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

• Sponsor: Bellicum Pharmaceuticals
• Information provided by (Responsible Party): Bellicum Pharmaceuticals

Study Description

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 Syndromes; Primary Immune Deficiency Disorder; Osteopetrosis; Cytopenia; Hemoglobinopathy in Children; Anemia, Aplastic	Biological: BPX-501 T cells; Drug: AP1903	Phase 1; Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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 that does not adequately respond to standard of care therapy.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	120 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 :	June 2019
Estimated Study Completion Date :	December 2020

Arms and Interventions

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 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; T cells transduced with CaspaCIDe® safety switch; Drug: AP1903; administered to inactivate BPX-501 cells in the event of GVHD; Other Name: rimiducid

Outcome Measures

Primary Outcome Measures :

1. non-relapse/transplant related mortality (TRM/NRM) [ Time Frame: 1 year ]
   To maintain the cumulative incidence of non-relapse/transplant related mortality (TRM/NRM) at 1 year in subjects given the MTD defined during the Phase I portion of the study comparable to that of a historical cohort of subjects given the alpha/beta T-cell depleted HSCT without any T-cell add-back (i.e., below 10%)

Secondary Outcome Measures :

1. Disease-free survival [ Time Frame: 2 years ]
   Disease-free survival rates after transplantation
2. Relapse [ Time Frame: 1 year ]
   Cumulative incidence of relapse
3. acute GVHD [ Time Frame: 1 year ]
   Cumulative incidence and severity of acute GVHD
4. chronic GVHD [ Time Frame: 2 years ]
   Cumulative incidence and severity of chroonic GVHD
5. Kinetics of donor cell engraftment [ Time Frame: 3 times per week after transplant until the neutrophil count reaches 0.5 x 10E9/L. Thereafter, at least 2 times per week until the neutrophil count is > 1.0 x 10E9/L and platelets > 100 x 10E9/L. ]
   time to hematopoietic recovery defined as: neutrophils > 0.5 x 10E9/L for 3 consecutive days together with platelet count > 20 x 10E9/L and without platelet support for 7 consecutive days

Eligibility Criteria

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Ages Eligible for Study:	1 Month to 26 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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. 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.

Contacts and Locations

Locations

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United States, California
Children's Hospital Los Angeles
Los Angeles, California, United States, 90027
Stanford University; Division of Pediatric Stem Cell Transplant & Regenerative Medicine
Palo Alto, California, United States, 94304
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
United States, Georgia
Children's Healthcare of Atlanta
Atlanta, Georgia, United States, 30322
United States, Massachusetts
Dana-Farber Boston Children's Cancer and Blood Disorders Center
Boston, Massachusetts, United States, 02215
United States, New York
Children's Hospital at Montefiore
Bronx, New York, United States, 10467
United States, Oregon
Oregon Health Sciences University - Doernbecher Children's Hospital
Portland, Oregon, United States, 97239
United States, Texas
University of Texas Southwestern-Children's Medical Center
Dallas, Texas, United States, 77390
Baylor College of Medicine/ Texas Children's Hospital
Houston, Texas, United States, 77030
United States, Washington
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States, 98109

Sponsors and Collaborators

Bellicum Pharmaceuticals

Investigators

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Principal Investigator:	Neena Kapoor, MD	Children's Hospital of LA

More Information

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Responsible Party:	Bellicum Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT03301168 History of Changes
Other Study ID Numbers:	BP-U-004
First Posted:	October 4, 2017
Last Update Posted:	April 19, 2019
Last Verified:	April 2019

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Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No
Product Manufactured in and Exported from the U.S.:		Yes

Keywords provided by Bellicum Pharmaceuticals:

ALL; AML; hematologic neoplasms	hematologic malignancies; primary immune deficiences; allogeneic stem cell transplant

Additional relevant MeSH terms:

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Leukemia; Myelodysplastic Syndromes; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Lymphoma, Non-Hodgkin; Immunologic Deficiency Syndromes; Hemoglobinopathies; Osteopetrosis; Anemia, Aplastic; Leukemia, Myeloid, Acute; Leukemia, Myeloid; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases	Hematologic Diseases; Precancerous Conditions; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma; Genetic Diseases, Inborn; Osteosclerosis; Osteochondrodysplasias; Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Anemia