Study of Rondecabtagene Autoleucel in Aggressive Large B-Cell Lymphoma

Lyell Immunopharma

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Relapsed Non-Hodgkin Lymphoma; Large B-cell Lymphoma; Non-Hodgkin Lymphoma; Refractory Non-Hodgkin Lymphoma

Treatments: Drug: Rondecabtagene autoleucel (ronde-cel); Drug: Fludarabine; Drug: Cyclophosphamide

Study type: Interventional

Funder types: Industry

Identifiers

NCT05826535

LYL314-101

Details and patient eligibility

About

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.

Full 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.

Enrollment: 270 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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270 participants in 6 patient groups

Ph1, 3rd or later line, 3L+ have not received prior CAR T (Cohort 1)

Experimental group

Treatment:

Drug: Cyclophosphamide

Drug: Fludarabine

Drug: Rondecabtagene autoleucel (ronde-cel)

Ph1 CAR T experienced, 3L+ received at least two or more prior lines of treatment (Cohort 2)

Experimental group

Treatment:

Drug: Cyclophosphamide

Drug: Fludarabine

Drug: Rondecabtagene autoleucel (ronde-cel)

Ph1, 2L Refractory/relapse within 1 year of 1st-line therapy & no prior CAR T (Cohort 3)

Experimental group

Treatment:

Drug: Cyclophosphamide

Drug: Fludarabine

Drug: Rondecabtagene autoleucel (ronde-cel)

Ph1 (T-cell engager experienced, 3L+) received at least 2 prior lines including 1 TCE (Cohort 4)

Experimental group

Treatment:

Drug: Cyclophosphamide

Drug: Fludarabine

Drug: Rondecabtagene autoleucel (ronde-cel)

Ph1 high risk 1st line, PET-positive after 2-3 cycles chemoimmunotherapy, no prior CAR T (Cohort 5)

Experimental group

Treatment:

Drug: Cyclophosphamide

Drug: Fludarabine

Drug: Rondecabtagene autoleucel (ronde-cel)

Ph2, 3rd or later line, have not received prior CAR T (Cohort 1)

Experimental group

Description:

Single dose determined during Phase 1.

Treatment:

Drug: Cyclophosphamide

Drug: Fludarabine

Drug: Rondecabtagene autoleucel (ronde-cel)