Phase I/II Study of SY-3505 in Patients With ALK-positive Advanced Non-small Cell Lung Cancer

Inclusion Criteria:

1. Male or female, age ≥ 18 years at the time of screening.
2. Must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
3. Estimated Life expectancy ≥ 12 weeks.
4. Must have either at least one measurable lesion with no prior local treatment ormeasurable lesions with definite progression (Bone metastases alone were not accepted)after local treatment per Response Evaluation Criteria in Solid Tumors (RECIST)version 1.1.
5. Dose-escalation phase: patients must have histological or cytological confirmedALK-positive advanced NSCLC. Dose-expansion phase: patients must have histological orcytological confirmed ALK-positive advanced NSCLC and progressed after at least oneprior line of ALK TKI therapy. Phase II: patients must have histological orcytological confirmed ALK-positive advanced NSCLC and progressed after only alectinibor ≥2 prior ALK TKIs treatment. The pathological report requires either positivity forALK gene expression determined by fluorescence in-situ hybridization (FISH) assay,immunohistochemistry (IHC), reverse transcription-polymerase chain reaction (RT-PCR),next-generation sequencing (NGS) or other identified methods from previous reports andprovide tissue for ALK retest if possible or providing tissue for ALK test if noprevious report is available.
6. Patients without brain metastasis or with asymptomatic brain metastases (no need forintervention or stable more than 4 weeks after treated).
7. Adequate organ function within 10 days prior to the study of treatment as defined inthe below: Hepatic function Total serum bilirubin (TBIL) ≤ 1.5 times upper limit of normal (ULN); Aspartatetransaminase (AST), alanine transaminase (ALT) and γ- glutamyltransferase (GGT) ≤ 2.5times ULN if no demonstrable liver metastases, or otherwise ≤ 5 times ULN. Bone marrow function Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L; Platelets (PLT) count ≥ 100 x 10⁹/L;Hemoglobin (Hb) ≥ 90 g/L. Renal function Creatinine clearance ≥ 60 mL/min. Pancreatic function Serum total amylase ≤1.5 times ULN; Serum lipase ≤ 1.5 times ULN. Blood glucose Fasting Blood Glucose (FBG) ≤ 200 mg/dL (11.1 mmol/L). Serum lipid Serum cholesterol ≤ 500 mg/dL (12.92 mmol/L). Cardiac function Left ventricular ejection fraction (LVEF) ≥ 50%.
8. Any toxicity of previous antineoplastic treatments was restored to ≤ 1 (except hairloss).
9. Female patients with reproductive potential must have a negative serum pregnancy test,male and female patients of childbearing potential must be willing to completelyabstain or agree to use an appropriate method of contraception during the entire studyduration and for at least 3 months after the last dose of study medication.
10. Willingness and ability to give informed consent and follow protocol procedures, andcomply with follow-up visit requirements.

Exclusion Criteria:

1. Any of the following within 6 months prior to starting trial treatment:Cerebrovascular accident/ stroke, myocardial infarction, severe/ unstable angina,congestive heart failure (New York Heart Association Classification Class ≥II),second- or third- degree atrioventricular (AV) block (unless paced) or any AV blockwith PR interval >220 msec, or any grade of uncontrolled atrial fibrillation.
2. ECG evaluated QT interval corrected (Fridericia) (QTcF) of > 450 msec in males or > 470 msec in females or congenital long QT syndrome.
3. Grade ≥ 3 peripheral neuropathy (CTCAE version 5.0).
4. Any active autoimmune diseases or history of autoimmune diseases that requirelong-term steroid or other immunosuppressants treatment.
5. Previous medical history of interstitial lung disease, drug-induced interstitial lungdisease, radiation pneumonitis which required steroid treatment, or any evidence ofclinically active interstitial lung disease.
6. Patients being treated with any anticoagulants, prone to bleeding, or have acoagulation disorder.
7. Active hepatitis (Hepatitis B: HBsAg-positive and HBV-DNA ≥ 2000 IU/ mL; Hepatitis B:HCV antibody-positive and HCV-RNA ≥ 1000 IU/ml), HIV antibody-positive; Activesyphilis.
8. Patient underwent major surgery within 4 weeks prior to starting trial treatment.
9. Patients received radical radiotherapy within 4 weeks, palliative radiotherapy within 2 weeks, or radioactive agents (strontium, samarium, etc.) within 8 weeks prior tostarting trial treatment.
10. Patients received systemic antitumor therapy, including chemotherapy, immunotherapy,biotherapy (cancer vaccine, cytokine or cancer growth control factor), or clearlyindicated antitumor traditional Chinese medicine within 4 weeks (targeted therapywithin 2 weeks) prior to starting trial treatment.
11. Patients treated with the following drugs and could not be discontinued at least 7days prior to starting trial treatment and during the entire study duration: drugsknown to be strong inducers or suppressors of CYP3A (for details, see prohibitedcombination drugs in this trial).
12. Patients with any active infection requiring systemic therapy within 4 weeks prior tostarting trial treatment.
13. Comorbidities that may seriously endanger the patient's safety or affect thecompletion of the trial, such as severe diabetes, according to the judgment ofinvestigator.
14. A clear previous history of neurological or psychiatric disorders, including dementiaor diagnosed epilepsy for any reason.
15. With a history (within 5 years) or presence of other malignancies, excluding curedskin basal cell carcinoma and carcinoma in situ of the cervix.
16. Other situations that may increase the risks related to the study medication,interfere with the interpretation of the study results, affect compliance of thetrial, etc. are determined by the investigator to be not suitable for the trial.
17. In phase II: previously received third-generation ALK TKIs.