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Study of Kappa Chimeric Antigen Receptor (CAR) T Lymphocytes Co-Expressing the Kappa and CD28 CARs for Relapsed/Refractory Kappa+ Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

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ClinicalTrials.gov Identifier: NCT04223765
Recruitment Status : Recruiting
First Posted : January 10, 2020
Last Update Posted : July 7, 2021
Sponsor:
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center

Brief Summary:

This study will combine both T cells and antibodies in order to create a more effective treatment. The treatment tested in this study uses modified T-cells called Autologous T Lymphocyte Chimeric Antigen Receptor (ATLCAR) cells targeted against the kappa light chain antibody on cancer cells. For this study, the anti-kappa light chain antibody has been changed so instead of floating free in the blood, a part of it is now joined to the T cells. Only the part of the antibody that sticks to the lymphoma cells is attached to the T cells. When an antibody is joined to a T cell in this way, it is called a chimeric receptor. The kappa light chain chimeric (combination) receptor-activated T cells are called ATLCAR.κ.28 cells. These cells may be able to destroy lymphoma cancer cells. They do not, however, last very long in the body so their chances of fighting the cancer are unknown.

Previous studies have shown that a new gene can be put into T cells to increase their ability to recognize and kill cancer cells. A gene is a unit of DNA. Genes make up the chemical structure carrying your genetic information that may determine human characteristics (i.e., eye color, height and sex). The new gene that is put in the T cells in this study makes an antibody called an anti-kappa light chain. This anti-kappa light chain antibody usually floats around in the blood. The antibody can detect and stick to cancer cells called lymphoma cells because they have a substance on the outside of the cells called kappa light chains.

The purpose of this study is to determine whether receiving the ATLCAR.κ.28 cells is safe and tolerable and learn more about the side effects and how effective these cells are in fighting lymphoma. Initially, the study doctors will test different doses of the ATLCAR.κ.28, to see which dose is safer for use in lymphoma patients. Once a safe dose is identified, the study team will administer this dose to more patients, to learn about how these cells affect lymphoma cancer cells and identify other side effects they might have on the body.

This is the first time ATLCAR.κ.28 cells are given to patients with lymphoma. The Food and Drug Administration (FDA), has not approved giving ATLCAR.κ.28 as treatment for lymphoma. This is the first step in determining whether giving ATLCAR.κ.28 to others with lymphoma in the future will help them.


Condition or disease Intervention/treatment Phase
Mantle Cell Lymphoma Follicular Lymphoma Splenic Marginal Zone Lymphoma Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue Nodal Marginal Zone Lymphoma Indolent Non-hodgkin Lymphoma Drug: CAR.k.28 Drug: Fludarabine Drug: Cyclophosphamide Drug: Bendamustine Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Study of the Administration of T Lymphocytes Expressing the Kappa Chimeric Antigen Receptor (CAR) and CD28 Endodomain for Relapsed/Refractory Kappa+ Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.
Actual Study Start Date : November 12, 2020
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2038


Arm Intervention/treatment
Experimental: CAR.k.28/CAR.k.4-1BB
Up to 12 patients will receive a single infusion of CAR.k.28. The starting dose will be 2.5x10^5 cells/kg of each product. Up to 3 dose levels of CAR.k.28 cells will be tested with at least 3 patients enrolled at each dose cohort before dose escalation is considered based on the incidence of dose limiting toxicity (DLT). An expansion cohort will enroll up to 8 patients at the recommended phase 2 dose. Prior to receiving the infusions, patients will undergo lymphodepletion with fludarabine and bendamustine. Patients with a known history of intolerance to bendamustine may be considered for lymphodepletion with fludarabine and cyclophosphamide.
Drug: CAR.k.28
Three dose levels will be evaluated: Dose level 1 (5x10^5 cells/kg), Dose level 2 (1x10^6), and dose level 3 (2x10^6 cells/kg).
Other Name: Kappa Chimeric Antigen Receptor and CD28 Endodomain

Drug: Fludarabine
30 mg/m^2/day IV for 3 consecutive days
Other Name: FLUDARA

Drug: Cyclophosphamide
500 mg/m^2/day IV for 3 consecutive days
Other Name: Cytoxan

Drug: Bendamustine
70 mg/m^2/day administered over 3 consecutive days.
Other Name: Bendeka, Treanda




Primary Outcome Measures :
  1. Number of participants with adverse events as a measure of safety and tolerability of CAR.κ.28 ATL cells [ Time Frame: 4 weeks ]
    Toxicity is classified and graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Grade 1 Mild; asymptomatic or mild symptoms; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to Adverse Event (AE). Immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms will be graded per American Society for Blood and Marrow Transplantation (ASBMT) ICANS Consensus Grading for Adults (scale from 1-mild to 4-critical) and cytokine release syndrome (CRS) symptoms will be graded according to ASBMT CRS Consensus Grading (a scale from 1-mild to 5-death).


Secondary Outcome Measures :
  1. Median progression free survival (PFS) after infusion of CAR.κ.28 cells [ Time Frame: 15 years ]
    PFS is defined from day of CAR.κ.28 infusion to relapse (in patients with a documented complete response after conditioning chemotherapy) or progression (in patients without complete response after conditioning chemotherapy), or death as a result of any cause per revised Lugano criteria for Non-Hodgkin Lymphoma (NHL) and International Workshop on Chronic Lymphocytic Leukemia (IWCLL) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL).

  2. Median overall survival (OS) after administration of CAR.κ.28 cells [ Time Frame: 15 years ]
    Overall survival will be measured from the date of administration of CAR.κ.28 infusion to date of death

  3. Objective response rate by 8 weeks and best overall response rate post CAR.κ.28 cell administration [ Time Frame: 8 weeks ]
    The objective response rate will be defined as the rate of complete responses (CR) + partial responses (PR) by 8 weeks post CAR.κ.28 infusion per revised Lugano criteria for Non-Hodgkin Lymphoma (NHL). For Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) patients, the rate of CR + PR will be defined by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria by 8 weeks post-CAR.κ.28 infusion


Other Outcome Measures:
  1. Duration of response after administration of CAR.κ.28 cells [ Time Frame: 15 years ]
    The duration of response will be defined as time from documentation of tumor response to disease progression. Response will be evaluated per Lugano criteria for Non-Hodgkin Lymphoma (NHL) or International Workshop on Chronic Lymphocytic Leukemia (IWCLL) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) .



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

SUBJECT ELIGIBILITY

Note: During the period of cell procurement and CAR.κ.28 T cell production, subjects are allowed to receive additional standard of care chemotherapy to stabilize their disease if the treating physician feels it is in the subject's best interest. For subjects requiring bridging chemotherapy while awaiting manufacture of their CAR.κ.28 T-cells, details regarding treatment(s) administered including dose, frequency, number of cycles, etc. will be collected.

Inclusion Criteria for the Study

Unless otherwise noted, subjects must meet all of the following criteria to participate in this study:

  1. Written informed consent and HIPAA authorization for release of personal health information.
  2. Adults ≥18 years of age.
  3. Diagnosis of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma OR histologically confirmed B-cell NHL, including the following types defined by WHO 2016:

    Aggressive Lymphomas:

    • DLBCL not otherwise specified (NOS)
    • T cell/histiocyte rich large B cell lymphoma; primary cutaneous DLBCL, leg type; EBV-positive DLBCL NOS; DLBCL associated with chronic inflammation; Lymphomatoid granulomatosis; Large B-cell lymphoma with IRF4 rearrangement; Intravascular large B-cell lymphoma; ALK-positive large B-cell lymphoma
    • Primary mediastinal (thymic) large B-cell lymphoma
    • High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement; high grade B-cell lymphoma, NOS
    • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma
    • Transformation of indolent lymphoma or CLL to DLBCL will also be included
    • Burkitt lymphoma

    Indolent Lymphomas:

    • Follicular lymphoma grade 1-3b
    • Splenic marginal zone lymphoma
    • Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue
    • Nodal marginal zone lymphoma
    • Mantle cell lymphoma
    • Subjects with CNS disease will not be excluded as long it has been stable for 3 months

    Subjects with bone marrow only involvement are eligible

  4. Subjects relapsed after autologous or allogeneic stem cell transplant are eligible for this study.
  5. Subjects who have received prior CD19-directed CAR therapies for relapsed/refractory disease are eligible for this study. However, at least 3 months must have passed since the subject received CD19 CAR-T cells.
  6. Patients with aggressive lymphomas must have relapsed or refractory disease after having received at least 2 prior lines of systemic therapy, including, at a minimum:

    • An anti-CD20 monoclonal antibody
    • An anthracycline containing chemotherapy regimen (if eligible)
    • An autologous stem cell transplant (if eligible)
  7. For indolent lymphomas, subjects must have received at least 2 prior lines of therapy for their lymphoma
  8. Subjects with specifically relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma must have received at least 2 prior therapy regimens which can include, but not limited to:

    • A combination of an anti-CD20 monoclonal antibody and an alkylating agent, OR
    • A Bruton's Tyrosine Kinase Inhibitor, OR
    • A BCL-2 inhibitor in combination with an anti-CD20 monoclonal antibody
  9. Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
  10. Kappa-positive expression on lymphoma or CLL/SLL tissue sample, or kappa restriction on flow cytometry (archival or fresh) as confirmed by institutional hematopathology standard (result must be confirmed at the time of cell procurement).
  11. Karnofsky score of > 60% (see Appendix C).
  12. Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study, and for 6 months after the study is concluded. Female subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. The two birth control methods can be composed of: two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. Female subjects of childbearing potential will also be instructed to tell their male partners to use a condom.

Exclusion Criteria for the Study

Subjects meeting any of the following exclusion criteria will not be able to participate in this study (procurement, lymphodepletion and cell infusion):

  1. A diagnosis of lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia or multiple myeloma.
  2. A history of intolerance to bendamustine or fludarabine. Note: subjects with known history of intolerance to bendamustine may be considered for lymphodepletion with cyclophosphamide and fludarabine at the discretion of the clinical investigator.
  3. Subject is pregnant or lactating.
  4. Tumor in a location where enlargement could cause airway obstruction.
  5. Current use of systemic corticosteroids at doses ≥10 mg prednisone daily or its equivalent; those receiving <10 mg daily may be enrolled at discretion of investigator.
  6. Active infection with HTLV, HCV (can be pending at the time of cell procurement; only those samples confirming lack of active infection will be used to generate transduced cells) defined as not being well controlled on therapy as well as no history of HIV. Subjects are required to have negative HIV antibody, negative HTLV1 and HTLV2 antibodies, negative hepatitis B surface antigen, and negative HCV antibody or viral load.
  7. Subjects who are positive for hepatitis B surface antigen (can be pending at the time of cell procurement; only those samples confirming lack of active infection will be used to generate transduced cells) are excluded. Subjects who are hepatitis B surface antigen negative but hepatitis B core antibody positive must have their hepatitis B viral load checked. These subjects will be excluded if their viral load is positive at baseline (when tested during screening for procurement). Subjects who are core antibody positive and viral load negative at baseline will be considered eligible.

Eligibility Criteria to be Met Prior to Procurement

  1. Subject has signed a consent to undergo cell procurement.
  2. Evidence of adequate organ function as defined by:

    • Hemoglobin ≥ 8.0 g/dL (transfusion independent for 2 weeks prior to enrollment)
    • Total bilirubin <1.5 × ULN (subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level >1.5 mg/dL if their conjugated bilirubin is <1.5 × ULN)
    • AST and ALT < 5x ULN
    • Pulse oximetry of >90% on room air
    • Creatinine ≤1.5x ULN or Creatinine Clearance (CrCl) >60 mL/min per Cockcroft and Gault (see Appendix F).
  3. Imaging results from within 120 days prior to procurement to assess presence of active disease.
  4. Confirmed kappa-positive expression on lymphoma or CLL/SLL tissue or bone marrow sample (archival or fresh) as confirmed by pathology.
  5. Subject has adequate cardiac function, defined as:

    • No ECG evidence of acute ischemia
    • No ECG evidence of active, clinically significant conduction system abnormalities
    • Prior to study entry, any ECG abnormality at screening not felt to put the subject at risk has to be documented by the investigator as not medically significant
    • No uncontrolled angina or severe ventricular arrhythmia
    • Left ventricular ejection fraction (LVEF) >40% as measured by ECHO, with no additional evidence of decompensated heart failure, performed within 30 days prior to procurement
  6. In women of child-bearing potential, negative serum pregnancy test within 72 hours prior to procurement or documentation that the subject is post-menopausal. Post-menopausal status must be confirmed with documentation of absence of menses for > 1 year.

Eligibility Criteria to be Met Prior to Lymphodepletion

  1. Written informed consent to enroll in the CAR-T cell therapy trial must be obtained prior to lymphodepletion.
  2. The last bridging therapy should be completed at least 3 weeks prior to lymphodepletion. Subjects who have received bridging therapy will be reassessed with imaging within 5 days prior to lymphodepletion and at least 3 weeks after bridging therapy. If a patient did not receive bridging chemotherapy, they will e imaged within 10 days prior to lymphodepletion.
  3. Adequate organ function per the following criteria are required prior to lymphodepletion:

    • Adequate bone marrow function, as defined by:

      • ANC >1.0 × 109/L
      • Platelets >50 × 109/L unless related to lymphoma involvement (independent of transfusion within 7 days of lymphodepletion)
    • Total bilirubin ≤1.5× ULN (subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level >1.5 mg/dL if their conjugated bilirubin is <1.5× ULN)
    • AST and ALT ≤ 5× ULN
    • Pulse oximetry of > 90% on room air
    • Creatinine <1.5x ULN or Creatinine clearance (CrCl) >60 mL/min per Cockcroft and Gault (see Appendix F),
  4. If subjects display any clinical signs or symptoms of cardiac dysfunction after receiving bridging chemotherapy, they will undergo repeat ECG and ECHO to reassess their cardiac function and status
  5. In female subjects of childbearing potential, a negative serum pregnancy test within 72 hours prior to l ymphodepletion or documentation that the subject is post-menopausal or has been surgically sterilized.

    Post-menopausal status must be confirmed with documentation of absence of menses for > 1 year.

  6. In subjects with CLL/SLL, a bone marrow biopsy within 28 days prior to lymphodepletion.
  7. Subjects must have autologous transduced activated T-cells that meet the Certificate of Analysis (CofA) acceptance criteria.
  8. Has not received any investigational agents or received any tumor vaccines within the previous six weeks prior to lymphodepletion.
  9. Has not received chemotherapy or immunotherapy within the previous 3 weeks prior to lymphodepletion.
  10. Subjects may not be receiving strong inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) up through

72 hours after the last dose of bendamustine, as these may increase plasma concentrations of bendamustine, and decrease plasma concentrations of its metabolites. See http://medicine.iupui.edu/clinpharm/ddis/ for an updated list of strong inhibitors of CYP1A2 (additionally, see Appendix I: Prohibited Medications or Those to Use with Caution) 11 Subject is not taking a prohibited or contraindicated medication listed in Section 5.12 and Appendix I: Prohibited Medications or Those to Use with Caution prior to lymphodepletion. Contraindicated medications should be discontinued at least two weeks prior to the scheduled lymphodepletion or by at least 5 half-lives of the contraindicated medication, whichever is shorter. 12 No evidence of uncontrolled infection or sepsis.

Eligibility Criteria to be Met Prior to Cell Infusion After Lymphodepletion

  1. No evidence of uncontrolled infection or sepsis.
  2. Evidence of adequate organ function as defined by:

    1. Total bilirubin ≤2 × ULN, unless attributed to Gilbert's syndrome
    2. AST < 5 × ULN
    3. ALT < 5 × ULN
    4. Creatinine ≤ 1.5 × ULN or Creatinine clearance (CrCl) >60 mL/min per Cockcroft and Gault (see Appendix F)
  3. Subject has no clinical indication of rapidly progressing disease in the opinion of the clinical investigator.
  4. Subject is a good candidate for treatment with CAR.κ.28 cell product per the clinical investigator's discretion.

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): NCT04223765


Contacts
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Contact: Catherine Cheng 919-445-4208 catherine_cheng@med.unc.edu
Contact: Spencer Laing 919-962-8618 spencer.laing@med.unc.edu

Locations
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United States, North Carolina
Lineberger Comprehensive Cancer Center at University of North Carolina Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Catherine Cheng    919-445-4208    catherine_cheng@med.unc.edu   
Contact: Caroline Babinec    (919) 962-7426    caroline_babinec@med.unc.edu   
Principal Investigator: Natalie Grover, MD         
Sub-Investigator: Paul Armistead         
Sub-Investigator: Anne Beaven, MD         
Sub-Investigator: James Coghill         
Sub-Investigator: Christopher Dittus, MD         
Sub-Investigator: Gianpietro Dotti         
Sub-Investigator: Paul Eldridge         
Sub-Investigator: Katarzyna Jamieson         
Sub-Investigator: Emily Kassam         
Sub-Investigator: Grace Park         
Sub-Investigator: Alicia Pinto         
Sub-Investigator: Marcie Riches         
Sub-Investigator: Barbara Savoldo         
Sub-Investigator: Jonathan Serody, MD         
Sub-Investigator: Thomas Shea, MD         
Sub-Investigator: Benjamin Vincent         
Sub-Investigator: Kimberly Wehner         
Sub-Investigator: William Wood         
Sub-Investigator: Ashley Zanter         
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
Investigators
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Principal Investigator: Natalie Grover, MD UNC Lineberger Comprehensive Cancer Center
Additional Information:
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Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT04223765    
Other Study ID Numbers: LCCC 1811-ATL
First Posted: January 10, 2020    Key Record Dates
Last Update Posted: July 7, 2021
Last Verified: June 2021

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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 UNC Lineberger Comprehensive Cancer Center:
CAR T cells
Kappa
CD28
Lymphoma
T lymphocytes
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, B-Cell, Marginal Zone
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia
Leukemia, B-Cell
Lymphoma, B-Cell
Cyclophosphamide
Bendamustine Hydrochloride
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