Sickle Cell Disease MedDRA version: 21.0 Level: PT Classification code 10040644 Term: Sickle cell disease System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Product Name: TCRsbCD19PBSC
Pharmaceutical Form: Infusion
Current Sponsor code: TCRabCD19PBSC
Other descriptive name: Mobilized peripheral blood stem cells from allogeinic donors depleted on TCR a/ß+
Sponsors
University Hospital of Regensburg
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion criteria* (for the experimental arms) * The transplant indication for patients with a MSD follows the respective local and national guidelines • Age 2 yrs to 35yrs • Homozygous hemoglobin S disease or heterozygous hemoglobin SC or S 0/+ • Study specific consent given • Preexisting severe or moderate SCD related complications (at least one): o Clinically significant neurological event (stroke) or deficit o Silent crisis, neurocognitive deficit o Pathological angio-MRI with TOF Sequence o TCD velocity >200 cm/s at 2 occasions >1 month apart o More than 5 vaso-occlusive crises (VOC) in the past 1 year or more than 20 VOC in a lifetime o Two or more episodes of acute chest syndrome (ACS) in a lifetime or one episode of ACS in the past 24 months o Chronic transfusion requirement or more than 8 transfusions or one exchange transfusion in a lifetime o Transfusion-refractory allo-immunization o More than five SCD-related hospitalizations in a lifetime o Beginning pulmonary hypertension o Osteonecrosis at more than 2 sites o Beginning SCD Nephropathy o Recurrent priapism (>2) Are the trial subjects under 18? yes Number of subjects for this age range: 148 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 64 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Exclusion criteria (for both arms) • Karnofsky or Lansky Performance Score grade II hypertension by Common Toxicity Criteria (CTC) • Renal function: o Estimated creatinine clearance (for patients > 12 years) lower than 50.0 mL/minute o for pediatric patients (> 1 year to 12 years), GFR estimated by the updated Schwartz formula 70.0 mL/min/1.73 m2 for inclusion or o Creatinine clearance below threshold defined for stem cell transplantation according to local clinical standard • Pulmonary function: o DLCO 3 x the upper limit of normal (ULN) (unless elevated bilirubin is attributed to Gilbert’s Syndrome) and ALT/AST > 2.5x the ULN. o Chronic active viral hepatitis • Women who are pregnant (positive serum or urine ßHCG) or breastfeeding. Note: Women of childbearing potential must have a negative serum pregnancy test at study entry. • Adults of reproductive potential not willing to use an effective method of birth control during study treatment up to the end of follow-up >24 months after HSCT) • History of uncontrolled autoimmune disease or on active treatment • Patient unable to comply with the treatment protocol • Prior autologous or allogeneic HSCT • Vaccination with a live virus vaccine during the trial • HIV infection • Patients with a history of psychiatric illness or a condition which could interfere with their ability to understand the requirements of the study (this includes alcoholism/drug addiction) • Patients unwilling or unable to comply with the protocol or unable to give informed consent. • Concurrent severe or uncontrolled medical disease (e.g. uncontrolled diabetes, congestive heart failure, myocardial infarction within 6 months prior to the study, unstable and uncontrolled hypertension, chronic renal disease, or active uncontrolled infection) which by assessment of the treating physician could compromise participation in the study. • Patients with prior malignancies, except resected non-melanoma or treated cervical carcinoma in situ. Cancer treated with curative intent >5 years previously will be allowed. Cancer treated with curative intent < 5 years previously will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The objective of this phase II trial is to prove that EFS following T-Haplo-SCT (experimental group E) is non-inferior to matched sibling donor (MSD) HSCT (reference group R) as well as evaluation of safety/tolerability and feasibility of haploidentical PBSC grafts depleted of TCR a/ß+ and CD19+ cells using the CliniMACS TCR a/ß/CD19 System in adult and paediatric patients with sickle cell disease: Incidence of disease free survival and grade III–IV acute graft-versus-host disease (GVHD) until Day 100 post-transplantation;Secondary Objective: - Incidence of grade I-II acute GVHD until Day 100 post-transplantation - Incidence and severity of chronic GVHD 1 year after omission of immunosuppression - Incidence of TRM at all visits throughout the study - Incidence and severity of acute infusional toxicities - Graft failure from Day 0 to Day 28 - Neutrophil and platelet engraftment Day 0 to Day 28 - OS at Day 100 and after 1 year - Disease-free survival Day 100 and after 1 year - Transfusion requirement from Day 0 to Day 100 - QoL at baseline, Day 100 + after 1 year - Donor chimerism - Split chimerism - Reconstitution of T, B, NK, T regulatory (Treg) cell subsets by immune cell phenotyping - Infections: Incidence of CMV, ADV, EBV and aspergillus, as well as other viral, bacterial and fungal infections - Incidence, severity and type of AEs/SAEs - Vital signs + physical examination - Safety laboratory (blood count, blood chemistry) - Fertility - Incidence and severity of transplant-related neurotoxicity and PRES;Primary end point(s): Primary efficacy endpoint: Composite Endpoint: Event free survival (EFS). Event is defined as incidence of acute GvHD (Grade III – IV), chronic GvHD (moderate/severe), graft failure (GF), or death (from any reason).;Timepoint(s) of evaluation of this end point: before HSCT, Day+100, +180, +240, 1 year 1,5 years and 2 years after HSCT | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key secondary endpoint(s): (i) Overall survival (OS); (ii) Disease-free survival (DFS); (iii) Graft failure (GF); (iv) Immune-reconstitution; (v) Quality of life (QOL); (vi) Fertility;Timepoint(s) of evaluation of this end point: before HSCT, Day+100, +180, +240, 1 year 1,5 years and 2 years after HSCT | — |
Countries
Austria, Belgium, Finland, Germany, Italy, Spain, Sweden, Switzerland, United Kingdom
Outcome results
None listed