Transplantation of Clustered Regularly Interspaced Short Palindromic Repeats Modified Hematopoietic Progenitor Stem Cells (CRISPR_SCD001) in Patients With Severe Sickle Cell Disease
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|ClinicalTrials.gov Identifier: NCT04774536|
Recruitment Status : Not yet recruiting
First Posted : March 1, 2021
Last Update Posted : April 27, 2022
|Condition or disease||Intervention/treatment||Phase|
|Sickle Cell Disease||Drug: CRISPR_SCD001||Phase 1 Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||9 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Transplantation of CRISPRCas9 Corrected Hematopoietic Stem Cells (CRISPR_SCD001) in Patients With Severe Sickle Cell Disease|
|Estimated Study Start Date :||December 1, 2022|
|Estimated Primary Completion Date :||December 1, 2024|
|Estimated Study Completion Date :||December 1, 2027|
Experimental: CRISPR_SCD001 Drug Product
CRISPR_SCD001 Drug Product (autologous CD34+ cell-enriched population that contains cells modified by the CRISPR-Cas9 ribonucleoprotein) dose will be ≥3.0×106 CD34+ cells/kg recipient weight for each subject and the upper limit cell dose is 20 ×106 CD34+ cells/kg.
CRISPR_SCD001 is administered by IV infusion following myeloablative conditioning with busulfan.
- Incidence of adverse events and grade 3 or higher serious adverse events, using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) [ Time Frame: 24 months post-transplant ]The adverse event rate will be summarized using descriptive statistics, together with 95% confidence intervals where appropriate. No formal statistical hypothesis testing will be performed. Adverse events defined: failure of engraftment, malignant clonal expansion related to genomic editing or death.
- Change in the annualized vaso-occlusive pain event (VOE) rates. [ Time Frame: 24 months pre-transplant to 24 months post-transplant ]Change in the annualized vast-occlusive pain event (VOE) rates comparing the 24 months before with 24 months after the infusion of drug product.
- Graft rejection defined as having an absolute neutrophil count (ANC) < 500 at 42 days post-infusion [ Time Frame: 42 days post-transplant ]A delay in platelet and/or neutrophil engraftment will be captured.
- Time to neutrophil recovery defined as the first of 3 measurements on different days when the patient has an absolute neutrophil count (ANC) of ≥500/µL after transplant. [ Time Frame: 24 months post-transplant ]Neutrophil recovery as part of the overall hematological recovery.
- Time to platelet recovery is defined as the first day of a minimum of 3 measurements on different days that the patient has achieved a platelet count > 50,000/µL AND did not receive a platelet transfusion in the previous 7 days. [ Time Frame: baseline, through 24 months post-transplant ]Platelet recovery as part of the overall hematological recovery.
- Rate of improvement in Hemoglobin S (HbS) fraction as measured by hemoglobin electrophoresis, as percent of total. [ Time Frame: baseline, through 24 months post-transplant ]Hemolysis markers.
- Rate of normalization in hemoglobin (hgb) level as measured by clinical hematology (laboratory) test. [ Time Frame: baseline, through 24 months post-transplant ]Hemolysis markers.
- Rate of normalization of lactate dehydrogenase (LDH), reticulocyte count, and haptoglobin, as measured by clinical hematology and serum chemistry (laboratory) tests. [ Time Frame: baseline, through 24 months post-transplant ]Hemolysis markers.
- Frequency of hepatic veno-occlusive disease (VOD) as measured by Seattle or Baltimore Criteria for VOD Diagnosis. [ Time Frame: 24 months post-transplant ]Hematologic and non-hematologic toxicities of autologous transplantation with CRISPR-Cas9 sickle-corrected HSPCs.
- Frequency of hepatic idiopathic pneumonia syndrome (IPS) as measured by the Idiopathic pneumonia syndrome (IPS) criteria. [ Time Frame: 24 months post-transplant ]Hematologic and non-hematologic toxicities of autologous transplantation with CRISPR-Cas9 sickle-corrected HSPCs.
- Frequency of central nervous system (CNS) toxicity (reversible posterior leukoencephalopathy syndrome [RPLS] or posterior reversible encephalopathy syndrome [PRES], hemorrhage, and seizures). [ Time Frame: 24 months post-transplant ]Hematologic and non-hematologic toxicities of autologous transplantation with CRISPR-Cas9 sickle-corrected HSPCs.
- Frequency of cytomegalovirus (CMV) infection, invasive fungal infection, and any other serious viral or bacterial infection [ Time Frame: 24 months post-transplant ]
- Frequency of sickle gene-editing (correction and insertion/deletion) and off-target site-1 editing in marrow and peripheral blood mononuclear cells. [ Time Frame: 3 months, 1 and 2 years post-transplant ]Stability of gene-editing in hematopoietic cells by genotyping studies.
- Rate of sickle-related events other than severe VOE and end organ function. [ Time Frame: 24 months post-infusion ]Rate of sickle-related complications after infusion
- Patient-reported quality of life (pain and fatigue domains) as measured by the use of Patient Reported Outcome Measurement Information System (PROMIS) modules. [ Time Frame: baseline, and 1 and 2 years post-transplant ]
Change in quality of life score at baseline (prior to the initiation of hydroxyurea), 1 year and 2 years post-stem cell infusion accessed using Patient Reported Outcome Measurement Information System (PROMIS) modules. The PROMIS modules rate the following areas:
- Physical Function and Sleep Quality on a scale of 1 (not good) to 5 (good).
- Anxiety, Depression, Fatigue, Pain Interference and the Ability to Participate in Social Roles and Activities on a scale of 1 (never) to 5 (always).
- Pain Intensity on a scale from 0 (no pain) to 10 (worst pain imaginable).
- Change from baseline in cardiac-pulmonary function via pulmonary function tests [ Time Frame: Through 1 and 2 years post-transplant ]
- Change from baseline in cardiac-pulmonary function via echocardiogram (tricuspid regurgitant jet velocity [TRJV], LVEF). [ Time Frame: Through 1 and 2 years post-transplant ]
- Change from baseline in meters walked during 6-minute walk test (6MWD) [ Time Frame: Through 1 and 2 years post-transplant ]
- Event-free survival defined as survival without clinical and hematological evidence of the underlying Sickle Cell Disease (SCD) [ Time Frame: 1 and 2 years post-transplant ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04774536
|Contact: Mark Walters, MD||(510) 428-3374||Mark.Walters@ucsf.edu|
|Contact: Christina Chun, MPH||(415) 502-2558||Christina.Chun@ucsf.edu|
|United States, California|
|University of California, Los Angeles|
|Los Angeles, California, United States, 90095|
|Contact: Augustine Fernandes, PhD email@example.com|
|Principal Investigator: Donald B Kohn, MD|
|UCSF Benioff Children's Hospital|
|Oakland, California, United States, 94609|
|Contact: Cyrus Bascon 510-428-3885 ext 6953 Cyrus.Bascon@ucsf.edu|
|Principal Investigator: Mark Walters, MD|
|Principal Investigator:||Mark Walters, MD||UCSF Benioff Children's Hospital Oakland|