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
CRISPR Therapeutics AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age =18 and =35 years of age. 2. Able to provide written informed consent. 3. Diagnosis of transfusion-dependent ß-thalassemia (TDT) as defined by: a. Documented homozygous ß-thalassemia (with the exception of the ß0/ß0 genotype) 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 ß0/ß0 genotypes are defined using the HbVar Database. b. A history of at least 100 mL/kg/year or 10 units/year of packed Red Blood Cell (RBC) transfusions in the prior 2 years before signing the consent. 4. Karnofsky performance status of =80%. 5. Eligible for autologous stem cell transplant as per investigator’s judgment. 6. Access to detailed medical records on packed RBC transfusions, including volume or units of packed RBCs and associated pre-transfusion Hb values, and in-patient hospitalizations, for at least the 2 years prior to consent. 7. Female subjects of childbearing potential (postmenarcheal, has an intact uterus and at least 1 ovary, and is less than 1 year postmenopausal) must agree to use acceptable method(s) of contraception from consent through at least 6 months after CTX001 infusion. 8. Male subjects must agree to use effective contraception (including condoms) from start of busulfan conditioning through at least 6 months after CTX001 infusion. 9. Willing to participate in an additional long-term follow-up study or registry after completion of this study. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 12 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. An available 10/10 Human Leukocyte Antigen (HLA)-matched related donor. 2. Prior allo-hematopoietic stem cell transplant (HSCT). 3. Subjects with associated a-thalassemia and >1 alpha chain deletion. 4. Subjects with a ß0/ß0 thalassemia genotype or 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 (WBC) count 3 x the upper limit of normal (ULN), or direct bilirubin value >2 x the 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, or active hepatitis on liver biopsy. Liver biopsy is required when liver iron concentration (LIC) is =15 mg/g on T2* MRI of liver. If a liver biopsy has been performed less than 6 months prior to consent, it does not need to be repeated. 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 m^2. 13. Diffusing capacity of the lungs for carbon monoxide (DLco) <50% of predicted (corrected for hemoglobin and/or alveolar volume). 14. Prior treatment with gene therapy. 15. Intolerance or known sensitivity to plerixafor, granulocyte colony stimulating factor (G-CSF) products (e.g., filgrastim), or busulfan. Prior anaphylaxis with excipients of CTX001 product (Dimethyl sulfoxide [DMSO], Dextran). 16. Positive serology for human immunodeficiency virus-1 (HIV-1) or human immunodeficiency virus-2 (HIV-2), hepatitis B virus (HBV; hepatitis B core antibody [HBcAb] and positive HBV polymerase chain reaction [PCR]), or hepatitis C virus (HCV) (positive HCV PCR). Positive serology for syphilis, toxoplasmosis or any other infectious disease marker as required by local testing for cellular processing. 17. Participation in another clinical study with an investigational drug within 30 days of screening or fewer than 5 half-lives of the investigational agent, whichever is longer from screening. 18. An assessment by the investigator that the subject would not comply with the study procedures outlined in the protocol. 19. Pregnant or breastfeeding females.
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 bone marrow cells • 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: • Proportion of subjects with engraftment. Engraftment is defined as ANC =500/µL for three consecutive days. Engraftment failure is defined as any subject not achieving neutrophil engraftment by Day +42 following CTX001 infusion or if backup unmodified CD34+ cells are utilized. • Time to engraftment. • Frequency and severity of collected AEs from signing of informed consent through Month 24 visit as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03. • Incidence of transplant related mortality (TRM) at 100 days and 1 year post-CTX001 infusion. TRM is defined as death possibly related to the transplantation procedure as assessed by the investigator. • All-cause mortality. Primary Efficacy: • Proportion of subjects achieving transfusion reduction for at least 6 months (TR6). ;Timepoint(s) of evaluation of this end point: • Safety: see above • Proportion of subjects achieving TR6: 3 months post-CTX001 infusion for at least 6 months at the time of analysis | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key Secondary Efficacy: • Proportion of subjects achieving transfusion independence for at least 6 months (TI6). Secondary Endpoints: • Proportion of subjects achieving transfusion reduction for at least 12 months (TR12). • Proportion of subjects achieving transfusion independence for at least 12 months (TI12). • Proportion of alleles with intended genetic modification present in peripheral blood leukocytes. • Proportion of alleles with intended genetic modification present in bone marrow cells. • Change in fetal hemoglobin concentration (pre-transfusion) over time. • Change in health-related quality of life (HRQoL) from baseline over time using EQ-5D-5L and FACT-BMT. • Change in parameters of iron overload, including: o Liver iron concentration (LIC) 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: • Proportion of subjects achieving TI6: 3 months post-CTX001 infusion for at least 6 months at the time of analysis • Proportion of subjects achieving TR12: 3 months post-CTX001 infusion for at least 12 months at the time of analysis • Proportion of subjects achieving TI12: 3 months post-CTX001 infusion for at least 12 months at the time of analysis • Proportion of alleles with intended genetic modification present in peripheral blood leukocytes and bone marrow cells, change in HbF levels (pre-transfusion): at Months 1, 2, 3, 4, 5, 6, 9, 12, 18, 24 • Change in HRQoL: at Months 3, 6, 12, 18, 24 • Change in parameters of iron overload: o Change in serum ferritin level: continuous variable over time. o Change in LIC: at Months 12 and 24 o Change in Cardiac T2*: at Months 12 and 24 | — |
Countries
Canada, Germany, Italy, United Kingdom
Contacts
Public ContactSenior Medical Director
CRISPR Therapeutics
Outcome results
None listed