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
Overview
- Phase
- Phase 1
- Intervention
- OTQ923
- Conditions
- Sickle Cell Disease
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 4
- Locations
- 3
- Primary Endpoint
- Fetal hemoglobin (HbF) expression 6 months after hematopoietic stem cell transplant (HSCT)
- Status
- Terminated
- Last Updated
- 3 months ago
Overview
Brief Summary
This study evaluated 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.
Detailed Description
CADPT03A12101 was a multicenter, multi-part, first-in-human, proof-of-concept, open label non-randomized, clinical study in Sickle Cell Disease (SCD) subjects. This study included 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 was divided into the following parts: * Part A - Adult subjects were dosed with OTQ923. * Part B - Assessment of OTQ923 in pediatric patients, however Part B was not opened.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male or female subjects age 2-40 years inclusive
- •Confirmed diagnosis of sickle cell disease with globin typing (e.g. HbSS, HbSC, HbS/β0-thalassemia or others)
- •Performance status \>70% (Karnofsky for subjects \>16 years of age and Lansky for subjects \<16 years of age)
- •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
- •Subjects, who have failed, not tolerated or refused hydroxyurea therapy.
Exclusion Criteria
- •Available matched related donor for HSCT
- •Clinically significant active infection
- •Seropositive for HIV or HTLV
- •Active known malignancy, myelodysplasia, abnormal cytogenetics or immunodeficiency
- •Prior HSCT or gene therapy
- •Known hepatic cirrhosis, bridging hepatic fibrosis or active hepatitis
- •Protocol defined iron overload
- •Cerebrovascular procedure within one year, including pial synangiosis for Moyamoya
- •Severe or progressive arteriopathy or cerebrovascular disease, including Moyamoya
- •Other protocol defined inclusion/exclusion criteria may apply
Arms & Interventions
OTQ923
Single intravenous infusion of OTQ923 Part A - Adults treated with OTQ923; Part B - Children age 2-17 treated with OTQ923 based on review of data from Part A by Health agency after a formal interim analysis.
Intervention: OTQ923
Outcomes
Primary Outcomes
Fetal hemoglobin (HbF) expression 6 months after hematopoietic stem cell transplant (HSCT)
Time Frame: at 6 months
Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.
Time to reach absolute neutrophil count (ANC) ≥500/μL for 3 consecutive days
Time Frame: up to 24 months
Time to engraftment is defined as first of 3 consecutive days when an absolute neutrophil count (ANC) ≥500/μL after receiving OTQ923 was reached.
Number of participants with adverse events and serious adverse events
Time Frame: up to 24 months
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.
Secondary Outcomes
- Number of participants with treatment induced anti-Cas9 humoral and cellular immunogenicity(up to 24 months)
- Transplant-related mortality(up to 24 months)
- Overall Survival(up to 24 months)
- Durability of hematologic engraftment(up to 24 months)
- Proportion of subject to achieve 30% of total HbF at 12 months(12 months)
- Time to achieve 30% total HbF(up to 24 months)
- Time to peak total HbF(up to 24 months)
- Percentage of edited WBC and bone marrow cells by time points(up to 24 months)
- Number of participants with change from baseline of annualized VOC rate by 65%(Baseline, 12 months)
- 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%(Bseline, 12 months)
- Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures(up to 24 months)