Efficacy Safety Study of Gene Therapy for Sickle Cell DiseaseSCD Using Autologous CD34+ Cells Transduced ex Vivo, Carrying a Corrected Globin Gene and a Silencing RNA.

Phase 2RecruitingNCT07432867

Assistance Publique - Hôpitaux de Paris15 enrolled

Overview

The purpose of this study is to evaluate the Safety and Efficacy of DREAM01, a gene therapy for Sickle Cell Disease (SCD). The therapy consists of transplanting autologous CD34+ cells transduced ex vivo with a bifunctional lentiviral vector expressing βAS3m-globin and an anti-βS miRNA. It aims to reduce or eliminate vaso-occlusive events and long-term organ damage in severe SCD patients lacking a Human Leukocyte Antigen (HLA) identical sibling donor.

Sickle cell anaemia is a hereditary disease caused by a mutation in the gene for beta haemoglobin, essential for oxygen transport by red blood cells. This genetic mutation causes a deformation of the red blood cells, giving them a crescent shape (also known as a sickle) and leading to their massive destruction, resulting in anaemia. Other serious consequences are linked to this disease, such as recurrent painful obstructive crises, known as vaso-occlusive crises (VOC), as well as strokes, acute respiratory syndromes (ARS) and multi-organ damage. All these complications are linked to the obstruction of capillaries caused by deformed red blood cells. Management of the disease consists of regular transfusions of healthy red blood cells and/or specific drug therapy such as hydroxyurea (HU). HU increases the production of foetal haemoglobin, which can prevent the deformation of red blood cells characteristic of sickle cell disease. By reducing the number of sickle-shaped red blood cells, hydroxyurea helps reduce the frequency of painful attacks and other complications associated with the disease. During these painful attacks, deformed red blood cells block small blood vessels, leading to intense pain and organ damage. These treatments help prevent the risks associated with the disease, but also entail transfusion-related risks (immunological response that may prevent the necessary transfusion). The only curative treatment to date is a bone marrow transplant from a compatible sibling donor. Bone marrow contains stem cells capable of producing blood cells (red blood cells, white blood cells and platelets) throughout an individual's life. Unfortunately, this treatment is only available for 25% of patients, and is associated with significant immunological complications caused by the white blood cells present in the graft (graft-versus-host disease) or risk of rejection (if partially compatible donor). The aim of this study is to treat patients with severe sickle cell disease with a new experimental gene therapy treatment. This is a new therapeutic approach for patients without a compatible donor, and patients will be followed for 2 years.

Study Type

INTERVENTIONAL

Interventions

DREAM01 drug productGENETIC

Each patient will receive a single IV infusion of DREAM01, autologous CD34+ stem cells transduced with βAS3m/miR7m lentiviral vector

anti-inflammatory therapyDRUG

Patient will receive anti-inflammatory therapy if necessary

Eligibility

Sex: ALLMin age: 12 YearsMax age: 35 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age 12 - 35 years * Acceptation of myelogram (bone marrow aspiration) * Diagnosis of HbSS by Hb electrophoresis and genetic analysis to analyse the alpha locus * Clinical history or ongoing evidence of severe sickle cell anemia with one OR more of the following clinical complications demonstrating disease severity: * At least 3 vaso-occlusive crises requiring hospitalization, under hydroxyurea or transfusion, within 2 years prior to enrolment * One severe acute chest syndrome (ACS) hospitalized in the intensive care unit * At least 2 episodes of ACS, including one under HU. * Acute priapism (at least 2 episodes \>3h in the preceding year or in the year prior to the start of a regular transfusion program), OR stuttering priapism ≥ 1 by week under sickle cell treatment (HU, transfusion or phlebotomy). * Tricuspid regurgitation velocity \>2.8m/s on cardiac echocardiograph without pulmonary hypertension confirmed by right heart catheterization (mPAP\>\<25mmHg) * Failed hydroxyurea (HU) therapy, OR Inadequate clinical response to HU, defined as any one of the following outcomes, while on HU for at least 3 months: 2 or more acute sickle pain crisis requiring hospitalization, requirement of transfusion to maintain Hb \>6.0g/dL, an episode of ACS despite adequate supportive care measures * Karnovsky/Lansky performance score ≥ 60% * Sexually active patients must be willing to use an acceptable method of double-barrier contraception for at least 12 months post-infusion (beyond 12 months at the discretion of the investigator) * Procedure for obtaining consent (adults, dependent minors, to give their consent) * Affiliation to social security Exclusion Criteria: * Existence of a matched sibling donor * Based on myelogram, the presence of chromosomal (detected by karyotyping) or molecular abnormalities (detected by NGS) and retained dangerous by the Hemato-Oncology referent and validated during a specific multidisciplinary concerted meeting * Hematologic evaluation: Leukopenia (WBC \<3,000/µL) or neutropenia (ANC \<1,000/µL) or thrombocytopenia (platelet count \<100,000/µL) within 90 days prior to mobilization or harvest (not due to an erythrapheresis procedure or possible acute viral infection) * PT/INR or PTT \>1.5 times the upper limit of normal (ULN) or clinically significant bleeding disorder * Two alpha deletions (risk of alpha-thalassemia after gene therapy) * Hypersensitivity to the active substances of the administered drugs (plerixafor, busulfan, anti-inflammatory therapy) or to any of their excipients * Patients who have already been treated with gene therapy Evaluations within 6 months prior to screening visit: * ALT or AST \>3 times ULN * Severe liver iron overload evaluated by MRI (\>15mg Fe/g dry weight or \>270umol Fe/g dry weight) or liver cirrhosis suspicion on echography or elastometry or CT scan or MRI AND confirmed by histology * Measured GFR \<60ml/min/1.73 m² * Cardiac evaluation: LVEF \<40% by cardiac echocardiogram or by MUGA scan or clinically significant ECG abnormalities * Stroke with significant CNS sequelae i.e., Rankin \>2 * Specific sickle cell disease cerebral vasculopathy confirmed by MRA (magnetic resonance angiography) OR transcranial doppler ultrasound with or without Moya-moya WITH an indication of chronic transfusion program (target HbS\<30%) * Lung interstitial infiltrate AND Forced Vital Capacity less than 70% AND DLCO less than 60% at steady state * Confirmed pulmonary hypertension defined by a right heart catheterization (PAPm \>25 mmHg). Right heart catheterization is required if tricuspid regurgitation velocity \>2.8m/s on cardiac echocardiograph OR \>2.5m/s with an abnormal Brain Natriuretic Peptide dosage or an important decrease in transcutaneous Hb O2 saturation during the 6 minutes' walk test. * Seropositivity for HIV (Human Immunodeficiency Virus), HCV (Hepatitis C Virus), HTLV-1 (Human T-Lymphotropic Virus), or active Hepatitis B Virus, or active infection by CMV or parvovirus B19, based on positive blood PCR. * Pregnancy or breastfeeding in a postpartum female * Any current cancer or prior history of a malignant disease, with the exception of curatively treated non-melanoma skin cancer * Immediate family member with an established or suspected Familial Cancer Syndrome * Diagnosis of significant psychiatric disorder of the subject that could seriously impede the ability to participate in the study * Patients who failed previous HSCT * Any clinically significant active infection * Participation in another clinical study with an investigational drug within 30 days of screening * Any condition, based on perspective of the medical monitor and treating investigator, which may lead to increased safety risk or inability to comply with the protocol

Locations (1)

Department of Biotherapy, Necker-Enfants Malades Hospital

Paris, Île-de-France Region, France

RECRUITING

Outcomes

Primary Outcomes

Neutrophil recovery

Neutrophil recovery defined as the first of three consecutive days with an ANC of \> 500/µL

Time frame: within the 24 months following IV infusion of DREAM01

Platelet recovery

Platelet recovery defined as the first of three consecutive days with a platelet count of \> 20.000/µL sustained without platelet transfusion for at least seven days

Time frame: within the 24 months following IV infusion of DREAM01

In vivo engraftment (neutrophils and platelets)

hematopoietic reconstitution after IV infusion of the drug product

Time frame: every 3 months between 3 to 24 months following IV infusion of DREAM01

Adverse event

Adverse event will be measured using CTCAE

Time frame: within the 24 months following IV infusion of DREAM01

Transplant-related mortality (TRM)

Transplant-related mortality

Time frame: within 100 days following IV infusion of DREAM01

Transplant-related mortality (TRM)

Transplant-related mortality

Time frame: within the first year following IV infusion of DREAM01

All-cause mortality

Mortality

Time frame: Up to the 24 months following IV infusion of DREAM01

Efficacy of DREAM01

absence of vaso-occlusive events (VOE) in patients who have discontinued the transfusion program or/and hydroxyurea

Time frame: between 3 and 15 months following IV infusion of DREAM01

Efficacy of anti-inflammatory therapy

Decrease of HSPCs inflammation assessed through a reduction of the score and/or the number of inflammatory pathways (among the 6 pathways established) by transcriptomic analysis on HSPCs between inclusion and after 3 months of anti-inflammatory therapy treatment before infusion

Time frame: within the 3 months following administration of anti-inflammatory therapy

Secondary Outcomes

Annualized rate of VOE

Proportion of subjects with reduction in annualized rate of VOE at the time of analysis from baseline by at least 90% up to 24 months after DREAM01 infusion

Time frame: Up to the 24 months following IV infusion of DREAM01

Transfusion requirement

Number of transfusion requirement

Time frame: Up to the 24 months following IV infusion of DREAM01

Change in number of units of RBCs transfused

change in number of units of RBCs transfused for SCD-related indications over time

Time frame: Up to the 24 months following IV infusion of DREAM01

Percentage of HbAS3

Measure of HbAS3

Time frame: Up to the 24 months following IV infusion of DREAM01

Percentage of HbS

Measure of Measure of HbS

Time frame: Up to the 24 months following IV infusion of DREAM01

Quantification of the transgene copy number (VCN)

Quantification of the transgene copy number (VCN) on drug substance at time of cryopreservation, on PBMC, sorted T-CD3+ and sorted NK cells

Time frame: Up to the 24 months following IV infusion of DREAM01

Rate of hemolysis

Biological parameters that reflect hemolysis : Total hemoglobin, Reticulocytes, lactate dehydrogenase LDH, circulating erythroblasts, haptoglobin, free plasmatic heme, no conjugated bilirubin, erythropoietin EPO

Time frame: Up to the 24 months following IV infusion of DREAM01

Rate of anemia

Biological parameters that reflect anemia : Total hemoglobin, Reticulocytes, lactate dehydrogenase LDH, circulating erythroblasts, haptoglobin, free plasmatic heme, no conjugated bilirubin, erythropoietin EPO

Central Contacts

Marina CAVAZZANA, MD, PhD

CONTACT

01 44 49 50 68 m.cavazzana@aphp.fr

Nelly BRIAND, PhD

CONTACT

01 44 38 18 62 nelly.briand@aphp.fr

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Time frame: Up to the 24 months following IV infusion of DREAM01

Changes in brain function

Occurrence of ischemic lesions, vascular stenosis, aneurysm assessed using cervical doppler ultrasound and cerebral MRI

Time frame: Up to the 24 months following IV infusion of DREAM01

Changes in brain function

Occurrence of pathological flow acceleration or vascular stenosis using carotid and transcranial Doppler ultrasound

Time frame: Up to the 24 months following IV infusion of DREAM01

Changes in ocular function

Assessed Using Fundus examination

Time frame: Up to the 24 months following IV infusion of DREAM01

Changes in ocular function

Assessed Using angiography

Time frame: Up to the 24 months following IV infusion of DREAM01

Changes in cardiac function

evaluated through electrocardiographic (ECG) assessment

Time frame: Up to the 24 months following IV infusion of DREAM01

Changes in the occurrence of left ventricular ejection fraction [LVEF] right and left atrial

Occurrence of left ventricular ejection fraction \[LVEF\], right and left atrial, left assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography

Time frame: Up to the 24 months following IV infusion of DREAM01

Changes in left ventricular size

Changes in left ventricular size assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography

Time frame: Up to the 24 months following IV infusion of DREAM01

Changes in left ventricular wall thickness

Changes in the left ventricular wall thickness assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography

Time frame: Up to the 24 months following IV infusion of DREAM01

Changes in systolic pulmonary artery pressure [sPAP]

Changes in systolic pulmonary artery pressure \[sPAP\], assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography

Time frame: Up to the 24 months following IV infusion of DREAM01

Changes in tricuspid regurgitation velocity [TRV]

Changes in tricuspid regurgitation velocity \[TRV\] assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography

Time frame: Up to the 24 months following IV infusion of DREAM01

Changes in E/A ratio

Changes in of E/A ratio assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography

Time frame: Up to the 24 months following IV infusion of DREAM01

Change in serum electrolyte panel

Time frame: Up to the 24 months following IV infusion of DREAM01

Change in serum creatinine

Time frame: Up to the 24 months following IV infusion of DREAM01

Change in estimated glomerular filtration rate (eGFR)

Renal function assessed through estimated glomerular filtration rate (eGFR) calculated using CKD-EPI equation

Time frame: Up to the 24 months following IV infusion of DREAM01

Change in urinary microalbumin

Time frame: Up to the 24 months following IV infusion of DREAM01

Change in protein excretion

Time frame: Up to the 24 months following IV infusion of DREAM01

Change in urinary creatinine

Time frame: Up to the 24 months following IV infusion of DREAM01

Changes in creatinine clearence

Time frame: Up to the 24 months following IV infusion of DREAM01

Change in liver enzyme AST

Time frame: Up to the 24 months following IV infusion of DREAM01

Change in liver enzyme ALT

Time frame: Up to the 24 months following IV infusion of DREAM01

Change in liver enzyme GGT

Time frame: Up to the 24 months following IV infusion of DREAM01

Changes in in liver enzyme ALP

Time frame: Up to the 24 months following IV infusion of DREAM01

Change in total bilirubin

Time frame: Up to the 24 months following IV infusion of DREAM01

Change in unconjugated (free) bilirubin

Time frame: Up to the 24 months following IV infusion of DREAM01

Changes in hepatic function

Description of hepatic morphology assessed through abdominal ultrasound

Time frame: Up to the 24 months following IV infusion of DREAM01

Change in diffusing capacity for carbon monoxide (DLCO)

Time frame: Up to the 24 months following IV infusion of DREAM01

Change in vital capacity (VC)

Time frame: Up to the 24 months following IV infusion of DREAM01

Change in residual volume (RV)

Time frame: Up to the 24 months following IV infusion of DREAM01

Change in FEV1/FVC ratio (Tiffeneau index)

Time frame: Up to the 24 months following IV infusion of DREAM01

Changes in bone metabolism

Assessed through Osteodensitometry, osteoarticular MRI

Time frame: Up to the 24 months following IV infusion of DREAM01

Changes in muscular function

Assessed through physical capacity testing

Time frame: Up to the 24 months following IV infusion of DREAM01

Occurrence of iron overload

Efficacy

Time frame: Up to the 24 months following IV infusion of DREAM01

Fertility evaluation

Safety

Time frame: Up to the 24 months following IV infusion of DREAM01

Walk ability

6-minute walk-test

Time frame: Up to the 24 months following IV infusion of DREAM01

Jump

Vertical jump test : The jump height will be recorded using video analysis software. The average height of the 3 jumps will be calculated

Time frame: Up to the 24 months following IV infusion of DREAM01

Cardiopulmonary capacity

Cardiopulmonary exercise test, using the Cardio Pulmonary Exercise Test

Time frame: Up to the 24 months following IV infusion of DREAM01

Physical ability

Physical ability questionnaire, using the Global physical activity questionnaire (GPAQ) (16 items) developed by WHO

Time frame: Up to the 24 months following IV infusion of DREAM01

Quality of life Evaluation : patient health

Medical Outcomes Study Short Form 36 SF-36 .The Short Form (36) Health Survey is a 36-item, patient-reported survey of patient health

Time frame: Up to the 24 months following IV infusion of DREAM01

Quality of life Evaluation : fatigue

FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue Scale) FACIT-Fatigue is a 13-item self-report scale that assesses fatigue and its effect on daily activities and function.

Time frame: Up to the 24 months following IV infusion of DREAM01

Quality of life Evaluation : physical, mental, and social health

PROMIS (Patient-Reported Outcomes Measurement Information System) PROMIS® (Patient-Reported Outcomes Measurement Information System) is a set of person-centered measures that evaluates and monitors physical, mental, and social health in adults and children.

Time frame: Up to the 24 months following IV infusion of DREAM01

Health-realted Quality of life Evaluation

Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales PedsQL is a modular system that assesses health-related quality of life in healthy and ill children and adolescents. It combines generic core scales and disease-specific modules into one measurement system.

Time frame: Up to the 24 months following IV infusion of DREAM01

Changes in brain function

Description of neuropsychological status using functional performance testing

Time frame: Up to the 24 months following IV infusion of DREAM01

Change in hepatic function

Occurrence of fibrosis and cirrhosis assessed through Liver elastography

Time frame: Up to the 24 months following IV infusion of DREAM01

Change in hepatic function

Occurence of intrahepatic iron deposition assessed through liver MRI

Time frame: Up to the 24 months following IV infusion of DREAM01

Efficacy Safety Study of Gene Therapy for Sickle Cell DiseaseSCD Using Autologous CD34+ Cells Transduced ex Vivo, Carrying a Corrected Globin Gene and a Silencing RNA.

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts