Details

IRB Study Number 25-652

Status Recruiting

Phases Phase 1, Phase 2

Location Cleveland Clinic Main Campus

Institute Taussig Cancer Institute

Description

Description

Primary Objectives

Phase I:

• To evaluate the safety and tolerability a single dose of LYL314 administered as a single agent

• To determine the RP2D for LYL314

Phase II:

•To estimate the efficacy of LYL314, as measured by ORR

Secondary Objectives

Phase I and Phase II:

• To evaluate the efficacy of LYL314

• To evaluate the feasibility of treatment with LYL314

• To evaluate the pharmacokinetics of LYL314 when administered as a single agent

Exploratory Objectives

Phase I and Phase II:

• To characterize biomarkers associated with response

• To estimate the incidence of anti-CAR antibodies

• To evaluate the efficacy of LYL314 retreatment

Inclusion Criteria

Inclusion 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
    NOTE: Participants with tFL must have received at least one of their prior lines of therapy after transformation to DLBCL 4b. Cohort 5 (High-risk first-line) participants must have high-risk large B-cell lymphoma, defined in protocol.

  5. Relapsed or refractory disease, defined by the following:
    • Disease progression after last regimen (including salvage therapy after 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 μL

  9. Platelet count ≥ 50,000/μL

  10. Absolute lymphocyte count (ALC) ≥ 200/μL

  11. Adequate renal, hepatic, pulmonary, and cardiac function defined as:
    • Creatinine clearance (as estimated by Cockcroft-Gault formula or other institutional standard method) ≥ 45 ml/min
    • Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3 upper limit of normal (ULN)
    • Total bilirubin ≤ 2 ULN. Exception for elevated bilirubin secondary to Gilbert’s disease. Confirmation of Gilbert’s diagnosis requires: elevated unconjugated (indirect) bilirubin values; normal complete blood count in the previous 12 months, blood smear, and reticulocyte count; normal aminotransferases and alkaline phosphatase in previous 12 months.
    •New York Heart Association (NYHA) classification I or II AND left ventricular ejection fraction (LVEF) ≥ 50% with no evidence of clinically significant pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings
    • No clinically significant pleural effusion
    • Baseline oxygen saturation ≥ 92% on room air

  12. Participants of childbearing potential must have a negative serum or urine pregnancy test. Participants who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential.

  13. Participants of both sexes must be willing and able to practice birth control from the time of consent through 1 year after the last dose of cyclophosphamide.

  14. Willing and able to undergo at least one leukapheresis procedure.

  15. Willing and able to remain within 60 minutes of travel time to the study site until 14 days after the time of LYL314 administration.

Exclusion Criteria

Exclusion Criteria

  1. History of malignancy other than non-melanoma skin cancer or carcinoma in situ (eg, 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, eg, in the adjuvant setting, are not excluded.

  2. Active CNS involvement by malignancy on magnetic resonance imaging (MRI) or by lumbar puncture.

  3. History of cardiac lymphoma involvement or Epstein-Barr virus (EBV)+ lymphoma

  4. Ongoing or impending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome, known vascular invasion)

  5. Received the following therapies in the specified time frame prior to enrollment/leukapheresis:
    •Any systemic therapy within two weeks
    •Any systemic inhibitory/stimulatory immune checkpoint molecule therapy within 3 half-lives prior to enrollment (eg, ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists)
    •Fludarabine within 12 weeks
    •Alemtuzumab, bendamustine, or antithymocyte globulin (ATG) within 6 months
    • Any T cell engager/bispecific antibody therapy such as CD20/CD3 or CD19/CD3 bispecific antibodies within 4 weeks. Participants with prior TCE therapy will be enrolled in the TCE-experienced cohort only if at least 4 weeks since last TCE dose (Cohort 4).
    •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 noted in protocol.

  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 (eg, 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 (eg, 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 Sponsor’s Medical Monitor.

  13. Treatment with or expected requirement for systemic corticosteroids (> 5 mg prednisone equivalent per day) or immunosuppressive medications within 7 days prior to enrollment/leukapheresis
    • Inhaled, intranasal, intra-articular, or topical steroids (including ocular) at standard doses are permitted .
    • Participants who have received a one-time dose of corticosteroids (eg, dexamethasone for nausea, contrast allergy) may be enrolled in the study after discussion with and approval by the Sponsor’s Medical Monitor.

  14. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management. Simple urinary tract infection, uncomplicated bacterial pharyngitis or a localized non-clinically significant infection are permitted if responding to active treatment and after consultation with the Sponsor’s Medical Monitor.

  15. Has a history of or active viral infection including any of the following:
    • Human immunodeficiency virus (HIV) positive by serologic testing which is confirmed by nucleic acid testing. Must test negative for HIV.
    • Hepatitis B virus (HBV) or hepatitis C virus (HCV). Participants must test negative for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), and HCV antibody.

Please see protocol for full list of exclusion criteria