Study of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Sickle Cell Disease (SCD)
- Registration Number
- NCT04443907
- Lead Sponsor
- Novartis Pharmaceuticals
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 5
- 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.
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description OTQ923 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.
- Primary Outcome Measures
Name Time Method Fetal hemoglobin (HbF) expression 6 months after hematopoietic stem cell transplant (HSCT) 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 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 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 Outcome Measures
Name Time Method Number of participants with treatment induced anti-Cas9 humoral and cellular immunogenicity up to 24 months To evaluate presence of pre-existing or treatment induced anti-Cas9 humoral and cellular immunogenicity
Transplant-related mortality up to 24 months Assessment of mortality
Overall Survival up to 24 months To evaluate the overall survival which is defined as the time from date of start of treatment to date of death to any cause.
Durability of hematologic engraftment up to 24 months 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
Proportion of subject to achieve 30% of total HbF at 12 months 12 months Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.
Time to achieve 30% total HbF up to 24 months Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.
Time to peak total HbF up to 24 months Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.
Percentage of edited WBC and bone marrow cells by time points up to 24 months Assessment of in vivo cellular kinetics
Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures up to 24 months Determine health status following instruments ASCQ-ME pain impact
Number of participants with change from baseline of annualized VOC rate by 65% Baseline, 12 months The annualized rate at baseline will be compared to that of vaso-occlusive crises (VOC) at 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 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.
Trial Locations
- Locations (3)
University of Chicago
🇺🇸Chicago, Illinois, United States
Memorial Sloan Kettering Cancer Ctr
🇺🇸New York, New York, United States
St Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States