a study of a166 in patients with advanced solid malignant tumors

Conditions: Breast Cancer

Summary: this is a single arm, open-label, dose-escalation and dose-expansion phase i study evaluating a166 in patients with her2-expressing locally advanced or metastatic solid 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).

Eligibility criteria:
inclusion criteria: 1. voluntarily sign informed consent form; 2. age ≥ 18 years old, no gender limit; 3. patients had a histologically confirmed incurable locally advanced or metastatic solid tumors; 4. 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＋; 5. patients unable to benefit from the available standard treatment according to the judgment of the investigator; 6. 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; 7. 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; 8. creatinine clearance rate ≥ 50 ml/min; 9. patients had an eastern cooperative oncology group (ecog)performance status of 0 or 1, the expected survival time is ≥ 3 months; 10. 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; 11. 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: 1. 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); 2. history of ≥ grade 3 allergic reaction to trastuzumab; 3. permanent with drawal of trastuzumab due to any previous toxicity; 4. patients with brain metastases who have symptoms or who have received the radiotherapy or surgery within 3 months before the first administration; 5. patients requiring oxygen therapy in daily activities; 6. grade 2 or higher peripheral neuropathy; 7. any chemotherapy, hormone therapy (except dexamethasone), radiotherapy, immunotherapy or biological therapy received within 4 weeks before the first administration; 8. prior-treatment with other clinical research drugs within 4 weeks before the first administration; 9. patients who have undergone major surgery within 4 weeks before the first administration; 10. 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; 11. known active human immunodeficiency virus (hiv); 12. systemic diseases that cannot be controlled, including diabetes, hypertension, pulmonary fibrosis, acute lung disease, interstitial lung disease, glaucoma, etc according to investigator's judgment; 13. current pregnancy or lactation; 14. qtc interval\> 470 ms according to the baseline measurement:; 15. left ventricular ejection fraction (lvef) \<45% according to the echocardiogram (echo) or multi-gate circuit controlled acquisition (muga) ; 16. previous cumulative doxorubicin accumulation \> 360 mg/m2 or its equivalent dose;