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

Phase 1

Active, not recruiting

• Conditions: Myelodysplastic Syndromes; Acute Lymphoblastic Leukemia; Primary Immune Deficiency Disorder; Osteopetrosis; Cytopenia; Leukemia, Acute Myeloid (AML), Child; Hemoglobinopathy in Children; Lymphoma, Non-Hodgkin; Anemia, Aplastic
• Interventions: Biological: BPX-501 T cells; Drug: Rimiducid

• Registration Number: NCT03301168
• Lead Sponsor: Bellicum Pharmaceuticals

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 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.

Study Timeline

• Study Start: 2014-04
• Study First Submitted: 2017-09-29
• Study First Submitted QC: 2017-10-03
• Study First Posted: 2017-10-04
• Primary Completion: 2021-05-11
• Status Verified: 2022-05
• Last Update Submitted: 2022-07-10
• Last Update Posted: 2022-07-12
• Study Completion: 2034-05

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 120

Inclusion Criteria

1. Age > 1 month and < 26 years

2. Life expectancy > 10 weeks

3. Subjects deemed eligible for allogeneic stem cell transplantation.

4. 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);

5. Non-malignant disorders amenable to cure by an allograft:

   1. primary immune deficiencies,
   2. severe aplastic anemia not responding to immune suppressive therapy,
   3. osteopetrosis,
   4. hemoglobinopathies, (thalassemias, and sickle cell anemia, and Diamond-Blackfan anemia among others)
   5. 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.

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

7. A minimum genotypic identical match of 5/ 10 is required.

8. 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.

9. Lansky/Karnofsky score > 50

10. Signed written informed consent

Exclusion Criteria

1. Greater than Grade II acute GVHD or chronic extensive GVHD due to a previous allograft at the time of inclusion
2. Subject receiving an immunosuppressive treatment for GVHD treatment due to a previous allograft at the time of inclusion
3. Dysfunction of liver (ALT/AST > 5 times normal value, or bilirubin > 3 times normal value), or of renal function (creatinine clearance < 30 mL / min)
4. Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or left ventricular ejection fraction < 40%)
5. Current active infectious disease (including positive HIV serology or viral RNA)
6. Serious concurrent uncontrolled medical disorder
7. Pregnant or breastfeeding subject
8. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
BPX-501 T cells and Rimiducid	BPX-501 T cells	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.
BPX-501 T cells and Rimiducid	Rimiducid	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.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (10)

Stanford University - Division of Pediatric Stem Cell Transplant & Regenerative Medicine; 🇺🇸 Palo Alto, California, United States

Children's National Medical Center; 🇺🇸 Washington, District of Columbia, United States

Children's Hospital Los Angeles; 🇺🇸 Los Angeles, California, United States

Fred Hutchinson Cancer Research Center; 🇺🇸 Seattle, Washington, United States

Dana-Farber Boston Children's Cancer and Blood Disorders Center; 🇺🇸 Boston, Massachusetts, United States

University of Texas Southwestern-Children's Medical Center; 🇺🇸 Dallas, Texas, United States

Baylor College of Medicine/ Texas Children's Hospital; 🇺🇸 Houston, Texas, United States

Oregon Health Sciences University - Doernbecher Children's Hospital; 🇺🇸 Portland, Oregon, United States

Children's Healthcare of Atlanta; 🇺🇸 Atlanta, Georgia, United States

Children's Hospital at Montefiore; 🇺🇸 Bronx, New York, United States