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Transplantation of Clustered Regularly Interspaced Short Palindromic Repeats Modified Hematopoietic Progenitor Stem Cells (CRISPR_SCD001) in Patients With Severe Sickle Cell Disease

Studies

Study First Submitted Date 2021-02-17
Study First Posted Date 2021-03-01
Last Update Posted Date 2023-07-07
Start Month Year June 1, 2024
Primary Completion Month Year June 1, 2025
Verification Month Year July 2023
Verification Date 2023-07-31
Last Update Posted Date 2023-07-07

Detailed Descriptions

Sequence: 20782356
Description This is an open label, non-randomized, 2-center, phase 1/2 trial of a single infusion of sickle allele modified CD34+ HSPCs in subjects with severe SCD. The primary endpoint of the trial will determine the safety of CRISPR_SCD001 through a 3+3 design with staggered enrollment and a pause in enrollment for safety review after each of the first 3 patients has had drug product infused. After safety is assessed in the 3rd patient, enrollment of the next 3 patients will not be staggered. The first six subjects will be adults. If CRISPR_SCD001 is determined to be safe in the first six subjects, the trial will continue to enroll 3 adolescents 12 – 18 years of age to evaluate the safety in younger patients. The younger age cohort also will follow staggered enrollment.

Facilities

Sequence: 200608669 Sequence: 200608670
Name University of California, Los Angeles Name UCSF Benioff Children's Hospital
City Los Angeles City Oakland
State California State California
Zip 90095 Zip 94609
Country United States Country United States

Facility Contacts

Sequence: 28186281 Sequence: 28186282
Facility Id 200608669 Facility Id 200608670
Contact Type primary Contact Type primary
Name Augustine Fernandes, PhD Name Cyrus Bascon
Email afernandes@mednet.ucla.edu Email Cyrus.Bascon@ucsf.edu
Phone 510-428-3885
Phone Extension 6953

Facility Investigators

Sequence: 18380031 Sequence: 18380032
Facility Id 200608669 Facility Id 200608670
Role Principal Investigator Role Principal Investigator
Name Donald B Kohn, MD Name Mark Walters, MD

Conditions

Sequence: 52326499
Name Sickle Cell Disease
Downcase Name sickle cell disease

Id Information

Sequence: 40269684
Id Source org_study_id
Id Value 21-33287

Countries

Sequence: 42689310
Name United States
Removed False

Design Groups

Sequence: 55766158
Group Type Experimental
Title CRISPR_SCD001 Drug Product
Description 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.

Interventions

Sequence: 52637437
Intervention Type Drug
Name CRISPR_SCD001
Description CRISPR_SCD001 is administered by IV infusion following myeloablative conditioning with busulfan.

Design Outcomes

Sequence: 177953271 Sequence: 177953272 Sequence: 177953273 Sequence: 177953274 Sequence: 177953275 Sequence: 177953276 Sequence: 177953277 Sequence: 177953278 Sequence: 177953279 Sequence: 177953280 Sequence: 177953281 Sequence: 177953282 Sequence: 177953283 Sequence: 177953284 Sequence: 177953285 Sequence: 177953286 Sequence: 177953287 Sequence: 177953288 Sequence: 177953289
Outcome Type primary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type secondary Outcome Type other Outcome Type other Outcome Type other Outcome Type other Outcome Type other Outcome Type other
Measure 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) Measure Change in the annualized vaso-occlusive pain event (VOE) rates. Measure Graft rejection defined as having an absolute neutrophil count (ANC) < 500 at 42 days post-infusion Measure 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. Measure 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. Measure Rate of improvement in Hemoglobin S (HbS) fraction as measured by hemoglobin electrophoresis, as percent of total. Measure Rate of normalization in hemoglobin (hgb) level as measured by clinical hematology (laboratory) test. Measure Rate of normalization of lactate dehydrogenase (LDH), reticulocyte count, and haptoglobin, as measured by clinical hematology and serum chemistry (laboratory) tests. Measure Frequency of hepatic veno-occlusive disease (VOD) as measured by Seattle or Baltimore Criteria for VOD Diagnosis. Measure Frequency of hepatic idiopathic pneumonia syndrome (IPS) as measured by the Idiopathic pneumonia syndrome (IPS) criteria. Measure Frequency of central nervous system (CNS) toxicity (reversible posterior leukoencephalopathy syndrome [RPLS] or posterior reversible encephalopathy syndrome [PRES], hemorrhage, and seizures). Measure Frequency of cytomegalovirus (CMV) infection, invasive fungal infection, and any other serious viral or bacterial infection Measure Frequency of sickle gene-editing (correction and insertion/deletion) and off-target site-1 editing in marrow and peripheral blood mononuclear cells. Measure Rate of sickle-related events other than severe VOE and end organ function. Measure Patient-reported quality of life (pain and fatigue domains) as measured by the use of Patient Reported Outcome Measurement Information System (PROMIS) modules. Measure Change from baseline in cardiac-pulmonary function via pulmonary function tests Measure Change from baseline in cardiac-pulmonary function via echocardiogram (tricuspid regurgitant jet velocity [TRJV], LVEF). Measure Change from baseline in meters walked during 6-minute walk test (6MWD) Measure Event-free survival defined as survival without clinical and hematological evidence of the underlying Sickle Cell Disease (SCD)
Time Frame 24 months post-transplant Time Frame 24 months pre-transplant to 24 months post-transplant Time Frame 42 days post-transplant Time Frame 24 months post-transplant Time Frame baseline, through 24 months post-transplant Time Frame baseline, through 24 months post-transplant Time Frame baseline, through 24 months post-transplant Time Frame baseline, through 24 months post-transplant Time Frame 24 months post-transplant Time Frame 24 months post-transplant Time Frame 24 months post-transplant Time Frame 24 months post-transplant Time Frame 3 months, 1 and 2 years post-transplant Time Frame 24 months post-infusion Time Frame baseline, and 1 and 2 years post-transplant Time Frame Through 1 and 2 years post-transplant Time Frame Through 1 and 2 years post-transplant Time Frame Through 1 and 2 years post-transplant Time Frame 1 and 2 years post-transplant
Description 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. Description Change in the annualized vast-occlusive pain event (VOE) rates comparing the 24 months before with 24 months after the infusion of drug product. Description A delay in platelet and/or neutrophil engraftment will be captured. Description Neutrophil recovery as part of the overall hematological recovery. Description Platelet recovery as part of the overall hematological recovery. Description Hemolysis markers. Description Hemolysis markers. Description Hemolysis markers. Description Hematologic and non-hematologic toxicities of autologous transplantation with CRISPR-Cas9 sickle-corrected HSPCs. Description Hematologic and non-hematologic toxicities of autologous transplantation with CRISPR-Cas9 sickle-corrected HSPCs. Description Hematologic and non-hematologic toxicities of autologous transplantation with CRISPR-Cas9 sickle-corrected HSPCs. Description Hematologic and non-hematologic toxicities of autologous transplantation with CRISPR-Cas9 sickle-corrected HSPCs. Description Stability of gene-editing in hematopoietic cells by genotyping studies. Description Rate of sickle-related complications after infusion Description 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).

Browse Conditions

Sequence: 194077731 Sequence: 194077732 Sequence: 194077733 Sequence: 194077734 Sequence: 194077735 Sequence: 194077736 Sequence: 194077737
Mesh Term Anemia, Sickle Cell Mesh Term Anemia, Hemolytic, Congenital Mesh Term Anemia, Hemolytic Mesh Term Anemia Mesh Term Hematologic Diseases Mesh Term Hemoglobinopathies Mesh Term Genetic Diseases, Inborn
Downcase Mesh Term anemia, sickle cell Downcase Mesh Term anemia, hemolytic, congenital Downcase Mesh Term anemia, hemolytic Downcase Mesh Term anemia Downcase Mesh Term hematologic diseases Downcase Mesh Term hemoglobinopathies Downcase Mesh Term genetic diseases, inborn
Mesh Type mesh-list Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor

Sponsors

Sequence: 48464718 Sequence: 48464719 Sequence: 48464720
Agency Class OTHER Agency Class OTHER Agency Class OTHER
Lead Or Collaborator lead Lead Or Collaborator collaborator Lead Or Collaborator collaborator
Name Mark Walters, MD Name University of California, Los Angeles Name University of California, Berkeley

Overall Officials

Sequence: 29367896
Role Principal Investigator
Name Mark Walters, MD
Affiliation UCSF Benioff Children's Hospital Oakland

Central Contacts

Sequence: 12047669 Sequence: 12047670
Contact Type primary Contact Type backup
Name Mark Walters, MD Name Christina Chun, MPH
Phone (510) 428-3374 Phone (415) 502-2558
Email Mark.Walters@ucsf.edu Email Christina.Chun@ucsf.edu
Role Contact Role Contact

Design Group Interventions

Sequence: 68359060
Design Group Id 55766158
Intervention Id 52637437

Eligibilities

Sequence: 30855316
Gender All
Minimum Age 12 Years
Maximum Age 35 Years
Healthy Volunteers No
Criteria Inclusion Criteria: Male or female 12.00 – 34.99 years of age (at time of consent) who have one or more of the following: History of two or more episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea); History of at least 4 severe vaso-occlusive pain events in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea); painful episodes related to or any sickle-related acute event are acceptable; a severe painful vaso-occlusive event is defined as receiving analgesic treatment (opioid or other analgesic) for longer than 24 -hours in a hospital or emergency room (ER) observation unit visit or at least 2 visits in a day unit or ER over 72 hours with both visits requiring intravenous analgesics. Participants must have adequate physical function as measured by all of the following: Karnofsky performance score ≥60. Cardiac function: Left ventricular ejection fraction (LVEF) >40%; or LV shortening fraction > 26% by cardiac echocardiogram or by (multiple-gated acquisition) MUGA scan. Pulmonary function: Pulse oximetry with a baseline O2 saturation of ≥85% and diffusion capacity of lung for carbon monoxide(DLCO) > 40% (corrected for hemoglobin). Renal function: Serum creatinine ≤ 1.5 x upper limit of normal for age and estimated or measured creatinine clearance ≥ 70 mL/min/1.73 m2. Hepatic function: i. Serum conjugated (direct) bilirubin < 2x upper limit of normal for age as per local laboratory. Participants with hyperbilirubinemia as the result of hyperhemolysis, or a severe drop in hemoglobin post blood transfusion, are not excluded. ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AS < 5 times upper limit of normal as per local laboratory. f. Liver MRI using a validated methodology per institutional preference (T2* or R2* or by ferriscan [R2 MRI]) for estimation of hepatic iron content is required for participants who are currently receiving ≥8 packed red blood cell transfusions per year for ≥1 year or have received ≥20 packed red blood cell transfusions (lifetime cumulative). Participants who have hepatic iron content ≥ 8 mg Fe/g liver dry weight by liver MRI must have a Gastroenterology/hepatology consultation with liver biopsy and histological examination including documentation of the absence of cirrhosis, bridging fibrosis[1], and active hepatitis. Written informed consent or assent obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study. Exclusion Criteria: Participants with uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment (currently taking medication with evidence of progression of clinical symptoms or radiologic findings). Participants with evidence of HIV infection or seropositivity for HIV or active hepatitis B or C. Participants who have received a Hematopoietic Cell Transplant (HCT) Participants who have received a solid organ transplant. Participants who have participated in another clinical trial in which the participant received an investigational or off-label use of a drug or device within 3 months prior to enrollment. Females who are pregnant or breast feeding. Females of child bearing potential (to include all female participants > 10 years of age, unless postmenopausal for a minimum of 1 year before the time of consent or surgically sterilized) who do not agree to practice two (2) effective methods of contraception at the same time, or who do not agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject, from the time of signing of informed consent through 12 months post-stem cell infusion. Males (even if surgically sterilized) who do not agree to practice effective barrier contraception, or who do not agree to practice true abstinence from the time of signing informed consent through 12 months post-stem cell infusion. Participants who have had a stroke OR who are receiving red blood cell (RBC) transfusions to prevent primary stroke or silent cerebral infarction. Patients who have a human leukocyte antigen identical (HLA-ID) sibling donor Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data. Any non-homozygous sickle hemoglobin (HbSS) genotype of SCD
Adult True
Child True
Older Adult False

Calculated Values

Sequence: 254311814
Number Of Facilities 2
Registered In Calendar Year 2021
Were Results Reported False
Has Us Facility True
Has Single Facility False
Minimum Age Num 12
Maximum Age Num 35
Minimum Age Unit Years
Maximum Age Unit Years
Number Of Primary Outcomes To Measure 1
Number Of Secondary Outcomes To Measure 12
Number Of Other Outcomes To Measure 6

Designs

Sequence: 30601158
Allocation N/A
Intervention Model Single Group Assignment
Observational Model
Primary Purpose Treatment
Time Perspective
Masking None (Open Label)

Responsible Parties

Sequence: 28967668
Responsible Party Type Sponsor-Investigator
Name Mark Walters, MD
Title Professor in Residence
Affiliation University of California, San Francisco