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CD19+ Specific Chimeric Antigen Receptor T Cells in Treating Participants With CD19+ Lymphoid Malignancies

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ClinicalTrials.gov Identifier: NCT03579888
Recruitment Status : Not yet recruiting
First Posted : July 9, 2018
Last Update Posted : October 23, 2018
Sponsor:
Collaborators:
Ziopharm Oncology
Precigen, Inc
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
This phase I trial studies the side effects and best dose of CD19 positive (+) specific chimeric antigen receptor T cells in treating participants with CD19+ lymphoid malignancies, such as acute lymphoblastic leukemia, non-Hodgkin lymphoma, small lymphocytic lymphoma, or chronic lymphocytic lymphoma. Sometimes researchers change the genetic material in the cells of a participant's T cells using a process called gene transfer. Researchers then inject the changed T-cells into the body of the participant. The genetically modified CD19+ specific chimeric antigen receptor T cells may or may not be able to attack cancer cells in participants with CD19+ lymphoid malignancies.

Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Blasts More Than 5 Percent of Bone Marrow Nucleated Cells Blasts More Than 5 Percent of Peripheral Blood White Cells CD19 Positive Chronic Lymphocytic Leukemia Minimal Residual Disease Non-Hodgkin Lymphoma Small Lymphocytic Lymphoma Biological: Autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T Cells Drug: Cyclophosphamide Drug: Fludarabine Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the safety and maximum tolerated dose (MTD) of genetically modified, CD19-specific T cells expressing membrane-bound form of IL-15 (mbIL15) and HER1t manufactured under point of care (P-O-C) process (P-O-C CD19-mbIL15-chimeric antigen receptor [CAR]-T cells) administered into patients with CD19+ advanced lymphoid malignancies.

SECONDARY OBJECTIVES:

I. To describe the feasibility of the P-O-C process. II. To determine the incidence and grading of cytokine release syndrome (CRS) and neurotoxicity.

III. To determine persistence of genetically modified T cells. IV. To determine if cetuximab can control numbers of infused T cells. V. To screen for the development of host immune responses against the transgenes (one or more of CAR, mbIL15, HER1t).

VI. To determine cytokine profile of the patient with infused T cells. VII. To describe the homing ability of the infused T cells. VIII. To assess disease response at day 30 and day 100. IX. To assess disease progression-free and overall survival. X. Emergence of CD19 negative (neg) malignant B cells.

OUTLINE: This is a dose-escalation study of CD19+ specific chimeric antigen receptor T cells.

CHEMOTHERAPY: Participants receive fludarabine intravenously (IV) over 1 hour and cyclophosphamide IV over 3 hours on days -5, -4, and -3 in the absence of disease progression or unacceptable toxicity.

T CELL INFUSION: Participants receive CD19+ specific chimeric antigen receptor T cells IV over 15-30 minutes on day 0 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed for up to 15 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Infusion of Minimally Expanded CD19+ Specific Chimeric Antigen Receptor T Cells for Patients With Advanced Lymphoid Malignancies
Estimated Study Start Date : December 2019
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2021


Arm Intervention/treatment
Experimental: Treatment (fludarabine, cyclophosphamide, T cell infusion)

CHEMOTHERAPY: Participants receive fludarabine IV over 1 hour and cyclophosphamide IV over 3 hours on days -5, -4, and -3 in the absence of disease progression or unacceptable toxicity.

T CELL INFUSION: Participants receive CD19+ specific chimeric antigen receptor T cells IV over 15-30 minutes on day 0 in the absence of disease progression or unacceptable toxicity.

Biological: Autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T Cells
Given IV
Other Name: CD19-CD8CD28zCAR-specific-mbIL15-HER1t T-lymphocytes; Autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-EGFRt T Cells

Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719

Drug: Fludarabine
Given IV
Other Name: Fluradosa




Primary Outcome Measures :
  1. Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 15 years ]
    Adverse events will be summarized by frequencies and percentages by dose level.

  2. Maximum tolerated dose (MTD) as determined by dose limiting toxicity (DLT) [ Time Frame: Up to 30 days post-infusion ]
    The MTD is defined as the highest dose at which no more than 1 of 6 patients experiences a DLT. The dose limiting toxicity is defined as CTCAE grades non-reversible grade 3, or any grade 4-5 allergic reactions related to the study cell infusion; CTCAE grades non-reversible grade 3, or any grade 4-5 autoimmune reactions related to the study cell infusion; or CTCAE grades non-reversible non-hematologic grade 3, or any grade 4-5 organ toxicity (cardiac, dermatologic, gastrointestinal, hepatic, pulmonary, renal/genitourinary, or neurologic) not pre-existing or due to the underlying malignancy and occurring within 30 days of study product infusion related to study cell infusion. The study will employ a standard 3+3 design to find the MTD of CD19-specific chimeric antigen receptor (CAR) T cell dose.


Secondary Outcome Measures :
  1. Incidence and grading of cytokine release syndrome (CRS) graded according to CTCAE [ Time Frame: Up to 12 months ]
  2. Persistence of genetically modified T cells [ Time Frame: Up to 12 months ]
    Persistence of genetically modified T cells will be assessed by the frequency of patients with any detectable CAR+ T cells.

  3. Change in numbers of infused T cells [ Time Frame: Up to 12 months ]
    For patients receiving cetuximab (i.e., those who experience >= grade 3 CRS), the change in infused CAR+ T cells from before cetuximab treatment to the nadir of CAR+ T cells after cetuximab summarized by mean, standard deviation, median, and range and days to achieve nadir.

  4. Development of host immune responses against transgenes [ Time Frame: Up to 12 months ]
    The development of host immune responses against the transgenes (one or more of CAR, mbIL15, HER1t) may be assessed by the percentage of patients with antibody formation against each one of the transgenes.

  5. Cytokine levels [ Time Frame: Up to 12 months ]
    Individual patient and aggregate cytokine levels (e.g., IL-15, IL-12, IL-8, etc.) will be summarized by means, standard deviations, medians, and ranges.

  6. Disease response [ Time Frame: At days 30 and 100 ]
    Percentage of patients experiencing disease response, defined as partial or complete clearance of disease e.g., by positron emission tomography (PET) and/or bone marrow report. Further, the percentage of responders with CD19+ lymphoma or leukemia will be reported. The percentage of patients who had T cells successfully prepared, released, and infused will be reported. Additional statistical analyses will be performed if deemed appropriate.

  7. Neurotoxicity graded according to CTCAE [ Time Frame: up to 12 months ]
  8. Persistence of genetically modified T cells [ Time Frame: up to 12 months ]
    Persistence of genetically modified T cells will be assessed by the percentage of patients with any detectable CAR+ T cells.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with a history of CD19+ lymphoid malignancy defined as acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), small lymphocytic lymphoma (SLL), or chronic lymphocytic leukemia (CLL) with active disease defined by presence of > 5% malignant blasts in bone marrow and/or peripheral blood, and/or minimal residual disease by flow cytometry or molecular analysis for fusion proteins, and/or positive imaging for extramedullary disease. Patients must have measurable disease at time of study treatment.
  • Confirmed history of CD19-positivity by flow cytometry for malignant cells.
  • Karnofsky performance scale > 70.
  • Patient able to provide written informed consent.
  • Patient able to provide written informed consent for the long-term follow-up (LTFU) gene therapy study.
  • Absolute T-cell count (ATC) at screening >= 0.07 K/microL. This is defined as CD3+ T-cell percent (expressed as fraction of 100%) multiplied by the absolute lymphocyte count (ALC, expressed in K/microL).
  • Patients at least 3 weeks from last cytotoxic chemotherapy. Patients may continue tyrosine kinase inhibitors or other targeted therapies until at least two weeks prior to administration of lymphodepleting chemotherapy.
  • Creatinine clearance (as estimated by Cockcroft Gault) >= 50 cc/min.
  • Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN) or =< 5 x ULN if documented liver metastases.
  • Total bilirubin =< 1.5 mg/dL, except in subjects with Gilbert's syndrome in whom total bilirubin must be =< 3.0 mg/dL.
  • Cardiac ejection fraction >= 40%, and no clinically significant electrocardiogram (ECG) findings.
  • No clinically significant pleural effusion, baseline oxygen saturation > 92% on room air.
  • Negative human anti-mouse antibody (HAMA) result.

Exclusion Criteria:

  • Positive beta human chorionic gonadotropin (HCG) in female of child-bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization or lactating females.
  • Patients with known allergy to bovine or murine products.
  • Positive serology for human immunodeficiency virus (HIV).
  • Active hepatitis B or active hepatitis C.
  • Has received a T-cell product within 6 weeks prior to planned infusion of genetically modified T cells.
  • Has received allogeneic hematopoietic cell transplantation (HSCT) within 3 months of planned infusion of genetically modified T cells; HSCT >= 3 months from CAR-T cell infusion eligible.
  • History of allergic reactions to cetuximab.
  • Active clinically significant infection within 7-days of study treatment.

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): NCT03579888


Contacts
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Contact: Partow Kebriaei 713-792-8750 pkebriae@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Not yet recruiting
Houston, Texas, United States, 77030
Contact       pkebriae@mdanderson.org   
Sponsors and Collaborators
M.D. Anderson Cancer Center
Ziopharm Oncology
Precigen, Inc
Investigators
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Principal Investigator: Partow Kebriaei M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03579888     History of Changes
Other Study ID Numbers: 2017-0908
NCI-2018-01110 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: July 9, 2018    Key Record Dates
Last Update Posted: October 23, 2018
Last Verified: October 2018

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

Additional relevant MeSH terms:
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Neoplasm, Residual
Neoplasms by Histologic Type
Neoplasms
Lymphoma
Leukemia
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Neoplastic Processes
Pathologic Processes
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites