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

• Fludarabine (Drug): Used for lymphodepletion
• Cyclophosphamide (Drug): Used for lymphodepletion
• NW-301V (Biological): NW-301V is an autologous TCR-T cell therapy targeting KRAS G12V in the context of HLA-A*11:01, administered intravenously after lymphodepletion.

Primary outcomes

• Phase 1a: Safety and tolerability of NW-301V in participants with advanced solid tumors [Through the study completion, an average of 2 years]: Type, frequency, and severity of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), abnormalities in vital signs, electrocardiograms (ECGs) and other laboratory results.
• Phase 1a: Maximum tolerated dose (MTD, if applicable) and provisional Recommended Phase 2 Dose (RP2D) [28 days]: Number of participants with dose-limiting toxicities (DLTs) and their types.
• Phase 1b: Safety and tolerability of NW-301V in PDAC, CRC and LUAD respectively under provisional RP2D [Through the study completion, an average of 2 years]: Type, frequency, and severity of TEAEs, SAEs, and abnormalities in vital signs, ECGs and other laboratory results.
• Phase 1b: Final RP2D of NW-301V [Up to 2 years]: Determine the final RP2D of NW-301V

Secondary outcomes

• Objective response rate (ORR) [Through the study completion, an average of 2 years]: Assessed by RECIST v1.1. (Phase 1a: in the entire cohort; Phase 1b: in PDAC, CRC and LUAD respectively)
• Disease control rate (DCR) [Through the study completion, an average of 2 years]: Assessed by RECIST v1.1. (Phase 1a: in the entire cohort; Phase 1b: in PDAC, CRC and LUAD respectively)
• Duration of response (DOR) [Through the study completion, an average of 2 years]: Assessed by RECIST v1.1. (Phase 1a: in the entire cohort; Phase 1b: in PDAC, CRC and LUAD respectively)
• Progression-free survival (PFS) [Through the study completion, an average of 2 years]: Assessed by RECIST v1.1. (Phase 1a: in the entire cohort; Phase 1b: in PDAC, CRC and LUAD respectively)
• Overall survival (OS) [Through the study completion, an average of 2 years]: (Phase 1a: in the entire cohort; Phase 1b: in PDAC, CRC and LUAD respectively)
• Maximum blood concentration (Cmax) of NW-301V [Through the study completion, an average of 2 years]
• Time to maximum concentration (Tmax) of NW-301V [Through the study completion, an average of 2 years]
• Persistence of NW-301V TCR-T cells in vivo [Through the study completion, an average of 2 years]: Determined by qPCR-measured gene copies

Sex: All, ages: 18 Years to 75 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)