A Phase 1b-2, Open-Label, Dose-Escalation, Expansion and Optimization Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of LRK-4189 Alone and in Combination with mFOLFOX6 or FOLFIRI in Patients with Solid Tumors

Solid tumors

Part 1: Incidence, type and severity of adverse events (AEs) and serious AEs (SAEs), dose-limiting toxicity (DLT), treatment interruptions and discontinuations, by grade and attribution, safety labs and test results  PK parameters as below  If feasible, PD parameters as below  Shrinkage of target lesions, Part 2 : Per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) [Eisenhauer 2009]: Objective response rate (ORR); Disease control rate (DCR), comprising ORR + stable disease (SD) (on at least 2 post-baseline timepoints > 4 weeks apart); Duration of response (DOR); Progression-free survival (PFS); Overall survival (OS), Part 3: Safety parameters as for Part 1; Efficacy parameters as for Part 2; PK parameters as for secondary endpoints; PD parameters as for exploratory endpoints

All that can be determined of: Time to maximum concentration (tmax);Terminal half-life (t½); Maximum observed concentration (Cmax);Area under the concentApparent volume of distribution at steady state (Vss/F);Mean residence time (MRT)ration-time curve from time zero to 24 hours and last detectable concentration (AUC0-24, AUClast); Area under the concentration-time curve from time zero extrapolated to infinity (AUC∞);Apparent total clearance (CL/F);Terminal elimination rate constant (λz);Appa, Safety parameters as Part 1, Safety parameters as Part 1;Efficacy parameters as Part 2;PK parameters as above, PD measurements in blood and/or tumor tissue for some or all of: Peripheral blood mononuclear cells (PBMCs): target degradation; PBMCs: immune cell frequency; PBMCs: activation state; Circulating tumor DNA (ctDNA); Bulk or single cell RNAseq or other nucleic acid testing; Whole exome sequencing of tumor; Serum for secreted protein (cytokine, chemokine) analysis ;Immunohistochemistry (IHC) for tumor and immune markers of PD including target degradation.

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