First in Human Dose Escalation Study of YL-13027 in Subjects With Advanced Stage Solid Tumors
First in Human Dose Escalation Study of YL-13027 in Subjects With Advanced Stage Solid Tumors
YL-13027-001 is a phase I open-label, first in human, dose escalation study which investigate
 the tolerability, safety, pharmacokinetics (PK) and efficacy of YL-13027 in subjects with
 advanced stage solid tumors.
This is a open-label, single-center, dose-escalation, phase I study of YL-13027 comprised of
 a dose escalation part and a dose expansion part in subjects with advanced stage solid
 tumors. The study will investigate the tolerability, safety, pharmacokinetics (PK) and
 efficacy of YL-13027, and will define the maximum tolerated dose (MTD) of YL-13027 using an
 accelerated titration test and 3+3 design. a dose expansion part will identify the
 recommended phase 2 dose. YL-13027 is an orally bioavailable small molecule that inhibits
 protein serine/threonine kinase of activin receptor-like kinase 5 (ALK5) and blocks
 intracellular signaling of TGF-β by inhibiting the phosphorylation of ALK5 substrates. In
 this clinical trial, YL-13027 is given orally daily. A treatment cycle is defined as 28 days.
 Adverse events (AEs) were graded by NCI-CTCAE V5.0. Efficacy was evaluated according to
 RECIST V1.1.
Inclusion Criteria:

 1. Males and/or females age from 18 to 75;

 2. Histologically or cytologically confirmed patients with advanced malignant solid
 tumors, eligible patients must have failed standard treatment, no standard treatment,
 or not suitable for standard treatment at this stage as determined by the
 investigator;

 3. In the dose escalation portion, both measurable and non-measurable tumor lesions were
 acceptable according to RECIST1.1 criteria;There was at least one measurable tumor
 lesion in the dose expansion portion;

 4. Eastern Cooperative Oncology Group performance status of 0 to 1;

 5. Life expectancy of at least 3 months;

 6. Acceptable organ function: Absolute neutrophil count(ANC)≥1.5×109/L; Platelet
 count(PLT)≥100×109/L; Hemoglobin(Hb)≥90 g/L; Total bilirubin(TBIL)≤1.5×Upper limit of
 normal value(ULN); Alanine aminotransferase(ALT)≤2.5×ULN; Aspartate
 aminotransferase(AST)≤2.5×ULN; Creatinine(Cr)≤1.5×ULN; Creatinine clearance
 ≥50ml/min;Left Ventricular Ejection Fractions(LVEF)≥50%； QTcF<450 ms;

 7. The washout period from the last time accepting any anti-tumor treatment (including
 radiation therapy, chemotherapy, hormone therapy, surgery, or molecular targeted
 therapy) to participating in this test should be 3 weeks or more.The washout period of
 oral fluorouracil should be 2 weeks or more, and that of mitomycin and
 nitrosocarbamide should be 6 weeks or more;

 8. Fertile male and female must agree to use medically approved contraceptives during the
 study and within 6 months after the last dose of the study;

 9. Female who is capable of conceiving:Blood pregnancy tests should be negative 7 days
 before the first dose; Patients cannot breastfeed, if the subject has stopped
 breastfeeding at the time of study entry, the cessation of breastfeeding must be from
 the day of first dose to more than 30 days after the last dose;

 10. The last time participate in an investigational drug study should be more than one
 month prior to the study entry;

 11. According to the judgment of the investigator, the subject has high compliance and is
 willing to complete the experiment and comply with the protocol;

 12. Voluntary participation in this clinical trial, understanding of the study procedures
 and the ability to sign informed consent forms (ICFs).

 Exclusion Criteria:

 1. There are third interstitial effusions (such as massive pleural effusion and ascites)
 which can not be controlled by drainage or other methods;

 2. Within 3 months before the first dose, grade 3 or grade 4 gastrointestinal bleeding or
 varicose bleeding and requiring blood transfusion or endoscopic or surgical
 intervention has happened;

 3. Medical history of difficulty in swallowing, malabsorption, or other chronic
 gastrointestinal disease, or conditions that may hamper compliance and/or absorption
 of the tested product;

 4. subjects with a definitely history of neurological or psychiatric disorders;

 5. Known infection with human immunodeficiency virus (HIV), hepatitis B virus(HBV), or
 hepatitis C virus (HCV);

 6. History of immunodeficiency, including HIV positive test, other acquired or congenital
 immunodeficiency disorders, organ transplantation or allogeneic bone marrow
 transplantation;

 7. Exists moderate or severe heart disease: (1) Within 6 months before the first
 dose,myocardial infarction, angina, grade III/IV congestive heart failure, pericardial
 effusion, uncontrollable severe hypertension (up to 150/90 mmHg or less) (2) ECG
 abnormalities with clinical significance: symptomatic or persistent atrial or
 ventricular arrhythmias, degree II or III atrioventricular block, bundle branch block,
 ventricular hypertrophy; (3) The echocardiogram shows significant abnormalities: For
 example, moderate or severe heart valve function defects are assessed according to the
 normal lower limit of the institution;Patients with minor or mild valve regurgitation
 (tricuspid, pulmonary, mitral, or aortic) can be included in this study (4) Laboratory
 examination shows brain natriuretic peptide or troponin T levels increases (5) Various
 factors that may increase the risk of QTcF prolonging or arrhythmia events. For
 example, hypokalemia, congenital long QT syndrome, may prolong the QT interval of
 various combined drugs, etc. (6) Predisposition factors cause the development of
 ascending aorta or aortic arch aneurysm: For example, marfan syndrome, CT records of
 the history of cardiac vascular injury; (7) History of heart or aortic surgery.

 8. Patients with central nervous system metastasis;

 9. At the beginning of the study, the unrecovered toxicity of the previous treatment
 exceeded CTCAE5.0 grade 1(except for hair loss);

 10. Previously treated with TGF-β inhibitors;

 11. According to the judgement of the researcher,there are concomitant diseases that
 seriously endanger the safety of patients or affect the completion of the study (such
 as severe hypertension, diabetes, thyroid diseases, etc.).

 12. subjects, in the opinion of the the Investigator, who are unsuitable to participate in
 the study for any other reason.