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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Biological: OTQ923
* Biological: OTQ923


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OTQ923<br>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. | Biological: OTQ923<br>* Single intravenous infusion of OTQ923 cell suspension<br>* Other names: Adult Part A;Biological: OTQ923<br>* Single intravenous infusion of OTQ923, based on review of data from Part A by Health agencies after a formal interim analysis<br>* Other names: Children 2-17 years old - Part B;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| Time to achieve 30% total HbF | Assessment of HbF expression will be done by measuring total fetal hemoglobin over time. | up to 24 months | 
| Time to peak total HbF | Assessment of HbF expression will be done by measuring total fetal hemoglobin over time. | up to 24 months | 
| Percentage of edited WBC and bone marrow cells by time points | Assessment of in vivo cellular kinetics | up to 24 months | 
| 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 | 
| 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 | 
| Transplant-related mortality | Assessment of mortality | up to 24 months | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gene therapy, genome-edited hematopoietic stem and progenitor cellular therapy, sickle cell, autologous transplant, BCL11A