Patients with Sickle Cell disease MedDRA version: 20.0 Level: LLT Classification code 10040644 Term: Sickle cell disease System Organ Class: 100000004850
Conditions
Interventions
Product Name: Cellules CD34+modifiées par vecteur globe1beta AS3
Pharmaceutical Form: Solution for infusion
Concentration number: cellules-
Sponsors
ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: iIndividuals eligible to participate in this study must meet all of the following criteria: " Age 5 - 35 years " Diagnosis of HbSS 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: 1. At least 3 vaso occlusive crises requiring hospitalization, under hydroxyurea or transfusion, within 2 years prior to enrollment 2. One severe acute chest syndrome (ACS) hospitalized in intensive care unit 3. At least 2 episodes of ACS within the prior 3 years), including one under HU. 4. 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). 5. Cerebral vasculopathy confirmed by MRA (magnetic resonance angiography) without Moya-moya 6. Presence of sickle cell cardiomyopathy documented by Doppler echocardiography (left ventricular ejection fraction (LVEF) 2.5m/s on cardiac echocardiograph), 7. 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 g/dl from pre-HU baseline or requires transfusion to maintain Hb > 6.0 g/dL, Has 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 of a social security regime (or exemption), Are the trial subjects under 18? yes Number of subjects for this age range: 6 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 4 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study:Existence of a matched sibling donor Patients who have started new treatment for SCD within 6months of enrollment "Hematologic evaluation: Leukopenia (WBC 1.5 times upper limit of normal (ULN) or clinically significant bleeding disorder "Evaluations within 6 months prior to screening visit:ALT or AST > 1.5 times ULN "Liver Cirrhosis suspicion on echography, CT scan or MRI AND confirmed by histology Liver iron > 125 µmol/g by MRIMeasured GFR 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;Each patient will receive a single intravenous infusion of the DREPAGLOBE drug product at dose range of 3 to 20 million CD34+ cells/kg post-transduction.Source of CD34+ will be : 1)Bone- Marrow 2)CD34 + mobilized with Plerixafor after a single or multiple harvests3)The DREPAGLOBE drug product consists in autologous CD34+ hematopoietic stem cells transduced with Self-inactivating lentiviral vector (GLOBE1 AS3) encoding the human ?AS3-globin gene and suspended in HSA (5% Albunorm™) in the final immediate container for the intended medical use. All subjects are to receive the DREPAGLOBE drug product on Day 1 via IV infusion according to applicable SOPs, with vital signs being monitored concurrently. The minimum dose to be administered is 3.0×106 CD34+ cells/kg.Exchange transfusion before the mobilization procedure ;Mobilization by Plerixaf
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the study is to assess the initial safety and tolerability of treatment with DREPAGLOBE drug product, including the mobilization procedure with Perixaflor, conditioning regimen and transplantation with GLOBE1 betaAS3 lentiviral vector gene modified autologous CD34+cells in up to 10 severe SCD patients;Secondary Objective: The secondary objectives of the study are: "To assess the initial efficacy of treatment with GLOBE1 beta AS3-globin modified autologous CD34+ stem cells. "To assess the long-term safety and efficacy of treatment with DREPAGLOBE drug product ;Primary end point(s): The primary endpoints of this study are safety. Safety in the first 6 months following IV infusion of DREPAGLOBE drug product, as assessed by: "Incidence of transplant related mortality up to 100 days post treatment "Incidence of the need for rescue autologous bone marrow transplant up to 100 days post treatment "Frequency and severity of clinical AEs and laboratory parameters "Incidence of RCL Incidence of clinically detectable malignancy and/or abnormal clonal dominance assessed as related to study treatment The secondary efficacy endpoints, as assessed in the first 6 months following transplantation, are: oIn vivo engraftment through hematopoietic reconstitution after IV infusion of the DREPAGLOBE drug product, i.e. neutrophil and platelet recovery (neutrophil recovery defined as the first of three consecutive days with an ANC of > 500/uL and platelet recovery defined as the first of three consecutive days with a platelet count of > 20000/uL sustained without platelet transfusion for at least seven days) oPercentage HbAS3. The other endpoints are long-term safety and efficacy (throughout the 24-month follow-up phase) as measured by: oMonitoring the frequency and severity of adverse events based on NCI CTCAE v4.03 oAbsence of RCL oAbsence of clinically detectable malignancy or abnormal clonal dominance assessed as related to study treatment oPr | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary efficacy endpoints, as assessed in the first 6 months following transplantation, are: • In vivo engraftment through hematopoietic reconstitution after IV infusion of BMN 285, i.e. neutrophil and platelet recovery (neutrophil recovery defined as the first of three consecutive days with an ANC of > 500/uL and platelet recovery defined as the first of three consecutive days with a platelet count of > 20000/uL sustained without platelet transfusion for at least seven days) • Percentage HbAS3. The other endpoints are long-term safety and efficacy (throughout the 24-month follow-up phase) as measured by: • Monitoring the frequency and severity of adverse events based on NCI CTCAE v4.03 • Absence of RCL • Absence of clinically detectable malignancy or abnormal clonal dominance assessed as related to study treatment • Protein expression through percentage of anti-sickling Hb • Percentage HbAS3 The secondary efficacy endpoints, as assessed in the first 6 months following transplantation, are: • In vivo engraftment through hematopoietic reconstitution after IV infusion of BMN 285, i.e. neutrophil and platelet recovery (neutrophil recovery defined as the first of three consecutive days with an ANC of > 500/uL and platelet recovery defined as the first of three consecutive days with a platelet count of > 20000/uL sustained without platelet transfusion for at least seven days) • Percentage HbAS3. The other endpoints are long-term safety and efficacy (throughout the 24-month follow-up phase) as measured by: • Monitoring the frequency and severity of adverse events based on NCI CTCAE v4.03 • Absence of RCL • Absence of clinically detectable malignancy or abnormal clonal dominance assessed as related to study treatment • Protein expression through percentage of anti-sickling Hb • Percentage HbAS3 ;Timepoint(s) of evaluation of this end point: The other endpoints are long-term safety and efficacy (throughout the 24-month follow | — |
Countries
France
Contacts
Public ContactDRCI Hôpital St Louis
ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
Outcome results
None listed