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

Study Description

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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).

Condition or disease	Intervention/treatment	Phase
Acute Lymphoblastic Leukemia; Leukemia, Acute Myeloid (AML), Child; Lymphoma, Non-Hodgkin; Myelodysplastic Syndrome; Immunologic Deficiency Syndromes	Biological: BPX-501 T cells and AP1903; Drug: AP1903	Phase 1; Phase 2

Detailed Description:

This is a Phase 2 extension 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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	193 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase II Extension Study of CaspaCIDe T Cells (BPX-501) From an HLA-partially Matched Family Donor After Negative Selection of TCR αβ+T Cells in Pediatric Patients Affected by Hematological Disorders
Actual Study Start Date :	April 2014
Estimated Primary Completion Date :	December 2018
Estimated Study Completion Date :	December 2019

Arms and Interventions

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Arm	Intervention/treatment
Experimental: BPX-501 T cells and AP1903; TCR alpha beta depleted graft infusion with addback of BPX-501 T cells. 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 and AP1903; Biological: T cells transduced with CaspaCIDe suicide gene Drug: AP1903; AP1903 administered to treat GVHD; Other Name: rimiducid

Outcome Measures

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Primary Outcome Measures :

1. Event-Free -Survival [ Time Frame: 180 days after transplant ]
   events include TRM (or NRM for malignant patients), severe GVHD (acute Grade 2-4 organ or extensive chronic GVHD) and life threatening infections (Grade 4)

Secondary Outcome Measures :

1. TRM (non-malignant) or NRM (malignant) [ Time Frame: 100 days and 180 days after transplant ]
   transplant related mortality or non relapse mortality (patients with malignant disease)
2. Cumulative incidence and severity of acute (grade 2-4) and chronic GvHD at 180 days [ Time Frame: 180 days after transplant ]
   grades 2-4 acute and chronic GvHD
3. Time to resolution of acute GvHD after administration of rimiducid [ Time Frame: 180 days after transplant ]
   resolution of acute GvHD
4. Immune reconstitution [ Time Frame: 180 days after transplant ]
   absolute CD3, CD4 and CD8 count

Eligibility Criteria

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Ages Eligible for Study:	1 Month to 18 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

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Locations

Italy
IRCCS Ospedale Pediatrico Bambino Gesù
Roma, Italy, 00161
Spain
Unidad de Trasplante Hematopoyético, Hospital Niño Jesús
Madrid, Spain
United Kingdom
Institute of Child Health & Great Ormond Street Hospital
London, United Kingdom, WC1N 1EH
Great North Children's Hospital
Newcastle Upon Tyne, United Kingdom, NE1 4LP

Sponsors and Collaborators

Bellicum Pharmaceuticals

Investigators

Principal Investigator:	Franco Locatelli, MD	Prof. IRCCS Ospedale Pediatrico Bambino Gesù

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Bellicum Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT02065869 History of Changes
Other Study ID Numbers:	BP-004
First Posted:	February 19, 2014
Last Update Posted:	March 5, 2018
Last Verified:	December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Bellicum Pharmaceuticals:

ALL; AML; hematologic neoplasms; hematologic malignancies; primary immune deficiences

Additional relevant MeSH terms:

Syndrome; Leukemia; Myelodysplastic Syndromes; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Lymphoma, Non-Hodgkin; Immunologic Deficiency Syndromes; Leukemia, Myeloid, Acute; Leukemia, Myeloid; Disease	Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma