Transfusion-Dependent ß Thalassemia MedDRA version: 20.0 Level: PT Classification code 10043391 Term: Thalassaemia beta System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Sponsors
Vertex Pharmaceuticals Incorporated
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Subjects 12 to 35 years of age, inclusive on the date of informed consent 2. Subject (or their legally authorized representative or guardian) will sign and date an informed consent form (ICF) and, where applicable, an assent form 3. Diagnosis of transfusion-dependent ß-thalassemia (TDT) as defined by: a. Documented homozygous ß-thalassemia or compound heterozygous ß-thalassemia including ß-thalassemia/hemoglobin E (HbE). Subjects can be enrolled based on historical data, but a confirmation of the genotype using the study central laboratory will be required before busulfan conditioning. The ß^0 and non ß^0 genotypes are defined using the HbVar Database. b. A history of at least 100 mL/kg/year or 10 units/year of packed RBC transfusions in the prior 2 years before signing the consent or the last rescreening for patients going through repeat screening. 4. Karnofsky performance status of =80% for subjects =16 years of age. Lansky performance status of =80% for subjects =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. A willing and healthy 10/10 human leukocyte antigen (HLA)-matched related donor is available per investigator's judgement. 2. Prior allogeneic HSCT. 3. Subjects with associated a-thalassemia and >1 alpha deletion or alpha multiplications. 4. Subjects with sickle cell beta thalassemia variant. 5. Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator. 6. White blood cell count 3 x the upper limit of normal (ULN), or direct bilirubin value >2.5 x ULN, or: b. Baseline prothrombin time (International Normalized Ratio; INR) >1.5 x ULN, or c. History of cirrhosis or any evidence of bridging fibrosis on a prior liver biopsy, if available d. Subjects with active hepatitis infection (see criterion 16). e. Subjects with history of chronic hepatitis infection are also excluded unless liver biopsy within 3 months prior to or at screening shows no evidence of bridging fibrosis or cirrhosis f. Liver iron content (LIC) =15 mg/g on R2* MRI of liver, unless liver biopsy within 3 months prior to or at screening shows no evidence of bridging fibrosis or cirrhosis. 11. A cardiac T2* <10 ms by MRI or left ventricular ejection fraction (LVEF) <45% by echocardiogram. 12. Baseline estimated glomerular filtration rate <60 mL/min/1.73 m2. 13. Diffusion capacity of the lungs for carbon monoxide (DLco) <50% of predicted (corrected for hemoglobin and/or alveolar volume). 14. Prior treatment with gene therapy/editing product. 15. Intolerance, contraindication, or known sensitivity to plerixafor, GCSF products (e.g., filgrastim), or busulfan. Prior anaphylaxis with excipients of CTX001 product (dimethyl sulfoxide [DMSO], Dextran). 16. Positive serology for the presence of human immunodeficiency virus-1 (HIV-1) or human immunodeficiency virus-2 (HIV-2) (positive for both antigen/antibody AND nucleic acid tests [NAT]), hepatitis B virus (HBV) (positive for Hepatitis B core antibody [HBcAb] or positive hepatitis B surface antigen (HBsAg) AND for NAT tests), syphilis [positive screening AND positive confirmatory tests (RPR or treponemal specific test)], or hepatitis C virus (HCV positive for both antibody [HCAb] and for NAT tests). Additional infectious disease markers should be obtained and tested as required by the local authority for the collection and processing of cellular therapy products. These additional tests (e.g., HTLV-1, HTLV-2, malaria, tuberculosis, toxoplasmosis, Trypanosoma cruzi, or West Nile virus) will be evaluated to determine overall impact to the patient and manufacturing of CTX001
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the safety and efficacy of a single dose of autologous CRISPR-Cas9 modified CD34+ hHSPCs (CTX001) in subjects with transfusion-dependent ß-thalassemia (TDT) ;Secondary Objective: • To quantify percentage of edited alleles in peripheral blood leukocytes and CD34+ cells of the bone marrow • To assess the production of HbF post-CTX001 infusion • To assess the effects of infusion of CTX001 on disease-specific events and clinical status;Primary end point(s): Safety Endpoints: • Successful neutrophil engraftment. • Time to neutrophil engraftment. • Time to platelet engraftment • Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, and vital signs • Incidence of transplant related mortality (TRM) within 100 days and within 1 year post-CTX001 infusion. • All-cause mortality. Primary Efficacy Endpoint: • Proportion of subjects achieving TI12, defined as maintaining weighted average Hb =9 g/dL without RBC transfusions for at least 12 consecutive months any time after CTX001 infusion. The evaluation of TI12 starts 60 days after last RBC transfusion for post-transplant support or TDT disease management.;Timepoint(s) of evaluation of this end point: Refer to E.5.1 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key Secondary Efficacy Endpoint: • Proportion of subjects achieving TI6, defined as maintaining weighted average Hb =9 g/dL without RBC transfusions for at least 6 consecutive months any time after CTX001 infusion. The evaluation of TI6 starts 60 days after last RBC transfusion for post-transplant support or TDT disease management. Secondary Endpoints: • Proportion of subjects achieving at least 95%, 90%, 85%, 75%, 50% reduction from baseline in annualized transfusions up to 24 months starting 60 days after CTX001 infusion. • Relative change from baseline in transfusions up to 24 months starting 60 days after CTX001 infusion • Duration of transfusion free in subjects who have achieved TI12 • Proportion of alleles with intended genetic modification present in peripheral blood leukocytes over time. Intended genetic modifications are indels that modify the sequence of the erythrocyte-specific enhancer in intron 2 of BCL11A • Proportion of alleles with intended genetic modification present in CD34+ cells of the bone marrow over time • Fetal hemoglobin concentration (pre-transfusion) over time • Total hemoglobin concentration (pre-transfusion) over time • Change in patient reported outcomes (PROs) over time using EuroQol Quality of Life Scale (EQ 5D 5L) for subjects =18 years old, EQ 5D-Y for subjects <18 years old), functional assessment of cancer therapy bone marrow transplant (FACT-BMT) for subjects =18 years old, and Pediatric Quality of Life Inventory (PedsQL) for subjects <18 years old • Change in parameters of iron overload, including: o Liver iron concentration (LIC) from baseline as assessed by R2* magnetic resonance imaging (MRI) and cardiac iron content (CIC) from baseline as assessed by T2* MRI o Change in serum ferritin level from baseline over time • Proportion of subjects receiving iron chelation therapy over time;Timepoint(s) of evaluation of this end point: Refer to E.5.2 | — |
Countries
Canada, Germany, Greece, Italy, United Kingdom, United States
Contacts
Public ContactClinical Trials and Medical Info
Vertex Pharmaceuticals Incorporated
Outcome results
None listed