Colorectal Cancer
Conditions
Keywords
relapsed metastatic colorectal cancer, refractory metastatic colorectal cancer, chimeric antigen receptors (CAR), colorectal cancer, metastatic colorectal cancer, mCRC, CAR T-cell, guanylyl cyclase C, GCC, colorectal neoplasms, autologous T cells
Brief summary
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
DRUGLYL273
Single infusion of Chimeric Antigen Receptor (CAR) transduced autologous T cells administered intravenously (i.v.)
Sponsors
Lyell Immunopharma, Inc.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Phase 1: Incidence of adverse events (AEs) defined as dose-limiting toxicities (DLTs) during 3+3 dose escalation study | 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 | 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 | 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 | Baseline to Month 18 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 and 2: Evaluate the efficacy of LYL273 | 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 | ORR based on investigator assessment per RECIST Version 1.1 criteria |
| Phase 2: Evaluate the efficacy of LYL273 | 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 | Duration of response based on IRC assessment per RECIST Version 1.1 criteria |
| Phase 1 and 2: Overall Survival (OS) | Infusion (Day 0) until date of death from any cause | Overall survival (OS) |
| Phase 2: Incidence and severity of adverse events | Infusion (Day 0) to 3 months | — |
| Phase 1 and 2: Cellular Kinetics | Infusion (Day 0) up to 18 months | Maximum concentration (Cmax), time to peak cell expansion (Tmax), area under the concentration curve from time 0 to Day 28 (AUC0-28), and cellular persistence (time of last measurable concentration \[Tlast\]) for the GCC CAR T cells |
Countries
United States
Outcome results
None listed