Clinical trial NCT04443907: 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
Overall status: TERMINATED
Phase: PHASE1
Conditions: Sickle Cell Disease
Keywords: Gene therapy
genome-edited hematopoietic stem and progenitor cellular therapy
sickle cell
autologous transplant
BCL11A
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2020-06-23
Enrollment: 4
Sex: ALL
Minimum age (years): 2
Maximum age (years): 40
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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/β0-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

Primary outcomes:
measure: Number of participants with adverse events and serious adverse events
timeFrame: up to 24 months
measure: Fetal hemoglobin (HbF) expression 6 months after hematopoietic stem cell transplant (HSCT)
timeFrame: at 6 months
measure: Time to reach absolute neutrophil count (ANC) ≥500/μL for 3 consecutive days
timeFrame: up to 24 months
Secondary outcomes:
measure: Durability of hematologic engraftment
timeFrame: up to 24 months
measure: Proportion of subject to achieve 30% of total HbF at 12 months
timeFrame: 12 months
measure: Time to achieve 30% total HbF
timeFrame: up to 24 months
measure: Time to peak total HbF
timeFrame: up to 24 months
measure: Percentage of edited WBC and bone marrow cells by time points
timeFrame: up to 24 months
measure: Number of participants with treatment induced anti-Cas9 humoral and cellular immunogenicity
timeFrame: up to 24 months
measure: Overall Survival
timeFrame: up to 24 months
measure: Transplant-related mortality
timeFrame: up to 24 months
measure: Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures
timeFrame: up to 24 months
measure: Number of participants with change from baseline of annualized VOC rate by 65%
timeFrame: Baseline, 12 months
measure: 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%
timeFrame: Bseline, 12 months
measure: Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures
timeFrame: up to 24 months
measure: Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures
timeFrame: up to 24 months
measure: Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures
timeFrame: up to 24 months
measure: Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures
timeFrame: up to 24 months
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Ctr
state: New York
city: Memphis
country: United States
facility: St Jude Children's Research Hospital
state: Tennessee
Study officials:
References: