Overview

A Phase 1 Study Evaluating BAFFR-targeting CAR T Cells for Patients with Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma (B-NHL)

Eligibility

Inclusion Criteria:

• 1. Documented informed consent of the participant and/or legally authorized representative.
• 2. Agreement to allow the use of archival tissue from diagnostic tumor biopsies
  • If unavailable, exceptions may be granted with Study PI approval.
• 3. Age: ≥ 18 years
• 4. ECOG ≤ 2
• 5. Histologically confirmed diagnosis of B-NHL, as follows:
  • Large B-cell lymphoma (LBCL) patients including the following types defined by World Health Organization (WHO) 2016 classification - DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma (HGBCL) with or without MYC and BCL2 and/or BCL6 rearrangement, transformed follicular lymphoma (tFL), and transformed marginal zone lymphoma (tMZL) - as well as follicular lymphoma (FL) Grade 3b, who have received at least 2 prior lines of standard therapy (described in NCCN guidelines), which must contain an anti-CD20 targeted agent (unless documented CD20 negative) and an anthracycline.
  • Mantle Cell Lymphoma (MCL) patients with:
    • Primary refractory MCL (with or without prior BTK inhibitor) defined as lymphoma did not respond to a first line therapy or the response did not last longer than 6 months from an initial response, or
      • Relapsed MCL defined as recurrence of disease after an initial response lasting longer than 6 months, must have had at least 1 prior regimen that must include a BTK inhibitor, or
      • Newly diagnosed MCL without standard of care (SOC) options (e.g., TP53 mutation, ineligible for intensive chemotherapy) are eligible after discussion with PI.
  • Follicular lymphoma (FL) Grades 1-3a and marginal zone lymphoma (MZL) patients

    who are relapsed or refractory to at least one prior systemic treatment regimen which must include an anti-CD20 targeted agent (unless documented CD20 negative), and for whom there is no readily available therapy expected to improve survival (e.g., standard chemotherapy, ASCT).

        Note: all the above B-NHL subtypes are eligible during the dose-finding portion. During
        dose expansion, only MCL patients and large B-cell lymphoma (LBCL) patients are eligible.
        • 6. Evidence of positive BAFF-R expression on the lymphoma cells at the time of enrollment
        is required.
        i. Archival tissue is allowed if there is a significant safety risk for a repeat biopsy or
        if the lymphoma site is not accessible and as long as the patient has not received any
        anti-BAFFR treatment.
        ii. Bone marrow biopsy is optional at enrollment IF patient already has biopsy proven
        active disease elsewhere.
          -  7. Measurable disease by CT scan (≥1.5 cm) or evidence of blood, gastrointestinal,
             skin, bone marrow or spleen involvement
          -  8. Prior CAR T cell therapy is allowed if at least 3 months have elapsed prior to
             leukapheresis procedure i. If participant received prior CD19-CAR T cells persistence
             must be evaluated and found to be <5% prior to leukapheresis procedure
          -  9. Fully recovered from the acute toxic effects (except alopecia) to ≤ Grade 1 to
             prior anti-cancer therapy
          -  10. No known contraindications to leukapheresis, steroids or tocilizumab.
          -  11. Total bilirubin ≤ 1.5 X ULN (unless has Gilbert's disease), then ≥ 3.0 x ULN and
             direct bilirubin ≤ 1.5 x ULN)
          -  12. Blood counts:
               -  Absolute Neutrophil count (ANC ≥1000 cells/ul)*
                  o Growth factor use within 7 days prior screening is not allowed
               -  Platelet count ≥75,000/ul. Transfusion with 7 days prior to screening is not
                  allowed*
                    -  Exception: participants with bone marrow involvement do not need to meet
                       this criteria
          -  13. AST < 3 x ULN
          -  14. ALT < 3 x ULN
          -  15. Creatinine clearance of ≥ 50 mL/min per 24 hour urine test or the Cockcroft-Gault
             formula
          -  16. Left ventricular ejection fraction (LVEF) ≥ 45% Note: To be performed within 28
             days prior to start of protocol therapy.
          -  17. QTc ≤ 480 ms Note: To be performed within 28 days prior to start of protocol
             therapy.
          -  18. O2 saturation > 91% on room air.
          -  19. Seronegative for HIV Ag/Ab combo, HCV*, active HBV (Surface Antigen Negative)
             *If seropositive for HIV, HCV or HBV (surface antigen or core antibody positive),
             nucleic acid quantitation must be performed. Viral load must be undetectable.
          -  20. Women of childbearing potential (WOCBP): negative urine or serum pregnancy test.
             *If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
             test will be required.
          -  21. Agreement by females and males of childbearing potential* to use an effective
             method of birth control or abstain from heterosexual activity for the course of the
             study through at least 3 months after the last dose of protocol therapy.
               -  Childbearing potential defined as not being surgically sterilized (men and women)
                  or have not been free from menses for > 1 year (women only).
        Exclusion Criteria:
          -  1. Prior allogeneic stem cell transplant.
          -  2. Autologous stem cell transplant within 6 months prior to leukapheresis
          -  3. Concurrent use of systemic steroids or chronic use of immunosuppressant
             medications. Recent or current use of inhaled steroids is not exclusionary.
             Physiologic replacement of steroids (i.e., prednisone ≤ 7.5 mg/day or hydrocortisone ≤
             20 mg/day) is allowed. During study participation, participants may receive systemic
             corticosteroids as needed for treatment-emergent comorbid conditions.
          -  4. Cardiac lymphoma involvement
          -  5. Requirement for urgent therapy due to tumor mass effects such as bowel obstruction
             or blood vessel compression
          -  6. Auto-immune disease or condition requiring systemic immunosuppressant therapy,
             including uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic
             thrombocytopenic purpura (ITP).
          -  7. Primary immunodeficiency
          -  8. Class III/IV cardiovascular disability according to the New York Heart Association
             (NYHA) Classification.
          -  9. History of clinically significant arrhythmia. Paroxysmal atrial fibrillation or
             flutter that is stable on medical management at least 2 weeks prior to enrollment is
             allowed.
          -  10. History or prior diagnosis of optic neuritis or other immunologic or inflammatory
             disease affecting the central nervous system, including seizure disorder.
          -  11. History of allergic reactions attributed to compounds of similar chemical or
             biologic composition to study agent, including lymphodepletion agents and tocilizumab.
          -  12. History of stroke or intracranial hemorrhage within 6 months of enrollment.
          -  13. History of venous thrombotic embolism (VTE) within 6 months of enrollment with
             exception of central line associated VTE.
          -  14. History of other malignancies, except for malignancy surgically resected (or
             treated with other modalities) with curative intent, basal cell carcinoma of the skin
             or localized squamous cell carcinoma of the skin; non-muscle invasive bladder cancer;
             malignancy treated with curative intent with no known active disease present for ≥ 3
             years.
          -  15. Clinically significant uncontrolled illness.
          -  16. Active systemic uncontrolled infection requiring antimicrobials.
          -  17. Active CNS MCL or History of CNS MCL within 3 months prior to screening
          -  18. Females only: Pregnant or breastfeeding i. Any other condition that would, in the
             Investigator's judgment, contraindicate the patient's participation in the clinical
             study due to safety concerns with clinical study procedures.
          -  19. Prospective participants who, in the opinion of the investigator, may not be able
             to comply with all study procedures (including compliance issues related to
             feasibility/logistics).