A Study of SI-B003, a PD-1/CTLA-4 Bispecific Antibody, in Patients With Advanced Solid Tumors

Inclusion Criteria:

1. The participants could understand and sign the informed consent form, and mustparticipate voluntarily.

2. No gender limit.

3. Age: ≥18 years old and ≤75 years old (phase Ia); ≥18 years old (phase Ib).

4. Expected survival time ≥ 3 months.

5. Histologically or cytologically confirmed recurrent or metastatic solid tumor,clinical stage IIIB/IV, with radiographic or other objective evidence of diseaseprogression after standard therapy; Or subjects were patients with solid tumors thatwere refractory to treatment, patients with solid tumors that did not have standardtreatment, or patients who could not tolerate or had contraindications to standardtreatment.

6. For the phase Ib study: Cohort_A: Histologically or cytologically confirmed advanced gastric adenocarcinoma (GC) or gastroesophageal junction (GEJ) adenocarcinoma after exposure toplatinum-based chemotherapy after receiving only first-line anti-PD-1 (L1)monoclonal antibody during systemic therapy; Cohort_B: Histologically orcytologically confirmed patients with malignant mesothelioma not suitable forsurgery;

7. Consent to provide archival tumor tissue or fresh tissue samples of the primary ormetastatic tumor, if not available, at the discretion of the investigator (only forstage Ib );

8. At least one measurable lesion that meets the definition of RECIST v1.1 at baseline (only for stage Ib).

9. Patients treated with anti-PD-1 (L1) -containing monoclonal antibody must haveprogression of resistance after benefit from anti-PD-1 (L1) -containing monoclonalantibody (phase Ib only);

10. Physical fitness score ECOG 0 or 1 point.

11. The adverse reactions of previous antineoplastic therapy returned to CTCAE 5.0 grade ≤1 (except for toxicities without safety risks judged by investigators, such asalopecia, grade 2 peripheral neurotoxicity, and hypothyroidism stable with hormonereplacement therapy);

12. No severe cardiac dysfunction, left ventricular ejection fraction ≥50%;

13. The organ function within 7 days prior to the first administration meets thefollowing requirements:

14. Bone marrow: absolute neutrophil count (ANC) ≥1.5×109/L, hemoglobin ≥90 g/L,platelet count ≥100×109/L (participants with liver cancer ANC ≥75×109/L);

15. Liver: total bilirubin (TBIL) ≤1.5 ULN (TBIL ≤3 ULN in participants withGilbert's syndrome, liver cancer or liver metastasis), transaminase (AST/ALT) ≤ 3 ULN (for participants with liver cancer or liver metastasis ≤ 5.0 ULN); forparticipants with liver cancer or liver metastasis, transaminase ≥ 3 ULN andTBIL ≥ 1.5 ULN must be excluded;

16. Kidney: Creatinine (Cr) ≤1.5 ULN and creatinine clearance rate (Ccr) ≥ 50mL/min (according to Cockcroft-Gault formula).

17. Female participants with fertility or male participants whose partners are fertilemust take effective contraceptive measures from 7 days prior to the firstadministration to 24 weeks after the administration. Female participants withfertility must have a negative serum/urine pregnancy test in 7 days prior to thefirst dose.

18. The participants are capable and willing to comply with the visits, treatment plans,laboratory examinations and other study-related procedures stipulated in the studyprotocol.

Exclusion Criteria:

1. Parenchymal or leptomeningeal metastases with clinical symptoms who were judged bythe investigator to be ineligible for enrollment;

2. Participants who participated in any other clinical trial within 28 days before theadministration of this trial, except for clinical trials of marketed drugs;

3. Chemotherapy, biological therapy, immunotherapy, radical radiotherapy, majorsurgery, targeted therapy (including small molecule inhibitor of tyrosine kinase),and other anti-tumor therapy within 4 weeks or 5 half-lives (whichever is shorter)prior to the first administration; mitomycin and nitrosoureas treatment within 6weeks prior to the first administration; oral fluorouracil-like drugs such as S-1,capecitabine, or palliative radiotherapy within 2weeks prior to the firstadministration.

4. Major surgery (investigator-defined) within 4 weeks before the first dose.

5. In 14 days prior to administration of this study, those who have received systemiccorticosteroids (>10mg/day prednisone, or equivalent other corticosteroids) orimmunosuppressive therapy should be excluded except for those who have receivedinhaled or topical corticosteroids, or hormone therapy of physiological replacementdose due to adrenal insufficiency.

6. Pulmonary disease grade ≥3 according to NCI-CTCAE v5.0; Patients with existinginterstitial lung disease (ILD).

7. Severe systemic infection occurred within 4 weeks before screening, including butnot limited to severe pneumonia caused by fungi, bacteria, viruses, bacteremia, orserious infectious complications.

8. Participants at risk of active autoimmune diseases, or with a history of autoimmunediseases, including but not limited to Crohn's disease, ulcerative colitis, systemiclupus erythematosus, sarcoidosis, Wegener syndrome (polyangiitis granuloma Disease,Graves' disease, rheumatoid arthritis, pituitary inflammation, uveitis), autoimmunehepatitis, systemic sclerosis, Hashimoto's thyroiditis, autoimmune vasculitis,autoimmune neuropathy (Guillain-Barré syndrome), etc. Except for the followingconditions: Type I diabetes, hormone replacement therapy for stable hypothyroidism (including hypothyroidism caused by autoimmune thyroid disease), psoriasis orvitiligo that does not require systemic treatment.

9. Complicated with other malignant tumors within 2 years prior to the firstadministration, except for cured skin squamous cell carcinoma, basal cell carcinoma,superficial bladder cancer, prostate/cervix/breast carcinoma in situ (only phaseIb).

10. Participants with human immunodeficiency virus antibody (HIVAb) positive, activetuberculosis, active hepatitis B virus infection (HBV-DNA copy number> 104) orhepatitis C virus (HCV) infection.

11. Participants with poorly controlled hypertension by two kinds of antihypertensivedrugs (systolic blood pressure>150 mmHg or diastolic blood pressure>100 mmHg).

12. A history of severe cardiovascular and cerebrovascular diseases, including but notlimited to: Severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmiarequiring clinical intervention, Ⅲ degree atrioventricular block, etc. At rest, the QT interval was prolonged (QTc > 450 msec in men or QTc > 470 msec inwomen); Acute coronary syndrome, congestive heart failure, aortic dissection,stroke, or other grade 3 or higher cardiovascular and cerebrovascular eventsoccurred within 6 months before the first dose; Patients with New York HeartAssociation (NYHA) functional class ≥II heart failure.

13. Previous history of allogeneic bone marrow or organ transplantation.

14. Participants who have a history of allergies to recombinant humanized antibodies orhuman-mouse chimeric antibodies or any of the components of SI-B003.

15. In the adjuvant (or neoadjuvant) treatment of anthracyclines, the cumulative dose ofanthracyclines is> 360 mg/m2.

16. Pregnant or breastfeeding women.

17. Other conditions that the investigator believes that it is not suitable forparticipating in this clinical trial.