Study of LYL314 in Aggressive Large B-Cell Lymphoma

Eligibility Criteria

• 1. Age 18 years or older at time of informed consent
• 2. Willing and able to provide written informed consent
• 3. Histologically confirmed aggressive NHL, including the following types defined by the World Health Organization (WHO 2017):
• * DLBCL
• * DLBCL arising from follicular lymphoma (transformed FL, tFL)
• * Primary mediastinal (thymic) large B-cell lymphoma (PMBCL)
• * High-grade large B-cell lymphoma with or without MYC and BCL2 and/or BCL6 rearrangement (HGBL)
• * Grade 3B follicular lymphoma/Large cell follicular lymphoma (FL3B)
• 4. Received at least two prior lines of therapy for Cohorts 1, 2, and 4 and one prior line of therapy for Cohort 3. Prior therapy must have included:
• * Anti-CD20 monoclonal antibody, and
• * An anthracycline containing chemotherapy regimen
• * Participants with tFL must have received at least one of their prior lines of therapy after transformation to DLBCL
• 5. Relapsed or refractory disease, defined by the following:
• * Disease progression after last regimen (including salvage therapy after autologous stem cell transplantation \[ASCT\]). In participants who have only received front-line therapy, progression should be ≤ 12 months of first-line therapy (applicable for Cohort 3)
• * In patients who received one line of therapy, refractory disease is defined as failure to achieve at least a PR after at least 4 cycles of therapy (applicable for Cohort 3)
• * In patients who received two or more lines of therapy (Cohorts 1, 2, and 4), refractory disease is defined as failure to achieve a CR to last line of therapy (including CAR T and/or salvage therapy).
• 6. At least 1 measurable lesion (per Lugano classification). Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy
• 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 or ECOG 0 to 2 (Cohort 5)
• 8. Absolute neutrophil count (ANC) ≥ 1000/uL
• 9. Platelet count ≥ 50,000/uL
• 10. Absolute lymphocyte count (ALC) ≥ 200/uL
• 1. History of malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g., cervix, bladder, breast) unless disease-free for at least 3 years. Participants who have received therapy for a prior malignancy within the prior 3 years, e.g., in the adjuvant setting, are not excluded
• 2. Active central nervous system (CNS) involvement by malignancy on magnetic resonance imaging (MRI) or by lumbar puncture. Participants with prior evidence of brain metastasis treated at least 8 weeks prior to enrollment will not be excluded for participation if CNS disease is deemed stable at the time of study enrollment
• 3. History of cardiac lymphoma involvement or Epstein-Barr virus (EBV)+ lymphoma
• 4. Ongoing or impending oncologic emergency (e.g., tumor mass effect, tumor lysis syndrome, known vascular invasion)
• 5. Received the following therapies in the specified time frame prior to enrollment/leukapheresis
• 1. Any systemic therapy within 2 weeks
• 2. Any systemic inhibitory/stimulatory immune checkpoint molecule therapy within 3 half-lives prior to enrollment (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists)
• 3. Fludarabine within 12 weeks
• 4. Alemtuzumab, bendamustine or antithymocyte globuline (ATG) within 6 months
• 5. Any T cell engager/bispecific antibody therapy such as CD20/CD3 or CD19/CD3 bispecific antibodies within 4 weeks
• 6. Any experimental therapy within 4 weeks or 5 half-lives (whichever is shorter)
• 6. Received radiation therapy within 3 weeks prior to enrollment/leukapheresis
• 7. Experiencing non-hematologic toxicities due to prior therapy. Exceptions include: stable and recovered to grade ≤ 1 or non-clinically significant toxicities such as (1) alopecia, (2) toxicities where Grade 2 is solely defined by participant receiving hormone replacement therapy for endocrinopathies resulting from previous checkpoint inhibitor therapy, (3) Grade 2 lymphopenia, and (4) hearing loss or Grade 2 neuropathy associated with prior treatment with taxanes or platinating agents
• 8. History of allogeneic stem cell or solid organ transplantation
• 9. Receipt of autologous stem cell transplantation within 6 weeks prior to enrollment/leukapheresis
• 10. History of prior genetically modified cell therapy other than a product targeting CD19 with an FMC63-based CAR (e.g., axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), or lisocabtagene maraleucel (liso-cel). For all other CAR T cell therapy treatments, discussion with the Sponsor's Medical Monitor is required
• 11. Primary immunodeficiency
• 12. History of autoimmune disease (e.g., Crohn's disease, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years. Participants who have other autoimmune condition(s) considered to be associated with underlying malignancy may be enrolled in the study after discussion with and approval of the Medical Monitor.