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

• ClinicalTrials.gov Identifier: NCT02140554
• Recruitment Status: Active, not recruiting
• First Posted: May 16, 2014
• Last Update Posted: July 19, 2022
• Sponsor: bluebird bio
• Information provided by (Responsible Party): bluebird bio

Study Description

Brief 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).

Condition or disease	Intervention/treatment	Phase
Sickle Cell Disease	Genetic: bb1111	Phase 1; Phase 2

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: August 2014
• Estimated Primary Completion Date: July 2023
• Estimated Study Completion Date: February 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Group A; Subjects will have rescue cells collected by bone marrow harvest, and will receive treatment of bb1111 manufactured with autologous CD34+ hematopoietic stem cells (HSCs) collected by bone marrow harvest transduced with BB305 lentiviral vector encoding the human beta-A-T87Q globin gene. *No Longer Recruiting	Genetic: bb1111; bb1111 is administered by IV infusion following myeloablative conditioning with busulfan.; Other Names: lovotibeglogene autotemcel; lovo-cel; LentiGlobin BB305 Drug Product for SCD; autologous CD34+ cell-enriched population from patients with SCD that contains HSCs transduced with BB305 lentiviral vector encoding the βA-T87Q-globin gene, suspended in cryopreservation solution
Experimental: Group B; Group B1: Subjects will have rescue cells collected by bone marrow harvest, and will receive treatment of bb1111 manufactured with autologous CD34+ hematopoietic stem cells (HSCs) collected by bone marrow harvest transduced with BB305 lentiviral vector encoding the human beta-A-T87Q globin gene. *No Longer Recruiting Group B2: Plerixafor mobilization and apheresis will be used for collection of rescue cells and exploratory manufacturing development. Subjects will receive treatment of bb1111 manufactured with autologous CD34+ hematopoietic stem cells (HSCs) collected by bone marrow harvest transduced with BB305 lentiviral vector encoding the human beta-A-T87Q globin gene. *No Longer Recruiting	Genetic: bb1111; bb1111 is administered by IV infusion following myeloablative conditioning with busulfan.; Other Names: lovotibeglogene autotemcel; lovo-cel; LentiGlobin BB305 Drug Product for SCD; autologous CD34+ cell-enriched population from patients with SCD that contains HSCs transduced with BB305 lentiviral vector encoding the βA-T87Q-globin gene, suspended in cryopreservation solution
Experimental: Group C; Plerixafor mobilization and apheresis will be used for collection of rescue cells, and subjects will receive treatment of bb1111 manufactured with autologous CD34+ hematopoietic stem cells (HSCs) collected by plerixafor mobilization and apheresis transduced with BB305 lentiviral vector encoding the human beta-A-T87Q globin gene.	Genetic: bb1111; bb1111 is administered by IV infusion following myeloablative conditioning with busulfan.; Other Names: lovotibeglogene autotemcel; lovo-cel; LentiGlobin BB305 Drug Product for SCD; autologous CD34+ cell-enriched population from patients with SCD that contains HSCs transduced with BB305 lentiviral vector encoding the βA-T87Q-globin gene, suspended in cryopreservation solution

Outcome Measures

Primary Outcome Measures :

1. VOE-CR [ Time Frame: 6-18 months post-transplant ]
   Proportion of subjects achieving complete resolution of VOEs between 6 months and 18 months after drug product infusion

Secondary Outcome Measures :

1. sVOE-CR [ Time Frame: 6-18 months post-transplant ]
   Proportion of subjects achieving complete resolution of severe vaso-occlusive events, between 6 months and 18 months after drug product infusion
2. Proportion of Subjects achieving Globin Response [ Time Frame: 6-24 months post-transplant ]

   Globin Response, defined as meeting the following criteria for a continuous period of at least 6 months after drug product infusion:

   1. Weighted average HbAT87Q percentage of non-transfused total Hb ≥30% AND
   2. 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
3. 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 [ Time Frame: Through Month 24 post-transplant ]
4. 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 [ Time Frame: Through Month 24 post-transplant ]
5. VOE-CR24 [ Time Frame: 6-24 months post-transplant ]
   Proportion of subject achieving complete resolution of VOEs between 6 months and 24 months after drug product infusion
6. sVOE-CR24 [ Time Frame: 6-24 months post-transplant ]
   Proportion of subjects achieving complete resolution of severe VOEs between 6 months and 24 months after drug product infusion
7. sVOE-75 [ Time Frame: Through Month 24 post-transplant ]
   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
8. Proportion of subjects who meet the definition of Globin Response at Month 24 [ Time Frame: Month 24 post-transplant ]
9. Duration of Globin Response [ Time Frame: 6-24 months post-transplant ]
10. Weighted average non-transfused total Hb [ Time Frame: Month 6, 12, 18, and 24 post-transplant ]
11. Weighted average HbS percentage of non-transfused total Hb [ Time Frame: Month 6, 12, 18, and 24 post-transplant ]
12. Weighted average HbAT87Q percentage of non-transfused total Hb [ Time Frame: Month 6, 12, 18, and 24 post-transplant ]
13. Weighted average HbS percentage of non-transfused total Hb ≤ 70%, ≤ 60%, ≤ 50% [ Time Frame: Month 6, 12, 18, and 24 post-transplant ]
14. Weighted average non-HbS percentage of non-transfused total Hb [ Time Frame: Month 6, 12, 18, and 24 post-transplant ]
15. Average and median of non-transfused total Hb over time [ Time Frame: Through Month 24 post-transplant ]
16. Average and median of HbS percentage of non-transfused total Hb over time [ Time Frame: Through Month 24 post-transplant ]
17. Average and median of HbAT87Q percentage of non-transfused total Hb over time [ Time Frame: Through Month 24 post-transplant ]
18. Average and median of non-HbS percentage of non-transfused total Hb over time [ Time Frame: Through Month 24 post-transplant ]
19. Change from baseline in hemolysis markers [ Time Frame: Through Month 24 post-transplant ]
20. Change from baseline in markers of iron stores [ Time Frame: Through Month 24 post-transplant ]
21. Change from baseline in annualized frequency and volume of packed red blood cell (pRBC) transfusions [ Time Frame: 6 - 24 months post-transplant ]
22. Change from baseline in markers of stress erythropoiesis [ Time Frame: Through Month 24 post-transplant ]
23. Change from baseline in renal function as measured by eGFR [ Time Frame: Through Month 24 post-transplant ]
24. Change from baseline in cardiac-pulmonary function via echocardiogram (tricuspid regurgitant jet velocity [TRJV], LVEF) [ Time Frame: Through Month 24 post-transplant ]
25. Change from baseline in cardiac-pulmonary function via pulmonary function tests [ Time Frame: Through Month 24 post-transplant ]
26. Change from baseline in meters walked during 6-minute walk test [ Time Frame: Through Month 24 post-transplant ]
27. Change from baseline in annualized VOE-related hospital admissions [ Time Frame: From post-transplant hospital discharge to Month 24 post-transplant ]
28. Change from baseline in annualized total days hospitalized [ Time Frame: From post-transplant hospital discharge to Month 24 post-transplant ]
29. Change from baseline in patient-reported quality of life, as measured by Patient Reported Outcomes Measurement Information System (PROMIS) [ Time Frame: Month 3, 6, 12, 18, and 24 post-transplant ]

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 50 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Be ≥12 and ≤50 of age at time of consent.
2. Diagnosis of sickle cell disease (SCD), with either βS/βS or βS/β0 or βS/β+ 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.

Contacts and Locations

Locations

United States, Alabama

Birmingham, Alabama, United States

United States, California

Oakland, California, United States

United States, Georgia

Atlanta, Georgia, United States, 30322

United States, Illinois

Chicago, Illinois, United States

United States, Maryland

Bethesda, Maryland, United States

United States, New Jersey

Hackensack, New Jersey, United States

United States, New York

Hyde Park, New York, United States

New York, New York, United States

United States, North Carolina

Chapel Hill, North Carolina, United States

United States, Pennsylvania

Philadelphia, Pennsylvania, United States

United States, South Carolina

Charleston, South Carolina, United States

Sponsors and Collaborators

bluebird bio

Investigators

• Study Director: Anjulika Chawla, MD, FAAP; bluebird bio, Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kanter J, Thompson AA, Pierciey FJ Jr, Hsieh M, Uchida N, Leboulch P, Schmidt M, Bonner M, Guo R, Miller A, Ribeil JA, Davidson D, Asmal M, Walters MC, Tisdale JF. Lovo-cel gene therapy for sickle cell disease: Treatment process evolution and outcomes in the initial groups of the HGB-206 study. Am J Hematol. 2023 Jan;98(1):11-22. doi: 10.1002/ajh.26741. Epub 2022 Oct 10.

Del Pozo Martin Y. 2021 ASH annual meeting. Lancet Haematol. 2022 Feb;9(2):e92-e93. doi: 10.1016/S2352-3026(21)00384-7. Epub 2021 Dec 16. No abstract available.

Kanter J, Walters MC, Krishnamurti L, Mapara MY, Kwiatkowski JL, Rifkin-Zenenberg S, Aygun B, Kasow KA, Pierciey FJ Jr, Bonner M, Miller A, Zhang X, Lynch J, Kim D, Ribeil JA, Asmal M, Goyal S, Thompson AA, Tisdale JF. Biologic and Clinical Efficacy of LentiGlobin for Sickle Cell Disease. N Engl J Med. 2022 Feb 17;386(7):617-628. doi: 10.1056/NEJMoa2117175. Epub 2021 Dec 12.

Jones RJ, DeBaun MR. Leukemia after gene therapy for sickle cell disease: insertional mutagenesis, busulfan, both, or neither. Blood. 2021 Sep 16;138(11):942-947. doi: 10.1182/blood.2021011488.

Del Pozo Martin Y. 47th Annual Meeting of the EBMT. Lancet Haematol. 2021 May;8(5):e317-e318. doi: 10.1016/S2352-3026(21)00104-6. Epub 2021 Mar 31. No abstract available.

• Responsible Party: bluebird bio
• ClinicalTrials.gov Identifier: NCT02140554
• Other Study ID Numbers: HGB-206
• First Posted: May 16, 2014
• Last Update Posted: July 19, 2022
• Last Verified: July 2022

Additional relevant MeSH terms:

Anemia, Sickle Cell; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn