Phase 1 Study of NW-301V TCR-T Cells in Advanced Solid Tumors With KRAS G12V Mutation

This is a single-arm, multicenter, open-label, Phase 1a/1b dose-escalation and dose-expansion study designed to evaluate the safety, preliminary antitumor activity, and pharmacokinetic/pharmacodynamic (PK/PD) characteristics of NW-301V, an autologous TCR-T cell therapy, in Chinese adult participants with advanced malignant solid tumors harboring a KRAS G12V mutation.

There are 2 parts in this study： * Phase 1a: Dose Escalation. A conventional 3+3 dose escalation design will be used to assess the safety/tolerability, pharmacokinetics (PK) and preliminary antitumor activity of NW-301V in participants with advanced or locally unresectable solid tumors who meet the enrollment criteria. A provisional Recommended Phase 2 Dose (RP2D) of NW-301V will be determined. * Phase 1b: Dose expansion. Participants with pancreatic ductal adenocarcinoma (PDAC), colorectal adenocarcinoma (CRC) or lung adenocarcinoma (LUAD) who meet the eligibility criteria will be enrolled into three separate disease-specific cohorts. The final RP2D will be determined. Participants who meet the protocol-defined eligibility criteria during screening will undergo leukapheresis for the manufacture of NW-301V. Prior to NW-301V infusion, participants will receive a lymphodepletion (LD) regimen consisting of fludarabine and cyclophosphamide. Participants will be closely monitored for safety, tolerability and treatment response throughout the study.

Drug: Fludarabine. Used for lymphodepletion

Drug: Cyclophosphamide. Used for lymphodepletion

Biological: NW-301V. NW-301V is an autologous TCR-T cell therapy targeting KRAS G12V in the context of HLA-A\*11:01, administered intravenously after lymphodepletion.

NW-301V (experimental): Participants receive lymphodepletion and a single infusion of NW-301V, an autologous TCR-T cell therapy targeting KRAS G12V. In Phase 1a (dose escalation), two dose levels at 4×10\^9 (±30%) and 8×10\^9 (±30%) TCR-T+ cells will be tested. In Phase 1b (dose expansion), NW-301V will be administered at provisional RP2D in 3 tumor-specific cohorts (Cohort A: pancreatic ductal adenocarcinoma; Cohort B: colorectal adenocarcinoma; Cohort C: lung adenocarcinoma), each containing around 20 participants.

Phase 1a: Safety and tolerability of NW-301V in participants with advanced solid tumors. Type, frequency, and severity of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), abnormalities in vital signs, electrocardiograms (ECGs) and other laboratory results. Time frame: Through the study completion, an average of 2 years.

Phase 1a: Maximum tolerated dose (MTD, if applicable) and provisional Recommended Phase 2 Dose (RP2D). Number of participants with dose-limiting toxicities (DLTs) and their types. Time frame: 28 days.

Phase 1b: Safety and tolerability of NW-301V in PDAC, CRC and LUAD respectively under provisional RP2D. Type, frequency, and severity of TEAEs, SAEs, and abnormalities in vital signs, ECGs and other laboratory results. Time frame: Through the study completion, an average of 2 years.

Phase 1b: Final RP2D of NW-301V. Determine the final RP2D of NW-301V Time frame: Up to 2 years.

Objective response rate (ORR). Time frame: Through the study completion, an average of 2 years.

Disease control rate (DCR). Time frame: Through the study completion, an average of 2 years.

Duration of response (DOR). Time frame: Through the study completion, an average of 2 years.

Progression-free survival (PFS). Time frame: Through the study completion, an average of 2 years.

Overall survival (OS). Time frame: Through the study completion, an average of 2 years.

Maximum blood concentration (Cmax) of NW-301V. Time frame: Through the study completion, an average of 2 years.

Key Inclusion Criteria: Applicable to both Phase 1a and 1b: * Age between 18-75 years * HLA-A\*11:01 positive * Tumor confirmed to have KRAS G12V mutation * At least one measurable lesion according to RECIST 1.1 * ECOG 0-1 * Life expectancy \> 3 months before leukapheresis * Adequate organ functions prior to leukapheresis and lymphodepletion For Phase 1a only: * Histologically or pathologically confirmed, advanced or unresectable solid tumors including, but not limited to, pancreatic ductal adenocarcinoma (PDAC), colorectal adenocarcinoma (CRC), and lung adenocarcinoma (LUAD) * Participants must have no standard treatment options available or are unable to tolerate currently available standard treatment For Phase 1b only: * Cohort A: Histologically or pathologically confirmed advanced or locally advanced unresectable PDAC that had failed or progressed after at least 1 line of prior systemic therapy * Cohort B: Histologically or pathologically confirmed advanced CRC that had failed or progressed after at least 2 lines of prior systemic therapies * Cohort C: Histologically or pathologically confirmed advanced LUAD that had failed or progressed after at least 1 line of prior systemic therapy (Additional protocol-defined Inclusion criteria may apply) Key Exclusion Criteria: Applicable to both Phase 1a and 1b: * Received the following treatments: Cytotoxic chemotherapy or immunosuppressive agents within 2 weeks prior to leukapheresis, or within 1 week prior to lymphodepletion; Antibodies or other biologic therapy within 3 weeks prior to leukapheresis, or within 2 weeks prior to lymphodepletion; * History of allergic reactions to cyclophosphamide, fludarabine, or any other chemical or biological components of the drugs used in this study * History of chronic or recurrent severe autoimmune disease, or active immune disease requiring treatment with steroids or other immunosuppressive agents within 1 year prior to leukapheresis or lymphodepletion * Have symptomatic CNS metastases * Have leptomeningeal disease or carcinomatous meningitis * Have ongoing or active infection * Breastfeeding or pregnant (Additional protocol-defined Inclusion criteria may apply)

Enrollment: 66 participants (estimated).