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出境医 / 临床实验 / Safety and Efficacy of Gene Therapy of the Sickle Cell Disease by Transplantation of an Autologous CD34+ Enriched Cell Fraction That Contains CD34+ Cells Transduced ex Vivo With the GLOBE1 Lentiviral Vector Expressing the βAS3 Globin Gene in Patients With

Safety and Efficacy of Gene Therapy of the Sickle Cell Disease by Transplantation of an Autologous CD34+ Enriched Cell Fraction That Contains CD34+ Cells Transduced ex Vivo With the GLOBE1 Lentiviral Vector Expressing the βAS3 Globin Gene in Patients With

Study Description
Brief Summary:
The purpose of this study is to evaluate the Safety and Efficacy of Gene Therapy of the Sickle Cell disease by Transplantation of an Autologous CD34+ enriched cell fraction that contains CD34+ cells transduced ex vivo with the GLOBE1 lentiviral vector expressing the βAS3 globin gene (GLOBE1 βAS3 Modified Autologous CD34+ Cells) in Patients with Sickle Cell Disease (SCD)

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Genetic: DREPAGLOBE drug product Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Open Label Study Evaluating the Safety and Efficacy of Gene Therapy of the Sickle Cell Disease by Transplantation of an Autologous CD34+ Enriched Cell Fraction That Contains CD34+ Cells Transduced ex Vivo With the GLOBE1 Lentiviral Vector Expressing the βAS3 Globin Gene (GLOBE1 βAS3 Modified Autologous CD34+ Cells) in Patients With Sickle Cell Disease (SCD)
Actual Study Start Date : November 12, 2019
Estimated Primary Completion Date : February 12, 2022
Estimated Study Completion Date : November 12, 2024
Arms and Interventions
Arm Intervention/treatment
Experimental: DREPAGLOBE drug product
The DREPAGLOBE is a genetically modified cell therapy product that consists of autologous human CD34+ hematopoietic stem and progenitor cells (HSPCs) that are enriched in CD34+ cells which have been transduced ex vivo with the lentiviral vector, GLOBE1, expressing an anti-sickling β-globin protein (AS3) containing three amino acid substitutions in the wild-type β-globin gene.
 Genetic: DREPAGLOBE drug product
Each patient will receive a single IV infusion of DREPAGLOBE drug product
Outcome Measures
Primary Outcome Measures :
  1. Incidence of transplant related mortality [ Time Frame: up to 100 days post treatment ]
    To evaluate the procedure safety

  2. Incidence of the need for rescue autologous bone marrow transplant [ Time Frame: up to 100 days post treatment ]
    To evaluate the procedure safety

  3. Frequency and severity of AEs post transplant transplant [ Time Frame: 6 months post-transplant ]
    Based on the United States national Cancer Institute Common Terminology Criteria for Adverse Events v4.03 To evaluate the procedure safety

  4. Incidence of vector-derived Replication competent lentivirus (RCL) [ Time Frame: 6 months post-transplant ]
    To evaluate the procedure safety

  5. Incidence of clinically detectable malignancy and/or abnormal clonal dominance assessed as related to study treatment [ Time Frame: 6 months post-transplant ]
    To evaluate the procedure safety.It will be evaluated by vector insertion site analysis (VISA.


Secondary Outcome Measures :
  1. Concentration of neutrophil [ Time Frame: 6 months post-transplant ]
    To evaluate the efficacy

  2. Concentration of platelet [ Time Frame: 6 months post-transplant ]
    To evaluate the efficacy. It will be quantified by High performance liquid chromatography

  3. Percentage HbAS3 [ Time Frame: 6 months post-transplant ]
    To evaluate the efficacy. It will be quantified by High performance liquid chromatography It will be quantified by High performance liquid chromatography

  4. Frequency and severity of adverse events [ Time Frame: 24 months post-transplant ]
    based on the United States national Cancer Institute Common Terminology Criteria for Adverse Events v4.03 To evaluate the long -term safety

  5. Absence of RCL (Replication competent lentivirus) [ Time Frame: 24 months post-transplant ]
    To evaluate the long -term safety

  6. Absence of clinically detectable malignancy or abnormal clonal dominance assessed as related to study treatment [ Time Frame: 24 months post-transplant ]
    To evaluate the long -term safety. It will be evaluated by vector insertion site analysis (VISA).

  7. Protein expression through percentage of anti-sickling Hb [ Time Frame: 24 months post-transplant ]
    To evaluate the long -term efficacy


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   5 Years to 35 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • - Age 5 - 35 years
  • Diagnosis of HbSS or S-beta zero thalassemia by Hb electrophoresis or genetic analysis.

  • 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 enrollment
    • One severe acute chest syndrome (ACS) hospitalized in intensive care unit
    • At least 2 episodes of ACS within the prior 3 years), 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).
    • Cerebral vasculopathy confirmed by MRA (magnetic resonance angiography) without Moya-moya
    • Presence of sickle cell cardiomyopathy documented by Doppler echocardiography (left ventricular ejection fraction (LVEF) <55% AND tricuspid regurgitation velocity >2.5m/s on cardiac echocardiograph),
    • Tricuspid regurgitation velocity >2.8m/s on cardiac echocardiograph without pulmonary hypertension confirmed by right heart catheterization (mPAP<25mmHg)
  • Failed hydroxyurea (HU) therapy, were unable to tolerate HU therapy, or, if 18 years of age or older, have actively made the choice to not take the recommended daily HU regimen. 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 crises requiring hospitalization, no rise in Hb >1.5 gm/dl from pre-HU baseline or requires transfusion to maintain Hb > 6.0 gm/dL, had 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)

Exclusion Criteria:

  • Existence of a matched sibling donor
  • Patients who have started new treatment for SCD within 6months of enrollment
  • Hematologic evaluation: Leukopenia (WBC < 3000 µL) ( en cours) or neutropenia (ANC < 1000 µL) or thrombocytopenia (platelet count < 100,000 µL) (not due to an erythropheresis procedure)
  • PT/INR or PTT > 1.5 times upper limit of normal (ULN) or clinically significant bleeding disorder
  • Evaluations within 6 months prior to screening visit:
  • ALT or AST > 3 times ULN
  • Liver Cirrhosis suspicion on echography, CT scan or MRI AND confirmed by histology
  • Cardiac evaluation: LVEF < 40% by cardiac echocardiogram or by MUGA scan
  • Stroke with significant CNS sequelae i.e., Rankin > 2
  • 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>25mmHg). 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 impeded the ability to participate in the study
  • Patients who failed previous HSCT and are severely ill
  • 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
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Marina CAVAZZANA, MD & PhD +33 144495068 m.cavazzana@aphp.fr
Contact: Valérie JOLAINE, Manager +33 1 42 19 28 79 valerie.jolaine@aphp.fr

Locations
Layout table for location information
France
Department of Biotherapy, Necker-Enfants Malades Hospital Recruiting
Paris, France, 75015
Contact: Marina CAVAZZANA, MD & PhD    +33 144495068    m.cavazzana@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
Layout table for investigator information
Study Director: Pablo BARTULOCCI, MD & PhD Department of internal medicine, Henri-Mondor Hospital, Creteil, France.
Tracking Information
First Submitted Date  ICMJE May 14, 2019
First Posted Date  ICMJE May 28, 2019
Last Update Posted Date August 24, 2020
Actual Study Start Date  ICMJE November 12, 2019
Estimated Primary Completion Date February 12, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 24, 2019)
  • Incidence of transplant related mortality [ Time Frame: up to 100 days post treatment ]
    To evaluate the procedure safety
  • Incidence of the need for rescue autologous bone marrow transplant [ Time Frame: up to 100 days post treatment ]
    To evaluate the procedure safety
  • Frequency and severity of AEs post transplant transplant [ Time Frame: 6 months post-transplant ]
    Based on the United States national Cancer Institute Common Terminology Criteria for Adverse Events v4.03 To evaluate the procedure safety
  • Incidence of vector-derived Replication competent lentivirus (RCL) [ Time Frame: 6 months post-transplant ]
    To evaluate the procedure safety
  • Incidence of clinically detectable malignancy and/or abnormal clonal dominance assessed as related to study treatment [ Time Frame: 6 months post-transplant ]
    To evaluate the procedure safety.It will be evaluated by vector insertion site analysis (VISA.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 24, 2019)
  • Concentration of neutrophil [ Time Frame: 6 months post-transplant ]
    To evaluate the efficacy
  • Concentration of platelet [ Time Frame: 6 months post-transplant ]
    To evaluate the efficacy. It will be quantified by High performance liquid chromatography
  • Percentage HbAS3 [ Time Frame: 6 months post-transplant ]
    To evaluate the efficacy. It will be quantified by High performance liquid chromatography It will be quantified by High performance liquid chromatography
  • Frequency and severity of adverse events [ Time Frame: 24 months post-transplant ]
    based on the United States national Cancer Institute Common Terminology Criteria for Adverse Events v4.03 To evaluate the long -term safety
  • Absence of RCL (Replication competent lentivirus) [ Time Frame: 24 months post-transplant ]
    To evaluate the long -term safety
  • Absence of clinically detectable malignancy or abnormal clonal dominance assessed as related to study treatment [ Time Frame: 24 months post-transplant ]
    To evaluate the long -term safety. It will be evaluated by vector insertion site analysis (VISA).
  • Protein expression through percentage of anti-sickling Hb [ Time Frame: 24 months post-transplant ]
    To evaluate the long -term efficacy
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy of Gene Therapy of the Sickle Cell Disease by Transplantation of an Autologous CD34+ Enriched Cell Fraction That Contains CD34+ Cells Transduced ex Vivo With the GLOBE1 Lentiviral Vector Expressing the βAS3 Globin Gene in Patients With Sickle Cell Disease (DREPAGLOBE)
Official Title  ICMJE A Phase 1/2 Open Label Study Evaluating the Safety and Efficacy of Gene Therapy of the Sickle Cell Disease by Transplantation of an Autologous CD34+ Enriched Cell Fraction That Contains CD34+ Cells Transduced ex Vivo With the GLOBE1 Lentiviral Vector Expressing the βAS3 Globin Gene (GLOBE1 βAS3 Modified Autologous CD34+ Cells) in Patients With Sickle Cell Disease (SCD)
Brief Summary The purpose of this study is to evaluate the Safety and Efficacy of Gene Therapy of the Sickle Cell disease by Transplantation of an Autologous CD34+ enriched cell fraction that contains CD34+ cells transduced ex vivo with the GLOBE1 lentiviral vector expressing the βAS3 globin gene (GLOBE1 βAS3 Modified Autologous CD34+ Cells) in Patients with Sickle Cell Disease (SCD)
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Sickle Cell Disease
Intervention  ICMJE Genetic: DREPAGLOBE drug product
Each patient will receive a single IV infusion of DREPAGLOBE drug product
Study Arms  ICMJE Experimental: DREPAGLOBE drug product
The DREPAGLOBE is a genetically modified cell therapy product that consists of autologous human CD34+ hematopoietic stem and progenitor cells (HSPCs) that are enriched in CD34+ cells which have been transduced ex vivo with the lentiviral vector, GLOBE1, expressing an anti-sickling β-globin protein (AS3) containing three amino acid substitutions in the wild-type β-globin gene.
Intervention: Genetic: DREPAGLOBE drug product
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 24, 2019) 		10
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 12, 2024
Estimated Primary Completion Date February 12, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • - Age 5 - 35 years
  • Diagnosis of HbSS or S-beta zero thalassemia by Hb electrophoresis or genetic analysis.

  • 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 enrollment
    • One severe acute chest syndrome (ACS) hospitalized in intensive care unit
    • At least 2 episodes of ACS within the prior 3 years), 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).
    • Cerebral vasculopathy confirmed by MRA (magnetic resonance angiography) without Moya-moya
    • Presence of sickle cell cardiomyopathy documented by Doppler echocardiography (left ventricular ejection fraction (LVEF) <55% AND tricuspid regurgitation velocity >2.5m/s on cardiac echocardiograph),
    • Tricuspid regurgitation velocity >2.8m/s on cardiac echocardiograph without pulmonary hypertension confirmed by right heart catheterization (mPAP<25mmHg)
  • Failed hydroxyurea (HU) therapy, were unable to tolerate HU therapy, or, if 18 years of age or older, have actively made the choice to not take the recommended daily HU regimen. 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 crises requiring hospitalization, no rise in Hb >1.5 gm/dl from pre-HU baseline or requires transfusion to maintain Hb > 6.0 gm/dL, had 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)

Exclusion Criteria:

  • Existence of a matched sibling donor
  • Patients who have started new treatment for SCD within 6months of enrollment
  • Hematologic evaluation: Leukopenia (WBC < 3000 µL) ( en cours) or neutropenia (ANC < 1000 µL) or thrombocytopenia (platelet count < 100,000 µL) (not due to an erythropheresis procedure)
  • PT/INR or PTT > 1.5 times upper limit of normal (ULN) or clinically significant bleeding disorder
  • Evaluations within 6 months prior to screening visit:
  • ALT or AST > 3 times ULN
  • Liver Cirrhosis suspicion on echography, CT scan or MRI AND confirmed by histology
  • Cardiac evaluation: LVEF < 40% by cardiac echocardiogram or by MUGA scan
  • Stroke with significant CNS sequelae i.e., Rankin > 2
  • 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>25mmHg). 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 impeded the ability to participate in the study
  • Patients who failed previous HSCT and are severely ill
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 5 Years to 35 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Marina CAVAZZANA, MD & PhD +33 144495068 m.cavazzana@aphp.fr
Contact: Valérie JOLAINE, Manager +33 1 42 19 28 79 valerie.jolaine@aphp.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03964792
Other Study ID Numbers  ICMJE P170006J
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Pablo BARTULOCCI, MD & PhD Department of internal medicine, Henri-Mondor Hospital, Creteil, France.
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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