Safety Study of Gene Modified Donor T-cells Following Partially Mismatched Stem Cell Transplant

NCT01744223 | Active Not Recruiting Phase 1 FDA Drug

• 1 other identifier: BP-001
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 8

Brief Summary

This study will evaluate patients with blood cell cancers who are going to have an allogeneic (donor) blood stem cell transplant from a partially matched relative. The research study will test whether immune cells, called T cells, which come from the donor relative and are specially grown in the laboratory and then given back to the patient along with the stem cell transplant (T cell addback), can help the immune system recover faster after the transplant. As a safety measure, these T cells have been "programmed" with a "self-destruct switch" so that if, after they have been given to the patient, the T cells start to react against the tissues (called "graft versus host" disease, GVHD), the T cells can be destroyed.

Conditions

Acute Lymphoblastic Leukemia; Acute Myelogenous Leukemia; Lymphoma; Myelodysplastic Syndromes

Keywords

iCaspase9; iCasp9; Inducible Caspase; AP1903; Dimerizer drug; T depleted; Suicide gene; CD-34 selection; haplotransplantation; Graft versus host disease; Allogenic transplantation

Outcome Measures

Primary Outcomes (4)

• BPX-501 Safety

  To evaluate the safety of infusion of each of 4 dose cohorts of BPX-501 (2x105, 5x105, 1x106 and 3x106 cells/kg) after transplantation of partially mismatched T cell depleted hematopoietic stem cell transplant (HSCT)

  24 months

• Rimiducid Safety

  To evaluate the safety of the infusion of the rimiducid in subjects who received BPX-501 and have developed visceral or steroid refractory graft-versus-host-disease

  24 months

• MTD

  To determine the maximum dose of BPX-501 (up to 3x106 cells/kg) that results in an adjusted cumulative incidence by Day 100 of no more than 45% Grade II - IV aGVHD and / or no more than 17% Grade III -IV aGVHD.

  24 months

• Immune Reconstitution

  To assess immune reconstitution for each dose cohort

  24 months

Secondary Outcomes (9)

• Efficacy- NRM

  100, 180 days and 1 year

• Efficacy- DFS

  24 months

• Efficacy- TRM

  24 months

• Efficacy- Relapse

  24 months

• Incidence of engraftment

  24 months

Study Arms (4)

SCT, BPX-501 dose 1, Rimiducid if needed

EXPERIMENTAL

2x10E5 BPX-501 (rivogenlecleucel) cells per kg infused after TCR alpha beta depleted donor stem cell transplant. Rimiducid: Dimerizer drug administered by intravenous infusion in those subjects with acute GVHD with no response to steroids and/or other aGVHD medications or worsening in stage or grade of aGVHD after 48 hours. Subjects with chronic GvHD who do not respond to steroids/systemic therapies within 7 days, or there is a worsening in cGVHD, patients may then receive rimiducid.

Biological: BPX-501 dose 1; Drug: Rimiducid; Procedure: SCT

SCT, BPX-501 dose 2, Rimiducid if needed

EXPERIMENTAL

5x10E5 BPX-501 (rivogenlecleucel) cells per kg infused after TCR alpha beta depleted donor stem cell transplant. Rimiducid: Dimerizer drug administered by intravenous infusion in those subjects with acute GVHD with no response to steroids and/or other aGVHD medications or worsening in stage or grade of aGVHD after 48 hours. Subjects with chronic GvHD who do not respond to steroids/systemic therapies within 7 days, or there is a worsening in cGVHD, patients may then receive rimiducid.

Drug: Rimiducid; Biological: BPX-501 dose 2; Procedure: SCT

SCT, BPX-501 dose 3, Rimiducid if needed

EXPERIMENTAL

1x10E6 BPX-501 (rivogenlecleucel) cells per kg infused after TCR alpha beta depleted donor stem cell transplant. Rimiducid: Dimerizer drug administered by intravenous infusion in those subjects with acute GVHD with no response to steroids and/or other aGVHD medications or worsening in stage or grade of aGVHD after 48 hours. Subjects with chronic GvHD who do not respond to steroids/systemic therapies within 7 days, or there is a worsening in cGVHD, patients may then receive rimiducid.

Drug: Rimiducid; Biological: BPX-501 dose 3; Procedure: SCT

SCT, BPX-501 dose 4, Rimiducid if needed

EXPERIMENTAL

3x10E6 BPX-501 (rivogenlecleucel) cells per kg infused after TCR alpha beta depleted donor stem cell transplant . Rimiducid: Dimerizer drug administered by intravenous infusion in those subjects with acute GVHD with no response to steroids and/or other aGVHD medications or worsening in stage or grade of aGVHD after 48 hours. Subjects with chronic GvHD who do not respond to steroids/systemic therapies within 7 days, or there is a worsening in cGVHD, patients may then receive rimiducid.

Drug: Rimiducid; Biological: BPX-501 dose 4; Procedure: SCT

Interventions

BPX-501 dose 1 BIOLOGICAL

Subjects will receive 2x10E5 donor T cells/kg genetically modified with BPZ-1001 retroviral vector containing the iCasp suicide gene (BPX-501) after stem cell transplant.

Also known as: rivogenlecleucel

SCT, BPX-501 dose 1, Rimiducid if needed

Rimiducid DRUG

Dimerizer drug administered by intravenous infusion in those subjects who develop GVHD after infusion of BPX-501 cells.

Also known as: AP1903

SCT, BPX-501 dose 1, Rimiducid if needed; SCT, BPX-501 dose 2, Rimiducid if needed; SCT, BPX-501 dose 3, Rimiducid if needed; SCT, BPX-501 dose 4, Rimiducid if needed

BPX-501 dose 2 BIOLOGICAL

Subjects will receive 5x10E5 donor T cells/kg genetically modified with BPZ-1001 retroviral vector containing the iCasp suicide gene (BPX-501) after stem cell transplant.

Also known as: rivogenlecleucel

SCT, BPX-501 dose 2, Rimiducid if needed

BPX-501 dose 3 BIOLOGICAL

Subjects will receive 1x10E6 donor T cells/kg genetically modified with BPZ-1001 retroviral vector containing the iCasp suicide gene (BPX-501) after stem cell transplant.

Also known as: rivogenlecleucel

SCT, BPX-501 dose 3, Rimiducid if needed

BPX-501 dose 4 BIOLOGICAL

Subjects will receive 3x10E6 donor T cells/kg genetically modified with BPZ-1001 retroviral vector containing the iCasp suicide gene (BPX-501) after stem cell transplant.

Also known as: rivogenlecleucel

SCT, BPX-501 dose 4, Rimiducid if needed

SCT PROCEDURE

all subjects will receive an alpha beta depleted donor transplant as part of treatment

SCT, BPX-501 dose 1, Rimiducid if needed; SCT, BPX-501 dose 2, Rimiducid if needed; SCT, BPX-501 dose 3, Rimiducid if needed; SCT, BPX-501 dose 4, Rimiducid if needed

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent
• Age ≥ 18 years and ≤ 65 years
• Deemed eligible for allogeneic stem cell transplantation
• Lack of suitable conventional donor (i.e. 8/8 related or unrelated donor) or presence of rapidly progressive disease not permitting time to identify an unrelated donor
• HLA typing will be performed at high resolution (allele level) for the HLA-A, -B, Cw, and DRBl, and loci
• A minimum genotypic identical match of 4/8 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, and HLA-DRB1
• Subjects with adequate organ functions as measured by:
• Cardiac: Left ventricular ejection fraction at rest must be ≥ 45%
• Hepatic: Bilirubin ≤ 2.5 mg/dL and ALT, AST and Alkaline Phosphatase \< 5 x ULN
• Renal: Serum creatinine within normal range for age or creatinine clearance, or with a recommended GFR ≥ 50 mL/min/1.73m2
• Pulmonary: FEV 1, FVC and DLCO (diffusion capacity) ≥ 50% predicted (corrected for hemoglobin); or O2 saturation \> 92% on room air
• Clinical diagnosis of one of the following:
• a. Acute Leukemia (includes T lymphoblastic lymphoma) in 2nd or subsequent complete remission (CR) i. Acute Lymphoblastic Leukemia (ALL) in 2nd or subsequent CR. ALL shall be morphologic remission at the time of transplant. Morphologic remission is defined that subjects with normal neutrophil and platelet counts, less than 5% blast cells in a bone marrow (BM) smear and no extramedullary disease ii. Acute Myeloid Leukemia (AML) in 2nd or subsequent CR with or without persistent minimal residual disease b. High-risk ALL in 1st CR (including features such as those in i-iii) i. Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), MLL rearrangements ii. Subjects over 30 years of age, or iii. Time to complete remission was greater than 4 weeks. c. High-risk AML in 1st CR (including features such as those listed in i-vii) i. Greater than 1 cycle of induction therapy required to achieve remission ii. Preceding myelodysplastic syndrome (MDS) iii. Presence of FLT3 abnormalities iv. FAB M6 or M7 leukemia v. Adverse cytogenetics for overall survival such as those associated with MDS vi. Complex karyotype (\>3 abnormalities), or vii. Any of the following: inv(3) or t(3;3), t(6;9), t(6;11), + 8 \[alone or with other abnormalities except for t(8;21), t(9;11), inv(16) or t(16;16)\], t(l1;19)(q23;p13.1) d. High risk Myelodysplastic Syndrome e. Non-Hodgkin's Lymphoma relapsed after autologous transplantation f. Non-Hodgkin's Lymphoma with insufficient autologous hematopoietic stem cells to undergo autologous transplantation g. CML i. in first chronic phase that has not attained at least a complete cytogenetic remission after exposure to at least 3 tyrosine kinase inhibitors ii. in accelerated phase that has not attained at least a complete cytogenetic remission iii. in second chronic phase
• Performance status: Karnofsky score ≥60%.

You may not qualify if:

• HLA 8/8 allele matched (HLA-A,-B,-Cw,-DRBl) related or unrelated donor able to donate.
• Autologous hematopoietic stem cell transplant \< 3 months prior to enrollment.
• Pregnancy or breast-feeding.
• Evidence of HIV infection or known HIV positive serology.
• Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings). The treating physician will make final determination.
• Non-hematologic malignancy within prior three (3) years, with the exception of squamous cell or basal cell skin carcinoma.
• Prior allogeneic hematopoietic stem cell transplant.
• Subjects with a history of primary idiopathic myelofibrosis.
• Bovine product allergy.

Sponsors & Collaborators

• Bellicum Pharmaceuticals: lead

Study Sites (8)

Emory University Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

University Hospitals of Cleveland

Cleveland, Ohio, 44106, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Baylor Sammons Cancer Center

Dallas, Texas, 75246, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109, United States

Location

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Lymphoma; Myelodysplastic Syndromes; Graft vs Host Disease

Interventions

AP 1903 reagent

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Bone Marrow Diseases

Study Officials

• Bellicum Pharmaceuticals

  Bellicum Pharmaceuticals, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: December 5, 2012
• First Posted: December 6, 2012
• Study Start: March 1, 2013
• Primary Completion: October 9, 2019
• Study Completion (Estimated): October 1, 2032
• Last Updated: July 12, 2022

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (8)