A Study of DCTY1102 Injection in Participants With Advanced Solid Tumors

A Phase I/II Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetic Characteristics and Preliminary Clinical Efficacy of DCTY1102 Injection in the Treatment of Participants With Advanced Malignant Tumors Harboring KRAS/NRAS G12D Mutation Positivity and HLA-A*11:01 Genotype

This is a Phase 1/2, open-label, single-arm, multicenter study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of DCTY1102 Injection in participants with advanced malignant tumors harboring KRAS/NRAS G12D mutations and positive for HLA-A11:01. DCTY1102 Injection is an autologous genetically modified T-cell receptor (TCR) T-cell therapy product targeting the KRAS/NRAS G12D mutant neoantigen presented in the context of HLA-A11:01. Eligible participants will receive lymphodepleting conditioning with fludarabine and cyclophosphamide, followed by a single intravenous infusion of DCTY1102.

The Phase 1 dose-escalation stage will employ a standard 3+3 design with three planned dose levels: 3×10⁹, 6×10⁹, and 9×10⁹ CD8⁺ TCR⁺ T cells (±20%). The primary objectives are to evaluate the safety and tolerability of DCTY1102, determine the maximum tolerated dose (MTD), and identify the recommended Phase 2 dose (RP2D), with a dose-limiting toxicity (DLT) assessment period of 28 days post-infusion. Secondary objectives include characterization of pharmacokinetic (PK) profiles, preliminary assessment of anti-tumor activity, evaluation of pharmacodynamic (PD) changes, and assessment of immunogenicity.

The Phase 2 dose-expansion stage will enroll approximately 12 to 20 participants at the RP2D/MTD to further evaluate the objective response rate (ORR) as the primary efficacy endpoint, as well as long-term safety, extended PK/PD profiling, and immunogenicity.

Inclusion Criteria:

1. Before conducting any research-related operations, an informed consent form (ICF) must be signed;
2. Age should be between 18 and 70 years old;
3. Participants with advanced malignant tumors (including but not limited to pancreatic cancer, colorectal cancer, lung cancer, etc.) diagnosed by histological or cytological methods, who have failed standard treatment (disease progression after treatment) or have treatment intolerance;
4. Must meet the following two criteria simultaneously:

1) HLA-A*11:01 genotype, and no HLA-A*68:01 subtype; 2) Tumor KRAS/NRAS G12D mutation is positive; Tumor tissue samples of eligible participants must be collected and sent to a third-party central laboratory for testing, for retrospective analysis; 5. At least one measurable lesion (according to RECIST v1.1); 6. ECOG score of 0-1 and expected survival period greater than 3 months; 7. Sufficient organ function; 8. For women of childbearing age who have not undergone sterilization surgery before menopause, they must agree to use effective contraceptive measures from the start of chemotherapy to one year after the cell infusion, and the serum pregnancy test must be negative within 14 days before the cell infusion; 9. For men who have not undergone sterilization surgery, they must agree to use effective contraceptive measures from the start of chemotherapy until one year after the cell infusion.

Exclusion Criteria:

1. There are cases where the third interstitial fluid accumulation cannot be controlled clinically and fails to reach a stable state after treatment. According to the investigators' judgment, such participants are not suitable for inclusion in the study.
2. Within 4 weeks before reinfusion, the participant has received the last dose of anti-tumor treatment (chemotherapy, endocrine therapy, targeted therapy, immunotherapy, interventional therapy, or traditional Chinese medicine treatment with anti-tumor indications, etc.).
3. Within 4 weeks before apheresis, the participant has received live or attenuated live vaccine vaccination.
4. The participant has received any gene-engineered T-cell therapy before.
5. The participant is known to have an allergic reaction to any component used in the treatment of this study.
6. The participant has not recovered to a CTCAE v6.0 grade ≤ 1 level (excluding any level of hair loss, grade ≤ 2 peripheral sensory neuropathy, and toxicity judged by the investigator as safe) from previous surgery or treatment-related adverse reactions.
7. The participant has a history of meningeal metastasis or central nervous system metastasis, or has a clear underlying disease of the central nervous system within 6 months before apheresis and significant symptoms remaining; participants with asymptomatic brain metastasis or those whose symptoms have stabilized after treatment of brain metastasis lesions (such as surgery, radiotherapy) and do not require steroid use can participate in this study.
8. Hypertension that is poorly controlled (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 100 mmHg after treatment) or clinically significant cardiovascular diseases (such as cerebrovascular accident within 6 months before signing the principal informed consent form, myocardial infarction within 6 months before signing the principal informed consent form, unstable angina pectoris, congestive heart failure classified as NYHA grade II or above, or severe arrhythmia that cannot be controlled by medication or has potential impact on the study treatment); if the electrocardiogram shows clinically significant abnormalities in 3 consecutive times (each interval of at least 5 minutes) or the average QTcF is ≥ 450 ms.
9. Complicated with other serious organic diseases or mental disorders.
10. Systemic active infection.
11. Known HIV infection (positive anti-HIV antibody), or active hepatitis B (positive HBsAg test, or positive HBcAb test and positive HBV-DNA test), or active hepatitis C (positive anti-HCV antibody test and positive HCV-RNA test), or active syphilis infection.
12. Diagnosed with immunodeficiency or autoimmune diseases, and the participant has received or is expected to receive high-dose systemic steroid treatment (prednisone daily dose over 10 mg or equivalent) or any other form of immunosuppressive treatment within 7 days before apheresis or during the period of apheresis to reinfusion.
13. Within 2 weeks before apheresis and 2 weeks before reinfusion, plans to use hydroxyurea, immunomodulatory drugs (such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), cytarabine, etc.).
14. History of organ transplantation, allogeneic stem cell transplantation and renal replacement therapy.
15. Known uncontrolled diabetes, pulmonary fibrosis, interstitial lung disease, acute lung disease or liver failure.
16. Known alcohol and/or drug abusers.
17. Pregnant or lactating women.
18. Participants with any medical conditions or diseases that the investigator deems may affect the conduct of this study.
19. Participants judged by the investigators to be unable to complete all visits or procedures required by the study protocol (including the follow-up period), or have insufficient compliance to participate in this study, or the investigator considers them unsuitable for inclusion.