Study of Gene Modified Donor T-cells Following TCR Alpha Beta Positive Depleted Stem Cell Transplant

Study Overview
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Brief Summary
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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
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This is a Phase 1/2 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 that does not adequately respond to standard of care therapy.

Official Title
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Phase I/II Study of CaspaCIDe® T Cells From an HLA-Partially Matched Family Donor After Negative Selection of TCR αβ+T Cells in Pediatric Patients Affected by Hematological Disorders

Conditions
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Acute Lymphoblastic Leukemia, Leukemia, Acute Myeloid (AML), Child, Lymphoma, Non-Hodgkin, Myelodysplastic Syndromes, Primary Immune Deficiency Disorder, Osteopetrosis, Cytopenia, Hemoglobinopathy in Children, Anemia, Aplastic

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 1 month and < 26 years Life expectancy > 10 weeks Subjects deemed eligible for allogeneic stem cell transplantation. Subjects with life-threatening hematological malignancies (high-risk ALL in 1st CR, ALL in 2nd or subsequent CR, AML in 1st CR, AML in 2nd or subsequent CR, myelodysplastic syndromes, non-Hodgkin lymphomas in 2nd or subsequent CR, other hematologic malignancies eligible for stem cell transplantation per institutional standard); Non-malignant disorders amenable to cure by an allograft: primary immune deficiencies, severe aplastic anemia not responding to immune suppressive therapy, osteopetrosis, hemoglobinopathies, (thalassemias, and sickle cell anemia, and Diamond-Blackfan anemia among others) congenital/hereditary cytopenia, including Fanconi Anemia before any clonal malignant evolution (MDS, AML) Note: Subjects will be eligible if they meet either item 4 OR item 5. 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, 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 written informed consent Exclusion Criteria: Greater than Grade II acute GVHD or chronic extensive GVHD due to a previous allograft at the time of inclusion Subject receiving an immunosuppressive treatment for GVHD treatment due to a previous allograft at the time of inclusion Dysfunction of liver (ALT/AST > 5 times normal value, or bilirubin > 3 times normal value), or of renal function (creatinine clearance < 30 mL / min) Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or left ventricular ejection fraction < 40%) Current active infectious disease (including positive HIV serology or viral RNA) Serious concurrent uncontrolled medical disorder Pregnant or breastfeeding subject For subjects who have received more than 1 x 10E5 alpha/beta T cells/kg with the graft infusion the clinical trial site must contact the sponsor for approval to be eligible to receive BPX-501 infusion.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 26 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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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. Rimiducid: Dimerizer drug administered to subjects who present with Grade I-IV acute GVHD with inadequate response to steroids within 48 hours of treatment or mild to severe chronic GVHD with inadequate response to steroids within 7 days of treatment. | Biological: BPX-501 T cells<br>* T cells transduced with CaspaCIDe® safety switch<br>* Other names: rivogenlecleucel;Drug: Rimiducid<br>* administered to inactivate BPX-501 cells in the event of GVHD<br>* Other names: AP1903;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Event | Demonstrate safety of BPX-501 MTD | Month 24 | 
| TRM/NRM | Assess the cumulative incidence of non-relapse/transplant related mortality | Day 180, Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival | Disease-free survival rates after transplantation | Month 24 | 
| Relapse | Cumulative incidence of relapse | Month 12 | 
| Engraftment | Cumulative incidence of neutrophil and platelet engraftment, primary & secondary graft failure | Month 24 | 
| GvHD | Cumulative incidence and severity of acute and chronic GvHD | Month 24 | 
| Rimiducid Efficacy | Time to resolution of acute or chronic GvHD after administration of rimiducid | Month 24 | 
| Infection | Rate of infectious complications | Month 24 | 
| Hospitalizations | Duration of hospitalization and rehospitalization | Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALL, AML, hematologic neoplasms, hematologic malignancies, primary immune deficiences, allogeneic stem cell transplant