A Study of A166 in Patients With Advanced Solid Malignant Tumors

The first stage will determine the recommended stage 2 dose (RS2D) in patients with unresectable, locally advanced or metastatic HER2-expressing solid tumors based on safety, tolerability, pharmacokinetic characteristics and antitumor activity. The second stage will assess the safety, tolerability, pharmacokinetic characteristics and antitumor activity in dose-expansion cohorts (RS2D:3.6 mg/kg, 4.8 mg/kg and 6.0 mg/kg dose groups).

Inclusion criteria

• Voluntarily sign informed consent form;
• Age ≥ 18 years old, no gender limit;
• Patients had a histologically confirmed incurable locally advanced or metastatic solid tumors;
• Determined HER2-positive disease (detected by ISH or NGS) or HER2-expressing disease by evaluation or detection. Definition of HER2 expression in this study: Immunohistochemistry [IHC] ≥ 1＋;
• Patients unable to benefit from the available standard treatment according to the judgment of the investigator;
• White blood cell count (WBC) ≥ 4.0×109/L or ≥ lower limit of normal value; Neutrophil count (NEUT) ≥ 1.5×109/L; Platelet count (PLT) ≥ 100×109/L; Hemoglobin concentration ≥ 9.0 g/dL;
• Total bilirubin (TBIL) ≤ 1.5×ULN. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase ≤ 2.5 times the upper limit of normal (ULN). For patients with liver metastases, ALT and AST ≤ 5 times ULN, and for patients with liver and/or bone metastases, alkaline phosphatase ≤ 5 times ULN;
• Creatinine clearance rate ≥ 50 ml/min;
• Patients had an Eastern Cooperative Oncology Group (ECOG)performance status of 0 or 1, the expected survival time is ≥ 3 months;
• During the study period and within 7 months after the final administration of A166, patients with fertility (regardless of male and female) must receive effective medical contraceptive measures;
• The patients must recover from all acute toxicities of the previous treatment (relieved to grade 1 or baseline), except for hair loss and vitiligo;

Exclusion criteria

• Severe or uncontrollable heart disease requiring treatment, or grade 3 or 4 congestive heart failure according to the New York Society of Cardiology (NYHA), or unstable angina pectoris that cannot be controlled by drugs, or history of myocardial infarction within 6 months prior to enrollment, or severe arrhythmia requiring medical treatment (except for atrial fibrillation or paroxysmal supraventricular tachycardia);
• History of ≥ Grade 3 allergic reaction to trastuzumab;
• Permanent with drawal of trastuzumab due to any previous toxicity;
• Patients with brain metastases who have symptoms or who have received the radiotherapy or surgery within 3 months before the first administration;
• Patients requiring oxygen therapy in daily activities;
• Grade 2 or higher peripheral neuropathy;
• Any chemotherapy, hormone therapy (except dexamethasone), radiotherapy, immunotherapy or biological therapy received within 4 weeks before the first administration;
• Prior-treatment with other clinical research drugs within 4 weeks before the first administration;
• Patients who have undergone major surgery within 4 weeks before the first administration;
• Active hepatitis B (hepatitis B surface antigen positive and HBV-DNA higher than the upper limit of reference value) or hepatitis C (positive hepatitis C virus antibody and HCV-RNA higher than the upper limit of reference value); current or past alcoholics ; Liver cirrhosis;
• Known active human immunodeficiency virus (HIV);
• Systemic diseases that cannot be controlled, including diabetes, hypertension, pulmonary fibrosis, acute lung disease, interstitial lung disease, glaucoma, etc according to investigator's judgment;
• Current pregnancy or lactation;
• QTc interval> 470 ms according to the baseline measurement:;
• Left ventricular ejection fraction (LVEF) <45% according to the echocardiogram (ECHO) or multi-gate circuit controlled acquisition (MUGA) ;
• Previous cumulative doxorubicin accumulation > 360 mg/m2 or its equivalent dose;