Phase I Study of HSK42360 in Malignant Brain Tumors With BRAF V600 Mutation

Inclusion criteria

• Age ≥6 and <18 years.
• Karnofsky/Lansky Performance Status >60.
• Life expectancy ≥ 3 months.
• Patients with recurrent malignant brain tumors confirmed by histology or cytology, who have failed standard treatment (disease progression after treatment or intolerable treatment); patients who have previously received BRAF and/or MEK inhibitor therapy are allowed to be included in this study.
• Positive BRAF V600 mutation result confirmed prior to the administration of HSK42360.
• Patients will provide blood or tumor sample according to their own willingness.
• Measurable disease by RANO criteria.
• Patients with inactive CNS lesions, or patients treated with ≤5mg/day corticosteroid and without convulsion for ≥2 weeks.
• Adequate hematologic, hepatic, and renal function.
• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days after the last dose.

Exclusion criteria

• Patients with NF1 mutation.
• malignant tumor within 2 years, with the exception of cutaneous squamous cell carcinoma, cervical carcinoma in situ, papillary thyroid carcinoma, or other tumors with low malignancy.
• Uncontrollable pleural effusion, ascites, or pericardial effusion per protocol.
• Treatment with any of the following:

Prior treatment with anti-tumor drug within 4 weeks or approximately 5 × t1/2 prior to the first dose of HSK42360, whichever is shorter; Prior treatment with nitrosourea or mitomycin C within 6 weeks prior to the first dose of HSK42360; Prior treatment with palliative radiotherapy or anti-tumor herbs within 2 weeks prior to the first dose of HSK42360; Prior treatment with radiotherapy, electric field therapy, or other anti-tumor therapies within 4 weeks prior to the first dose of HSK42360.

• Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment, with the exception of alopecia, dermal toxicity, and other toxicity considering no safety risks by investigator.
• Any disease which would preclude drug absorption, metabolism or pharmacokinetics, eg. active peptic ulcer or chronic gastroesophageal reflux disease.
• Patient who have clinically significant or uncontrolled cardiac disease, include: QTc interval ≥ 450 msec; any clinically significant arrhythmia; left ventricular ejection fraction < 50%; myocardial infarction, unstable angina, or class III/IV cardiac failure by the NYHA that occurred within 6 months prior to the first dose of HSK42360.
• Any thromboembolic events within 6 months prior to the first dose of HSK42360; any familial or aquired thrombophilia.
• Any unstable systemic disease, eg. severe metabolic disease: liver cirrhosis, renal failure, or uremia.
• Treatment with inhibitors/inducers for CYP3A4, or substrates of CYP3A4, CYP2C9, CYP2C8, OATP1B1, OATP1B3, OAT1, OAT3, P-gp or BCRP within 14 days or approximately 5 × t1/2 prior to the first dose of HSK42360, whichever is shorter.
• Patient with cognitive dysfunction, or history of mental illness, other uncontrolled comorbidities, alcohol dependence, hormone dependence or drug abuse.
• Autologous transplantation surgery within 3 months prior to the first dose of HSK42360; Allogeneic transplantation, or stem-cell Transplant surgery within 6 months prior to the first dose of HSK42360; Major surgery or significant traumatic injury occurring within 4 weeks prior to the first dose of HSK42360.
• Patient with a history of immunodeficiency, including HIV positive, or other acquired/congenital immunodeficiency diseases.
• Patient with severe retinal abnormalities and uveitis.
• Patient with active hepatitis B or hepatitis C.
• Allergic to any HSK42360 active constituent or ingredients.
• Participate in other clinical trials within 4 weeks prior to the first dose of HSK42360.
• Positive pregnancy test, or breastfeeding.
• Any other circumstances that would, in the investigator's judgment, prevent the subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures.