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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetic Profile and Preliminary Efficacy of SYH2043 in Patients With Advanced Malignant Tumors

Conditions
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Advanced Malignant Tumors

Intervention / Treatment
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* Drug: SYH2043


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SYH2043<br>Patients will receive SYH2043 once everyday on day 1-21 of each 28-day cycle | Drug: SYH2043<br>* Patients will receive SYH2043 once everyday on day 1-21 of each 28-day cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AE | Occurrence and frequency of Adverse Event | Up to approximately 3 years | 
| SAE | Serious Adverse Event | Up to approximately 3 years | 
| DLT | Dose-limiting Toxicity (DLT) | At the end of Cycle 1 (each cycle is 28 days) | 
| MTD | The maximum tolerated dose (MTD) (if available) | At the end of Cycle 1 (each cycle is 28 days) | 
| RP2D | Recommended phase 2 dose (RP2D) in stage A | At the end of Stage A (approximately 1 year) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC | Area under the plasma concentration versus time curve (AUC) | Up to approximately 3 years | 
| Cmax | Peak Plasma Concentration (Cmax) | Up to approximately 3 years | 
| t1/2 | Half-life (t1/2) | Up to approximately 3 years | 
| Tmax | Time to peak drug concentration (Tmax) | Up to approximately 3 years | 
| Vz/F | Apparent volume of distribution | Up to approximately 3 years | 
| CL/F | Apparent clearance | Up to approximately 3 years | 
| pRb | Explore the relationship between phosphor-retinoblastoma protein (pRb) and efficacy | Up to approximately 3 years | 
| ORR | Objective Response Rate | Up to approximately 3 years | 
| PFS | Progression-free Survival | Up to approximately 3 years | 
| OS | Overall Survival | Up to approximately 3 years | 
| DoR | Duration of Response (DoR) | Up to approximately 3 years | 
| DCR | Disease Control Rate (DCR) | Up to approximately 3 years |