CAR-20/19-T Cells in Patients With Relapsed Refractory B Cell Malignancies
CAR-20/19-T Cells in Patients With Relapsed Refractory B Cell Malignancies
This is a Phase I/II, interventional, single-arm, open-label, treatment study designed to
 evaluate the safety and efficacy of Interleukin-7 and Interleukin-15 (IL-7/IL-15)
 manufactured chimeric antigen receptor (CAR)-20/19-T cells as well as the feasibility of a
 flexible manufacturing schema in adult patients with B cell malignancies that have failed
 prior therapies.
This is a Phase 1/Phase 2 study. The objectives are as follows:

 1. Phase 1/1b: Determine the safety of a fixed dose of 2.5 x 10^6 CAR-20/19-T cells/kg
 expanded with IL-7/IL-15 at 8 and 12-day manufacturing times in relapsed refractory
 B-cell non-Hodgkin lymphoma (NHL) followed by expansion cohorts.

 2. Phase 2:

 1. Determine the three-month complete response (CR) rate of CAR-20/19-T cells in
 Mantle Cell Lymphoma (MCL).

 2. Determine the feasibility of a flexible manufacturing process of CAR-20/19-T cells
 from patient apheresis products using the CliniMACS® Prodigy Cell processing
 device.
GENERAL INCLUSION CRITERIA FOR ALL PATIENTS

 1. Patients must be aged ≥18 years with relapsed or refractory B-cell non-Hodgkin
 Lymphoma.

 2. Absolute cluster of differentiation 3 (CD3) count ≥50 mm3.

 3. Magnetic resonance imaging (MRI) brain and Lumbar Puncture with cerebrospinal fluid
 (CSF) analysis by cytology and flow cytometry without evidence of central nervous
 system (CNS) involvement ONLY in patients with history of CNS involvement or clinical
 suspicion at the time of enrollment.

 4. Measurable disease must be documented within four weeks of the time of consent defined
 as nodal lesions greater than 20 mm in the long axis or extranodal lesions >10 mm in
 long and short axis OR bone marrow involvement that is biopsy proven.

 5. Karnofsky performance score ≥60.

 6. Adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine
 aminotransferase (ALT) <5 x upper limit of normal (ULN); serum bilirubin and alkaline
 phosphatase <5 x ULN, or considered not clinically significant as per the clinical PIs
 discretion (e.g. Gilbert's or indirect hyperbilirubinemia) or felt to be due to
 underlying disease.

 7. Adequate renal function, defined as creatinine clearance>40 ml/min.

 8. Able to provide written informed consent.

 9. Agree to practice birth control during the study.

 10. Adequate cardiac function as indicated by New York Heart Association (NYHA)
 classification I or II AND left ventricular ejection fraction of ≥35% (by cardiac
 echocardiogram (ECHO) or multigated acquisition scan (MUGA)) and adequate pulmonary
 function as indicated by room air oxygen saturation of ≥92%.

 11. Expected survival >12 weeks.

 12. Negative urine or serum pregnancy test in females of child bearing potential at study
 entry.

 13. Meet criteria for regarding fertility and contraception.

 14. No contraindication to central line access.

 Phase 1: 3+3 COHORT ELEGIBILITY CRITERIA

 1. Diagnosis of B-cell NHL including Follicular Lymphoma, Marginal Zone Lymphoma
 (splenic, nodal, extranodal), Mantle Cell Lymphoma, and Diffuse large B-cell lymphoma
 (DLBCL) with associated subtypes (aggressive B-cell lymphoma, T-cell/histocyte rich
 B-cell lymphoma, primary mediastinal B-cell lymphoma, Epstein-Barr virus-positive
 (EBV+) diffuse large B-cell lymphoma, transformed lymphoma such as transformed
 follicular or marginal zone, and Richter's transformation).

 2. Patients must have active, measurable disease as defined and meet one of the following
 criteria.

 1. Must have received Rituximab or another cluster of differentiation 20 (CD20)
 antibody and at minimum two different chemotherapy regimens appropriate for their
 disease and be ineligible to receive autologous transplant.

 2. Relapse post-autologous transplant

 3. Relapse post-allogeneic transplant

 4. Patients not previously treated with CAR-T cell therapy

 PHASE 1b and 2 COHORT ELEGIBILITY CRITERIA

 COHORT 1: 6-9 patient expansion with 8-day manufacturing (Phase 1b)

 1. Diagnosis of B-cell NHL including Follicular Lymphoma, Marginal Zone Lymphoma
 (splenic, nodal, extranodal), and DLBCL with associated subtypes (aggressive B-cell
 lymphoma, T-cell/histocyte rich B-cell lymphoma, primary mediastinal B-cell lymphoma,
 EBV+ diffuse large B-cell lymphoma, transformed lymphoma such as transformed
 follicular or marginal zone, and Richter's transformation).

 2. Patients must have active, measurable disease as defined and meet one of the following
 criteria:

 1. Must have received Rituximab or another cluster of differentiation 20 (CD20)
 antibody and at minimum two different chemotherapy regimens appropriate for their
 disease and be ineligible to receive autologous transplant.

 2. Relapse post-autologous transplant.

 3. Relapse post-allogeneic transplant.

 4. Relapse post-anti-cluster of differentiation 19 (CD19) CAR-T cell therapy.

 i. A maximum of 2 patients with prior CAR-T will be allowed in this cohort.

 COHORT 2: 6-9 patient expansion with 12-day manufacturing (Phase 1b)

 1. Diagnosis of B-cell NHL including Follicular Lymphoma, Marginal Zone Lymphoma (splenic,
 nodal, extranodal), and DLBCL with associated subtypes (aggressive B-cell lymphoma,
 T-cell/histocyte rich B-cell lymphoma, primary mediastinal B-cell lymphoma, EBV+ diffuse
 large B-cell lymphoma, transformed lymphoma such as transformed follicular or marginal
 zone, and Richter's transformation).

 2. Patients must have active, measurable disease as defined and meet one of the following
 criteria:

 1. Must have received Rituximab or another CD20 antibody and at minimum two different
 chemotherapy regimens appropriate for their disease and be ineligible to receive
 autologous transplant.

 2. Relapse post-autologous transplant.

 3. Relapse post-allogeneic transplant.

 4. Relapse post-anti-CD19 CAR-T cell therapy.

 i. A maximum of 2 patients with prior CAR-T will be allowed in this cohort.

 COHORT 3: Mantle Cell Lymphoma (Phase 2) 1. Diagnosis of Mantle Cell Lymphoma. 2. Patients
 must have active, measurable disease as previously designed and have relapsed, refractory
 disease as defined as one of the following:

 1. Relapsed disease after two lines of cytotoxic chemotherapy including administration of
 anti-CD20 antibody.

 2. Progressive disease after ≥second line Bruton tyrosine kinase (BTK) inhibitor.

 3. Relapse post-autologous transplant.

 4. Relapse post-allogeneic transplant.

 5. Relapse post anti-CD19 CAR-T cell therapy.

 i. A maximum of four patients with history of prior anti-CD19 CAR-T will be allowed in this
 cohort.

 Exclusion Criteria (all patients) A potential subject who meets any of the following
 exclusion criteria is ineligible to participate in the study.

 1. Positive beta-human chorionic gonadotropin (HCG) in female of child-bearing potential
 defined as per table 1.

 2. Confirmed active human immunodeficiency virus (HIV), Hepatitis B or C infection.

 3. History of significant autoimmune disease OR active, uncontrolled autoimmune
 phenomenon requiring steroid therapy defined as >20 mg of prednisone or equivalent
 daily.

 4. Presence of ≥grade 3 non-hematologic toxicities as per Common Terminology Criteria for
 Adverse Events (CTCAE) version 5.0 from any previous treatment unless it is felt to be
 due to underlying disease.

 5. Concurrent use of investigational therapeutic agents or enrollment on another
 therapeutic clinical trial at any institution. Minimum of 14 days or 5 half-lives of
 the drug (whichever is shorter) washout prior to apheresis.

 6. Refusal to participate in the long-term follow-up protocol.

 7. Patients with active CNS involvement by malignancy on magnetic resonance imaging (MRI)
 or by lumbar puncture.

 a. Patients with prior CNS disease that has been effectively treated will be eligible
 providing treatment was >4 weeks before enrollment and a remission documented within 8
 weeks of planned CAR-T cell infusion by MRI brain and CSF analysis.

 8. Previous recipients of allogeneic hematopoietic stem cell transplantation (AHCT) are
 excluded if they are <100 days' post-transplant, have evidence of active
 graft-versus-host-disease (GVHD) of any grade, or are currently on immunosuppression.

 9. Previous recipients of CAR-T cell therapy directed at either CD19 or CD20 are excluded
 if they are <100 days post prior CAR-T cell treatment (does not include
 re-enrollment).

 a. Patients with prior CAR-T treatment against CD19 or CD20 must have repeat biopsy
 post-CAR-T cell therapy confirming a minimum of 5% CD19 or CD20 positivity by
 immunohistochemistry or flow cytometry.

 10. Anti-CD20 antibody treatment within 4 weeks of cell infusion.

 11. Anti-CD19 antibody treatment within 4 weeks of cell infusion.

 12. Cytotoxic chemotherapy other than lymphodepletion within 14 days of CAR-T cell
 infusion (corticosteroids or targeted therapies for bridging allowable e.g.
 venetoclax, BTK inhibitors, lenalidomide, etc).

 13. Cytotoxic chemotherapy treatment within 10 days or steroid treatment (other than
 replacement dose steroids) within 7 days prior to apheresis collection for CAR-T
 cells.

 14. Patients post solid organ transplant who develop high grade lymphomas or leukemias.

 15. Concurrent active malignancy other than basal or squamous cell carcinomas of the skin.