Overview

Phase 1 study comprised of open-label, dose escalation and expansion cohort study of P-CD19CD20-ALLO1 allogeneic T stem cell memory (Tscm) CAR-T cells in subjects with relapsed/refractory B cell malignancies

Eligibility

Inclusion Criteria:

1. Must have signed written, informed consent.
2. Males or females ≥ 18 years of age.
3. Must have prior biopsy proven confirmed diagnosis of DLBCL, FL, MCL, MZL, PMBCL, or CLL.
4. Diagnosis of one of the following:
   1. DLBCL, FL, MCL, MZL, or PMBCL by World Health Organization (WHO) 2016 (Swerdlow,
   2. criteria
   3. CLL that meets published diagnostic criteria (Hallek, 2018):
   4. Monoclonal B cells (either kappa or lambda light chain restricted) that are clonally co-expressing ≥ 1 B cell marker (CD19, CD20, or CD23) and CD5.

             ii. Prolymphocytes comprising ≤ 55% of blood lymphocytes. iii. Presence of ≥ 5 × 109 B
             lymphocytes/L (5000/µL) in the peripheral blood (at any point since initial
             diagnosis).
          5. CLL must be documented as CD20-positive.
          6. CLL must be documented as active disease meeting ≥ 1 of the following iwCLL 2018
             criteria (Hallek, 2018) for requiring treatment:
               1. Evidence of progressive marrow failure as manifested by the development of, or
                  worsening of, anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia (platelets <
                  100,000/μL)
               2. Massive (i.e., ≥ 6 cm below the left costal margin), progressive, or symptomatic
                  splenomegaly.
               3. Massive nodes (i.e., ≥ 10 cm in the longest diameter), progressive, or
                  symptomatic lymphadenopathy.
               4. Progressive lymphocytosis with an increase of > 50% over a 2 month period or a
                  lymphocyte doubling time (LDT) of < 6 months. LDT may be obtained by linear
                  regression extrapolation of absolute lymphocyte count (ALC) obtained at intervals
                  of 2 weeks over an observation period of 2 to 3 months. In subjects with initial
                  blood lymphocyte counts of < 30 × 109/L (30,000/μL), LDT should not be used as a
                  single parameter to define indication for treatment. In addition, factors
                  contributing to lymphocytosis or lymphadenopathy other than CLL (e.g.,
                  infections) should be excluded.
               5. Constitutional symptoms documented in the subject's chart with supportive
                  objective measures, as appropriate, defined as ≥ 1 of the following
                  disease-related symptoms or signs:
             i. Unintentional weight loss ≥ 10% within the previous 6 months before Screening.
             ii. Significant fatigue (inability to work or perform usual activities). iii. Fevers
             higher than 100.5°F or 38.0°C for ≥ 2 weeks before Screening without evidence of
             infection.
             iv. Night sweats for > 1 month before Screening without evidence of infection.
          7. DLBCL, FL, MCL, MZL, or PMBCL must have measurable disease as defined by Lugano 2016
             criteria (Cheson, 2016).
          8. Must have relapsed/refractory disease as defined by the following:
               1. DLBCL, FL, MCL, or PMBCL: received at least 2 prior lines of therapy that must
                  include rituximab, cyclophosphamide, doxorubicin hydrochloride (i.e.,
                  hydroxydaunomycin), vincristine sulfate (i.e., oncovin), and prednisone (R-CHOP)
                  or equivalent regimen and either autologous stem cell transplant (ASCT) or
                  autologous CD19 targeting CAR-T therapy, or not a candidate for ASCT or
                  autologous CD19 targeting CAR-T.
                  OR
               2. MZL: received at least 2 prior lines of therapy that must include a CD20
                  monoclonal antibody (mAb) and a Bruton tyrosine kinase inhibitor (BTKi) OR
               3. CLL: received at least 2 prior lines of therapy that must include a CD20 mAb and
                  a BTKi
          9. Must be willing to practice birth control from the time of Screening and throughout
             the first year of the study after P-CD19CD20-ALLO1 administration (both males and
             females of childbearing potential).
         10. Must have a negative serum pregnancy test at Screening and a negative urine pregnancy
             test within 3 days prior to initiating the lymphodepletion chemotherapy regimen
             (females of childbearing potential).
         11. Must be at least 90 days since ASCT, if performed.
         12. Must be at least 3 months since autologous CAR-T therapy if such therapy was
             administered (medical monitor must approve prior CAR T therapy or other prior T cell
             targeted therapy).
         13. Must have adequate vital organ function, defined as follows (or medical monitor
             approval):
               1. Serum creatinine ≤ 1.5 mg/dL or estimated creatinine clearance
                  ≥ 30 mL/min as calculated using the Cockcroft Gault formula and not
                  dialysis-dependent.
               2. Adequate hematologic function, including:
             i. Absolute neutrophil count (ANC) ≥ 1000/μL in the absence of growth factor support
             (granulocyte-colony stimulating factor [G-CSF] within 7 days or peg-G-CSF within 14
             days) ii. Platelet count ≥ 50,000/μL in the absence of transfusion support (platelet
             transfusion within 7 days) iii. Hemoglobin ≥ 8 g/dL in the absence of transfusion
             support (red blood cell count or whole blood within 7 days) c. Aspartate transaminase
             (AST) and alanine aminotransferase (ALT) ≤ 3 × the upper limit of normal (ULN), and
             total bilirubin ≤ 2.0 mg/dL (unless there is a history of Gilbert's Syndrome in which
             case bilirubin levels ≤ 3 mg/dL).
             d. Left ventricular ejection fraction (LVEF) ≥ 45%. LVEF assessment must have been
             performed within 4 weeks of enrollment.
         14. Must have recovered from toxicities due to prior therapies to Grade ≤ 2 according to
             the NCI CTCAE v5.0 criteria or to the subject's prior baseline.
         15. Must have an ECOG performance status of 0 to 1.
        Exclusion Criteria:
          1. Is pregnant or lactating.
          2. Has inadequate venous access.
          3. Has active hemolytic anemia, POEMS syndrome (polyneuropathy, organomegaly,
             endocrinopathy, monoclonal protein, and skin changes), disseminated intravascular
             coagulation, leukostasis, or amyloidosis.
          4. Has an active second malignancy (not disease-free for at least 5 years) in addition to
             non-Hodgkin lymphoma or CLL, excluding low-risk neoplasms such as non-metastatic basal
             cell or cutaneous squamous cell carcinoma.
          5. Has active autoimmune disease, such as psoriasis, multiple sclerosis, lupus,
             rheumatoid arthritis, etc. (the medical monitor will determine if a disease is active
             and autoimmune).
          6. Has a history of significant central nervous system (CNS) disease, such as stroke,
             epilepsy, primary CNS lymphoma, etc. (the medical monitor will determine if
             significant).
          7. Has an active systemic infection (e.g., causing fevers or requiring antimicrobial
             treatment).
          8. Has a history of hepatitis B virus (HBV), hepatitis C virus (HCV), human
             immunodeficiency virus (HIV), or human T-lymphotropic virus (HTLV) infection, or any
             immunodeficiency syndrome. Subjects with a history of treated hepatitis C can be
             enrolled if negative by hepatitis C polymerase chain reaction (PCR) on multiple
             occasions and with medical monitor approval.
          9. Is positive for human herpes virus (HHV)-6 or HHV-7 infection by polymerase chain
             reaction (PCR) at the Screening Visit (subjects may be included in the study if they
             are HHV-6 or HHV-7 IgG antibody-positive but PCR-negative).
         10. Has New York Heart Association (NYHA) Class III or IV heart failure, unstable angina,
             or a history of myocardial infarction or significant arrhythmia (e.g., atrial
             fibrillation, sustained [> 30 seconds] ventricular tachyarrhythmias, etc.).
         11. Has any psychiatric or medical disorder (e.g., cardiovascular, endocrine, renal,
             gastrointestinal, genitourinary, immunodeficiency or pulmonary disorder not otherwise
             specified) that would, in the opinion of the Investigator or medical monitor, preclude
             safe participation in and/or adherence to the protocol (including medical conditions
             or laboratory findings that indicate a significant probability of not qualifying for
             or being unable to undergo, LD chemotherapy and/or CAR-T cell administration).
         12. Has received non-mAb anti-cancer medications within 2 weeks of the time of initiating
             LD chemotherapy.
         13. Has received mAb therapy within 4 weeks of initiating LD chemotherapy.
         14. Has received immunosuppressive medications within 2 weeks of the time of
             administration of P-CD19CD20-ALLO1, and/or expected to require them while on study
             (the medical monitor will determine if a medication is considered immunosuppressive).
         15. Has received systemic corticosteroid therapy ≥ 5 mg/day of prednisone or equivalent
             dose of another corticosteroid within 1 week or 5 half-lives (whichever is shorter) of
             the administration of P-CD19CD20-ALLO1 or is expected to require it during the course
             of the study. (Topical and inhaled steroids are permitted. Systemic corticosteroids
             are contraindicated after receiving P-CD19CD20-ALLO1 cells outside of study-specific
             guidance).
         16. Has CNS metastases or CNS involvement (including leptomeningeal carcinomatosis,
             cranial neuropathies or mass lesions, cauda equina syndrome and spinal cord
             compression).
         17. Has a history of severe immediate hypersensitivity reaction to any of the agents used
             in this study.
         18. Has a history of having undergone allogeneic or xenogeneic transplant, or has
             undergone autologous transplantation within 90 days. Subjects with prior history of
             allogeneic stem cell transplant may be enrolled if they are not on immunosuppressive
             medications and with medical monitor approval.
         19. Has received prior allogeneic genetically modified cellular therapy or was treated
             with experimental allogeneic cell therapy.
         20. History or Grade ≥ 3 HLH/MAS or neurotoxicity with prior therapies (all symptoms of
             HLH/MAS, neurotoxicity, or CRS from prior therapies must be resolved at the time of
             enrollment).
         21. Has positive DAT at Screening Visit