A Safety and Efficacy Study Evaluating CTX001 in Subjects With Transfusion-Dependent β-Thalassemia

Hematologic Diseases Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03655678
• Other study ID #: CTX001-111
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: September 14, 2018
• Est. completion date: August 2024

Study information

• Verified date: November 2023
• Source: Vertex Pharmaceuticals Incorporated
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a single-arm, open-label, multi-site, single-dose Phase 1/2/3 study in subjects 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 45
• Est. completion date: August 2024
• Est. primary completion date: August 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 35 Years

Eligibility

Key Inclusion Criteria:

• Diagnosis of transfusion-dependent ß-thalassemia (TDT) as defined by:

1. 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.

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.

• Subjects with associated a-thalassemia and >1 alpha deletion or alpha multiplications.

• Subjects 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.

Related Conditions & MeSH terms

• Beta-Thalassemia
• Genetic Diseases, Inborn
• Hematologic Diseases
• Hemoglobinopathies
• Thalassemia

Intervention

Biological:
• CTX001
Administered by IV infusion following myeloablative conditioning with busulfan

Locations

Country	Name	City	State
Canada	The Hospital for Sick Children	Toronto
Canada	British Columbia Children's Hospital	Vancouver
Germany	Universitätsklinikum Düsseldorf Hospital Duesseldorf	Düsseldorf
Germany	Regensburg University Hospital, Clinic and Polyclinic for Paediatric and Adolescent Medicine	Regensburg
Germany	University Hospital Tübingen	Tuebingen
Italy	Ospedale Pediatrico Bambino Gesù, IRCCS	Rome
United Kingdom	Imperial College Healthcare NHS Trust, Hammersmith Hospital	London
United Kingdom	University College London Hospitals NHS Foundation Trust	London
United States	Ann & Robert Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	The Children's Hospital at TriStar Centennial Medical Center/ Sarah Cannon Center for Blood Cancers	Nashville	Tennessee
United States	Columbia University Medical Center	New York	New York
United States	Columbia University Medical Center (21+ years)	New York	New York
United States	Lucile Packard Children's Hospital	Palo Alto	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Vertex Pharmaceuticals Incorporated	CRISPR Therapeutics

Countries where clinical trial is conducted

United States,  Canada,  Germany,  Italy,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of subjects achieving transfusion independence for at least 12 consecutive months (TI12)		From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion]
Primary	Proportion of subjects with engraftment (first day of 3 consecutive measurements of absolute neutrophil count [ANC] =500/µL on three different days)		Within 42 days after CTX001 infusion
Primary	Time to neutrophil and platelet engraftment		Days post-infusion to engraftment
Primary	Frequency and severity of collected adverse events (AEs)		Signing of informed consent through Month 24 visit
Primary	Incidence of transplant-related mortality (TRM)		Baseline (pre-transfusion) to 100 days and 1 year post-CTX001 infusion
Primary	All-cause mortality		Signing of informed consent through Month 24 visit
Secondary	Proportion of subjects achieving transfusion independence for at least 6 consecutive months (TI6)		From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion
Secondary	Proportion of subjects achieving at least 95 percent (%), 90%, 85%, 75%, and 50% reduction from baseline in annualized transfusions 60 days after CTX001 infusion		From Day 60 up to 24 months post-CTX001 infusion
Secondary	Relative change from baseline in transfusions 60 days after CTX001 infusion		From Day 60 up to 24 months post-CTX001 infusion
Secondary	Duration of transfusion free in subjects who have achieved TI12		From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion
Secondary	Proportion of alleles with intended genetic modification in peripheral blood leukocytes over time		Day 1 CTX001 infusion through Month 24 visit
Secondary	Proportion of alleles with intended genetic modification present in CD34+ cells of bone marrow over time		Day 1 CTX001 infusion through Month 24 visit
Secondary	Change in fetal hemoglobin concentration over time		Baseline (pre-transfusion) through Month 24 visit
Secondary	Change in total hemoglobin concentration over time		Baseline (pre-transfusion) through Month 24 visit
Secondary	Change in health-related quality of life (HRQoL) from baseline over time using EuroQol Questionnaire (5 dimensions - 5 levels of severity - EQ-5D-5L)	The EQ-5D-5L Questionnaire consists of the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The EQ-5D comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression, and 5 levels: no problems to extreme problems. The subject marks the most appropriate statement in each dimension, resulting in a 1-digit number for that dimension. The digits can be combined in a 5-digit number describing the subject's health state. The EQ VAS records the subject's self-rated health on a 100-point VAS, endpoints labelled "the best health you can imagine" and "the worst health you can imagine."	Screening visit through Month 24 visit
Secondary	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)	The FACT-BMT Questionnaire includes physical, social, family, emotional, and functional well-being, and treatment specific concerns of bone marrow transplantation. Each statement has a 5-point Likert-type response scale ranging from 0=not at all to 4=very much. The subject marks one number per line as it applies to the past 7 days. Questionnaires are scored; the higher the score, the better the QOL.	Screening visit through Month 24 visit
Secondary	Change in patient reported outcome (PRO) over time assessed using EQ-5D-Youth (EQ-5D-Y)		Screening visit through Month 24 visit
Secondary	Change in PRO over time assessed using pediatric quality of life inventory (PedsQL)		Screening visit through Month 24 visit
Secondary	Changes in liver iron concentration (LIC) and cardiac iron content (CIC) and ferritin parameters of iron overload		Screening visit through Month 24 visit
Secondary	Proportion of subjects receiving iron chelation therapy		1 month post-CTX001 infusion through Month 24 visit