IRB Study Number 24-818
Status Recruiting
Institute Taussig Cancer Institute
Description
2.1.1. Primary Objective
• To determine the safety and efficacy of a single dose of autologous CD34+ base edited HSCs (BEAM-101) in patients
with SCD and severe VOCs
2.2.1. Secondary Objectives
• To assess the safety and tolerability of treatment
• To determine the effects of treatment on VOCs and other SCD-related disease complications, including hospitalizations and RBC transfusion requirements
• To determine the effects of treatment on total Hb and %HbF expression
• To determine the effects of treatment on markers of hemolysis
• To determine the efficiency of gene editing in peripheral blood (PB) and BM cells
• To determine the effects of treatment on specified PROs
Inclusion Criteria
Ages ≥18 years to ≤35 years for the initial sentinel cohort and expansion cohorts. After DMC and FDA approval, the age range in the expansion cohort will broaden to ages ≥12 years up to ≤35 years.
Documented diagnosis of SCD with eligible genotype (βS/βS, βS/β0, or βS/β+) that is confirmed by Hb profile and genotyping data performed in a CLIA-certified laboratory.
Has at least 4 severe VOCs requiring medical attention despite HU or other supportive care measures in the 2-year period prior to provision of informed consent. Severe VOCs are defined by meeting any of the criteria that are detailed in Section 2.4.
Karnofsky Performance Status Scale score ≥60 (for patients ≥16 years of age) or Lansky Play Performance Scale score ≥60 (for patients <16 years of age).
Willingness to discontinue HU at least 30 days prior to stem cell mobilization through Day 100 after transplantation.
Provision of written informed consent and willingness to comply with study procedures; adolescent patients should provide written assent and their legal representative also must provide written informed consent and be willing to comply with study procedures.
Willingness to participate in this study and an LTFU study with the understanding that the total study participation is 15 years.
Females of childbearing potential (post menarche with an intact uterus and at least 1 ovary or less than 1 year postmenopausal) must agree to acceptable method(s) of contraception from the signing of informed consent through at least 6 months after IMP administration (Appendix 2).
Males of reproductive capacity must agree to use effective contraception from the start of mobilization through at least 6 months after IMP administration (Appendix 2).
Exclusion Criteria
Previous receipt of an autologous or allogeneic HSCT or solid organ transplantation.
Available and willing fully matched sibling donor.
Positive serology for:
a. Human immunodeficiency virus (HIV-1 or HIV 2)
b. Human T-cell lymphotropic virus (HTLV-1 or HTLV 2)
c. Hepatitis B (positive surface Ag or positive core Ab unless Hep B DNA negative by polymerase chain reaction [PCR])
d. Hepatitis C (if hepatitis C virus [HCV] antibody positive must be HCV RNA PCR negative)
Definite diagnosis of moyamoya syndrome on screening brain MRA.
HbF levels >20%, obtained at the time of screening on or off HU therapy. (Note: Screening HbF may be repeated up to 2 times after discontinuing HU and in such cases, screening HbF will be considered the lowest value after discontinuing HU and before starting the transfusion program.)
Active bacterial, viral, or fungal infection necessitating IV antimicrobial or antiviral therapy during screening.
Participation in another clinical study of an investigational agent within 30 days of screening.
Prior receipt of gene therapy.
Absolute neutrophil count (ANC) <1,000/mm3 or platelet count <75,000/mm3 that in the investigator’s judgment is not due to hypersplenism.
Estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 as determined by modification of diet in renal disease (MDRD) equation.
Advanced liver disease defined as:
a. Alanine aminotransferase (ALT) >3 × upper limit of normal (ULN) or serum direct bilirubin >2.5 × ULN or prothrombin time >1.5 × ULN
b. History of cirrhosis, extensive bridging fibrosis, or active hepatitis on liver biopsy
c. Presence of severe iron overload on liver MRI required at screening that demonstrates liver iron concentration ≥15 mg/g Fe (unless liver biopsy performed during screening conclusively rules out severe iron overload and does not reveal evidence of cirrhosis, bridging fibrosis, or active hepatitis)
Left ventricular ejection fraction (LVEF) <45% by ECHO or multigated acquisition scan or evidence of pulmonary hypertension requiring medical treatment.
Diffusing capacity of the lungs for carbon monoxide (DLCO) <50% predicted when corrected for alveolar volume or Hb level.
Known allergy or hypersensitivity to plerixafor, busulfan, or IMP excipients (including DMSO).
History of overt stroke.
History of clinically significant bleeding disorder (including history of hemorrhagic stroke, including if detected on screening imaging).
Requirement for anticoagulant treatment during conditioning and engraftment period (not including prophylaxis for thromboembolic events).
History of MDS or other hematologic malignancy (or evidence thereof on screening BM aspiration and biopsy as detailed in Section 6.1.1.2). History of other malignancy (except adequately treated nonmelanoma skin cancer) within the past 5 years or known family cancer susceptibility syndrome that has not been excluded as affecting the patient.
Any other severe or uncontrolled medical condition that, in the opinion of the investigator, would put the patient at undue risk as a result of study procedures and/or impair the ability to interpret study results, including but not limited to known or suspected active alcohol or drug abuse.
Female patient who is pregnant or breastfeeding.
Unable to safely stop transfusions after treatment, including history of confirmed, abnormal TCD exam (as defined by time-averaged mean of the maximum velocity [TAMMV] of ≥200 cm/s in the distal internal carotid artery or proximal middle cerebral artery, or for imaging TCD, a time-averaged mean maximum velocity of ≥185 cm/s) or other condition for which continued transfusions are indicated per investigator judgment.
Have >1 alpha globin gene deletion by genotyping.
Frequent (eg, >10 in the past year before screening) unplanned hospitalizations or emergency department visits that in the investigator’s judgment may be related to chronic pain rather than SCD-related acute pain crises.
