A Phase I Clinical Study of HLX316 in Participants With Advanced/Metastatic Solid Tumors

A Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetic Characteristics, and Preliminary Efficacy of HLX316 (B7-H3 Targeting Sialidase Fc Fusion Protein) in Participants With Advanced/Metastatic Solid Tumors

This study is an open-label, first-in-human Phase I clinical study to evaluate the safety, tolerability, PK characteristics, and preliminary antitumor activity of HLX316 in participants with advanced/metastatic solid tumors. The study will consist of 2 parts: a Phase Ia dose-escalation part and a Phase Ib dose-expansion part. Phase Ia and Phase Ib will focus on exploring the preliminary antitumor activity of HLX316 in participants with platinum-resistant ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.

Inclusion Criteria:

1. Fully understand the contents, process and possible adverse reactions of the study before the study, sign the informed consent form, voluntarily participate in the study, and be able to complete the study according to the requirements of the study protocol;

2. Aged ≥ 18 years at the time of signing ICF;

3. Participants with histologically or cytologically confirmed advanced or metastatic solid tumors who have failed at least one line of standard systemic therapy in the advanced or metastatic setting (participants who received neoadjuvant or adjuvant therapy and experienced progressive disease or relapse within 6 months after completion of such therapy will be considered to have failed one line of standard therapy), or for whom no effective standard therapy is available, or who are intolerant of or refuse standard systemic therapy;

4. At least 1 measurable lesion per RECIST v1.1 within 4 weeks prior to the first dose; for participants who have received prior radiotherapy, a previously irradiated lesion may be considered a target lesion if it is measurable per RECIST v1.1 and there is objective evidence of significant progression following radiotherapy; brain metastatic lesions may not serve as target lesions;

5. ECOG performance status of 0 or 1 within 7 days prior to the first dose;

6. Expected survival of more than 3 months;

7. At least 28 days must have elapsed between the first dose of investigational drug and any prior major surgical procedure, medical device treatment, local radiotherapy (except palliative radiotherapy for bone lesions), cytotoxic chemotherapy, immunotherapy, or biologic therapy; at least 14 days must have elapsed since prior small-molecule targeted therapy or hormonal therapy; at least 7 days must have elapsed since prior traditional Chinese medicine with antitumor indications or minor surgery; and any treatment-related AEs must have recovered to CTCAE v6.0 Grade ≤ 1 (except alopecia);

8. The participant agrees to provide archival tumor tissue specimen sufficient to meet testing requirements (from the most recent surgery or biopsy, preferably within 3 years) or agrees to undergo a fresh biopsy for tumor tissue collection (unless the investigator determines that the procedure would pose an unacceptable risk to the participant's safety), for assessment of tumor sialylation and protein expression including B7-H3; Note: Participants are required to provide a formalin-fixed, paraffin-embedded (FFPE) tumor sample (paraffin block or unstained sections, meeting quality control standards for testing) collected from a non-irradiated site at the time of or after the diagnosis of malignancy, from the most recent surgery or biopsy, along with the corresponding pathology report for the above specimen.

9. Adequate organ function confirmed by laboratory assessments performed within 7 days prior to the first dose of study drug (without receipt of transfusions, granulocyte colony-stimulating factors, or thrombopoietic agents within 14 days prior to the first dose):

   Hematologic System Absolute neutrophil count (ANC) ≥ 1.0 × 109/L Platelet count (PLT) ≥ 75 × 109/L Hemoglobin (Hb) ≥ 90 g/L Liver Function Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN), unless a known genetic cause of elevated bilirubin is present (e.g., Gilbert's syndrome) Alanine aminotransferase (ALT) ≤ ULN; ≤ 2.5 × ULN for participants with hepatic metastases or hepatocellular carcinoma Aspartate aminotransferase (AST) ≤ ULN; ≤ 2.5 × ULN for participants with hepatic metastases or hepatocellular carcinoma Renal Function Creatinine (Cr) ≤ 1.5 × ULN; if > 1.5 × ULN, creatinine clearance must be ≥ 40 mL/min (calculated using the Cockcroft-Gault formula) Coagulation Function (unless the participant is receiving anticoagulant therapy) Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN Prothrombin time (PT) ≤ 1.5 × ULN International normalized ratio (INR) ≤ 1.5 × ULN

10. Male and female participants of childbearing potential must agree to use at least 1 highly effective method of contraception during the study and for at least 6 months after the last dose of investigational drug; female participants of childbearing potential must have a negative pregnancy test within 7 days prior to enrollment.

11. The tumor type for participants with advanced solid tumors may be any of the following:

    • Platinum-resistant ovarian cancer
    • Other advanced/metastatic solid tumors with B7-H3 expression confirmed by IHC.

12. Participants with ovarian cancer, primary peritoneal cancer, or fallopian tube cancer must also meet all of the following criteria:

    • Histologically or pathologically confirmed epithelial ovarian cancer (EOC), fallopian tube cancer, or primary peritoneal cancer, with no evidence of non-epithelial carcinoma, borderline tumor, mucinous carcinoma (or seromucinous carcinoma with a predominant mucinous component), malignant Brenner tumor, or undifferentiated carcinoma.
    • Participants must have received at least 2 prior lines of therapy for metastatic ovarian cancer, including at least 1 platinum-based regimen, or must be intolerant to such standard treatments.
    • Must be platinum-resistant, defined as progressive disease confirmed by CA-125, clinical, or imaging assessment within 6 months after the last platinum-containing chemotherapy regimen.

Exclusion Criteria:

1. History of arterial thromboembolic events, stroke, or transient ischemic attack within the past 12 months.

2. History of symptomatic chronic heart failure (New York Heart Association [NYHA] Class II-IV or left ventricular ejection fraction [LVEF] < 50%) or history of arrhythmia requiring treatment (including QTc interval ≥ 450 ms in males or ≥ 470 ms in females) (QTc interval calculated using the Fridericia formula).

3. History of myocardial infarction or unstable angina within 6 months prior to the first dose of HLX316.

4. Evidence of active infection requiring intravenous antibiotic therapy during the screening period, or evidence of active infection requiring treatment within 7 days prior to the first dose of HLX316.

5. Active uncontrolled bleeding or bleeding tendency within 7 days prior to HLX316 administration.

6. Serious or non-healing wounds, fistulas, skin ulcers, or non-healing fractures within 7 days prior to HLX316 administration.

7. The participant has previously participated in this study.

8. The participant is currently participating in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up phase of an interventional study.

9. Receipt of any other therapy within 3 weeks or 5 half-lives prior to HLX316 administration, whichever is shorter.

10. Known infection with human immunodeficiency virus (HIV) (any HIV seropositivity or detectable human immunodeficiency virus type 1 ribonucleic acid [HIV RNA]).

11. Active syphilis infection, defined as positive serological test result that has not been adequately treated.

12. Active hepatitis B or hepatitis C infection. Participants with well-controlled hepatitis B virus/hepatitis C virus (HBV/HCV) infection may be eligible if the following criteria are met and after discussion with the Medical Monitor (MM):

    Hepatitis B:

    • Hepatitis B surface antigen (HBsAg)-positive (chronic HBV infection): participants are eligible if they are receiving antiviral therapy and hepatitis B virus deoxyribonucleic acid (HBV DNA) is controlled/undetectable.
    • HBsAg-negative and anti-hepatitis B core (HBc)-positive (resolved prior infection): eligible for enrollment. Prophylactic treatment should be considered and reactivation should be monitored.

    Hepatitis C

    • Prior HCV infection that has been successfully cured (ribonucleic acid [RNA] undetectable).
    • HCV Ab-positive but RNA-negative (spontaneous clearance).

13. Participants with untreated central nervous system (CNS) epidural tumors or metastases, or untreated brain metastases. Known leptomeningeal metastases, or uncontrolled or symptomatic central nervous system (CNS) metastases, manifesting as clinical symptoms, cerebral edema, spinal cord compression, and/or progressive growth. Participants with a history of CNS metastases or spinal cord compression may be enrolled if they have received definitive treatment and are considered clinically stable by the investigator after discontinuation of anticonvulsants and steroids for 8 weeks prior to initiation of study treatment. Participants with untreated, asymptomatic brain metastases (i.e., no neurological symptoms, no requirement for corticosteroids, no brain metastatic lesion with a longest diameter > 1.5 cm, and no significant edema peripheral to brain metastatic lesions) may be enrolled. Brain metastatic lesions will not be designated as target lesions.

14. Participants with current or prior autoimmune disease requiring systemic immunosuppressive therapy (including, but not limited to, inflammatory bowel disease, systemic lupus erythematosus, vasculitis, rheumatoid arthritis, scleroderma, multiple sclerosis, hemolytic anemia, Sjögren's syndrome, and sarcoidosis).

15. Current requirement for systemic corticosteroids or use of systemic corticosteroids within 4 weeks prior to enrollment (inhaled corticosteroids are permitted for participants with asthma or chronic obstructive pulmonary disease, as are other non-systemic steroids such as topically administered corticosteroids).

16. In the investigator's judgment, the participant has other serious illnesses that make participation in this study inappropriate.

17. Participant is unwilling or unable to follow protocol requirements.

18. Other primary malignancy within 3 years prior to enrollment that has not been treated with curative intent (the investigator may consider discussion with the Medical Monitor), excluding non-metastatic basal cell/squamous cell carcinoma of the skin or non-muscle-invasive bladder cancer.

19. Any condition that, in the investigator's judgment, may interfere with the evaluation of the investigational drug, participant safety, or interpretation of study results.