A Study of SY-3505 in Patients With Advanced LTK Fusion-Positive Solid Tumors

Inclusion Criteria:

• Patients must meet all of the following criteria to be eligible for this study:

1. Age ≥ 18 years at the time of signing the Informed Consent Form (ICF).
2. Histologically or cytologically confirmed locally advanced (as assessed by theinvestigator, unresectable tumor or tumor recurrence following standard therapywith evidence of progression [PD] or intolerance to prior therapy) or metastaticsolid tumor and failure of standard treatment with evidence of diseaseprogression on imaging.
3. Agreement to provide a required tumor tissue sample (preferably fresh biopsytissue or archived tumor tissue within 2 years prior to first dosing) that hasbeen tested by the central laboratory and determined to be positive for LTK genefusion.
4. At least one measurable extracranial lesion as defined by Response EvaluationCriteria in Solid Tumors (RECIST) v 1.1 criteria.
5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1.
6. Expected survival of ≥ 3 months.
7. Resolution of any treatment-related AEs related to prior anticancer therapy toNCI-CTCAE v 5.0 grade ≤ 1 (excluding toxicities judged by the investigator to beof no safety concern, e.g., hair loss, prior platinum-related grade 2 peripheralneuropathy) before the first dosing.
8. Organ function levels must meet the following requirements:
9. No blood products, hematopoietic growth factors (e.g., G-CSF,erythropoietin), or other drugs that correct abnormal blood counts for atleast 2 weeks before first dosing and the following blood counts: ANC ≥ 1.5 × 10^9/L, PLT count ≥ 100 × 10^9/L, Hb ≥ 90 g/L.
10. Liver function: TBIL ≤ 1.5 × upper limit of normal (ULN) in the absence ofliver metastases, and AST and ALT ≤ 2.5 × ULN; in the presence of livermetastases, AST and ALT ≤ 5.0 × ULN, and TBIL ≤ 3 × ULN.
11. Pancreatic function: Serum total amylase ≤ 1.5 × ULN and serum lipase ≤ 1.5 × ULN (subjects with serum total amylase > 1.5 × ULN but with serum lipasewithin the ULN range may be eligible).
12. Renal function: Creatinine clearance (Ccr) ≥ 50 mL/min (calculated using theCockcroft and Gault formula).
13. Coagulation function: International normalized ratio (INR) and prothrombintime (PT) ≤ 2 × ULN (except for patients receiving anticoagulant therapy).
14. Able to take oral medications and comply with scheduled visits and relatedprocedures per protocol.
15. Female subjects of childbearing potential must agree to use highly effectivecontraception during the entire study period and for at least 3 months after thelast dose

Exclusion Criteria:

• Patients who meet any of the following criteria are not eligible for this study:

1. Carrying known major driver gene mutations other than LTK gene, such as EGFR,MET, ALK, ROS1, NTRK, etc. (Patients with co-mutations may be discussed with theinvestigator for eligibility).
2. History of hypersensitivity reactions to any component or excipient of SY-3505capsules.
3. Concurrent primary malignancy, with the following exceptions: adequately treatedin situ carcinoma, non-melanoma skin cancer, in situ cervical cancer, or in situbreast cancer, and cured malignancies without recurrence for at least 2 yearsprior to study entry.
4. Symptomatic primary central nervous system (CNS) tumors, symptomatic CNSmetastases, leptomeningeal carcinomatosis, or untreated spinal cord compression.Patients with stable CNS disease (defined as no evidence of progression onimaging for at least 4 weeks prior to first dosing, with all neurologicalsymptoms returned to baseline, and without evidence of new or enlarging brainmetastases, and no CNS surgery or radiation treatment within 4 weeks prior tofirst dosing, and no stereotactic radiosurgery [SRS] within 2 weeks prior tofirst dosing, and no steroids for at least 2 weeks) are eligible. (Note:Carcinomatous meningitis is not allowed, regardless of clinical stability).
5. Presence of any of the following conditions or diseases at screening that areinadequately controlled with the best possible medical management:
6. Active systemic bacterial, viral, or fungal infections.
7. Pleural effusion, peritoneal effusion, or pericardial effusion that is notcontrolled after intervention (defined as significant if reaccumulation offluid requiring drainage occurs within 2 weeks of the prior interventionwith associated symptoms).
8. Poorly controlled diabetes mellitus (defined as fasting blood glucose ≥ 11.1mmol/L and/or HbA1c ≥ 8%).
9. Symptomatic hyperthyroidism or hypothyroidism not well controlled by medicalmanagement as assessed by the investigator.
10. Clinically significant electrolyte disturbances (e.g., severe hypocalcemia,hypomagnesemia, hypokalemia) as assessed by the investigator.
11. Clinically significant gastrointestinal diseases that may interfere with theabsorption of study drug (e.g., active ulcerative colitis, Crohn's disease,gastrointestinal ulcers, or major gastrointestinal surgery that might affectdrug absorption).
12. Severe cardiovascular diseases/abnormalities meeting any of the followingcriteria:
13. QT interval corrected for heart rate (QTcF) > 470 msec for females or > 450msec for males as calculated by the Fridericia formula during screening (subjects with suspected drug-induced QTcF prolongation that is assessed bythe investigator as safely controllable may be eligible after correctionwith medication).
14. Left ventricular ejection fraction (LVEF) < 50%.
15. Myocardial infarction, unstable angina, or clinically significantarrhythmias (e.g., grade 2 second-degree heart block or third-degree heartblock) within 6 months prior to the first dosing.
16. Class III or IV congestive heart failure as classified by the New York HeartAssociation (NYHA).
17. Poorly controlled hypertension, a history of unstable hypertension, or ahistory of poor compliance with antihypertensive treatment as assessed bythe investigator.
18. Active viral infections or a history of the following:
19. Active hepatitis B (HBV) infection (defined as HBsAg positive and HBV DNA ≥ 2 × 10^3 IU/mL at screening, unless HBV DNA levels have decreased to < 2 × 10^3 IU/mL after regular antiviral therapy, in which case the patient may beeligible), or active hepatitis C (HCV) infection (HCV RNA > centrallaboratory ULN) at screening.
20. HIV positivity at screening or known other immunodeficiency disease.
21. Previous organ transplantation, hematopoietic stem cell transplantation, orbone marrow transplantation.
22. Other significant systemic diseases, including but not limited to activepulmonary disease (e.g., active tuberculosis, interstitial lung disease), that,in the investigator's judgment, may affect the interpretation of study results orpose high risks to the patient.
23. Use of strong CYP3A4 inhibitors or inducers within 2 weeks before the firstdosing or during the study period, as follows:
24. CYP3A4 Inhibitors: Azanavir, Clarithromycin, Erdafitinib, Itraconazole,Ketoconazole, Nafitamone, Letermovir, Saquinavir, Telithromycin,Vinorelbine, Grapefruit (juice).
25. CYP3A4 Inducers: Carbamazepine, Phenobarbital, Phenytoin, Rifabutin,Rifampicin, St. John's Wort, Rifapentine.
26. Receipt of any of the following anticancer treatments:
27. Bone marrow radiation or extensive radiotherapy involving more than 30% ofthe bone marrow: within 4 weeks before first dosing.
28. Palliative radiotherapy: within 7 days before first dosing.
29. Other anticancer treatments such as chemotherapy, targeted therapy (immunotherapy or other antibody therapy), antitumor Chinese medicine, orothers: within 2 weeks before first dosing or within 5 half-lives of thetreatment (whichever is longer).
30. Major surgery within 4 weeks before first dosing (major surgery defined as asurgery grade ≥ 3, excluding placement of a central venous catheter, tumorpuncture biopsy, and gastrostomy tube placement) or significant traumatic injurythat has not fully recovered.
31. Participation in other clinical studies within 4 weeks before first dosing (except for those that do not use investigational drugs or investigationalmedical devices; subjects who have discontinued treatment from other clinicalstudies and are only undergoing follow-up are excluded).
32. Severe thromboembolic events within 1 year before the first dosing (e.g.,cerebrovascular accidents [including transient ischemic attacks], deep veinthrombosis, pulmonary embolism) or a bleeding tendency/risks within 30 daysbefore the first dosing (e.g., significant gastrointestinal bleeding).
33. Pregnant or lactating women.
34. Other circumstances, as determined by the investigator, which make the patientunsuitable for participation in this clinical trial, such as other serious acuteor chronic diseases that may increase the patient's related risks in the study orlaboratory abnormalities that may interfere with the interpretation of studyresults.