A Study of YL-17231 in Patients With Advanced Solid Tumors

This is a phase 1 open label multicenter study to evaluate the maximum tolerance, safety, tolerance and PK of oral YL-17231 in patients with advanced solid tumors with KRAS mutation, so as to confirm the recommended phase 2 dose of YL-17231 and obtain the preliminary efficacy information of patients with advanced solid tumors with KRAS mutation.

The study will be conducted in China to provide safety, efficacy and PK data. A dose escalation part 1 will be conducted to determine the MTD, DLTs, and part 2 will confirm the safety/tolerability of the recommended Phase 2 dose (RP2D), of YL-17231 given twice daily, in patients with advanced solid tumors to obtain preliminary efficacy information. PK samplings at single dose stage Day 1 and at steady-state conditions (Cycle 1, Day 14) will be performed.

Eligibility Criteria:
Inclusion Criteria:

The patients must meet all the following inclusion criteria to be eligible for enrollment in this trial:

1. Age between 18 and 75 years (inclusive), with no gender restriction.
2. Locally advanced or metastatic solid tumors diagnosed histologically and genomically confirmed with KRAS mutation, excluding patients with a clear KRAS wild-type test report in the case of pancreatic cancer.

   A. For patients with NSCLC, previous treatment failure based on platinum-based first-line therapy; B. For patients with colorectal cancer, previous experience with at least two lines of systemic therapy (patients with colorectal cancer and high microsatellite instability should have received PD-1 or PD-L1 therapy if clinically applicable); C. For patients with solid tumors other than NSCLC or colorectal cancer, at least one prior systemic treatment is required.
3. In the dose escalation phase, measurable or non-measurable tumor lesions are acceptable based on RECIST1.1 criteria; in the dose expansion phase, at least one measurable tumor lesion is required.
4. ECOG performance status (PS) of 0-1.
5. Estimated life expectancy of ≥3 months.
6. Good organ function levels:

   * Absolute neutrophil count (ANC) ≥1.5×109/L;
   * Platelet count (PLT) ≥100×109/L;
   * Hemoglobin (Hb) ≥90g/L (no blood transfusion within 14 days before screening);
   * Total bilirubin (TBIL) ≤1.5 times the upper limit of normal;
   * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times the upper limit of normal (≤5.0 times the upper limit of normal for patients with liver metastasis);
   * Serum creatinine (Cr) ≤1.5 times the upper limit of normal or creatinine clearance ≥50ml/min;
   * Left ventricular ejection fraction (LVEF) ≥50%;
   * Fridericia-corrected QT interval (QTcF) \<450ms.
7. Washout period of ≥4 weeks for macromolecular agents and intravenous chemotherapy drugs, and ≥2 weeks for oral fluoropyrimidine and small molecule targeted drugs.
8. Fertile males and females must agree to use medically approved contraceptive measures during the study period and for 6 months following the last administration of the study drug.
9. Women of childbearing potential must have a negative pregnancy test within 7 days prior to the first administration of the study drug; patients must not be breastfeeding, and if the subject has already ceased breastfeeding at the time of study entry, breastfeeding must have been discontinued from the day of the first administration of the study drug till at least 30 days after last administration of the study drug .
10. No previous treatment with investigational drugs within 1 month prior to participation in this trial.
11. High compliance and willingness to complete the trial as assessed by the investigator, and ability to adhere to the study protocol.
12. Voluntary participation in this clinical trial, understanding of the study procedures, and ability to provide written informed consent.

Exclusion Criteria:

Patients with any of the following conditions are not eligible for enrollment in this study:

1. Uncontrollable third-space effusion (such as large amounts of pleural or ascitic fluid).
2. Grade 3 or 4 gastrointestinal bleeding or variceal bleeding requiring transfusion, endoscopy, or surgical intervention within the past 3 months.
3. Previous diagnosis of other malignancies within the past five years, except for basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or cured in situ cervical cancer.
4. Inability to swallow, chronic diarrhea, or intestinal obstruction that could affect medication intake and absorption.
5. History of significant neurological or psychiatric disorders.
6. Active hepatitis B (positive for hepatitis B surface antigen and/or hepatitis B core antibody with HBV-DNA ≥103 copies/mL or ≥200 IU/mL) or hepatitis C (positive for hepatitis C virus antibody and/or HCV-RNA).
7. History of immunodeficiency, including positive HIV test, acquired or congenital immunodeficiency disorders, organ transplantation, or allogeneic bone marrow transplantation.
8. Major surgical procedures (excluding biopsy) within the past 4 weeks prior to the first administration of the study drug, significant trauma, or the need for elective surgery during the study period, or radical radiotherapy within the past 4 weeks prior to the first administration of the study drug.
9. Moderate or severe cardiac diseases:

   * Myocardial infarction, angina, III/IV congestive heart failure, pericardial effusion, or uncontrolled severe hypertension (up to 150/90 mmHg or below) within the past 6 months prior to the first administration of the study drug;
   * Clinically significant electrocardiogram abnormalities, such as symptomatic or persistent atrial or ventricular arrhythmias, second or third-degree atrioventricular block, bundle branch block, or ventricular hypertrophy;
   * Significant abnormalities on echocardiography, such as moderate or severe valvular dysfunction, assessed based on institutional lower limits; patients with minimal or mild valve regurgitation (tricuspid, pulmonary, mitral, or aortic) can be included in this study;
   * Various factors that may increase the risk of QTcF prolongation or cardiac arrhythmia events, such as hypokalemia, congenital long QT syndrome, or concomitant use of drugs that may prolong the QT interval.
10. Untreated brain metastases that meet one or more of the following criteria:

    * Requiring corticosteroids or dehydration treatment (excluding the use of antiepileptic drugs after surgery or radiotherapy);
    * Presence of clinically significant symptoms;
    * Tumor stability after radiotherapy or surgery lasting no longer than 4 weeks. Asymptomatic or controlled stable patients with treated brain metastases are eligible for enrollment.
11. Unresolved treatment-related toxicity greater than Grade 1 according to CTCAE 5.0 at the start of study treatment (alopecia excluded).
12. Medical conditions that, in the opinion of the investigator, pose a serious risk to patient safety or could interfere with the patient's ability to complete the study, such as uncontrolled diabetes, thyroid disease, interstitial lung disease, severe active infections, or uncontrolled chronic infections, Child-Pugh Class B or C liver cirrhosis.
13. Other reasons deemed unsuitable for participation in this study by the investigator.