A Study to Investigate Ronde-cel Versus Investigator's Choice CD19 CAR T-Cell Therapy

PiNACLE-H2H is a Phase 3 randomized controlled trial comparing the efficacy and safety of rondecabtagene autoleucel (ronde-cel, formerly known as LYL314) against the currently approved cluster of differentiation (CD)19 chimeric antigen receptor (CAR) T-cell therapies (axicabtagene ciloleucel \[axi-cel\] or lisocabtagene maraleucel \[liso-cel\]), in patients with aggressive LBCL that has relapsed or is refractory to first-line anti-CD20 antibody and anthracycline-containing chemotherapy.

Patients will be randomized (1:1) before leukapheresis to receive either:

* Ronde-cel; or
* Investigator's choice of axi-cel or liso-cel

Most patients who receive currently approved CD19-directed CAR T-cell therapies, including axi-cel and liso-cel, still experience progressive disease, often due to mechanisms such as CD19 antigen loss or T-cell exhaustion.

Ronde-cel is a novel, autologous, dual-targeting CD19/CD20 CAR T-cell product candidate enriched for CD62L-positive naïve and central memory T cells, which are associated with enhanced proliferation capacity and persistence. Ronde-cel is an "OR"-gated CAR construct that can fully activate upon recognition of either CD19 or CD20, aiming to improve durability of response despite antigen heterogeneity.

Approximately 400 participants will be enrolled. CAR T-cell therapy in both arms will be administered as a single intravenous infusion following fludarabine and cyclophosphamide lymphodepletion. Participants will be followed for 3 years for safety and efficacy, with long-term follow-up extending to 15 years.

• rondecabtagene autoleucel (Biological), also known as LYL314: An autologous, dual-targeting CD19/20 CAR T-cell candidate.
• axicabtagene ciloleucel (Biological), also known as Yescarta, axi-cel: An autologous CD19 CAR T-cell therapy
• lisocabtagene maraleucel (Biological), also known as Breyanzi, liso-cel: An autologous CD19 CAR T-cell therapy

Primary outcomes

• Event free survival [36 months]: The time interval from treatment initiation until the occurrence of a specific event of interest.

Secondary outcomes

• Overall Response Rate [36 months]: Best Overall Response per Lugano Criteria
• Complete Response Rate [36 months]: Complete Response per Lugano Criteria
• Progression Free Survial [36 months]: The length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse.
• Overall Survival [6 years]: The length of time from either the date of diagnosis or the start of treatment for a disease, that patients diagnosed with the disease, are still alive.
• Incidence and severity adverse events [36 months]: To assess safety defined as type and frequency of AEs, serious adverse events (SAEs), and laboratory abnormalities.

Sex: All, ages: 18 Years to any

Key Inclusion Criteria:

1. CAR T cell naïve and eligible to receive a CD19 CART-cell therapy
2. Histologically confirmed large B-cell lymphoma, including the following types defined by (WHO 2022) or International Consensus Classification (2022)

   * Diffuse large B-cell lymphoma (DLBCL)
   * Transformations of indolent B-cell lymphomas (excluding Richter's transformation)
   * DLBCL/High-grade B-cell lymphoma (HGBCL) with MYC and BCL2 rearrangements
   * High-grade B-cell lymphoma (HGBCL) not otherwise specified (HGBCL NOS)
   * Primary mediastinal large B-cell lymphoma (PMBCL)
   * Grade 3B follicular lymphoma/large cell follicular lymphoma (FL3B)
3. Relapsed or refractory disease after anti-CD20 antibody and anthracycline-containing first-line chemoimmunotherapy
4. Measurable disease by presence of \[18F\]-fluorodeoxyglucose PET/CT positive lesion during Screening per Lugano Criteria
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
6. Adequate hematological, renal, hepatic, pulmonary, and cardiac function

Key Exclusion Criteria:

1. Patients ineligible to receive CD19 CAR T-cell therapy
2. Primary CNS lymphoma
3. Patients with primary cutaneous LBCL, human herpes virus-8 positive lymphoma, Burkitt lymphoma, T cell histiocyte-rich lymphoma, or transformation from chronic lymphocytic leukemia/small lymphocytic lymphoma (Richter's transformation)
4. Patients with prior history of malignancy, other than aggressive relapsed or refractory LBCL, unless the patient has been free of the disease for ≥ 2 years
5. Patients with uncontrolled systemic fungal, bacterial, viral, or other infection (including tuberculosis) despite appropriate antibiotics or other treatment
6. Active autoimmune disease requiring ongoing systemic immunosuppressive therapy.

Note: Other protocol defined Inclusion/Exclusion criteria may apply