Clinical trial NCT03655678: A Safety and Efficacy Study Evaluating CTX001 in Participants With Transfusion-Dependent β-Thalassemia
Official title: A Phase 1/2/3 Study of the Safety and Efficacy of a Single Dose of Autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPCs) in Subjects With Transfusion-Dependent β-Thalassemia
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Beta-Thalassemia
Thalassemia
Genetic Diseases, Inborn
Hematologic Diseases
Hemoglobinopathies
Keywords: CRISPR-Cas9
Beta-Thalassemia
Hemoglobinopathies
Lead sponsor: Vertex Pharmaceuticals Incorporated
Sponsor class: INDUSTRY
Collaborators: name: CRISPR Therapeutics
First posted: 2018-08-31
Enrollment: 59
Sex: ALL
Minimum age (years): 12
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a single-arm, open-label, multi-site, single-dose Phase 1/2/3 study in participans with transfusion-dependent β-thalassemia (TDT). The study will evaluate the safety and efficacy of autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPCs) using CTX001.


Eligibility criteria: Key Inclusion Criteria:

* Diagnosis of transfusion-dependent β-thalassemia (TDT) as defined by

  1. Documented homozygous β-thalassemia or compound heterozygous β-thalassemia including β-thalassemia/hemoglobin E (HbE). Participants can be enrolled based on historical data, but a confirmation of the genotype using the study central laboratory will be required before busulfan conditioning
  2. 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 re-screening
* Eligible for autologous stem cell transplant as per investigator's judgment

Key Exclusion Criteria:

* A willing and healthy 10/10 Human Leukocyte Antigen (HLA)-matched related donor is available per investigator's judgement
* Prior allo-HSCT
* Participants with associated α-thalassemia and \>1 alpha deletion or alpha multiplications
* Participants with sickle cell beta thalassemia variant
* Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator
* White blood cell (WBC) count \<3 × 10\^9/L or platelet count \<50 × 10\^9/L not related to hypersplenism

Other protocol defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Proportion of participants achieving transfusion independence for at least 12 consecutive months (TI12)
timeFrame: From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion]
measure: Proportion of participants with engraftment (first day of 3 consecutive measurements of absolute neutrophil count [ANC] ≥500/µL on three different days)
timeFrame: Within 42 days after CTX001 infusion
measure: Time to neutrophil and platelet engraftment
timeFrame: Days post-infusion to engraftment
measure: Frequency and severity of collected adverse events (AEs)
timeFrame: Signing of informed consent through Month 24 visit
measure: Incidence of transplant-related mortality (TRM)
timeFrame: Baseline (pre-transfusion) to 100 days and 1 year post-CTX001 infusion
measure: All-cause mortality
timeFrame: Signing of informed consent through Month 24 visit
Secondary outcomes:
measure: Proportion of participants achieving transfusion independence for at least 6 consecutive months (TI6)
timeFrame: From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion
measure: Proportion of participants achieving at least 95 percent (%), 90%, 85%, 75%, and 50% reduction from baseline in annualized volume of RBC transfusions after Month 10 after CTX001 infusion
timeFrame: From Month 10 up to 24 months post-CTX001 infusion
measure: Relative reduction from baseline in annualized volume of RBC transfusions after Month 10 after CTX001 infusion
timeFrame: From Month 10 up to 24 months post-CTX001 infusion
measure: Duration of transfusion free in participants who have achieved TI12
timeFrame: From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion
measure: Proportion of alleles with intended genetic modification in peripheral blood leukocytes over time
timeFrame: Day 1 CTX001 infusion through Month 24 visit
measure: Proportion of alleles with intended genetic modification present in CD34+ cells of bone marrow over time
timeFrame: Day 1 CTX001 infusion through Month 24 visit
measure: Change in fetal hemoglobin concentration over time
timeFrame: Baseline (pre-transfusion) through Month 24 visit
measure: Change in total hemoglobin concentration over time
timeFrame: Baseline (pre-transfusion) through Month 24 visit
measure: Change in health-related quality of life (HRQoL) from baseline over time using EuroQol Questionnaire (5 dimensions - 5 levels of severity - EQ-5D-5L)
timeFrame: Screening visit through Month 24 visit
measure: Change in health-related quality of life (HRQoL) from baseline over time using the Functional assessment of cancer therapy-bone marrow transplant questionnaire (FACT-BMT)
timeFrame: Screening visit through Month 24 visit
measure: Change in patient reported outcome (PRO) over time assessed using EQ-5D-Youth (EQ-5D-Y)
timeFrame: Screening visit through Month 24 visit
measure: Change in PRO over time assessed using pediatric quality of life inventory (PedsQL)
timeFrame: Screening visit through Month 24 visit
measure: Changes in liver iron concentration (LIC) and cardiac iron content (CIC) and ferritin parameters of iron overload
timeFrame: Screening visit through Month 24 visit
measure: Proportion of participants receiving iron chelation therapy
timeFrame: 1 month post-CTX001 infusion through Month 24 visit
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital
state: California
city: Chicago
country: United States
facility: Ann & Robert Lurie Children's Hospital of Chicago
state: Illinois
city: New York
country: United States
facility: Columbia University Medical Center (21+ years)
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Nashville
country: United States
facility: The Children's Hospital at TriStar Centennial Medical Center/ Sarah Cannon Center for Blood Cancers
state: Tennessee
city: Toronto
country: Canada
facility: The Hospital for Sick Children
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf Hospital Duesseldorf
city: Regensburg
country: Germany
facility: Regensburg University Hospital, Clinic and Polyclinic for Paediatric and Adolescent Medicine
city: Tuebingen
country: Germany
facility: University Hospital Tübingen
city: Rome
country: Italy
facility: Ospedale Pediatrico Bambino Gesù, IRCCS
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust, Hammersmith Hospital
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
Study officials:
References:
citation: Brusson M, Miccio A. Genome editing approaches to beta-hemoglobinopathies. Prog Mol Biol Transl Sci. 2021;182:153-183. doi: 10.1016/bs.pmbts.2021.01.025. Epub 2021 Mar 1.
citation: Frangoul H, Altshuler D, Cappellini MD, Chen YS, Domm J, Eustace BK, Foell J, de la Fuente J, Grupp S, Handgretinger R, Ho TW, Kattamis A, Kernytsky A, Lekstrom-Himes J, Li AM, Locatelli F, Mapara MY, de Montalembert M, Rondelli D, Sharma A, Sheth S, Soni S, Steinberg MH, Wall D, Yen A, Corbacioglu S. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and beta-Thalassemia. N Engl J Med. 2021 Jan 21;384(3):252-260. doi: 10.1056/NEJMoa2031054. Epub 2020 Dec 5.