JAB-23E73 in Adult Participants With Advanced Solid Tumors With KRAS Alteration

This study is to evaluate the safety and tolerability of pan-KRAS inhibitor JAB-23E73 Monotherapy and in Combination with Other Agents in adult participants with advanced solid tumors

This is a multi-part, open-label, multi-center Phase 1/2a study evaluating JAB-23E73 as monotherapy (Part A) and in combination with other agents (Part B1: with cetuximab) in adult participants with advanced solid tumors. Part A will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anticancer activity of JAB-23E73 as a single agent in adult patients with advanced solid tumors with KRAS alteration. Part A consists of three phases: Phase 1a dose-escalation, Phase 1b dose expansion (dose optimization), and Phase 2a indication expansion. Part B1 will evaluate the safety, tolerability, PK, PDc, and preliminary anti-tumor efficacy of JAB-23E73 combined with cetuximab in adult participants with locally advanced or metastatic KRAS-altered CRC. Part B1 consists of two phases: Phase 1b dose escalation phase and Phase 2a dose expansion phase.

Drug: JAB-23E73. Oral administration

Drug: Cetuximab. Intravenous infusion

Part A (experimental): JAB-23E73 monotherapy.

Part B1 (experimental): JAB-23E73 combined with cetuximab

Part A: Number and proportion of patients who experience at least 1 dose-limiting toxicity (DLT) with treatment of JAB-23E73 monotherapy.. A DLT is defined as any toxicities that meet the criteria for a DLT defined in the protocol Time frame: Up to 1 year.

Part A: Safety and tolerability of JAB-23E73 monotherapy. Incidence, and severity of adverse events and changes in clinical laboratory tests and examinations. Time frame: Up to 2 years.

Part A: Objective response rate (ORR) of JAB-23E73 monotherapy.. ORR, defined as the percentage of patients with the best overall response of confirmed partial response (PR), or complete response (CR) per RECIST v1.1. Time frame: Up to 3 years.

Part B1: Safety, tolerability and RP2D of JAB-23E73 in combination with cetuximab.. Incidence, and severity of adverse events and changes in clinical laboratory tests and examinations. RP2D will be determined based on comprehensive available data Time frame: Up to 2 years.

Part B1: Objective response rate (ORR) of JAB-23E73 in combination with cetuximab.. ORR, defined as the percentage of patients with the best overall response of confirmed PR, or CR per RECIST v1.1. Time frame: Up to 3 years.

Part A: DOR, TTR, PFS, and DCR assessed by investigators, and OS of JAB-23E73 monotherapy. Time frame: Up to 3 years.

Part A: Pharmacokinetic (PK) profile of JAB-23E73 monotherapy. Time frame: Up to 2 years.

Part B1: DOR, TTR, PFS, and DCR assessed by investigators, and OS of JAB-23E73 in combination with cetuximab. Time frame: Up to 3 years.

Part B1: PK profile of JAB-23E73 in combination with cetuximab.. Time frame: Up to 2 years.

Inclusion Criteria: * Written informed consent. * Participant must be ≥18 years of age at the time of signing the Informed Consent Form (ICF). * Histologically or cytologically confirmed locally advanced or metastatic solid tumors that are not suitable for curative interventions and who have received relevant prior systemic therapy.(Part A) * Histologically/cytologically confirmed unresectable locally advanced or metastatic CRC who progressed on or were intolerant to ≥1 standard systemic regimen with fluorouracil derivatives, oxaliplatin, irinotecan, FDA-approved immunotherapy or targeted therapies.(Part B1 only) * Patients must have KRAS alterations. * Participants are required to provide an archived tumor sample. * Patients with a life expectancy ≥3 months. * ECOG performance status score of 0 or 1. * Patients must have at least one measurable lesion as defined by RECIST v1.1. Exclusion Criteria: * Inability to swallow oral medications, or presence of gastrointestinal dysfunction or gastrointestinal disorders that may significantly alter the absorption of the study drug. * Patients who have previously been treated with KRAS G12C inhibitors, KRAS G12D inhibitors, pan-RAS/pan-KRAS/multi-KRAS inhibitors, or similar agents. * Participants who have previously been treated with cetuximab or other EGFR antibodies (Part B1 only). * Known serious allergy to JAB-23E73 or excipient. * Patients with primary central nervous system tumors. * Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures or medical intervention. * QT interval\>470 msec. * LVEF ≤50% assessed by ECHO or MUGA.

Enrollment: 344 participants (estimated).