GENERAL INCLUSION CRITERIA FOR ALL PATIENTS. 1. Patients must be aged ≥18 years and ≤80 years with relapsed or refractory B-cell
non-Hodgkin Lymphoma.
2. Absolute cluster of differentiation 3 (CD3) count ≥50 mm^3.
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 EXCEPT Arm E subjects.
4. Measurable disease must be documented within four weeks of the time of consent defined
as nodal lesions greater than 15 mm in the long axis or extranodal lesions >10 mm in
long and short axis OR bone marrow involvement that is biopsy proven for B-cell NHL
(see separate criteria for CLL and primary/secondary CNS lymphoma).
5. Karnofsky performance score ≥70.
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. ANC≥1000 with no G-CSF within 72 hours or pegylated G-CSF within 14 days.
8. Platelets≥50,000 with no transfusion within 72 hours.
9. Adequate renal function, defined as creatinine clearance >60 ml/min AND serum Cr≤1.5
mg/dL.
a. No IV hydration within 24 hours of eligibility. b. No dialysis dependent renal
failure within three months of planned CAR infusion.
10. Able to provide written informed consent.
11. Agree to practice birth control during the study.
12. Adequate cardiac function as indicated by New York Heart Association (NYHA)
classification I or II AND left ventricular ejection fraction of ≥45% (by cardiac
echocardiogram (ECHO) or multigated acquisition scan (MUGA)) and adequate pulmonary
function as indicated by room air oxygen saturation of ≥92%.
13. Expected survival >12 weeks.
14. Negative urine or serum pregnancy test in females of child bearing potential at study
entry.
15. Meet criteria regarding fertility and contraception.
16. No contraindication to central line access.
17. Patient has demonstrated compliance to other therapies.
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 DLBCL with associated subtypes
(aggressive B-cell lymphoma, high grade 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. ARM A: Six to nine 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 two patients with prior CAR-T will be allowed in this cohort.
ARM B: Six to nine 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, high
grade 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 two patients with prior CAR-T will be allowed in this cohort.
ARM C: 24 patient cryopreservation 8/12 flexible manufacturing arm. 1. Diagnosis of B-cell NHL including Follicular Lymphoma, Marginal Zone Lymphoma
(splenic, nodal, extranodal), and DLBCL with associated subtypes (aggressive B-cell
lymphoma, high grade 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 a. 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 b. Relapse post-autologous transplant c. Relapse
post-allogeneic transplant d. Relapse post-anti-CD19 CAR-T cell therapy i. A maximum
of 2 patients with prior CAR-T will be allowed in this cohort. ARM D: Phase 1 and Phase 1b: CLL. 1. Diagnosis of B-cell CLL or small lymphocytic leukemia (SLL) 2. Failed/progressed or been
intolerant to two prior lines of therapy one of which MUST be either a covalent BTK
inhibitor (e.g. ibrutinib, acalabrutinib, zanabrutinib, etc) or BCL2 inhibitors (e.g.
venetoclax or other investigational BCL2) 3. Indication for treatment as defined as any of
the following:
1. measurable lymph nodes ≥ 1.5 cm in the greatest transverse diameter and/or
hepatomegaly or splenomegaly)
2. bone marrow involvement with ≥10% CLL involvement. ARM E: Phase 1 and Phase1b Relapsed/Refractory Primary or Secondary CNS Lymphoma. 1. Diagnosis of diffuse large B cell lymphoma (DLBCL) with associated subtypes
(aggressive B-cell lymphoma, high grade 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) with secondary CNS lymphoma involvement OR primary CNS lymphoma.
2. For Primary CNS lymphoma, relapsed or refractory following at least one line of
CNS-directed therapy.
3. Secondary CNS lymphoma relapsed or refractory following at least one line of
CNS-directed therapy for treatment of CNS lymphoma.
1. For patients with secondary central nervous system lymphoma (CNSL) with
concurrent systemic lymphoma, the concurrent systemic lymphoma must have relapsed
following at least 1 prior line of therapy (which must have included an anti-CD20
monoclonal antibody and an anthracycline)
4. Measurable CNS disease by either lumbar puncture (LP) with positivity in CNS by flow
cytometry or morphology for lymphoma cells OR magnetic resonance imaging (MRI) with
enhancing lesions ≥1 cm in size consistent with lymphoma. 5. Must have had prior treatment with high dose methotrexate defined as methotrexate
given intravenously at a dose ≥2500 mg/m^2 and either progression/relapse, stable
disease, or intolerance to at least one cycle of treatment.
Phase II Cohort: Mantle Cell Lymphoma. 1. Diagnosis of Mantle Cell Lymphoma. 2. Patients must have active, measurable disease as
previously defined 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 childbearing potential.
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 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 MRI or by lumbar puncture (Not
applicable to Arm E cohort.)
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. Prior allogeneic CAR T-cell therapy. 10. Previous recipients of autologous 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) or have >5% residual circulating CAR-T as measured by flow cytometry
using a CD19 CAR detection reagent (Miltenyi Biotec)
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. 11. Anti-CD20 antibody treatment within 4 weeks of cell infusion. 12. Anti-CD19 antibody treatment within 4 weeks of cell infusion. 13. Cytotoxic chemotherapy other than lymphodepletion within 14 days of CAR-T cell
infusion. 14. Cytotoxic chemotherapy treatment within 14 days or steroid treatment (other than
replacement dose steroids) within 7 days prior to apheresis collection for CAR-T cells. 15. Oral chemotherapeutic agents or antibody directed treatment within 7 days of apheresis. a. BTK inhibitors are allowed until 1-day prior to apheresis and can re-start until
1-day prior to lymphodepletion. 16. Patients post solid organ transplant who develop high grade lymphomas or leukemias. 17. Concurrent active malignancy other than basal or squamous cell carcinomas of the skin
(underlying low-grade lymphoma chronic lymphocytic leukemia/follicular lymphoma
(FL)/marginal zone lymphoma (MZL) is allowable in patients with transformed large cell
lymphoma)
SPECIAL CRITERIA REGARDING FERTILITY AND CONTRACEPTION. Female subjects of reproductive potential (women who have reached menarche or women who
have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses
within the preceding 24 months, or have not undergone a sterilization procedure
[hysterectomy or bilateral oophorectomy]) must have a negative serum or urine pregnancy
test performed as part of eligibility criteria Due to the high-risk level of this study,
while enrolled, all subjects must agree not to participate in a conception process (e.g.,
active attempt to become pregnant or to impregnate, sperm donation, in vitro
fertilization). Additionally, if participating in sexual activity that could lead to
pregnancy, the study subject must agree to use reliable and double barrier methods of
contraception during the follow-up period of the protocol.
Acceptable birth control includes a combination of two of the following methods:
- - Condoms (male or female) with or without a spermicidal agent.
- - Diaphragm or cervical cap with spermicide.
- Intrauterine device (IUD)
- Hormonal-based contraception Subjects who are not of reproductive potential (women who
are premenarche or have been post-menopausal for at least 24 consecutive months or
have undergone hysterectomy tubal ligation, salpingectomy, and/or bilateral
oophorectomy or men who have documented azoospermia) are eligible without requiring
the use of contraception
