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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

NCT04223765

Description:

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.

Related Conditions:
  • Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue
  • Follicular Lymphoma
  • Mantle Cell Lymphoma
  • Nodal Marginal Zone Lymphoma
  • Splenic Marginal Zone Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of Kappa Chimeric Antigen Receptor (CAR) T Lymphocytes Co-Expressing the Kappa and CD28 CARs for Relapsed/Refractory Kappa+ Non-Hodgkin Lymphoma
  • 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

Clinical Trial IDs

  • ORG STUDY ID: LCCC 1811-ATL
  • NCT ID: NCT04223765

Conditions

  • 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

Interventions

DrugSynonymsArms
CAR.k.28Kappa Chimeric Antigen Receptor and CD28 EndodomainCAR.k.28/CAR.k.4-1BB
FludarabineFLUDARACAR.k.28/CAR.k.4-1BB
CyclophosphamideCytoxanCAR.k.28/CAR.k.4-1BB
BendamustineBendeka, TreandaCAR.k.28/CAR.k.4-1BB

Purpose

The body has different ways of fighting infection and disease. No single way is perfect for fighting cancer. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are proteins that protect the body from disease caused by bacteria or toxic substances. Antibodies work by binding bacteria or substances, which stops them from growing and causing bad effects. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected with bacteria or viruses. Both antibodies and T cells have been used to treat patients with cancers. Given individually they have shown promise, but neither alone has been sufficient to treat cancer. 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.

Detailed Description

      This study is a single center, open-label phase 1 clinical trial designed to determine the
      safety of escalating doses of autologous activated T lymphocytes (ATLs) expressing the
      chimeric antigen receptor specific for the kappa-light chain of human immunoglobulins (CAR.κ)
      in subjects with relapsed/refractory kappa-positive (κ+) mantle cell and indolent non-Hodgkin
      lymphomas (NHL). During dose finding, up to 12 subjects will receive a single infusion of ATL
      product expressing the CAR.κ encoding the CD28 co-stimulatory endodomain (CAR.κ.28). The
      starting dose will be 5.0 × 105 cells/kg. Up to 3 dose levels of CAR.κ.28 cells will be
      tested with at least 3 subjects enrolled in each dose cohort before dose escalation is
      considered based on the incidence of dose limiting toxicity (DLT). Prior to receiving the
      cell product, subjects will undergo lymphodepletion with fludarabine and bendamustine or
      cyclophophamide. Dose escalation will be guided by the modified 3+3 design. Any dose level
      may be expanded to 4-9 subjects to obtain more data at that dose or to include subjects for
      which insufficient cells are manufactured to enroll on their assigned higher dose level. If
      due to the expansion the estimated DLT rate at a dose is ≥0.33, the study would not escalate
      to the next highest dose level and the recommended phase 2 dose (RP2D) would be exceeded. If
      needed, an expansion cohort will enroll up to 8 subjects at the RP2D to further assess safety
      and efficacy of CAR.κ.28 cells. Secondary endpoints include evaluation of progression free
      survival (PFS), response rate (RR), duration of response (DoR) and overall survival (OS). The
      persistence of CAR.κ.28 cells in the peripheral blood will be assessed as an exploratory
      objective. The final RP2D including expansion data will be the dose with the DLT rate closest
      to 0.2.

      The adoptive transfer of T cells targeting the kappa light chain (CAR.κ) is a promising
      treatment for patients with relapsed/refractory κ + NHL and has shown encouraging preclinical
      activity [37]. The CD8α stalk incorporated into CD28 signaling domain within the CAR, may
      improve the persistence of the CAR.κ T cells. Therefore, subjects in this study are being
      infused with this newly modified version of CAR.κ.28 so that persistence and efficacy will be
      improved compared to the older version of the CAR.κ molecule.

      We hypothesize that CAR.κ.28 will be well tolerated in subjects with relapsed/refractory
      indolent and aggressive lymphomas positive for the kappa light chain and will show efficacy.
      We also anticipate that CAR.κ.28 will show fast expansion in the peripheral blood in the
      first 2 - 3 weeks, but also longer term persistence than the previous version of CAR.κ.28.

      In this phase 1 single center study, peripheral blood will be collected for production of
      CAR.κ.28 cells prior to conditioning chemotherapy in subjects with relapsed/refractory κ+
      indolent lymphoma including follicular lymphoma grade 1-3b, splenic marginal zone lymphoma,
      extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone
      lymphoma, and mantle cell lymphoma. During the approximately 1-2 months necessary for CAR-T
      cell production, subjects may undergo standard of care treatment ("bridging therapy") per
      physician's discretion. Subjects must sign consent forms before cells are procured and again
      prior to undergoing lymphodepleting chemotherapy and cellular treatment. At 2-14 days
      (preferably 2-4 days) after lymphodepletion with bendamustine and fludarabine, we will infuse
      the CAR.κ.28 cell product. Subjects in this study will receive CAR.κ.28 cell product in one
      of the three planned dose escalation cohorts. Dose levels of CAR.κ.28 cells administered will
      range between 5.0 × 105 cells/kg and 2 × 106 cells/kg. These doses have been evaluated in
      previous phase 1 studies of CAR-T cell lymphocytes [37-39] including a phase 1 trial
      targeting the kappa light chain on malignant B cells in which the construct included the CD28
      co-stimulatory endodomain [37]. An expansion cohort will enroll up to 8 subjects at the RP2D
      to further assess safety and efficacy of CAR.κ.28 cells. In all subjects, we will measure the
      persistence of CAR.κ.28 cells in the peripheral blood at different time points by measuring
      the level of the transgene and by phenotypic analyses.

      OUTLINE

      Cell Procurement Peripheral blood, up to 300 mL (in up to 3 collections) will be obtained
      from subjects for cell procurement. In subjects with inadequate lymphocyte count in the
      peripheral blood, a leukapheresis may be performed to isolate sufficient T cells. The
      parameters for apheresis will be up to 2 blood volumes.

      Lymphodepleting Regimen Subjects will receive a "pre-conditioning" cytoreductive regimen of
      bendamustine 70 mg/m2/day administered IV followed by fludarabine 30 mg/m2/day administered
      IV over 3 consecutive days. These agents will be administered per institutional guidelines.
      Prophylaxis (e.g., hydration, antiemetics, etc.) needed prior to fludarabine and bendamustine
      chemotherapy will be provided per institutional guidelines. At the discretion of the clinical
      investigator, subjects with a known history of intolerance to bendamustine may be considered
      for lymphodepletion with cyclophosphamide 500 mg/m2/day administered IV followed by an IV
      dose of fludarabine 30 mg/m2/day administered over 3 consecutive days. These agents will be
      administered per institutional guidelines.

      Cell Administration The cellular product consisting of CAR.κ.28 cells will be administered by
      a licensed healthcare provider (oncology nurse or physician) via intravenous injection over 5
      - 10 minutes through either a peripheral or a central line. The volume of infusion will
      depend upon the concentration of the cells when frozen and the size of the subject. The
      expected volume will be 1-50cc.

      Post lymphodepletion, subjects who meet eligibility criteria for cellular therapy will
      receive CAR.κ.28 cells within 2 - 14 days, but preferably within 2-4 days, after completing
      the lymphodepleting chemotherapy regimen.

      During dose finding, a single dose of CAR.κ.28 will be given after lymphodepletion. The cell
      dose levels that will be evaluated are outlined below.

      Expansion Cohort, CAR.κ.28 will be given after lymphodepletion. Subjects will receive the
      RP2D.

      Duration of Therapy

      Therapy in LCCC1811-ATL involves a single cell infusion of ATLCAR cells. Treatment with at
      least one infusion will be administered unless:

        -  Subject decides to withdraw from study treatment, or

        -  General or specific changes in the subject's condition render the subject unacceptable
           for further treatment in the judgment of the investigator.

      Duration of Follow-up Subjects will be followed for up to 15 years for RCR evaluation or
      until death, whichever occurs first. In addition to this follow-up, subjects removed from
      study treatment for unacceptable adverse events will be followed until resolution or
      stabilization of the adverse event.

      Subjects who experience unequivocal disease progression and start alternate therapy after
      receiving a cell infusion still be required to complete abbreviated follow up procedures.
    

Trial Arms

NameTypeDescriptionInterventions
CAR.k.28/CAR.k.4-1BBExperimentalUp 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.
  • CAR.k.28
  • Fludarabine
  • Cyclophosphamide
  • Bendamustine

Eligibility Criteria

        Inclusion Criteria: Unless otherwise noted, subjects must meet all of the following
        criteria to participate in this 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 follicular lymphoma grade 1-3b, splenic marginal zone
             lymphoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue,
             nodal marginal zone lymphoma, and mantle cell lymphoma.

          4. Subjects relapsed after autologous or allogeneic stem cell transplant are eligible for
             this study.

          5. Subjects must have received at least 2 prior chemotherapy or immunochemotherapy
             regimens, which must include:

               -  An anti-CD20 monoclonal antibody, and

               -  An alkylating agent

          6. Kappa-positive expression on lymphoma 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).

          7. Karnofsky score of > 60% (see Appendix C).

          8. 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: Patients 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 chronic lymphocytic leukemia or 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 tissue 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 be 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 >75 × 109/L (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 lymphodepletion 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. Subjects must have autologous transduced activated T-cells that meet the Certificate
             of Analysis (CofA) acceptance criteria.

          7. Has not received any investigational agents or received any tumor vaccines within the
             previous six weeks prior to lymphodepletion.

          8. Has not received chemotherapy or immunotherapy within the previous 3 weeks prior to
             lymphodepletion.

          9. 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 H).

         10. Subject is not taking a prohibited or contraindicated medication listed in Section
             5.12 and Appendix H 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.

         11. 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 ≤ 1.53 × ULN or 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with adverse events as a measure of safety and tolerability of CAR.κ.28 ATL cells.
Time Frame:4 weeks
Safety Issue:
Description:Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). The NCI Common Terminology Criteria for Adverse Events is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 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 AE.

Secondary Outcome Measures

Measure:Median progression free survival (PFS) after infusion of CAR.κ.28 cells
Time Frame:15 years
Safety Issue:
Description: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 NHL.
Measure:Median overall survival (OS) after administration of CAR.κ.28 cells
Time Frame:15 years
Safety Issue:
Description:Overall survival will be measured from the date of administration of CAR.κ.28 infusion to date of death
Measure:Objective response rate by 8 weeks and best overall response rate post CAR.κ.28 cell administration
Time Frame:8 weeks
Safety Issue:
Description: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 NHL

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

Trial Keywords

  • CAR T cells
  • Kappa
  • CD28
  • Lymphoma
  • T lymphocytes

Last Updated

January 7, 2020