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

Official title

A Phase 3 Randomized Controlled Trial of Rondecabtagene Autoleucel , an Autologous, Dual-targeting CD19/CD20 CAR T-Cell Product Candidate, Vs. Investigator's Choice of CD19 CAR T-Cell Therapy in Patients With Relapsed or Refractory Large B-Cell Lymphoma in the Second-line Setting

Overview

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

• Biological rondecabtagene autoleucel
  An autologous, dual-targeting CD19/20 CAR T-cell candidate.
• Biological axicabtagene ciloleucel
  An autologous CD19 CAR T-cell therapy
• Biological lisocabtagene maraleucel
  An autologous CD19 CAR T-cell therapy

Primary outcome measures

• Event free survival [Time frame: 36 months]

Secondary outcome measures (5)

• Overall Response Rate [Time frame: 36 months]
• Complete Response Rate [Time frame: 36 months]
• Progression Free Survial [Time frame: 36 months]
• Overall Survival [Time frame: 6 years]
• Incidence and severity adverse events [Time frame: 36 months]

Eligibility criteria

Inclusion criteria

• CAR T cell naïve and eligible to receive a CD19 CART-cell therapy
• 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)
• Relapsed or refractory disease after anti-CD20 antibody and anthracycline-containing first-line chemoimmunotherapy
• Measurable disease by presence of \[18F\]-fluorodeoxyglucose PET/CT positive lesion during Screening per Lugano Criteria
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Adequate hematological, renal, hepatic, pulmonary, and cardiac function

Exclusion criteria

• Patients ineligible to receive CD19 CAR T-cell therapy
• Primary CNS lymphoma
• 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)
• 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
• Patients with uncontrolled systemic fungal, bacterial, viral, or other infection (including tuberculosis) despite appropriate antibiotics or other treatment
• Active autoimmune disease requiring ongoing systemic immunosuppressive therapy.

Note: Other protocol defined Inclusion/Exclusion criteria may apply

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 36 centers

• Banner MD Anderson Cancer Center — Gilbert
• Honor Health — Scottsdale
• Mayo Clinic Arizona — Scottsdale
• University of Arkansas — Little Rock
• Cedars-Sinai Medical Center — Los Angeles
• University of California, Los Angeles (UCLA) — Los Angeles
• University of California, Irvine — Orange
• University of Colorado — Aurora
• … and 28 more centers

Identifiers

NCT: NCT07188558 · LYL314-102

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗