A Study to Investigate LYL845 in Adults With Solid Tumors

Study Overview
=================
Brief Summary
-----------------
This is an open-label, multi-center, dose-escalation study with expansion cohorts, designed to evaluate the safety and anti-tumor activity of LYL845, an epigenetically reprogrammed tumor infiltrating lymphocyte (TIL) therapy, in participants with relapsed or refractory (R/R) metastatic or locally advanced melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer (CRC).

Detailed Description
-----------------
This is an open-label, multi-center, dose-escalation study with expansion cohorts, designed to evaluate the safety and anti-tumor activity of LYL845, an epigenetically reprogrammed tumor infiltrating lymphocyte (TIL) therapy, in participants with relapsed or refractory (R/R) metastatic or locally advanced melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer (CRC). During the dose-escalation phase of the study (Part A), participants with melanoma will be enrolled. Once a safe recommended Phase 2 dose range (RP2DR) has been established in Part A, enrollment will be expanded (Part B) to include additional participants with melanoma, NSCLC and CRC.

Official Title
-----------------
A Phase 1 Study to Assess the Safety and Efficacy of LYL845 in Adults With Relapsed and/or Refractory Metastatic or Locally Advanced Melanoma and Selected Solid Tumor Malignancies

Conditions
-----------------
Melanoma, Non-small Cell Lung Cancer, Colorectal Cancer

Intervention / Treatment
-----------------
* Biological: LYL845


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years up to ≤ 75 years at the time of informed consent Confirmed diagnosis of melanoma, non-small cell lung cancer (NSCLC), or colorectal cancer (CRC) that is metastatic or locally advanced or unresectable and is relapsed and/or refractory (R/R) after standard therapy for each tumor histology Participants must have received prior systemic treatment for their metastatic disease or locally advanced disease based on tumor type as follows: Melanoma: participants with disease progression following an immune checkpoint inhibitor (CPI) and if BRAF-mutated, BRAF/MEK inhibition NSCLC: participants with disease progression following at least 1 approved systemic therapy, including an immune CPI-containing regimen for appropriate patients or an approved targeted therapy for known molecular abnormalities if applicable to their disease CRC: participants with disease progression following at least 1 line of therapy, including a fluoropyrimidine with oxaliplatin or irinotecan. Microsatellite instability (MSI) high/mismatch repair deficient (dMMR) CRC participants must have disease progression following systemic therapy with immune CPIs. Measurable disease including at least 1 lesion that is safely resectable AND a target lesion to measure response and an additional lesion for biopsy Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Adequate organ and marrow function Women of childbearing potential must have a negative pregnancy test at screening All participants must agree to practice highly effective methods of contraception Exclusion Criteria: Prior treatment with adoptive cellular therapy Prior solid organ transplantation Central nervous system (CNS) involvement of disease that is extensive, symptomatic or untreated, or patients with leptomeningeal disease Uncontrolled or symptomatic pleural effusion or ascites Untreated or active systemic infection Active autoimmune disease requiring treatment or primary immunodeficiency syndrome Systemic corticosteroids at a dose of >10 mg of prednisone or equivalent per day Other primary malignancy within 3 years prior to enrollment Impaired cardiac function or clinically significant cardiovascular disease Required chronic anticoagulation, such as warfarin, low molecular weight heparin, or Factor Xa inhibitors Pregnant or nursing (lactating) women

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single-arm, open-label, dose-escalation and -expansion study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental LYL845<br>Epigenetically reprogrammed tumor infiltrating lymphocyte (TIL) therapy | Biological: LYL845<br>* LYL845 is an autologous tumor infiltrating lymphocyte (TIL) enhanced via Epi-R, a proprietary epigenetic reprogramming technology<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (DLTs) | Evaluate incidence of dose-limiting toxicities (DLTs) | Up to 2 years | 
| Incidence of treatment-emergent adverse events (TEAEs) | Evaluate incidence of treatment-emergent adverse events (TEAEs) | Up to 2 years | 
| Severity of treatment-emergent adverse events (TEAEs) | Evaluate severity of treatment-emergent adverse events (TEAEs) | Up to 2 years | 
| Determine recommended Phase 2 Dose Range (RP2DR) | Determine the recommended Phase 2 dose range (during dose-escalation phase) | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) by RECIST, version 1.1 | Evaluate anti-tumor activity of LYL845 based on overall response rate (ORR) by RECIST, version 1.1 | up to 2 years | 
| Complete response rate (CR) by RECIST, version 1.1 | Evaluate anti-tumor activity of LYL845 based on complete response rate (CR) by RECIST, version 1.1 | up to 2 years | 
| Duration of response (DOR) | Evaluate duration of response (DOR) | up to 2 years | 
| Progression-free survival (PFS) | Evaluate progression-free survival (PFS) | up to 2 years | 
| Overall survival (OS) | Evaluate overall survival (OS) | up to 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
TIL, tumor infiltrating lymphocyte, melanoma, non-small cell lung cancer, colorectal cancer, NSCLC, CRC, relapsed, refractory, locally advanced, advanced, metastatic, epigenetic