A Phase I/IIa Study of AL8326 Combined With Toripalimab in the Treatment of Advanced Solid Tumors.

Inclusion criteria

• Subjects must be able to understand and voluntarily sign a written informed consent form prior to the initiation of any study-related procedures.
• Age ≥ 18 years.
• Subjects with histologically confirmed advanced recurrent or metastatic solid tumors who meet one of the following conditions:

• Failure of standard therapy (disease progression after treatment or intolerance to treatment toxicity);
• no effective treatment available.
• Toripalimab monotherapy as a second-line or later standard treatment.
• Must have at least one measurable lesion as defined by RECIST 1.1.
• Prior cytotoxic chemotherapy must have been completed at least 4 weeks before enrollment, and any toxicities must have recovered to ≤ Grade 1 (except alopecia).
• Life expectancy of ≥ 12 weeks at the time of enrollment.
• ECOG performance status of 0 or 1.
• Adequate organ function:

• Bone marrow function: Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L (1500/mm³); Platelets ≥ 100 × 10⁹/L; Hemoglobin ≥ 9.0 g/dL.
• Renal function: Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or calculated creatinine clearance (Cockcroft-Gault formula) ≥ 60 mL/min.
• Hepatic function: Total bilirubin ≤ 1.5 × ULN (≤ 3.0 × ULN for subjects with Gilbert's syndrome); AST and ALT ≤ 2.5 × ULN in subjects without liver metastases, or ≤ 5 × ULN in subjects with liver metastases.
• Coagulation function: International normalized ratio (INR) ≤ 1.5; Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN.
• Left ventricular ejection fraction (LVEF) > 50% during screening.
• Systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg (without medication or controlled with a single agent).
• Females: Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to enrollment and must agree to use medically acceptable methods of contraception during the treatment period and for 3 months after the last dose; The patient must be non-lactating; Postmenopausal women (≥ 12 months of amenorrhea without other causes) or surgically sterilized (oophorectomy and/or hysterectomy) are not considered of childbearing potential. Their partners must use medically acceptable contraception during the treatment period and for 3 months after the last dose. Males: Surgically sterile or must agree to use medically acceptable contraception during the treatment period and for 3 months after the last dose; Their partners must use medically acceptable contraception during the same period.
• Ability and willingness to comply with the study protocol for the duration of the study and with follow-up procedures.

Exclusion criteria

• Received systemic cytotoxic therapy or investigational therapy within 28 days prior to initiation of study treatment, or non-cytotoxic, non-investigational therapy (e.g., radiotherapy, hormone therapy, targeted therapy, immunotherapy) within 14 days prior to initiation of study treatment.
• Major surgery (defined as requiring general anesthesia within 28 days before initiation of study treatment, or minor surgery requiring general anesthesia within 7 days before initiation of study treatment).
• Pregnant or lactating women.
• History of prior or concurrent second primary malignancy that, in the opinion of the investigator or sponsor, may interfere with the assessment of safety or efficacy of the study treatment.
• Subjects with active or untreated central nervous system (CNS) metastases; Subjects with stable brain metastases may be enrolled if they meet the following criteria: a) No radiological evidence of progression for ≥ 4 weeks after completion of treatment; b) Completion of treatment ≥ 28 days before the first dose of study drug; c) No requirement for systemic corticosteroids (>10 mg/day prednisone or equivalent) within ≤ 14 days prior to the first dose of study drug.
• Active, known, or suspected autoimmune disease or interstitial lung disease.
• Requirement for systemic therapy with corticosteroids or other immunosuppressive drugs within 14 days prior to initiation of study treatment.
• Peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal conditions with risk of perforation; History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to initiation of study treatment.
• Untreated deep vein thrombosis (DVT) within the past 6 months. Subjects with DVT treated with therapeutic anticoagulants (excluding therapeutic warfarin) for at least 14 days prior to initiation of study treatment are allowed.
• Uncontrolled infection.
• New York Heart Association (NYHA) Grade III or greater congestive heart failure.
• History of any of the following cardiac conditions within 6 months prior to initiation of study treatment:

• Cardiac angioplasty or stenting;
• Myocardial infarction;
• Unstable angina;
• Cerebrovascular accident.
• Presence of any unhealed wound, fracture, or ulcer, or symptomatic peripheral vascular disease.
• Evidence of hemorrhagic diathesis, coagulation disorder, or clinically significant bleeding (e.g., severe hematuria, gastrointestinal bleeding, hemoptysis) within 6 months prior to initiation of study treatment.
• QTcF ≥470 msec on screening ECG per Fridericia's formula.
• Urinalysis showing urine protein ≥ ++ and 24-hour urine protein quantification > 1.0 g within 28 days prior to initiation of study treatment.
• Positive hepatitis B surface antigen (HBsAg) with HBV-DNA above the lower limit of detection of the local laboratory; Positive hepatitis C antibody (anti-HCV) with HCV-RNA above the lower limit of detection of the local laboratory; Positive syphilis antibody; Positive human immunodeficiency virus (HIV) antibody test.
• History of organ transplantation.
• Clinical conditions affecting the intake or absorption of AL8326 (e.g., inability to swallow, chronic diarrhea, intestinal obstruction, malabsorption disorders, gastrectomy or small bowel resection).
• Use of prohibited concomitant medications within 14 days prior to initiation of study treatment.
• Receipt of red blood cell or platelet transfusion within 14 days prior to initiation of study treatment.
• Known allergy, hypersensitivity, or intolerance to protein therapies, or history of any severe drug allergy (e.g., anaphylaxis, hepatotoxicity, immune-mediated thrombocytopenia or anemia).
• Any severe and/or unstable pre-existing medical, psychiatric, or other condition that may jeopardize subject safety, obtaining informed consent, compliance with study procedures, or achievement of study objectives.