Study of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Sickle Cell Disease (SCD)

Sickle Cell Disease Clinical Trial

Official title:

A First-in-patient Phase I/II Clinical Study to Investigate the Safety, Tolerability and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Subjects With Severe Complications of Sickle Cell Disease

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04443907
• Other study ID #: CADPT03A12101
• Secondary ID: 2019-003489-41
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: August 26, 2020
• Est. completion date: September 18, 2026

Study information

• Verified date: January 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is evaluating a genome-edited, autologous, hematopoietic stem and progenitor cell (HSPC) product - OTQ923 to reduce the biologic activity of BCL11A, increasing fetal hemoglobin (HbF) and reducing complications of sickle cell disease.

Description:

CADPT03A12101 is a multicenter, multi-part, first-in-human, proof-of-concept, open label non-randomized, clinical study in Sickle Cell Disease (SCD) subjects. This study includes apheresis of mobilized hematopoietic stem and progenitor cells (HSPCs), ex vivo CRISPR/Cas9-mediated genome editing and expansion, followed by myeloablative conditioning and autologous hematopoietic stem cell transplant (HSCT) with follow-up for a minimum of one year and up to two years. The study is divided into the following parts: - Part A - Adult subjects dosed with OTQ923. - Part B - Assessment of OTQ923 in pediatric patients. Part B will not be opened.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 5
• Est. completion date: September 18, 2026
• Est. primary completion date: August 19, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 40 Years

Eligibility

Inclusion Criteria:

1. Male or female subjects age 2-40 years inclusive

2. Confirmed diagnosis of sickle cell disease with globin typing (e.g. HbSS, HbSC, HbS/ß0-thalassemia or others)

3. Performance status >70% (Karnofsky for subjects >16 years of age and Lansky for subjects <16 years of age)

4. At least one of the following indicators of disease severity as defined in the protocol - Vaso-occlusive pain crisis, Acute chest syndrome, Recurrent priapism, prior stroke, receive chronic transfusions, Red cell alloimmunization

5. Subjects, who have failed, not tolerated or refused hydroxyurea therapy.

Exclusion Criteria:

1. Available matched related donor for HSCT

2. Clinically significant active infection

3. Seropositive for HIV or HTLV

4. Active known malignancy, myelodysplasia, abnormal cytogenetics or immunodeficiency

5. Prior HSCT or gene therapy

6. Known hepatic cirrhosis, bridging hepatic fibrosis or active hepatitis

7. Protocol defined iron overload

8. Cerebrovascular procedure within one year, including pial synangiosis for Moyamoya

9. Severe or progressive arteriopathy or cerebrovascular disease, including Moyamoya Other protocol defined inclusion/exclusion criteria may apply

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Biological:
• OTQ923
Single intravenous infusion of OTQ923 cell suspension
• OTQ923
Single intravenous infusion of OTQ923, based on review of data from Part A by Health agencies after a formal interim analysis

Locations

Country	Name	City	State
United States	University of Chicago SC - 2	Chicago	Illinois
United States	St Jude Children's Research Hospital	Memphis	Tennessee
United States	Memorial Sloan Kettering Cancer Ctr	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants with adverse events and serious adverse events	Number of participants with adverse events (AEs) and serious adverse events (SAEs), including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs.	up to 24 months
Primary	Fetal hemoglobin (HbF) expression after hematopoietic stem cell transplant (HSCT)	Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.	up to 24 months
Primary	Time to reach absolute neutrophil count (ANC) =500/µL for 3 consecutive days	Time to engraftment is defined as first of 3 consecutive days when an absolute neutrophil count (ANC) =500/µL after receiving OTQ923 was reached.	up to 24 months
Secondary	Durability of hematologic engraftment	Engraftment durability/persistence by measuring the proportion of alleles with on-target CRISPR modification in peripheral blood (total white blood cells (WBC)) and bone marrow over time up to 24 months	up to 24 months
Secondary	Proportion of subject to achieve 30% of total HbF at 12 months	Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.	12 months
Secondary	Time to achieve 30% total HbF	Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.	up to 24 months
Secondary	Time to peak total HbF	Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.	up to 24 months
Secondary	Percentage of edited WBC and bone marrow cells by time points	Assessment of in vivo cellular kinetics	up to 24 months
Secondary	Number of participants with treatment induced anti-Cas9 humoral and cellular immunogenicity	To evaluate presence of pre-existing or treatment induced anti-Cas9 humoral and cellular immunogenicity	up to 24 months
Secondary	Overall Survival	To evaluate the overall survival which is defined as the time from date of start of treatment to date of death to any cause.	up to 24 months
Secondary	Transplant-related mortality	Assessment of mortality	up to 24 months
Secondary	Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures	Determine health status following instruments ASCQ-ME emotional impact	up to 24 months
Secondary	Number of participants with change from baseline of annualized VOC rate by 65%	The annualized rate at baseline will be compared to that of vaso-occlusive crises (VOC) at 12 months.	Baseline, 12 months
Secondary	Number of participants with change from baseline of annualized SCD complications (aggregate of VOC, ACS, priapism and stroke) and if relevant, rate of transfusion by 65%	The annualized rate at baseline will be compared to that of aggregate Sickle Cell Disease (SCD) complications (VOC, acute chest syndrome (ACS), priapism, and stroke) and transfusions at 12 months.	Bseline, 12 months
Secondary	Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures	Determine health status following instruments PROMIS fatique	up to 24 months
Secondary	Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures	Determine health status following instruments PROMIS physical functioning	up to 24 months
Secondary	Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures	Determine health status following instruments ASCQ-ME sleep impact	up to 24 months
Secondary	Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures	Determine health status following instruments ASCQ-ME pain impact	up to 24 months