A Multicenter, Open-label, Phase II Clinical Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics (PK), and Immunogenicity of the Combination Therapy of SYS6026 in the Treatment of Advanced Solid Tumors

A Multicenter, Open-label, Phase II Clinical Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics (PK), and Immunogenicity of the Combination Therapy of SYS6026 in the Treatment of Advanced Solid Tumors

This trial is a multicenter, open-label, dose exploration and cohort expansion Phase II clinical study designed to evaluate the safety, immunogenicity, and preliminary efficacy of different dosing regimens of SYS6026 injection (hereinafter referred to as "SYS6026") combined with Enlonstobart in patients with unresectable locally advanced or metastatic solid tumors associated with HPV types 16 or 18. The study consists of two phases: dose exploration and cohort expansion.

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Joint Dose Exploration Phase:

In this phase of the dose-escalation design, the SYS6026 study plan establishes two dose groups. Enlonstobart is administered according to a fixed-dose regimen. The addition of additional dose levels for SYS6026 or the investigation of dosing intervals will be determined based on a comprehensive analysis of data from the monotherapy phase of SYS6026 in advanced solid tumors and the HSIL study.

Queue expansion phase: This phase comprises three queues that receive combined treatment with SYS6026 and Enlonstobart according to the selected RED dosing regimen determined through dose exploration.

Cohort 1 (Cervical Cancer Cohort) will enroll participants with HPV16/18-positive advanced cervical cancer who had failed at least one line of standard treatment,.

Cohort 2 (Other Solid Tumor Cohort) will enroll participants with HPV16/18 positive and other advanced solid tumors (including anal cancer, vaginal cancer, vulvar cancer, oropharyngeal cancer, oral cancer, laryngeal cancer, penile cancer, etc.) who had failed at least one line of standard therapy.

Cohort 3 (a randomized controlled cohort for first-line maintenance therapy in cervical cancer) will enroll participants with advanced recurrent or metastatic cervical cancer who have achieved response or disease stability after receiving first-line platinum-based chemotherapy plus Enlonstobart PD-(L)1 inhibitor ± bevacizumab,。

Inclusion Criteria:

1. Age ≥18 years;

2. Confirmation by the research center of HPV type 16 and/or 18 infection in tumor tissue;

3. Pathologically confirmed unresectable locally advanced or metastatic solid tumor;

4. ECOG PS score of 0-1;

5. Estimated survival of at least 3 months;

6. Normal function of major organs within 1 week prior to the initial vaccination/randomization (no administration of erythrocyte transfusion or hematopoietic stimulation factors [e.g., granulocyte colony-stimulating factor, erythropoietin, thrombopoietin] within 14 days before screening, and no platelet transfusion within 7 days before screening):

   1. ANC≥1.5×109/L；
   2. PLT≥100×109/L；
   3. Hb≥90 g/L；
   4. TBIL≤1.5×ULN，Participants with Gilbert syndrome
   5. TBIL≤3×ULN；
   6. ALT和AST≤2.5×ULN；
   7. Cr≤1.5×ULN，or creatinine clearance≥45 mL/min（Cockcroft-Gault）；
   8. APTT≤1.5×ULN，PT≤1.5×ULN，INR≤1.5×ULN。

7. Eligible participants of reproductive age (both males and females) must agree to use reliable contraceptive methods (hormonal contraceptives, barrier methods, or abstinence) with their partner from the date of signing the informed consent form until 6 months after the last dose administration.

   Applicable only during the combination dose exploration phase:

8. patients in advanced stages who have failed standard treatment (including disease progression or intolerance to standard therapy) and lack effective therapeutic options; where intolerance to standard therapy refers to permanent discontinuation of previous standard treatment requiring switching to alternative regimens; and meeting RECIST 1.1 criteria with at least one evaluable lesion.

9. According to RECIST 1.1, there must be at least one evaluable lesion;

   Applicable only to the queue expansion phase:

10. Enrollment during the queue expansion phase:

    1. Cluster 1: Advanced recurrent or metastatic cervical cancer that has failed at least one line of standard therapy;
    2. Cluster 2: Irresectable locally advanced or metastatic solid tumors (including anal, vulvar, vaginal, oropharyngeal, oral, laryngeal, and penile cancers) that have failed first-line standard therapy;
    3. Cluster 3 (randomized controlled cohort for first-line maintenance therapy in cervical cancer): PD-L1-positive advanced recurrent or metastatic cervical cancer patients who received platinum-based chemotherapy plus encetuximab/PD-(L)1 inhibitor ± bevacizumab for ≤6 cycles without progression, with the last antitumor treatment administered no later than 6 weeks prior to randomization.

11. Adequate tumor specimens can be provided for biomarker testing;

12. according to RECIST 1.1, there must be at least one measurable lesion (cohorts 1 and 2).

Exclusion Criteria:

1. Tumor tissue testing reveals co-infection with other high-risk HPV types;

2. Presence of two primary tumors (applicable only to Cohort 3); for patients not in Cohort 3, inclusion is permitted if they have two primary cancers that are unsuitable for surgery, have failed standard treatment, and are considered by investigators to benefit from this study;

3. Adverse reactions from prior antitumor therapy have not yet resolved to CTCAE Grade V5.0 level ≤1 (excluding alopecia or participants deemed clinically insignificant by investigators);

4. Participation in other clinical trials involving the study drug within 28 days prior to first administration/randomization, excluding observational (non-interventional) trials or follow-up phases of intervention trials;

5. Previous long-term (≥7 days) systemic use of immunosuppressants or initial systemic immunosuppressive therapy within 14 days prior to first administration/randomization;

6. Patients who have received whole blood, plasma, or immunoglobulin therapy within the past 1 month; those with clinically diagnosed known immunological dysfunction or impairment; or individuals with functional splenectomy or complete splenectomy due to any medical condition..

7. First administration of the vaccine/within 28 days prior to randomization, or planned administration of an attenuated live vaccine during the study period.

8. During the screening period, patients exhibited systemic active infections (defined as requiring intravenous administration of antibacterial, antifungal, or antiviral medications)..

9. Has a severe history of cardiovascular and cerebrovascular diseases, including but not limited to:

   1. .Heart failure classified as grade ≥2 according to the NYHA classification;
   2. first-time medication use or occurrence of myocardial infarction, treatment-needed arrhythmia, or unstable angina within 6 months prior to randomization;
   3. first-time medication use or occurrence of arterial/venous thrombosis or embolism (e.g., transient ischemic attack, cerebral hemorrhage, cerebral infarction [including lacunar infarction], deep vein thrombosis, or pulmonary embolism) within 6 months prior to randomization;
   4. QTcF> 450 ms;
   5. poorly controlled hypertension (systolic blood pressure ≥ 150 mmHg and/or diastolic blood pressure ≥ 90 mmHg during screening), with a history of hypertensive crisis or hypertensive encephalopathy.

10. Patients with active autoimmune diseases or a history of autoimmune disorders (e.g., myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, pituititis, uveitis, etc.) are eligible. Eligible conditions include well-controlled type 1 diabetes mellitus; hypothyroidism requiring only hormone replacement therapy and well-controlled; skin diseases (e.g., vitiligo, psoriasis, alopecia) not requiring systemic treatment; or participants with a predicted low risk of disease recurrence in the absence of external triggers..

11. Active hepatitis B (HBsAg-positive with HBV DNA ≥ 500 IU/mL or ≥ 2,500 copies/mL) or hepatitis C (HCV antibody-positive with HCV-RNA quantification ≥ the lower limit of the detection range) (Note: For HBsAg-positive patients, antiviral therapy is recommended prior to initial use of the study drug; nucleoside analogs such as entecavir or tenofovir disoproxil are preferred); co-infection with both HBV and HCV (HBsAg-positive and HCV antibody-positive) is not eligible for enrollment..

12. History of immunodeficiency or positive HIV antibody test;

13. Fever (axillary temperature ≥38.0°C) within 3 days prior to the first dose of the trial vaccine, acute illness within the previous 5 days, or acute exacerbation of a chronic condition; or use of antipyretics, analgesics, or anti-allergic medications within 3 days before the first vaccine dose;

14. Interstitial lung disease with accompanying symptoms/signs during screening (excluding radiation-induced localized interstitial pneumonia), non-infectious pneumonia requiring glucocorticoid therapy; history of specific pulmonary fibrosis, drug-induced pneumonia, specific pneumonia, or organized pneumonia (e.g., obstructive bronchiolitis, cryptogenic organized pneumonia);

15. Pregnant or breastfeeding women;

16. Known or suspected allergy to the trial drug or its components, severe allergy history, history of allergic diseases, or allergic predisposition;

17. Other circumstances that may interfere with participant compliance with the study protocol, compromise maximum benefit from participation, or affect study outcomes.