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T Lymphocytes Expressing the Kappa Chimeric Antigen Receptor (CAR) and CD28 Endodomain for the Treatment of Relapsed or Refractory B cell Non-Hodgkin Lymphoma or Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma

Trial Status: Active

This phase I trial studies the best dose of T lymphocytes expressing the kappa CAR and CD28 endodomain (CAR.kappa.28) in treating patients with kappa-positive B cell non-Hodgkin lymphoma or chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL) that has come back (relapsed) or does not respond to treatment (refractory). 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. The anti-kappa light chain antibody has been changed so that 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. These kappa light chain chimeric (combination) receptor-activated T cells, which are called ATLCAR.kappa.28, can kill some of the tumor. They do not, however, last very long in the body and so their chances of fighting the cancer are unknown.

Inclusion Criteria

  • Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information
  • Diagnosis of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma OR histologically confirmed B-cell NHL, including the following types defined by World Health Organization (WHO) 2016: * Aggressive lymphomas: ** Diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS) ** T cell/histiocyte rich large B cell lymphoma; primary cutaneous DLBCL, leg type; Epstein-Barr virus (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 central nervous system (CNS) disease will not be excluded as long it has been stable for 3 months * Subjects with bone marrow only involvement are eligible
  • Subjects relapsed after autologous or allogeneic stem cell transplant are eligible for this study
  • 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
  • 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)
  • For indolent lymphomas, subjects must have received at least 2 prior lines of therapy for their lymphoma
  • 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
  • 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
  • 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)
  • Karnofsky score of > 60%
  • 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
  • ELIGIBILITY CRITERIA PRIOR TO PROCUREMENT: Subject has signed a consent to undergo cell procurement
  • ELIGIBILITY CRITERIA PRIOR TO PROCUREMENT: Hemoglobin >= 8.0 g/dL (transfusion independent for 2 weeks prior to enrollment)
  • ELIGIBILITY CRITERIA PRIOR TO PROCUREMENT: Total bilirubin < 1.5 x upper limit of normal (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 x ULN)
  • ELIGIBILITY CRITERIA PRIOR TO PROCUREMENT: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5 x ULN
  • ELIGIBILITY CRITERIA PRIOR TO PROCUREMENT: Pulse oximetry > 90% on room air
  • ELIGIBILITY CRITERIA PRIOR TO PROCUREMENT: Creatinine =< 1.5 x ULN or creatinine clearance (CrCl) > 60 mL/min per Cockcroft and Gault
  • ELIGIBILITY CRITERIA PRIOR TO PROCUREMENT: Imaging results from within 120 days prior to procurement to assess presence of active disease
  • ELIGIBILITY CRITERIA PRIOR TO PROCUREMENT: Confirmed kappa-positive expression on lymphoma or CLL/SLL tissue or bone marrow sample (archival or fresh) as confirmed by pathology
  • ELIGIBILITY CRITERIA PRIOR TO PROCUREMENT: Subject has adequate cardiac function, defined as: * No electrocardiography (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 echocardiography (ECHO), with no additional evidence of decompensated heart failure, performed within 30 days prior to procurement
  • ELIGIBILITY CRITERIA PRIOR TO PROCUREMENT: 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 PRIOR TO LYMPHODEPLETION: Written informed consent to enroll in the CAR-T cell therapy trial must be obtained prior to lymphodepletion
  • ELIGIBILITY CRITERIA PRIOR TO LYMPHODEPLETION: 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
  • ELIGIBILITY CRITERIA PRIOR TO LYMPHODEPLETION: Absolute neutrophil count (ANC) > 1.0 x 10^9/L
  • ELIGIBILITY CRITERIA PRIOR TO LYMPHODEPLETION: Platelets > 50 x 10^9/L unless related to lymphoma involvement (independent of transfusion within 7 days of lymphodepletion)
  • ELIGIBILITY CRITERIA PRIOR TO LYMPHODEPLETION: Total bilirubin =< 1.5 x 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 x ULN)
  • ELIGIBILITY CRITERIA PRIOR TO LYMPHODEPLETION: AST and ALT =< 5 x ULN
  • ELIGIBILITY CRITERIA PRIOR TO LYMPHODEPLETION: Pulse oximetry of > 90% on room air
  • ELIGIBILITY CRITERIA PRIOR TO LYMPHODEPLETION: Creatinine =< 1.5 x ULN or creatinine clearance (CrCl) > 60 mL/min per Cockcroft and Gault
  • ELIGIBILITY CRITERIA PRIOR TO LYMPHODEPLETION: 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
  • ELIGIBILITY CRITERIA PRIOR TO LYMPHODEPLETION: 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
  • ELIGIBILITY CRITERIA PRIOR TO LYMPHODEPLETION: In subjects with CLL/SLL, a bone marrow biopsy within 28 days prior to lymphodepletion
  • ELIGIBILITY CRITERIA PRIOR TO LYMPHODEPLETION: Subjects must have autologous transduced activated T-cells that meet the Certificate of Analysis (CofA) acceptance criteria
  • ELIGIBILITY CRITERIA PRIOR TO LYMPHODEPLETION: Has not received any investigational agents or received any tumor vaccines within the previous six weeks prior to lymphodepletion
  • ELIGIBILITY CRITERIA PRIOR TO LYMPHODEPLETION: Has not received chemotherapy or immunotherapy within the previous 3 weeks prior to lymphodepletion
  • ELIGIBILITY CRITERIA PRIOR TO LYMPHODEPLETION: 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
  • ELIGIBILITY CRITERIA PRIOR TO LYMPHODEPLETION: Subject is not taking a prohibited or contraindicated medication 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
  • ELIGIBILITY CRITERIA PRIOR TO LYMPHODEPLETION: No evidence of uncontrolled infection or sepsis
  • ELIGIBILITY CRITERIA PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: No evidence of uncontrolled infection or sepsis
  • ELIGIBILITY CRITERIA PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: Total bilirubin =< 2 x ULN, unless attributed to Gilbert’s syndrome
  • ELIGIBILITY CRITERIA PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: AST =< 5 x ULN
  • ELIGIBILITY CRITERIA PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: ALT =< 5 x ULN
  • ELIGIBILITY CRITERIA PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: Creatinine =< 1.5 x ULN or creatinine clearance (CrCl) > 60 mL/min per Cockcroft and Gault
  • ELIGIBILITY CRITERIA PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: Subject has no clinical indication of rapidly progressing disease in the opinion of the clinical investigator
  • ELIGIBILITY CRITERIA PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: Subject is a good candidate for treatment with CAR.kappa.28 cell product per the clinical investigator’s discretion

Exclusion Criteria

  • A diagnosis of lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia or multiple myeloma
  • 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
  • Subject is pregnant or lactating
  • Tumor in a location where enlargement could cause airway obstruction
  • 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
  • Active infection with human T-lymphotropic virus (HTLV), hepatitis C virus (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 human immunodeficiency virus (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
  • 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

North Carolina

Chapel Hill
UNC Lineberger Comprehensive Cancer Center
Status: ACTIVE
Contact: Natalie S. Grover
Phone: 919-843-5968

PRIMARY OBJECTIVE:

I. To establish a safe/recommended phase 2 dose (i.e., number cells/kg) of CAR.kappa.28 to infuse after lymphodepletion in subjects with kappa-positive relapsed/refractory B cell non-Hodgkin lymphomas (B-NHL) and CLL/SLL.

SECONDARY OBJECTIVES:

I. To estimate median progression free survival (PFS) after infusion of CAR.kappa.28 in subjects with kappa-positive relapsed/refractory B-NHL and CLL/SLL.

II. To estimate median overall survival (OS) after administration of CAR.kappa.28 in subjects with kappa-positive relapsed/refractory B-NHL and CLL/SLL.

III. To estimate the objective response rate and best overall response rate post CAR.kappa.28 when administered in subjects with kappa-positive relapsed/refractory B-NHL and CLL/SLL.

IV. To estimate duration of response after administration of CAR.kappa.28 in subjects with kappa-positive relapsed/refractory B-NHL and CLL/SLL.

EXPLORATORY OBJECTIVES:

I. To measure the expansion and persistence of CAR.kappa.28 cells in peripheral blood.

II. To determine whether there are correlations between CAR.kappa.28 cell behavior and the integration locations of CAR.kappa.28.

OUTLINE: This is a dose escalation study of CAR.kappa.28.

LYMPHODEPLETION: Patients receive bendamustine intravenously (IV) and fludarabine IV on days 1-3 in the absence of disease progression or unacceptable toxicity. At the discretion of the clinical investigator, patients with an intolerance to bendamustine may receive cyclophosphamide IV and fludarabine IV on days 1-3 in the absence of disease progression or unacceptable toxicity.

TREATMENT: Within 2-14 days after completion of lymphodepletion, patients receive CAR.kappa.28 IV over 5-10 minutes.

After completion of study treatment, patients are followed up for 8 weeks, every 6 months for 5 years, and then annually for up to 15 years.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
UNC Lineberger Comprehensive Cancer Center

Principal Investigator
Natalie S. Grover

  • Primary ID LCCC1811-ATL
  • Secondary IDs NCI-2019-08780
  • Clinicaltrials.gov ID NCT04223765