 will be assessed. | Baseline up to Week 104 | 
| Change From Baseline in Peripheral Blood Sickle Hemoglobin (HbS) Levels | Change from baseline in peripheral blood HbS levels up to Week 104 will be assessed. | Baseline up to Week 104 | 
| Change From Baseline in Peripheral blood total hemoglobin (Hb) concentration | Change From baseline in peripheral blood total hemoglobin (Hb) concentration up to week 104 will be assessed. | Baseline up to Week 104 | 
| Change From Baseline in Reticulocyte Count | Change from baseline in reticulocyte count up to Week 104 will be assessed. | Baseline up to Week 104 | 
| Change From Baseline in Lactate Dehydrogenase (LDH) Levels | Change from baseline in LDH levels up to Week 104 will be assessed. | Baseline up to Week 104 | 
| Change From Baseline in Haptoglobin Levels | Change from baseline in haptoglobin levels up to Week 104 will be assessed. | Baseline up to Week 104 | 
| Change From Baseline in Serum Bilirubin Levels | Change from baseline in serum bilirubin levels up to Week 104 will be assessed. | Baseline up to Week 104 | 
| Change From Baseline in Patient-Reported Outcomes Measurement Information System 57 (PROMIS-57) Scale Score | Quality of life (QoL) measures including fatigue will be assessed using PROMIS-57 scale. This is a 57-item questionnaire with 8 questions per domain for assessing physical and mental well-being in participants with SCD. 57 questions are summed into a total score, which is transformed into an age specific normalized t-score with 50 representing normal, and lower scores representing increasing disability. | Baseline up to Week 104 | 
| Number of Participants With Sickle Cell Disease (SCD)-related Clinical Events | Number of participants with SCD-related clinical events (including vaso-occlusive crisis [VOC], pain episodes etc.) will be reported. | Baseline up to Week 104 | 
| Number of SCD Related Clinical Events by Severity | Severity will be categorized by toxicity grade according to CTCAE Version 5.0. AEs not listed in the CTCAE Version 5.0 will be evaluated by: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe or medically significant but not immediately life threatening, Grade 4=Life-threatening consequences; Grade 5=Death. | Baseline up to Week 104 | 
| Participants lymphocyte Counts | Lymphocyte counts will be measured to assess reconstitution of immune function post-BIVV003 transplantation. | At Weeks 13 and 52 | 
| Participants Immunoglobulin levels | Immunoglobulin levels will be measured to assess reconstitution of immune function post-BIVV003 transplantation. | At Weeks 13 and 52 | 
| Number of Red Blood Cell (RBC) Transfusions Received During the Post-transplantation Study Period | The number of RBC transfusions received during the Post-Transplantation study period will be reported. | Up to Week 104 | 
| Total Volume of RBC Transfused | Total volume of RBC transfused during the Post-Transplantation study period will be reported. | Up to Week 104 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intervention: Genetic: BIVV003, Drug: Busulfan, Biological: Plerixafor, Phase: Phase 1/2