Safety Study of Gene Modified Donor T-cells Following TCRαβ+ Depleted Stem Cell Transplant

Study Overview
=================
Brief Summary
-----------------
This study will evaluate pediatric patients with malignant or non-malignant blood cell disorders who are having a blood stem cell transplant depleted of T cell receptor (TCR) alfa and beta cells that comes from a partially matched family donor. The study will assess whether immune cells, called T cells, from the family donor, that are specially grown in the laboratory and given back to the patient along with the stem cell transplant can help the immune system recover faster after transplant. As a safety measure these T cells have been programmed with a self-destruct switch so that they can be destroyed if they start to react against tissues (Graft versus host disease).

Detailed Description
-----------------
This is a Phase I/II study evaluating the safety and feasibility of BPX-501 T cells infused after partially mismatched, related, TCR alpha beta T cell depleted hematopoietic stem cell transplant (HSCT) in pediatric patients. The purpose of this clinical trial is to determine whether BPX-501 infusion can enhance immune reconstitution in those patients with hematologic disorders, with the potential for reducing the severity and duration severe acute graft versus host disease (GvHD). The trial will also evaluate the treatment of GvHD by the infusion of dimerizer drug (AP1903/rimiducid) in those subjects who present with GVHD who progress or do not respond to standard of care treatment.

Official Title
-----------------
Phase I/II Study of CaspaCIDe T Cells (BPX-501; Rivogenlecleucel) From an HLA Partially Matched Family Donor After Negative Selection of TCRαβ+ T Cells in Paediatric Patients Affected by Haematological Disorders

Conditions
-----------------
Acute Lymphoblastic Leukemia, Leukemia, Acute Myeloid (AML), Child, Lymphoma, Non-Hodgkin, Myelodysplastic Syndrome, Primary Immunodeficiency, Anemia, Aplastic, Osteopetrosis, Hemoglobinopathies, Cytopenia, Fanconi Anemia, Diamond Blackfan Anemia, Thalassemia, Anemia, Sickle Cell

Intervention / Treatment
-----------------
* Biological: BPX-501 T cells
* Drug: Rimiducid


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age < 18 years and > 1 month (< 1 month upon approval by Sponsor) Life expectancy > 10 weeks Patients deemed clinically eligible for allogeneic stem cell transplantation. Patients may have failed prior allograft Patients with life-threatening acute leukemia (high-risk ALL in 1st CR, ALL in 2nd CR, high-risk AML in 1st CR, AML in 2nd CR.) or myelodysplastic syndromes. Morphological CR must be documented and minimal residual disease measurement before transplantation is recommended. Non-malignant disorders deemed curable by allogeneic transplantation: (a) primary immune deficiencies, (b) severe aplastic anemia not responding to immune suppressive therapy, (c) osteopetrosis, (d) selected cases of erythroid disorders such as β0 β0 thalassemia major, sickle cell disease, Diamond-Blackfan anemia, (e) congenital/hereditary cytopenia, including Fanconi Anemia before any clonal malignant evolution (MDS, AML). Note: Subjects will be eligible if they meet either item 5 OR item 6. Lack of suitable conventional donor (HLA identical sibling or HLA phenotypically identical relative or 10/10 unrelated donor evaluated using high resolution molecular typing) or presence of rapidly progressive disease not permitting time to identify an unrelated donor A minimum genotypic identical match of 5/10 is required. The donor and recipient must be identical, as determined by high resolution typing, on at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA- DRB1 and HLA-DQB1. Lansky/Karnofsky score > 50 Signed informed consent by the patient or the patient's parent or guardian for patients who are minors Exclusion Criteria: Greater than active Grade II acute GvHD or chronic extensive GvHD due to a previous allograft at the time of screening Patient receiving an immunosuppressive treatment for GvHD treatment due to a previous allograft at the time of screening Dysfunction of liver (ALT/AST > 5 times normal value, or bilirubin > 3 times normal value), or of renal function (creatinine clearance <30ml/min/1.73m2) Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or left ventricular ejection fraction < 40%) Current clinically active infectious disease (including positive HIV serology or viral RNA) Serious concurrent uncontrolled medical disorder Pregnant or breast feeding female patient Lack of parents'/guardian's informed consent for children who are minors.

Ages Eligible for Study
-----------------
Minimum Age: 1 Month
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BPX-501 T cells and rimiducid<br>TCR alpha beta depleted graft infusion with addback of BPX-501 T cells (rivogenlecleucel). Rimiducid/AP1903: Dimerizer drug administered to subjects who develop Grade III-IV acute GVHD, Grade II gut/liver acute GVDH or Grade I/II skin-only acute GvHD which is non-responsive after 7 days of standard of care treatment | Biological: BPX-501 T cells<br>* 1x10E6 cells/kg infused on Day 0<br>* Other names: Rivogenlecleucel;Drug: Rimiducid<br>* 0.4mg/kg administered IV to treat GVHD<br>* Other names: AP1903;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival (EFS) at 180 Days After Transplant | Events included transplant-related mortality (TRM) / non-relapse mortality (NRM), severe GvHD (acute Grades 2-4 organ or extensive chronic GvHD) and life-threatening infections (Grade 4). Time to the first event only is represented in the primary endpoint, if a subsequent event occurred in the same patient this was not captured in this outcome. There were no protocol-specified primary endpoints for Phase I of the study. | 180 days after transplant | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ALL, AML, hematologic neoplasms, hematologic malignancies, primary immune deficiences, hemoglobinopathy, congenital cytopenia, anemia