Large B-cell Lymphoma, Non-Hodgkin Lymphoma, Refractory Non-Hodgkin Lymphoma, Relapsed Non-Hodgkin Lymphoma
Conditions
Keywords
CAR T-cell, Non-Hodgkin Lymphoma, CD19/20, CD19, CD20, NHL, Diffuse Large B-cell lymphoma, DLBCL, Transformed follicular lymphoma, TFL, Primary mediastinal B-cell lymphoma, PMBCL, Follicular lymphoma Grade 3B, Large cell follicular lymphoma, Aggressive B-cell NHL, Refractory Aggressive B-Cell Lymphoma, Refractory B-Cell Non-Hodgkin Lymphoma, Lymphoma, Non-Hodgkin, Lymphoma, Lymphoma, Large B-Cell, Diffuse, Cyclophosphamide, Fludarabine, Lymphoma, Follicular, Lymphoma, B-cell, Immunosuppressive Agents, Immunologic Factors, Disease Attributes, Immune System Diseases, Recurrence, PiNACLE
Brief summary
This is a Phase 1/2, multi-center, open-label study evaluating the safety and efficacy of rondecabtagene autoleucel (ronde-cel) also known as LYL314, a dual-targeting chimeric antigen receptor (CAR) targeting cluster of differentiation (CD)19 and CD20 in participants with aggressive large B-cell lymphoma.
Detailed description
This is a Phase 1/2, multi-center, open-label study evaluating the safety and efficacy of ronde-cel, 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: (3rd or later line, 3L+) Participants who have received least two prior lines of treatment Cohort 2: (CAR T-cell experienced, 3L+): Participants who have received at least two prior lines of treatment including one prior CAR T. Cohort 3: (second line, 2L) Participants with refractory disease or relapse within one year of first-line therapy (second-line). Cohort 4: (TCE-experienced, 3L+) Participants have received prior T-cell engager therapy and have received at least two prior lines of treatment including one TCE therapy and have not received prior CAR T. Cohort 5: (high-risk 1st line) Participants receiving first-line treatment who remain with disease on positron emission tomography scanning (PET-positive) after 2 to 3 cycles of standard-of-care chemoimmunotherapy and have not received prior CAR T. 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 ronde-cel. Ronde-cel 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 ronde-cel treatment.
Interventions
DRUGRondecabtagene autoleucel (ronde-cel)
CAR T-cell therapy
DRUGFludarabine
Conditioning chemotherapy
DRUGCyclophosphamide
Conditioning chemotherapy
Sponsors
Lyell Immunopharma, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age 18 years or older 2. Willing and able to provide written informed consent 3. Histologically confirmed LBCL, including the following types defined by the World Health Organization (WHO 2022) or International Consensus Classification (2022) 4. Received at least two prior lines of therapy for Cohorts 1, 2, and 4 and one prior line of therapy for Cohort 3 5. Relapsed or refractory disease. 6. At least 1 measurable lesion (per Lugano classification) 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 Other protocol-defined criteria apply.
Exclusion criteria
1. History of malignancy other than non-melanoma skin cancer or carcinoma in situ unless disease-free for at least 3 years 2. Active central nervous system involvement 3. History of cardiac lymphoma involvement or Epstein-Barr virus (EBV)+ lymphoma 4. Ongoing or impending oncologic emergency 5. Recent systemic anti-cancer therapy or radiation 6. Ongoing non-hematologic toxicities due to prior therapy 7. History of allogeneic stem cell or solid organ transplantation 8. Autologous stem cell transplantation within 6 weeks 9. History of prior genetically modified cell therapy (Cohorts 1, 3, 4, 5) or no 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) (Cohort 2). 10. Primary immunodeficiency 11. History of autoimmune disease resulting in end organ injury or requiring recent therapy Other protocol-defined criteria apply.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Evaluate the safety and tolerability of a single dose of ronde-cel administered as a single agent | Baseline to Month 24 | Incidence of dose-limiting toxicities (DLTs) and other treatment-emergent adverse events (TEAEs) |
| Phase 2: Estimate the efficacy of ronde-cel, as measured by overall response rate (ORR) | Baseline to Month 24 | ORR based on Independent Review Committee (IRC) assessment per Lugano criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Evaluate the efficacy of ronde-cel | Baseline to Month 24 | Overall response rate (ORR), Complete response rate (CRR), duration of response (DOR), duration of complete response (DOCR), progression free survival (PFS) based on Investigator assessment until a pivotal trial (Phase 2) portion is initiated at which time all scans will be reviewed by an IRC assessment (Cohort 1) per Lugano criteria |
| Phase 1: Evaluate the feasibility of treatment with ronde-cel | Baseline to Month 24 | Proportion of enrolled participants who receive the target dose of ronde-cel |
| Phase 1: Evaluate the pharmacokinetics of ronde-cel when administered as a single agent | Baseline to Month 24 | Maximum concentration (Cmax), area under the curve from time 0 to Day 28 (AUC0-28) and persistence of ronde-cel |
| Phase 2: Estimate the efficacy of ronde-cel | Baseline to Month 24 | ORR based on Investigator assessment per Lugano criteria |
| Phase 2: Evaluate the safety and tolerability of a single dose of ronde-cel administered as a single agent | Baseline to Month 24 | Incidence and severity of TEAEs |
| Phase 2: Evaluate the pharmacokinetics of ronde-cel when administered as a single agent | Baseline to Month 24 | Maximum concentration (Cmax), area under the curve from time 0 to Day 28 (AUC0-28) and persistence of ronde-cel |
Countries
Australia, United States
Contacts
CONTACTStephen Simko, MD
Outcome results
None listed