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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01744223
Recruitment Status : Active, not recruiting
First Posted : December 6, 2012
Last Update Posted : October 9, 2020
Sponsor:
Information provided by (Responsible Party):
Bellicum Pharmaceuticals

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.

Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Acute Myelogenous Leukemia Lymphoma Myelodysplastic Syndromes Biological: BPX-501 dose 1 Drug: Rimiducid Biological: BPX-501 dose 2 Biological: BPX-501 dose 3 Biological: BPX-501 dose 4 Procedure: SCT Phase 1 Phase 2

Expanded Access : An investigational treatment associated with this study is no longer available outside the clinical trial.   More info ...

Detailed Description:
This is a Phase1/2 dose escalation study evaluating the safety and feasibility of BPX-501 infused after partially mismatched, related (haploidentical), T cell-depleted HSCT. The purpose of this clinical trial is to determine whether BPX-501 infusion can facilitate engraftment, enhance immune reconstitution and potentially improve the graft versus leukemia (GVL) effect, with the potential for reducing the severity and duration of severe acute graft versus host disease (GvHD). The trial will evaluate the treatment of GvHD by the infusion of dimerizer drug (Rimiducid) in those subjects who present with GvHD that does not adequately respond to standard of care therapy.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Dose Escalation Study Evaluating Safety and Feasibility of BPX-501 T Cells After Partially Mismatched, Related, T Cell-Depleted HSCT (Hematopoietic Stem Cell Transplant)
Study Start Date : March 2013
Actual Primary Completion Date : October 2019
Estimated Study Completion Date : November 2032


Arm Intervention/treatment
Experimental: SCT, BPX-501 dose 1, Rimiducid if needed

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
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.
Other Name: rivogenlecleucel

Drug: Rimiducid
Dimerizer drug administered by intravenous infusion in those subjects who develop GVHD after infusion of BPX-501 cells.
Other Name: AP1903

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

Experimental: SCT, BPX-501 dose 2, Rimiducid if needed

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
Dimerizer drug administered by intravenous infusion in those subjects who develop GVHD after infusion of BPX-501 cells.
Other Name: AP1903

Biological: BPX-501 dose 2
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.
Other Name: rivogenlecleucel

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

Experimental: SCT, BPX-501 dose 3, Rimiducid if needed

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
Dimerizer drug administered by intravenous infusion in those subjects who develop GVHD after infusion of BPX-501 cells.
Other Name: AP1903

Biological: BPX-501 dose 3
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.
Other Name: rivogenlecleucel

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

Experimental: SCT, BPX-501 dose 4, Rimiducid if needed

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
Dimerizer drug administered by intravenous infusion in those subjects who develop GVHD after infusion of BPX-501 cells.
Other Name: AP1903

Biological: BPX-501 dose 4
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.
Other Name: rivogenlecleucel

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




Primary Outcome Measures :
  1. BPX-501 Safety [ Time Frame: 24 months ]
    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)

  2. Rimiducid Safety [ Time Frame: 24 months ]
    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

  3. MTD [ Time Frame: 24 months ]
    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.

  4. Immune Reconstitution [ Time Frame: 24 months ]
    To assess immune reconstitution for each dose cohort


Secondary Outcome Measures :
  1. Efficacy- NRM [ Time Frame: 100, 180 days and 1 year ]
    Non-Relapse Mortality (NRM)

  2. Efficacy- DFS [ Time Frame: 24 months ]
    Disease-free survival

  3. Efficacy- TRM [ Time Frame: 24 months ]
    Transplant related mortality (TRM)

  4. Efficacy- Relapse [ Time Frame: 24 months ]
    Incidence of Relapse

  5. Incidence of engraftment [ Time Frame: 24 months ]
    Evaluation of neutrophil and platelet engraftment, kinetics of donor cell engraftment and graft failure

  6. GvHD [ Time Frame: 24 months ]
    Incidence and severity of acute and chronic GvHD

  7. GvHD post Rimiducid Administration [ Time Frame: 24 months ]
    Time to resolution of acute GvHD after administration of Rimiducid

  8. BPX-501 Safety Profile [ Time Frame: 24 months ]
    Characterize the safety profile of BPX-501 including evaluation of high grade toxicity and infectious complications

  9. Pharmacokinetics of Rimiducid [ Time Frame: 24 months ]
    Pharmacokinetic disposition of Rimiducid



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed informed consent
  2. Age ≥ 18 years and ≤ 65 years
  3. Deemed eligible for allogeneic stem cell transplantation
  4. 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
  5. 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
  6. Subjects with adequate organ functions as measured by:

    1. Cardiac: Left ventricular ejection fraction at rest must be ≥ 45%
    2. Hepatic: Bilirubin ≤ 2.5 mg/dL and ALT, AST and Alkaline Phosphatase < 5 x ULN
    3. Renal: Serum creatinine within normal range for age or creatinine clearance, or with a recommended GFR ≥ 50 mL/min/1.73m2
    4. Pulmonary: FEV 1, FVC and DLCO (diffusion capacity) ≥ 50% predicted (corrected for hemoglobin); or O2 saturation > 92% on room air
  7. 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

  8. Performance status: Karnofsky score ≥60%.
  9. Patient with hematologic malignancy not responding to /or not eligible for conventional therapy and are approved by Sponsor

Exclusion Criteria:

  1. HLA 8/8 allele matched (HLA-A,-B,-Cw,-DRBl) related or unrelated donor able to donate.
  2. Autologous hematopoietic stem cell transplant < 3 months prior to enrollment.
  3. Pregnancy or breast-feeding.
  4. Evidence of HIV infection or known HIV positive serology.
  5. 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.
  6. Non-hematologic malignancy within prior three (3) years, with the exception of squamous cell or basal cell skin carcinoma.
  7. Prior allogeneic hematopoietic stem cell transplant.
  8. Subjects with a history of primary idiopathic myelofibrosis.
  9. Bovine product allergy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01744223


Locations
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United States, Georgia
Emory University Winship Cancer Institute
Atlanta, Georgia, United States, 30322
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
United States, Ohio
University Hospitals of Cleveland
Cleveland, Ohio, United States, 44106
United States, Oregon
Oregon Health & Science University
Portland, Oregon, United States, 97239
United States, Texas
Baylor Sammons Cancer Center
Dallas, Texas, United States, 75246
UT Southwestern Medical Center
Dallas, Texas, United States, 75390
United States, Washington
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Bellicum Pharmaceuticals
Investigators
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Study Director: Bellicum Pharmaceuticals Bellicum Pharmaceuticals, Inc.
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Responsible Party: Bellicum Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01744223    
Other Study ID Numbers: BP-001
First Posted: December 6, 2012    Key Record Dates
Last Update Posted: October 9, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Bellicum Pharmaceuticals:
iCaspase9
iCasp9
Inducible Caspase
AP1903
Dimerizer drug
T depleted
Suicide gene
CD-34 selection
haplotransplantation
Graft versus host disease
Allogenic transplantation
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases