The Phase I/Phase II Clinical Study of VC004 in Patients With Localized Advanced/Metastatic Solid Tumors

Inclusion Criteria:

• All subjects or legal representatives are willing and able to sign ICF approved by theethics committee before starting any screening procedures；
• Male or female, age ≥18 years old
• Patients with locally advanced or metastatic solid tumors diagnosed by histology orcytology, or currently have no standard treatment, have failed the standard treatment,or are intolerant to the standard treatment or are not suitable for the standardtreatment at this stage。 The first part of the dose escalation stage: locally advancedor metastatic solid tumors, including but not limited to salivary gland cancer,thyroid cancer, soft tissue sarcoma, liposarcoma, etc.
• Subject's baseline lesion requirements: According to the definition of RECIST v1.1 orRANO, the subject must have at least one measurable lesion (applicable to NTRKfusion-positive locally advanced or metastatic solid tumors)。
• Subjects with primary central nervous system (CNS) tumors must meet the followingcriteria (only the first part of the dose expansion phase and the second part areapplicable)
• According to the guidelines or CNS tumor type, have received treatment includingradiotherapy and/or chemotherapy, and the interval between radiotherapy and thefirst treatment with study drug is at least 12 weeks.
• According to the definition of RANO, there is at least one measurable lesion inmagnetic resonance imaging (MRI), which can be visualized on ≥2 axial films witha thickness of 5 mm, and the longitudinal diameters perpendicular to each otherare> 10 mm.
• The imaging examination was performed within 28 days before enrollment. If youreceive glucocorticoid treatment, a stable dose of glucocorticoid is required atleast 5 days before imaging evaluation.
• The Eastern Cooperative Oncology Group (ECOG) score is ≤2 points (0-1 points arerequired for the dose-escalation stage)
• The estimated survival time is ≥12 weeks.
• The subject must have appropriate organ and hematological functions (have not receivedblood transfusion, EPO, G-CSF or other medical supportive treatment within 14 daysbefore the administration of the study drug)。
• Premenopausal women who are likely to have children must have a pregnancy test within 7 days before starting treatment. The pregnancy test must be negative and must benon-lactating; Infertile women may not undergo pregnancy tests and contraception, butthey must meet the following requirements: age 50 years or older, not using hormonetherapy and menopause for at least 12 months, or have undergone sterilization. Allenrolled patients (whether male or female) should take adequate contraceptive measuresthroughout the treatment period and 180 days after the end of treatment.

Exclusion Criteria:

• Patients have previously received any of the following treatments:
• Patients have used any cytotoxic chemotherapeutic agents, targeted therapies,immunotherapies, or other anti-cancer drugs in the previous regimen within 4weeks before the first administration ( e.g.Nitrosourea or mitomycin C for 6weeks prior to first use of study drug, Oral fluorouracil and small-moleculetargeted drugs are administered 2 weeks prior to the first use of the study drugor within 5 half-lives of the drug, whichever is longer.).
• The time from receiving other experimental drugs or analogues to the first dosedoes not exceed the drug's 5 half-life or 14 days (whichever is longer).
• Patients have used chinese herbal medicines and chinese herbal preparations withantitumor as an indication, chinese herbal medicines and chinese herbalpreparations with tumor adjuvant therapeutic effect within 14 days before thefirst administration.
• Patients have undergone major surgery within 4 weeks prior to the first dose or areexpected to undergo major surgery during the trial (excluding vascular accessestablishment procedures, biopsy procedures)
• Adverse reactions caused by previous treatment have not recovered to ≤1 grade (thedose-escalation stage does not include ≤2 grade hair loss, and the dose expansionstage and phase II clinical trials are comprehensively evaluated by the investigator).
• Primary central nervous system malignancy (only the first part of the dose escalationphase).
• Patients are known to have symptomatic or untreated brain metastases or other centralnervous system metastases.CNS lesions that remain stable or show improvement aftertreatment with complete resection and/or radiation therapy are excluded, but requireno glucocorticoids to control neurological symptoms within 14 days prior to entry intothis study.
• There is any clinical basis suggesting a severe or uncontrolled systemic disease forwhich the investigator believes the patient is unsuitable for trial participation orwhich would affect the patient's compliance with the study protocol, such as stable ordecompensated respiratory disease, cerebrovascular disease, liver disease, renaldisease, uncontrolled diabetes, aortic dissection, aortic aneurysm, activebleeding-prone body, or those requiring systemic anti-infective therapy.
• Any clinically serious gastrointestinal abnormality that may affect the ingestion,transit, or absorption of study drugs.
• Patients have clinically significant cardiovascular diseases, including：
• Left ventricular ejection fraction (LVEF) ≤ 50% by echocardiography during thescreening period
• Heart Failure, New York Heart Association (NYHA) grade III and above
• Poorly controlled hypertension (BP ≥ 150/100 mmHg despite use of optimal therapy)
• Past or current cardiomyopathy
• Patients with atrial fibrillation and severe arrhythmia with ventricular rate> 100 bpm
• Unstable ischemic heart disease (myocardial infarction (MI) within 6 months priorto starting study treatment, or angina that requires >1 nitrate per week tocontrol symptoms)
• QTcF interval ≥450ms for males and ≥470ms for females (Fredericka formula: QTcF =QT/RR0.33)
• Patients had been treated with a strong CYP3A inhibitor or inducer within 7 days priorto the first administration of the study drug.
• Currently existing hepatitis B (hepatitis B surface antigen [HbsAg] positive or coreantibody [HbcAb] positive and HBV DNA positive), hepatitis C (HCV anti-positive andHCV RNA positive), human immunodeficiency virus (HIV) infection and syphilisinfection.
• Patients whom the investigators determine are not suitable for participation in thestudy for other reasons.
• Subjects are unwilling or unable to follow the protocol process.