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

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

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).

Study Overview

• Status: Terminated
• Conditions: Lymphoma, Non-Hodgkin; Acute Lymphoblastic Leukemia; Primary Immunodeficiency; Anemia, Sickle Cell; Hemoglobinopathies; Fanconi Anemia; Anemia, Aplastic; Myelodysplastic Syndrome; Thalassemia; Cytopenia; Diamond Blackfan Anemia; Osteopetrosis; Leukemia, Acute Myeloid (AML), Child
• Intervention / Treatment: Biological: BPX-501 T cells; Drug: Rimiducid

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.

• Study Type: Interventional
• Enrollment (Actual): 187
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Italy
  • Roma, Italy, 00161
    • IRCCS Ospedale Pediatrico Bambino Gesu
• United Kingdom
  • London, United Kingdom, NW3 2QG
    • Royal Free London NHS Foundation Trust
  • London, United Kingdom, WC1N 1EH
    • Institute of Child Health & Great Ormond Street Hospital
  • Newcastle Upon Tyne, United Kingdom, NE1 4LP
    • Great North Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age < 18 years and > 1 month (< 1 month upon approval by Sponsor)
2. Life expectancy > 10 weeks
3. Patients deemed clinically eligible for allogeneic stem cell transplantation.
4. Patients may have failed prior allograft
5. 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.

6. 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.

7. 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
8. A minimum genotypic identical match of 5/10 is required.
9. 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.
10. Lansky/Karnofsky score > 50
11. Signed informed consent by the patient or the patient's parent or guardian for patients who are minors

Exclusion Criteria:

1. Greater than active Grade II acute GvHD or chronic extensive GvHD due to a previous allograft at the time of screening
2. Patient receiving an immunosuppressive treatment for GvHD treatment due to a previous allograft at the time of screening
3. 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)
4. Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or left ventricular ejection fraction < 40%)
5. Current clinically active infectious disease (including positive HIV serology or viral RNA)
6. Serious concurrent uncontrolled medical disorder
7. Pregnant or breast feeding female patient
8. Lack of parents'/guardian's informed consent for children who are minors.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BPX-501 T cells and rimiducid; 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; 1x10E6 cells/kg infused on Day 0; Other Names: Rivogenlecleucel; Drug: Rimiducid; 0.4mg/kg administered IV to treat GVHD; 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

Collaborators and Investigators

• Sponsor: Bellicum Pharmaceuticals
• Investigators: Study Director: Bellicum Pharmaceuticals, Bellicum Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2014
• Primary Completion (Actual): June 1, 2020
• Study Completion (Actual): September 7, 2021

Study Registration Dates

• First Submitted: February 13, 2014
• First Submitted That Met QC Criteria: February 17, 2014
• First Posted (Estimated): February 19, 2014

Study Record Updates

• Last Update Posted (Actual): September 29, 2023
• Last Update Submitted That Met QC Criteria: September 22, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: AML; anemia; ALL; hematologic malignancies; hematologic neoplasms; congenital cytopenia; hemoglobinopathy; primary immune deficiences
• Additional Relevant MeSH Terms: Metabolic Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Musculoskeletal Diseases; Bone Diseases; DNA Repair-Deficiency Disorders; Leukemia, Lymphoid; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia, Hypoplastic, Congenital; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Lymphoma; Bone Diseases, Developmental; Osteochondrodysplasias; Leukemia, Myeloid; Red-Cell Aplasia, Pure; Osteosclerosis; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Primary Immunodeficiency Diseases; Anemia; Anemia, Sickle Cell; Fanconi Anemia; Thalassemia; Anemia, Aplastic; Hemoglobinopathies; Anemia, Diamond-Blackfan; Osteopetrosis
• Other Study ID Numbers: BP-004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No