Back to resultsStudy of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Sickle Cell Disease (SCD)
Primary Purpose
Sickle Cell Disease
Status
Active
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
OTQ923
OTQ923
Sponsored by
About this trial
This is an interventional treatment trial for Sickle Cell Disease focused on measuring Gene therapy, genome-edited hematopoietic stem and progenitor cellular therapy, sickle cell, autologous transplant, BCL11A
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
Sites / Locations
- University of Chicago SC - 2
- Memorial Sloan Kettering Cancer Ctr
- St Jude Children's Research Hospital
- Novartis Investigative Site
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
OTQ923
Arm Description
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.
Outcomes
Primary Outcome Measures
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.
Fetal hemoglobin (HbF) expression after hematopoietic stem cell transplant (HSCT)
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 to engraftment is defined as first of 3 consecutive days when an absolute neutrophil count (ANC) ≥500/μL after receiving OTQ923 was reached.
Secondary Outcome Measures
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
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.
Time to achieve 30% total HbF
Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.
Time to peak total HbF
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
Assessment of in vivo cellular kinetics
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
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.
Transplant-related mortality
Assessment of mortality
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
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.
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.
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
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
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
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
Full Information
NCT ID
NCT04443907
First Posted
April 29, 2020
Last Updated
September 8, 2023
Sponsor
Novartis Pharmaceuticals
1. Study Identification
Unique Protocol Identification Number
NCT04443907
Brief Title
Study of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Sickle Cell Disease (SCD)
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
Study Type
Interventional
2. Study Status
Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
August 26, 2020 (Actual)
Primary Completion Date
August 19, 2025 (Anticipated)
Study Completion Date
September 18, 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief 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.
Detailed 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease
Keywords
Gene therapy, genome-edited hematopoietic stem and progenitor cellular therapy, sickle cell, autologous transplant, BCL11A
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Masking Description
The is an open-label study.
Allocation
N/A
Enrollment
5 (Actual)
8. Arms, Groups, and Interventions
Arm Title
OTQ923
Arm Type
Experimental
Arm Description
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 Type
Biological
Intervention Name(s)
OTQ923
Other Intervention Name(s)
Adult Part A
Intervention Description
Single intravenous infusion of OTQ923 cell suspension
Intervention Type
Biological
Intervention Name(s)
OTQ923
Other Intervention Name(s)
Children 2-17 years old - Part B
Intervention Description
Single intravenous infusion of OTQ923, based on review of data from Part A by Health agencies after a formal interim analysis
Primary Outcome Measure Information:
Title
Number of participants with adverse events and serious adverse events
Description
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.
Time Frame
up to 24 months
Title
Fetal hemoglobin (HbF) expression after hematopoietic stem cell transplant (HSCT)
Description
Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.
Time Frame
up to 24 months
Title
Time to reach absolute neutrophil count (ANC) ≥500/μL for 3 consecutive days
Description
Time to engraftment is defined as first of 3 consecutive days when an absolute neutrophil count (ANC) ≥500/μL after receiving OTQ923 was reached.
Time Frame
up to 24 months
Secondary Outcome Measure Information:
Title
Durability of hematologic engraftment
Description
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
Time Frame
up to 24 months
Title
Proportion of subject to achieve 30% of total HbF at 12 months
Description
Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.
Time Frame
12 months
Title
Time to achieve 30% total HbF
Description
Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.
Time Frame
up to 24 months
Title
Time to peak total HbF
Description
Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.
Time Frame
up to 24 months
Title
Percentage of edited WBC and bone marrow cells by time points
Description
Assessment of in vivo cellular kinetics
Time Frame
up to 24 months
Title
Number of participants with treatment induced anti-Cas9 humoral and cellular immunogenicity
Description
To evaluate presence of pre-existing or treatment induced anti-Cas9 humoral and cellular immunogenicity
Time Frame
up to 24 months
Title
Overall Survival
Description
To evaluate the overall survival which is defined as the time from date of start of treatment to date of death to any cause.
Time Frame
up to 24 months
Title
Transplant-related mortality
Description
Assessment of mortality
Time Frame
up to 24 months
Title
Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures
Description
Determine health status following instruments ASCQ-ME emotional impact
Time Frame
up to 24 months
Title
Number of participants with change from baseline of annualized VOC rate by 65%
Description
The annualized rate at baseline will be compared to that of vaso-occlusive crises (VOC) at 12 months.
Time Frame
Baseline, 12 months
Title
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%
Description
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.
Time Frame
Bseline, 12 months
Title
Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures
Description
Determine health status following instruments PROMIS fatique
Time Frame
up to 24 months
Title
Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures
Description
Determine health status following instruments PROMIS physical functioning
Time Frame
up to 24 months
Title
Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures
Description
Determine health status following instruments ASCQ-ME sleep impact
Time Frame
up to 24 months
Title
Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures
Description
Determine health status following instruments ASCQ-ME pain impact
Time Frame
up to 24 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
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
Facility Information:
Facility Name
University of Chicago SC - 2
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Ctr
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
St Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105-3678
Country
United States
Facility Name
Novartis Investigative Site
City
Milano
State/Province
MI
ZIP/Postal Code
20132
Country
Italy
12. IPD Sharing Statement
Plan to Share IPD
No
IPD Sharing Plan Description
Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
Learn more about this trial
Study of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Sickle Cell Disease (SCD)
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