LYL273 for Patients With Relapsed or Refractory mCRC

Official title

A Phase 1/2 Multicenter Study Evaluating the Safety and Efficacy of LYL273 in Patients With Relapsed or Refractory Metastatic Colorectal Cancer

Overview

This is a Phase 1/2 open-label, multicenter study evaluating the safety and efficacy of LYL273 in participants with relapsed or refractory metastatic colorectal cancer.

Detailed description

LYL273-101 (CARABiNER) is a Phase 1/2 open label, multicenter study evaluating the safety, tolerability, clinical activity, pharmacokinetics and pharmacodynamics of LYL273, a GCC-targeted CAR T-cell product candidate enhanced with CD19 CAR expression and controlled cytokine release, in participants with relapsed or refractory metastatic colorectal cancer (mCRC).

The study may enroll multiple dose expansion cohorts at the Sponsor's discretion to further characterize the safety, feasibility, and preliminary antitumor activity of LYL273 under defined treatment conditions including those defined below.

1. Cohorts to explore alternative mCRC patient populations

Expansion cohorts may enroll a broader array of the mCRC population as listed below: * Earlier mCRC: Patients who have had a maximum of 1 prior line of systemic therapy 2. Cohorts to explore LYL273 in combination with other anti-cancer therapies Expansion cohorts may explore LYL273 in combination with consolidative radiotherapy.

Up to 18 participants will be enrolled into each expansion cohort with up to approximately 95 patients enrolled in the Phase 1 portion of the study.

The Phase 2 portion of the study will expand enrollment at the recommended Phase 2 dose of approximately 60 additional patients.

LYL273 treatment consists of a single infusion of CAR-transduced autologous T cells administered intravenously after a conditioning chemotherapy regimen consisting of fludarabine and cyclophosphamide, administered once, 3 days before LYL273 infusion.

Individual participants will remain in the active post-treatment follow-up (PTFU) period for up to 5 years. Participants will continue in long-term follow-up (LTFU) for 15 years from LYL273 treatment in a separate protocol.

Interventions

• Drug LYL273
  Single infusion of Chimeric Antigen Receptor (CAR) transduced autologous T cells administered intravenously (i.v.)

Primary outcome measures

• Phase 1: Incidence of adverse events (AEs) defined as dose-limiting toxicities (DLTs) during 3+3 dose escalation study [Time frame: Infusion (Day 0) to Day 28]
• Phase 1: Maximum tolerable dose (MTD) based on incidence of dose-limiting toxicities (DLTs) during 3+3 dose escalation study [Time frame: Infusion (Day 0) to Day 28]
• Phase 1: Recommended Phase 2 dose (RP2D) based on incidence of dose-limiting toxicities (DLTs) during 3+3 dose escalation study [Time frame: Infusion (Day 0) to Day 28]
• Phase 2: Estimate the efficacy of LYL273, as measured by overall response rate (ORR) based on Independent Review Committee (IRC) assessment per Response Evaluation Criteria in Solid Tumors RECIST Version 1.1 criteria [Time frame: Baseline to Month 18]

Secondary outcome measures (9)

• Phase 1 and 2: Evaluate the efficacy of LYL273 [Time frame: Infusion (Day 0) until the date of first documented confirmed complete or partial response per RECIST Version 1.1 criteria, assessed up to 18 months]
• Phase 1 and 2: Evaluate the efficacy of LYL273 [Time frame: Date of first documented confirmed complete or partial response per RECIST Version 1.1 criteria until the date of disease progression or recurrence or date of death whichever comes first]
• Phase 1 and 2: Evaluate the efficacy of LYL273 [Time frame: Infusion (Day 0) until the date of first documented confirmed complete or partial response per RECIST Version 1.1 criteria, assessed up to 18 months]
• Phase 2: Evaluate the efficacy of LYL273 [Time frame: Date of first documented confirmed complete or partial response per RECIST Version 1.1 criteria until the date of disease progression or recurrence or date of death whichever comes first]
• Phase 2: Evaluate the efficacy of LYL273 [Time frame: Infusion (Day 0) until the date of first documented confirmed complete or partial response per RECIST Version 1.1 criteria, assessed up to 18 months]
• Phase 1 and 2: Evaluate the efficacy of LYL273 [Time frame: Infusion (Day 0) until the date of first documented progression/recurrence or date of death from any cause, whichever comes first]
• Phase 1 and 2: Overall Survival (OS) [Time frame: Infusion (Day 0) until date of death from any cause]
• Phase 2: Incidence and severity of adverse events [Time frame: Infusion (Day 0) to 3 months]
• Phase 1 and 2: Cellular Kinetics [Time frame: Infusion (Day 0) up to 18 months]

Eligibility criteria

Inclusion criteria

• Adults > 18 years old
• Clinical and histopathological diagnosis of relapsed or refractory metastatic colorectal cancer
• Eastern Cooperative Oncology Group performance status of 0 or 1
• Limited liver disease (less than 7 lesions with largest lesion less than 3 cm)
• No surgical options with curative intent
• Received prior therapy with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy in the advanced or metastatic setting, an anti-vascular endothelial growth factor (anti-VEGF) biological therapy if not contraindicated, and if RAS wild-type an anti-epidermal growth factor receptor (anti-EGFR) therapy in a manner consistent with National Comprehensive Cancer Network (NCCN) guidelines. Treatment must have been discontinued for disease progression or intolerance to therapy
• Have at least one extracranial measurable target lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 standard

Exclusion criteria

• Participants with tumor lesion(s) in a location that may cause perforation of an organ or structure (such as the digestive tract, urinary bladder, or blood vessel) with LYL273 therapy
• Active central nervous system (CNS) involvement by malignancy on magnetic resonance imaging (MRI) or contrast-enhanced computed tomography (CT)
• History of or active viral infection including human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV)
• History or presence of CNS disorder, such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, cerebral edema, posterior reversible encephalopathy syndrome, or any autoimmune disease with CNS involvement in the 2-year period leading up to the study enrollment
• No active infectious diseases or comorbid conditions that would interfere with safety or data quality
• Pregnant or breast-feeding women

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

N/A

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 4 centers

• City of Hope Comprehensive Cancer Center — Duarte
• University of California San Francisco Medical Center — San Francisco
• University of Colorado Hospital - Anschutz Cancer Pavilion — Aurora
• Dana-Farber Cancer Institute — Boston

Identifiers

NCT: NCT05319314 · LYL273-101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗