Dose Escalation and Expansion Study of SYH2043 in Patients With Advanced Malignant Tumors

The aim of this study is designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of SYH2043 in patients with advanced malignant tumors.

This study is an open-label, single-arm, multi-center Phase I clinical study, which includes four stages:

A: Dose-escalation Stage: The dose escalation stage is divided into 5 dose levels, and a Bayesian Optimal Interval Design (BOIN) including accelerated titration will be used for dose escalation.

B: PK Expansion Stage: Two or three dose groups will be selected for PK expansion; After PK extension the cohort extension study will be conducted as required, and will include 4 cohorts according to the tumor types.

C: Combination dose Escalation: This study will use a 3+3 design with up to 2 dose escalation cohorts at increasing levels.

D: According to the results of stage C, 1-2 combination doses will be selected for combination dose expansion, and Simon 2 stage was adopted for the expansion stage.

Eligibility Criteria:
Inclusion Criteria:

* 1. Patients aged 18-75 years (inclusive);
* 2. Histological or cytological confirmation of advanced malignant tumors;
* 3. Patients who failed or were intolerant to standard treatment or had no standard treatment, and meet the criteria as below of the corresponding stages:

  * Part A and PK Expansion Stage of part B: advanced malignant tumors;
  * Cohort extension of part B: solid tumors such as locally advanced/metastatic breast cancer, relapsed/refractory ovarian cancer, locally advanced/metastatic liver cancer, etc;
  * Part C and D: locally advanced/metastatic breast cancer with histological confirmation of ER+, HER2-;
* 4. With at least one measurable lesion according to RECIST v1.1;
* 5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1;
* 6. Life expectancy greater than 3 months;
* 7. Main organs meet the following criteria within 7 days before treatment:

  * Hematology: no component blood transfusion, human granulocyte colony-stimulating factor (G-CSF), and erythropoietin (EPO) within 2 weeks prior to the investigational drug administration
  * Absolute neutrophil count (ANC) ≥1.5×10\^9/L;
  * Platelet count (PLT) ≥90×10\^9/L;
  * Hemoglobin (HGB) ≥90 g/L or ≥5.6 mmol/L;
  * Renal Function: Serum creatinine ≤ 1.5×ULN or creatinine clearance rate ≥ 50 mL/min;
  * Liver function: Total bilirubin (TBIL) ≤ 1.5×ULN, or ≤ 3×ULN for patients with Gilbert syndrome; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)≤ 2.5×ULN, or ≤ 5×ULN in case of liver metastases;
  * Coagulation Function: Activated partial thromboplastin time (APTT)≤ 2×ULN; International normalized ratio (INR)≤ 2×ULN;
* 8. The serum pregnancy test for women of childbearing potential (WOCBP) is negative within 7 days prior to the first dose of the investigational drug. Patient and his/her spouse must agree to take adequate contraception from signing of ICF to 6 months after the last dose, during which women should be non-lactating and men should refrain from donating sperms;
* 9. Patients voluntarily participate in this clinical study, understand the study procedures and sign the ICF.

Exclusion Criteria:

* 1. Have received anti-tumor treatments such as chemotherapy, radiotherapy, endocrine therapy, targeted therapy, immunotherapy, etc. within 4 weeks before the first dose of the investigational drug;
* 2. Have received other unmarketed clinical investigational drugs or treatments within 4 weeks before the first dose of the investigational drug;
* 3. Have received major surgery (excluding needle biopsy), or severe unhealed wounds, trauma, etc. within 4 weeks before the first dose of the investigational drug in the study;
* 4. Have received glucocorticoids for systemic therapy over 7 days (Prednisone\>10 mg/day or equivalent doses) or other immunosuppressant within 2 weeks before the first dose of investigational drug, and patients who need long-term use these therapies;
* 5. Have received potent inhibitors or inducers of CYP3A4 and inhibitors of P-gp within 1 weeks before the first dose of the investigational drug;
* 6. The adverse events due to previous anti-tumor treatments without recovering to Grade 1 (except for alopecia; some toxicities may be excluded as judged by the investigator) according to NCI-CTCAE v5.0;
* 7. Breast cancer patients with visceral crisis or symptomatic visceral metastasis;
* 8. With active central nervous system (CNS) metastasis and/or cancerous meningitis;
* 9. Active HBV or HCV infection (HbsAg positive and/or HBcAb positive with HBV DNA ≥ 2000 IU/mL, and HCVAb positive with HCV RNA positive), or HIV positive;
* 10. Participants with a history of severe cardiovascular disease;
* 11. Inability to swallow medications orally, or conditions that, in the judgment of the investigator, significantly affect gastrointestinal absorption;
* 12. Patients who have received a live attenuated vaccine within 2 weeks before the first use of the investigational drug or plan to receive during the study;
* 13. Other situations that the investigator considers not suitable for participating in the clinical study.