HEC-921 Injection as Monotherapy and in Combination With Antineoplastic Therapies in Patients With Advanced Malignant Solid Tumors

This is a Phase I open-label, multicenter study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) characteristics, immunogenicity and antitumor activity of HEC-921 injection as monotherapy and in combination with other antineoplastic therapies in patients with advanced malignant tumors. The recommended Phase II dose (RP2D) will be determined based on safety, tolerability, and pharmacokinetics.

Inclusion criteria

• Trial participants aged ≥18 years at the time of signing the informed consent form, either male or female;
• Patients with advanced malignant solid tumors confirmed by histology or cytology, who can provide archived or recently collected tumor tissue sections (recently collected samples are preferred), and meet the following requirements:

• Monotherapy dose escalation and dose expansion phases: Patients with advanced malignant solid tumors who have failed or are intolerant to standard therapy, or for whom no standard therapy exists, and whose tumor tissue is LY6G6D+. During the monotherapy dose escalation phase in the low-dose cohorts , there is no restriction on LY6G6D expression in participants' tumor tissue.
• Combination Therapy Phase: Histologically confirmed unresectable advanced colon adenocarcinoma or rectal adenocarcinoma, with no prior systemic therapy, deemed by the investigator suitable for receiving CAPOX combined with bevacizumab as first-line treatment for advanced disease; tumor tissue LY6G6D+ .
• Eastern Cooperative Oncology Group (ECOG) performance status: 0-1;
• Expected survival time ≥12 weeks;
• At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1);
• Adequate organ function:
• Female or male trial participants of childbearing potential must agree to have no plans for reproduction and to voluntarily use highly effective contraceptive measures with their partner during the study and for 6 months after the last dose; female trial participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose and must not be breastfeeding;
• The patient voluntarily participates, provides fully informed consent, signs the written informed consent form, and demonstrates good compliance.

Exclusion criteria

• Receipt of the following medications or treatments prior to the first dose:

• Received anti-tumor therapies such as chemotherapy or immunotherapy, or other investigational drugs within 3 weeks prior to the first dose; or received oral fluoropyrimidines, small-molecule targeted drugs, or traditional Chinese medicine with anti-tumor indications within 2 weeks prior to the first dose;
• Received radiotherapy (palliative radiotherapy for local bone/brain lesions is permitted if completed within 2 weeks prior to the first dose), major surgical procedures (not fully recovered from surgery or injury), or any live or attenuated live vaccines within 4 weeks prior to the first dose; or planned to receive live vaccines after enrollment;
• Patients who received systemic treatment with corticosteroids (prednisone >10 mg/day or equivalent) for more than 1 week or other immunosuppressants within 2 weeks prior to the first dose. Inhaled or topical corticosteroids, or systemic prednisone ≤10 mg/day or equivalent doses of similar drugs, are permitted;
• Presence of active central nervous system metastases. Screening is permitted if the patient previously received radiotherapy or surgery, imaging within 4 weeks prior to the first dose indicates stable brain metastases without progression or new neurological symptoms, and corticosteroid therapy was discontinued at least 2 weeks prior to the first dose. Patients with leptomeningeal metastases or brainstem metastases are excluded regardless of treatment status;
• Occurrence of immune-related adverse events leading to permanent discontinuation during prior treatment with immune checkpoint inhibitors (e.g., anti-PD-(L)1, CTLA-4, LAG-3 inhibitors, etc.);
• Prior receipt of LY6G6D-targeted therapy or 4-1BB (CD137)-related therapy (including CAR-T, monoclonal antibodies, bispecific antibodies, etc.);
• Presence of symptomatic pleural effusion, ascites, or pericardial effusion requiring repeated interventions (e.g., puncture or drainage);
• History of interstitial lung disease or prior non-infectious pneumonia treated with corticosteroids, or evidence of active pneumonia on imaging during the screening period;
• Toxicity from prior anti-tumor therapy has not recovered to ≤ Grade 1 as defined by the Common Terminology Criteria for Adverse Events (CTCAE v6.0) or to the level specified in the inclusion/exclusion criteria, except for the following: relevant toxicities deemed well-controlled by the investigator and not affecting the safety and compliance of the trial participant's use of the investigational; product may be enrolled upon confirmation with the Sponsor;
• Occurrence of a serious infection (CTCAE v6.0 > Grade 2) within 4 weeks prior to the first administration of the investigational product, such as severe pneumonia requiring hospitalization, bacteremia, or infectious complications; or occurrence of an active infection requiring intravenous anti-infective treatment or unexplained fever > 38.5°C within 2 weeks prior to the first administration of the investigational product (trial participants with fever caused by the tumor may be enrolled upon judgment by the investigator);
• Occurrence of gastrointestinal perforation, fistula, intra-abdominal abscess, bleeding, or a clear tendency to bleed (including but not limited to: severe esophageal-gastric varices with a risk of bleeding, local active gastrointestinal ulcer lesions [stable ulcer condition assessed by the investigator may be considered for inclusion], persistent positive fecal occult blood, etc.) within 6 months prior to randomization; for patients with persistent positive fecal occult blood, if they are patients with CRC or gastric cancer, and after detailed assessment it is deemed that the positive occult blood test is related to the tumor (e.g., local bleeding or ulcers caused by the tumor), and under tumor treatment or disease control, the gastrointestinal bleeding is stable and has not caused clinical symptoms (e.g., anemia, hypotension, etc.), they may be considered for inclusion;
• Severe cardiovascular or cerebrovascular disease, including but not limited to: myocardial infarction, severe/unstable angina, congestive heart failure (New York Heart Association [NYHA] functional class ≥2), clinically significant supraventricular or ventricular arrhythmias requiring pharmacological intervention, aortic aneurysm requiring surgical repair, any arterial thrombotic/embolic event, Grade 3 or higher (CTCAE v6.0) venous thrombotic/embolic event, transient ischemic attack, or cerebrovascular accident occurring within 6 months prior to the first study dose; left ventricular ejection fraction (LVEF) <50% by echocardiography; corrected QT interval (QTc) >480 ms (calculated using the Fridericia method; if QTc is abnormal, three consecutive measurements may be taken at 2-minute intervals and averaged);
• Active autoimmune disease requiring systemic treatment (e.g., corticosteroids or immunosuppressive drugs) within 2 years prior to the first dose, including but not limited to: systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, vasculitis, etc. However, screening is permitted for hypothyroidism, adrenal insufficiency, or hypopituitarism controlled solely by hormone replacement therapy; type 1 diabetes mellitus; psoriasis or vitiligo not requiring systemic treatment; and childhood asthma/allergies that have resolved;
• History of another malignant tumor within 5 years prior to the first dose; except for cured localized tumors, including carcinoma in situ of the cervix, basal cell carcinoma of the skin, and carcinoma in situ of the prostate;
• Active tuberculosis; hepatitis B (hepatitis B surface antigen [HBsAg] positive and HBV DNA >1000 copies/mL or 200 IU/mL); or hepatitis C (hepatitis C antibody [HCVAb] positive and HCV RNA above the lower limit of detection at the study center);
• History of immunodeficiency, including positive test for human immunodeficiency virus (HIV), or known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation; Other severe physical or mental illnesses or laboratory abnormalities that may increase the risk of participating in the study, affect treatment compliance, or interfere with study results, as determined by the investigator to render the participant unsuitable for this study.