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

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

Sponsors

Lead Sponsor: Bioverativ, a Sanofi company

Source Sanofi
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.

Overall Status Recruiting
Start Date June 28, 2019
Completion Date April 2023
Primary Completion Date April 2023
Phase Phase 1/Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Percentage of Participants who are Alive at Post-transplantation Day 100 Day 100
Percentage of Participants who are Alive at Post-transplantation Week 52 Week 52
Percentage of Participants who are Alive at Post-transplantation Week 104 Week 104
Percentage of Participants With Successful Engraftment Up to Day 42
Number of Participants With Adverse Events (AEs) Up to Week 104
Number of Participants With Serious Adverse Events (SAEs) Up to Week 104
Secondary Outcome
Measure 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 Up to Week 104
Percentage of Participants With Maintenance of Platelet count of >=50,000/mcL to last Participant Visit Up to Week 104
Change From Baseline in Peripheral Blood Fetal Hemoglobin (HbF) Levels Baseline up to Week 104
Change From Baseline in Peripheral Blood Percent (%)F cells Baseline up to Week 104
Change From Baseline in Peripheral Blood Sickle Hemoglobin (HbS) Levels Baseline up to Week 104
Change From Baseline in Peripheral blood total hemoglobin (Hb) concentration Baseline up to Week 104
Change From Baseline in Reticulocyte Count Baseline up to Week 104
Change From Baseline in Lactate Dehydrogenase (LDH) Levels Baseline up to Week 104
Change From Baseline in Haptoglobin Levels Baseline up to Week 104
Change From Baseline in Serum Bilirubin Levels Baseline up to Week 104
Change From Baseline in Patient-Reported Outcomes Measurement Information System 57 (PROMIS-57) Scale Score Baseline up to Week 104
Number of Participants With Sickle Cell Disease (SCD)-related Clinical Events Baseline up to Week 104
Number of SCD Related Clinical Events by Severity Baseline up to Week 104
Participants lymphocyte Counts At Weeks 13 and 52
Participants Immunoglobulin levels At Weeks 13 and 52
Number of Red Blood Cell (RBC) Transfusions Received During the Post-transplantation Study Period Up to Week 104
Total Volume of RBC Transfused Up to Week 104
Enrollment 8
Condition
Intervention

Intervention Type: Biological

Intervention Name: Plerixafor

Description: Plerixafor subcutaneous injection will be administered prior to apheresis.

Arm Group Label: BIVV003

Intervention Type: Drug

Intervention Name: Busulfan

Description: Busulfan IV infusion will be administered as myeloablative conditioning therapy.

Arm Group Label: BIVV003

Intervention Type: Genetic

Intervention Name: BIVV003

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

Arm Group Label: BIVV003

Other Name: Autologous CD34 + hematopoietic stem cells

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

Gender: All

Minimum Age: 18 Years

Maximum Age: 40 Years

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Clinical Sciences & Operations Study Director Sanofi
Overall Contact

Last Name: Trial Transparency email recommended (Toll free number for US & Canada)

Phone: 800-633-1610

Phone Ext.: 6

Email: [email protected]

Location
Facility: Status:
UCSF Benioff Children's Hospital | Oakland, California, 94609, United States Recruiting
University of California Davis Comprehensive Cancer Center | Sacramento, California, 95817, United States Recruiting
Children's Healthcare of Atlanta | Atlanta, Georgia, 30322, United States Recruiting
Karmanos Cancer Institute | Detroit, Michigan, 48201, United States Recruiting
Location Countries

United States

Verification Date

June 2020

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Label: BIVV003

Type: Experimental

Description: 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.

Acronym PRECIZN-1
Patient Data Yes
Study Design Info

Allocation: N/A

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov