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Study of LYL314 in Aggressive Large B-Cell Lymphoma

Purpose

Conditions

Relapsed Non-Hodgkin Lymphoma
Refractory Non-Hodgkin Lymphoma
Non-Hodgkin Lymphoma
Large B-cell Lymphoma

Eligibility

Eligible Ages: Over 18 Years
Eligible Sex: All
Accepts Healthy Volunteers: No

Inclusion Criteria

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 4b. Cohort 5 (High-risk first-line) participants must have high-risk large B-cell lymphoma 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 Other protocol-defined criteria apply.

Exclusion Criteria

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. Other protocol-defined criteria apply.

Study Design

Phase: Phase 1/Phase 2
Study Type: Interventional
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Primary Purpose: Treatment
Masking: None (Open Label)

Arm Groups

Arm	Description	Assigned Intervention
Experimental Phase 1 CAR T naïve (Cohort 1)		Drug: LYL314 CAR T-cell therapy Drug: Fludarabine Conditioning chemotherapy Drug: Cyclophosphamide Conditioning chemotherapy
Experimental Phase 1 CAR T experienced (Cohort 2)		Drug: LYL314 CAR T-cell therapy Drug: Fludarabine Conditioning chemotherapy Drug: Cyclophosphamide Conditioning chemotherapy
Experimental Phase 1 Refractory disease or relapse within one year of first-line therapy (Cohort 3)		Drug: LYL314 CAR T-cell therapy Drug: Fludarabine Conditioning chemotherapy Drug: Cyclophosphamide Conditioning chemotherapy
Experimental Phase 1 Received T-cell engager (TCE) therapy (Cohort 4)		Drug: LYL314 CAR T-cell therapy Drug: Fludarabine Conditioning chemotherapy Drug: Cyclophosphamide Conditioning chemotherapy
Experimental Phase 1 Receiving first-line treatment for high-risk large B-cell lymphoma (Cohort 5)		Drug: LYL314 CAR T-cell therapy Drug: Fludarabine Conditioning chemotherapy Drug: Cyclophosphamide Conditioning chemotherapy
Experimental Phase 2 CAR T naïve (Cohort 1)	Single dose determined during Phase 1.	Drug: LYL314 CAR T-cell therapy Drug: Fludarabine Conditioning chemotherapy Drug: Cyclophosphamide Conditioning chemotherapy

Recruiting Locations

University of California-Irvine Medical Center
Irvine 5359777, California 5332921 92697

Cedars-Sinai Medical Center
Los Angeles 5368361, California 5332921 90048

University of California, Los Angeles (UCLA) Medical Center
Los Angeles 5368361, California 5332921 90095

Scripps Clinic
San Diego 5391811, California 5332921 92037

Colorado Blood Cancer Institute
Denver 5419384, Colorado 5417618 80218

Augusta University Medical Center
Augusta 4180531, Georgia 4197000 30912

Indiana Blood and Marrow Transplantation
Indianapolis 4259418, Indiana 4921868 46237

University of Iowa
Iowa City 4862034, Iowa 4862182 52242

University of Louisville Brown Cancer Center
Louisville 4299276, Kentucky 6254925 40202

Louisiana State University Health Sciences Center
Shreveport 4341513, Louisiana 4331987 71130

Corewell Health
Grand Rapids 4994358, Michigan 5001836 49503

University of Nebraska Medical Center
Omaha 5074472, Nebraska 5073708 68198

University of New Mexico Comprehensive Cancer Center
Albuquerque 5454711, New Mexico 5481136 87131

Montefiore Medical Center
The Bronx 5110266, New York 5128638 10461

University of Cincinnati (UC) Physicians Company, LLC
Cincinnati 4508722, Ohio 5165418 45267

Cleveland Clinic
Cleveland 5150529, Ohio 5165418 44195

Lehigh Valley Topper Cancer Center Institute
Allentown 5178127, Pennsylvania 6254927 18103

Thomas Jefferson University
Philadelphia 4560349, Pennsylvania 6254927 19107

West Penn Hospital
Pittsburgh 5206379, Pennsylvania 6254927 15224

Baylor University Medical Center
Dallas 4684888, Texas 4736286 75246

Texas Transplant Institute
San Antonio 4726206, Texas 4736286 78229

Huntsman Cancer Institute
Salt Lake City 5780993, Utah 5549030 84112

Intermountain Healthcare
Salt Lake City 5780993, Utah 5549030 84143

Virginia Oncology Associates
Norfolk 4776222, Virginia 6254928 24502

Virginia Commonwealth University-Massey Cancer Center
Richmond 4781708, Virginia 6254928 23298

Medical College of Wisconsin
Milwaukee 5263045, Wisconsin 5279468 53226

More Details

NCT ID: NCT05826535
Status: Recruiting
Sponsor: Lyell Immunopharma, Inc.

Study Contact

Lyell Immunopharma Inc.
888-707-7917
clinicaltrials@lyell.com

Detailed Description

This is a Phase 1/2, multi-center, open-label study evaluating the safety and efficacy of LYL314, a dual-targeting chimeric antigen receptor (CAR) targeting cluster of differentiation (CD)19 and CD20 in participants with aggressive large B-cell lymphoma. Five cohorts of participants will be enrolled: Cohort 1: Participants who have not received a prior CAR T-cell product (CAR T naïve) and have received at least two or more prior lines of treatment (third-line or later). Cohort 2: Participants who have received a prior CAR T-cell product (CAR T experienced) and have received at least two or more prior lines of treatment including one CAR T-cell therapy. Cohort 3: Participants with refractory disease or relapse within one year of first-line therapy (second-line). Cohort 4: Participants who have received prior T-cell engager (TCE) therapy and have received at least two or more prior lines of treatment including one TCE therapy. Cohort 5: Participants receiving first-line treatment for high-risk large B-cell lymphoma who remain with disease on positron emission tomography scanning (PET-positive) after 2 to 3 cycles of standard-of-care chemoimmunotherapy (high-risk first-line). Up to approximately 150 participants (across all cohorts) will be enrolled in the dose finding Phase 1 part of the study. The Phase 2 pivotal study (PiNACLE) will expand enrollment of Cohort 1 to approximately 120 participants to further evaluate the safety and efficacy of LYL314. LYL314 treatment consists of a single administration of CAR transduced autologous T-cells administered intravenously after a conditioning chemotherapy regimen consisting of fludarabine and cyclophosphamide, administered over 3 days. Individual participants will remain in the active post-treatment follow-up (PTFU) period for approximately 2 years. Participants will continue in long-term follow-up (LTFU) for 15 years from LYL314 treatment.