Large B-cell Lymphoma, Lymphoma, B-Cell, Relapsed Non-Hodgkin Lymphoma, Refractory Non-Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Non-Hodgkin Lymphoma Refractory/ Relapsed, Diffuse Large B Cell Lymphoma (DLBCL), Diffuse Large B Cell Lymphoma Refractory, Diffuse Large B Cell Lymphoma Relapsed
Conditions
Keywords
Lymphoma, Non-Hodgkin Lymphoma, CAR T-Cell Therapy, CD19, CD19/CD20, Large B-cell Lymphoma
Brief summary
This Phase 3 study compares rondecabtagene autoleucel (ronde-cel), a dual-targeting CD19/CD20 CAR T-cell therapy, with investigator's choice of CD19 CAR T-cell therapy in patients with relapsed or refractory large B-cell lymphoma in the second-line setting.
Detailed description
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.
Interventions
BIOLOGICALrondecabtagene autoleucel
An autologous, dual-targeting CD19/20 CAR T-cell candidate.
BIOLOGICALaxicabtagene ciloleucel
An autologous CD19 CAR T-cell therapy
BIOLOGICALlisocabtagene maraleucel
An autologous CD19 CAR T-cell therapy
Sponsors
Lyell Immunopharma, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event free survival | 36 months | The time interval from treatment initiation until the occurrence of a specific event of interest. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Contacts
CONTACTDavid Shook, MD
CONTACTMary Lessig, MS
Outcome results
None listed