A Study of CS231295 in Patients With Advanced Solid Tumors

In this dose-escalation study, the "3+3" design will be employed for dose escalation decisions. 4 dose groups have been preset: 20 mg, 30 mg, 40 mg, 50 mg[LA2.1]. The starting dose is 20 mg, with each dose cohort enrolling 3-6 subjects. Each subject can participate in only one dosage group of the study. During the dose escalation, depending on the observed results of safety, pharmacokinetics (PK), and pharmacodynamics (PD), dose levels may be adjusted or removed, additional dose levels may be added and explored, including intermediate or higher dose levels or other dosing regimens. The dose escalation study includes a single-dose treatment period (C0) and a multiple-dose treatment period (C1, C2, …). During the treatment, subjects will first undergo a 6-day single-dose treatment period. Each subject will receive a single dose of oral CS231295 on Day 1 of the study, with no additional doses administered through Day 6. All subjects in each cohort (3 to 6 subjects) will initiate this single-dose period, followed by a continuous multiple-dose treatment period with a treatment cycle of 28 days and no drug-free intervals.

Patients continue the treatment cycle until disease progression per investigator assessment, unacceptable toxicity, death, withdrawal of consent, study termination, or other discontinuation criteria are met (whichever occurs first).

Inclusion criteria

Patients are eligible to be included in the study only if all of the following criteria apply:

• Subject provides voluntary informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol prior to performing any protocol-related procedures, including screening evaluations.
• Male or female ≥18 years at the time of Screening.
• Histologically or cytologically confirmed unresectable advanced, recurrent or metastatic solid tumors (including but not limited to small cell lung cancer (SCLC), brain gliomas, non-small cell lung cancer (NSCLC), pancreatic cancer, urothelial carcinoma, endometrial cancer, cervical cancer, ovarian cancer, breast cancer and liver cancer, etc.), who have failed or are intolerant to previous standard treatment (assessed by the investigator according to the diagnosis and treatment guidelines of the relevant disease) and currently have no standard treatment.

• Treatment failure must be documented by clear imaging or cell histopathology (such as cytology reports of new ascites or pleural effusion) to prove disease progression.
• Intolerance is defined as the termination of treatment due to adverse events that occur during treatment.
• Recurrence is based on imaging or cell histopathology results.
• At least one measurable target lesion (glioma, according to RANO 2.0; other solid tumors according to RECIST v1.1).

Note: The target lesion can be located in an area that has previously undergone radiotherapy. However, imaging examinations are required to confirm disease progression at the site after radiotherapy.

• Glioma: KPS score ≥ 60 points; other solid tumors: ECOG performance status score of 0 or 1 points.
• Life expectancy of ≥ 12 weeks.
• Major organ functions meet the following criteria:

(No blood components, hematopoietic growth factors, albumin, or other drugs deemed corrective treatment by the investigators should be used within 14 days prior to the screening, except for iron supplements.)

• Hematology:

• Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L,
• platelets ≥ 100 × 10^9/L,
• hemoglobin ≥ 100 g/L
• Biochemistry:

• Total serum bilirubin ≤ 1.5 x ULN (< 3.0 x ULN for patients with Gilbert's syndrome).
• In patients without hepatic metastasis: ALT and AST ≤1.5 × ULN.
• In patients with hepatic metastases, ALT and AST ≤3 × ULN.
• Measured or calculated creatinine clearance > 60 mL/min (according to the Cockcroft-Gault equation, using actual body weight)
• Coagulation Function: International Normalized Ratio (INR) < 1.5 × ULN; Prothrombin time (PT) and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN (for subjects receiving prophylactic anticoagulation therapy, the investigator should judge that both INR and APTT are within the safe and effective therapeutic range).
• Urine protein < 2+ by urinalysis. If patients have urine protein ≥2+ by urinalysis, a 24-hour urine protein quantification test should be performed. The patient cannot be enrolled if the quantified urine protein is ≥1 g/24 h. The patient can still be enrolled if the quantified urine protein is <1 g/24 h.
• Women of childbearing potential (WOCBP) must be willing and able to take highly effective contraceptive measures during the entire study treatment period and for 12 weeks after the last dose of the study drug (see Appendix 13.3 for details). Women of childbearing potential include premenopausal and not sterilized (by hysterectomy, bilateral ligation of fallopian tubes, or bilateral oophorectomy) females who have passed menarche.
• Male patients must be willing and able to use male condoms and their female partners who are WOCBP during the entire study treatment and for the 12 weeks after the last dose of the study drug (see Appendix 13.3 for details).

Exclusion criteria

Patients are excluded from the study if any of the following criteria apply:

• Received any form of intracranial radiotherapy within a specified time frame before the first dose of medication: 3 months for glioma and 2 weeks for other solid tumors.
• Any prior anti-tumor treatment such as radiotherapy (exclusion criterion #1 if intracranial radiotherapy), chemotherapy, immunotherapy, targeted therapy, cell therapy, endocrine anti-tumor therapy, tumor embolization, clinical trial drugs or devices that have not been approved for marketing, etc., within 28 days before the first medication.
• Patients have previously received treatment with Aurora kinase inhibitors.
• Has used a strong inducer or inhibitor of cytochrome P450 3A enzyme (CYP3A) within 14 days before the first dose of the study drug or is still within 7 half-lives of the drug (whichever is longer).
• Glioma: Use of > 5 mg/d dexamethasone or equivalent doses of other glucocorticoids for systemic treatment related to glioma within 1 week before the first dose.
• Major surgical procedures (craniotomy, thoracotomy, or laparotomy) or severe unhealed wounds, ulcers, or fractures performed within 4 weeks before the first dose of study medication.
• Any unresolved toxicity from previous anticancer therapy, defined as toxicities not yet resolved to NCI CTCAE Grade ≤1, except for alopecia or laboratory values deemed by the investigator to be of no clinical significance.
• History of another primary malignancy except for

• Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of the study drug and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated carcinoma in situ without evidence of disease
• Advanced solid tumors other than glioma: Patients with active or untreated brain metastases, leptomeningeal metastases, spinal cord compression, or leptomeningeal carcinomatosis at the screening are excluded. Participants with previous brain metastases may participate only if they satisfy all of the following:

• Has completed treatment (e.g., whole brain radiation treatment [WBRT], stereotactic radiosurgery, or equivalent)
• Have stable disease for more than 4 weeks at the screening tumor assessment as confirmed by MRI or CT brain (defined as 2 brain images, both of which are obtained after treatment to the brain metastases. These imaging scans should both be obtained at least four weeks apart and show no evidence of intracranial progression).
• Have been either off corticosteroids or on a stable or decreasing dose of 10 mg daily prednisone (or equivalent) for at least 2 weeks before the first dose of study medications.
• Have been off anticonvulsants for at least 2 weeks before the first dose of study medications.
• Combined with meningeal metastasis, except for glioma.
• Has severe brain herniation or a risk of brain herniation.
• Glioma: had a chip implant placed during glioma surgery.
• Pleural effusion, ascites, or pericardial effusion that have been drained within 1 month before the first dose of the study drug, or significant clinical symptoms (such as chest tightness, shortness of breath, dyspnea, etc.).
• Uncontrolled or significant cardiovascular diseases, including:

• New York Heart Association (NYHA) grade II or higher congestive cardiac failure, unstable angina pectoris, and/or myocardial infarction within the 6 months prior to the first dose of the investigational drug, clinically significant arrhythmia unable to be controlled with medical treatment or left ventricular ejection fraction (LVEF) < 50% at screening.
• Primary cardiomyopathies (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, indeterminate cardiomyopathy).
• Clinically significant history of prolonged QTc interval, or QTcF interval ≥470 ms, regardless of sex, during screening. If the report does not include a QTcF result, it must be calculated using the Fridericia correction formula (Fridericia QTc = QT/RR^0.33).
• Coronary heart disease with symptoms requiring medication.
• Major cerebrovascular accidents (including cerebral hemorrhage, transient ischemic attack, etc.) within 6 months before the first medication.
• Patient has hypertension at screening (defined as systolic blood pressure (SBP) ≥140 mmHg, diastolic blood pressure (DBP) ≥90 mmHg). [Patients with a known history of hypertension may be included if their blood pressure is well controlled on a single anti-hypertensive medication (SBP <140 mmHg and DBP <90 mmHg at screening). Additionally, these patients must not have experienced any changes in their blood pressure medication for at least three months prior to screening due to poor blood pressure control.]
• Other cardiovascular diseases that the investigator judge to be unsuitable for inclusion in the study
• Poorly controlled diabetes (fasting blood glucose > 10 mmol/L).
• Clinically significant gastrointestinal abnormalities that may affect the study drug's intake, transport, or absorption (e.g., inability to swallow, chronic diarrhea, intestinal obstruction, or having undergone a total gastrectomy), as determined by the investigator.
• Clinically significant hemoptysis or tumor bleeding occurred within 14 days before the first medication, or history of active bleeding within 2 months prior to enrollment, or are currently taking anticoagulant drugs, such as warfarin, Phenprocoumon (prophylactic use of low-dose aspirin, low molecular weight heparin is permitted), or have a definite predisposition to bleeding as determined by the investigator (e.g., esophageal varix associated with bleeding risk, local active ulcer lesions, positive occult fecal blood that cannot rule out gastrointestinal bleeding, and imaging evidence indicating tumor invasion or infiltration of large blood vessels).
• History of severe thromboembolic events (such as arterial thrombotic events, pulmonary embolism, or deep vein thrombosis) occurred within 6 months prior to the initiation of the first medication. Thrombosis of implanted venous infusion ports or catheters, superficial venous thrombosis, or thromboembolism that is assessed by the investigator to be stable and does not require emergency medical intervention during the expected trial period is not considered "serious" thromboembolism.
• Ongoing or active infections that require intravenous systemic treatment during the screening period. Severe infection within 28 days before the first medication (including but not limited to hospitalization due to infection, bacteremia, or severe pneumonia complications). Prophylactic antibiotic treatment (such as to prevent urinary tract infection or acute exacerbation of chronic obstructive pulmonary disease) can be included.
• Active tuberculosis infection (clinical evaluation that may include clinical history, physical examination, radiographic findings, or tuberculosis testing in accordance with local practice), currently receiving anti-tuberculosis treatment or having received anti-tuberculosis treatment within 1 year prior to the first use of the medication.
• Active hepatitis during the screening period: Hepatitis B surface antigen (HBsAg) positive with positive virus replication or hepatitis B core antibody (HBcAb) positive with positive virus replication. Hepatitis C antibody (HCV-Ab) positive with positive virus replication.
• HIV test positive or active syphilis infection (syphilis specific antibody and non-specific antibody positive) during screening.
• Known allergy or hypersensitivity to any of the study drugs or the study drug excipients.
• History of allogenic organ transplantation or allogeneic hematopoietic stem cell transplantation.
• History of drug or alcohol abuse disorders that may affect study participation and clinical outcomes according to the investigator's judgment.
• Mental or cognitive disorders that could limit their understanding, execution, and compliance with the informed consent form and the study.
• Pregnant or lactating women. Female participants of childbearing potential or male participants with partners of childbearing potential who are unwilling or unable to use effective contraception from 7 days before the first dose of medication until 3 months after the end of treatment. Female participants of childbearing potential with a positive pregnancy test result within 7 days before the first dose of medication.
• The investigator determined that the patient was unsuitable for participation in the study and was unlikely to comply with the study's procedures, restrictions, and requirements.