A Study Evaluating the Safety and Efficacy of bb1111 in Severe Sickle Cell Disease

Sickle Cell Disease Clinical Trial

Official title:

A Phase 1/2 Study Evaluating Gene Therapy by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With the LentiGlobin BB305 Lentiviral Vector in Subjects With Severe Sickle Cell Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02140554
• Other study ID #: HGB-206
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: February 2, 2015
• Est. completion date: January 30, 2024

Study information

• Verified date: February 2024
• Source: bluebird bio
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a non-randomized, open label, multi-site, single dose, Phase 1/2 study in approximately 50 adults and adolescents with severe SCD. The study will evaluate hematopoietic stem cell (HSC) transplantation (HSCT) using bb1111 (also known as LentiGlobin BB305 Drug Product for SCD).

Description:

Subject participation for this study will be 2 years post-transplant. Subjects who enroll in this study will be asked to participate in a subsequent long-term follow up study that will monitor the safety and efficacy of the treatment they receive for an additional 13 years for a total of 15 years post-drug product infusion.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: January 30, 2024
• Est. primary completion date: July 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 50 Years

Eligibility

Inclusion Criteria:

1. Be =12 and =50 of age at time of consent.

2. Diagnosis of sickle cell disease (SCD), with either ßS/ßS or ßS/ß0 or ßS/ß+ genotype.

3. Have severe SCD. i.e., in the setting of appropriate supportive care measures for SCD (e.g.,pain management plan) have experienced at least 4 severe VOEs in the 24 months prior to informed consent.

For the purposes of this study, a severe VOE is defined as an event with no medically determined cause other than a vaso-occlusion, requiring a = 24-hour hospital or Emergency Room (ER) observation unit visit or at least 2 visits to a day unit or ER over 72 hours with both visits requiring intravenous treatment. Exception: priapism does not require hospital admission but does require a medical facility visit; 4 priapism episodes that require a visit to a medical facility (without inpatient admission) are sufficient to meet criterion.

4. Karnofsky performance status of = 60 (=16 years of age) or a Lansky performance status of =60 (<16 years of age).

5. Have either experienced hydroxyurea (HU) failure at any point in the past or must have intolerance to HU (defined as patient being unable to continue to take HU per PI judgement).

6. Have been treated and followed for at least the past 24 months prior to Informed Consent in medical center(s) that maintained detailed records on SCD history.

Exclusion Criteria:

1. Positive for presence of human immunodeficiency virus type 1 or 2 (HIV-1 and HIV-2), hepatitis B virus (HBV), or hepatitis C (HCV).

2. Clinically significant and active bacterial, viral, fungal, or parasitic infection.

3. Inadequate bone marrow function, as defined by an absolute neutrophil count of < 1000/µL (< 500/µL for subjects on HU treatment) or a platelet count < 100,000/µL.

4. Any history of severe cerebral vasculopathy: defined by overt or hemorrhagic stroke; abnormal transcranial Doppler [=200 cm/sec] needing chronic transfusion; or occlusion or stenosis in the polygon of Willis; or presence of Moyamoya disease. Subjects with radiologic evidence of silent infarction in the absence of any of the above criteria would still be eligible

5. Advanced liver disease, defined as:

1. Persistent aspartate transaminase, alanine transaminase, or direct bilirubin value >3× the upper limit of normal (ULN), or

2. Baseline prothrombin time or partial thromboplastin time >1.5× ULN, suspected of arising from liver disease, or

3. Magnetic Resonance Imaging (MRI) of the liver demonstrating clear evidence of cirrhosis, or

4. MRI findings suggestive of active hepatitis, significant fibrosis, inconclusive evidence of cirrhosis, or liver iron concentration =15 mg/g require follow-up liver biopsy in subjects =18 years of age. In subjects <18 years of age, these MRI findings are exclusionary, unless in the opinion of the Investigator, a liver biopsy could provide additional data to confirm eligibility and would be safe to perform. If a liver biopsy is performed based on MRI findings, any evidence of cirrhosis, bridging fibrosis, or significant active hepatitis will be exclusionary.

6. Any contraindications to the use of plerixafor during the mobilization of hematopoietic stem cells and any contraindications to the use of busulfan and any other medicinal products required during the myeloablative conditioning, including hypersensitivity to the active substances or to any of the excipients.

7. Any prior or current malignancy or immunodeficiency disorder, except previously treated, non-life threatening, cured tumors such as squamous cell carcinoma of the skin.

8. Prior receipt of an allogeneic transplant.

9. Immediate family member with a known or suspected Familial Cancer Syndrome.

10. Diagnosis of significant psychiatric disorder of the subject that, in the Investigator's judgment, could seriously impede the ability to participate in the study.

11. Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile subjects.

12. Participation in another clinical study with an investigational drug within 30 days of Screening.

13. Prior receipt of gene therapy.

14. Patients needing curative anticoagulation therapy during the period of conditioning through platelet engraftment (patients on prophylactic doses of anticoagulants are eligible).

15. Unable to receive RBC transfusion.

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Genetic:
• bb1111
bb1111 is administered by IV infusion following myeloablative conditioning with busulfan.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
bluebird bio

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	VOE-CR	Proportion of subjects achieving complete resolution of VOEs between 6 months and 18 months after drug product infusion	6-18 months post-transplant
Secondary	sVOE-CR	Proportion of subjects achieving complete resolution of severe vaso-occlusive events, between 6 months and 18 months after drug product infusion	6-18 months post-transplant
Secondary	Proportion of Subjects achieving Globin Response	Globin Response, defined as meeting the following criteria for a continuous period of at least 6 months after drug product infusion: Weighted average HbAT87Q percentage of non-transfused total Hb =30% AND; Weighted average non-transfused total Hb increase of =3 g/dL compared to baseline total Hb OR weighted average non-transfused total Hb =10 g/dL	6-24 months post-transplant
Secondary	Change in the annualized number of vaso-occlusive events (VOEs) in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent		Through Month 24 post-transplant
Secondary	Change in the annualized number of severe VOEs in the 24 months after drug product infusion as compared to the 24 months prior to informed consent		Through Month 24 post-transplant
Secondary	VOE-CR24	Proportion of subject achieving complete resolution of VOEs between 6 months and 24 months after drug product infusion	6-24 months post-transplant
Secondary	sVOE-CR24	Proportion of subjects achieving complete resolution of severe VOEs between 6 months and 24 months after drug product infusion	6-24 months post-transplant
Secondary	sVOE-75	Proportion of subjects achieving a 75% reduction in annualized severe VOEs in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent	Through Month 24 post-transplant
Secondary	Proportion of subjects who meet the definition of Globin Response at Month 24		Month 24 post-transplant
Secondary	Duration of Globin Response		6-24 months post-transplant
Secondary	Weighted average non-transfused total Hb		Month 6, 12, 18, and 24 post-transplant
Secondary	Weighted average HbS percentage of non-transfused total Hb		Month 6, 12, 18, and 24 post-transplant
Secondary	Weighted average HbAT87Q percentage of non-transfused total Hb		Month 6, 12, 18, and 24 post-transplant
Secondary	Weighted average HbS percentage of non-transfused total Hb = 70%, = 60%, = 50%		Month 6, 12, 18, and 24 post-transplant
Secondary	Weighted average non-HbS percentage of non-transfused total Hb		Month 6, 12, 18, and 24 post-transplant
Secondary	Average and median of non-transfused total Hb over time		Through Month 24 post-transplant
Secondary	Average and median of HbS percentage of non-transfused total Hb over time		Through Month 24 post-transplant
Secondary	Average and median of HbAT87Q percentage of non-transfused total Hb over time		Through Month 24 post-transplant
Secondary	Average and median of non-HbS percentage of non-transfused total Hb over time		Through Month 24 post-transplant
Secondary	Change from baseline in hemolysis markers		Through Month 24 post-transplant
Secondary	Change from baseline in markers of iron stores		Through Month 24 post-transplant
Secondary	Change from baseline in annualized frequency and volume of packed red blood cell (pRBC) transfusions		6 - 24 months post-transplant
Secondary	Change from baseline in markers of stress erythropoiesis		Through Month 24 post-transplant
Secondary	Change from baseline in renal function as measured by eGFR		Through Month 24 post-transplant
Secondary	Change from baseline in cardiac-pulmonary function via echocardiogram (tricuspid regurgitant jet velocity [TRJV], LVEF)		Through Month 24 post-transplant
Secondary	Change from baseline in cardiac-pulmonary function via pulmonary function tests		Through Month 24 post-transplant
Secondary	Change from baseline in meters walked during 6-minute walk test		Through Month 24 post-transplant
Secondary	Change from baseline in annualized VOE-related hospital admissions		From post-transplant hospital discharge to Month 24 post-transplant
Secondary	Change from baseline in annualized total days hospitalized		From post-transplant hospital discharge to Month 24 post-transplant
Secondary	Change from baseline in patient-reported quality of life, as measured by Patient Reported Outcomes Measurement Information System (PROMIS)		Month 3, 6, 12, 18, and 24 post-transplant