Study of SYH2039 in Participants with Advanced Solid Tumors

This is a Phase 1, open-label, multicenter, dose escalation and expansion study of the safety, PK, PD and preliminary anti-tumor activity of SYH2039 in adult patients with selected advanced or metastatic advanced solid tumors who are unresponsive to standard of care therapy. SYH2039 is a small molecule inhibitor of methionine adenosyltransferase 2 alpha (MAT2A).


Eligibility Criteria:
Inclusion Criteria:

* 1. Aged ≥ 18 years (whichever is the day of signing the informed consent form (ICF)); 2. Histologically or cytologically confirmed advanced malignancies, the enrolled population in each phase of the study should meet the following requirements:

  1. Phase Ia dose escalation stage: advanced malignancies (MTAP-deleted advanced solid tumors are preferentially included);
  2. Phase Ia dose escalation phase backfill cohort and Phase Ib cohort expansion phase: tumors with MTAP deletion \[including but not limited to NSCLC, gastric adenocarcinoma (including adenocarcinoma of the gastroesophageal junction), esophageal cancer, bladder cancer, pancreatic cancer, mesothelioma, and other possible types of tumors\]; 3. Failure of adequate standard of care or no effective standard of care (Note: Treatment failure includes disease progression or intolerance of toxic side effects during or after treatment, as evidenced by medical records or imaging data); 4. Subjects enrolled in the Phase Ia Dose Escalation Phase Backfill Cohort and Phase Ib Cohort Expansion Phase require confirmation of MTAP deletion in tumor tissue by a central laboratory (NGS assay and/or IHC and/or FISH assay in tumor tissue from the central laboratory).

     5. At least one measurable lesion per RECIST 1.1 criteria; 6. Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1; 7. Life expectancy of ≥ 3 months; 8. Adequate organ and bone marrow function, laboratory results must meet the following criteria (no blood transfusion or hematopoietic stimulating factor therapy within 14 days):

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  1. Neutrophil count (ANC) ≥ 1.5 × 10\^9/L;
  2. Platelet count (PLT) ≥ 100 × 10\^9 /L;
  3. Hemoglobin (Hb) ≥ 90 g/L;
  4. Albumin (ALB) ≥ 30 g/L;
  5. Creatinine (SCr) ≤ 1.5 × ULN and creatinine clearance (Ccr) ≥ 50 mL/min (calculated by Cockcroft-Gault formula);
  6. Total bilirubin (TBIL) ≤ 1.5 × ULN, and for subjects with metastases to liver or hepatic cancer TBIL ≤ 3 × ULN;
  7. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5 × ULN for subjects with metastases to liver or hepatic cancer);
  8. Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN, international normalized ratio (INR) ≤ 1.5 × ULN; 9. Eligible subjects of childbearing potential (males and females) must agree to use reliable methods of contraception (hormonal contraceptives, barrier methods, or abstinence) with their partner during the study and for at least 6 months after the last dose. Women of childbearing potential must have a negative blood pregnancy test within 7 days prior to enrollment; 10. Subjects are fully informed about the study and voluntarily sign a written ICF.

Exclusion Criteria:

* 1. History of other malignancies or concurrent active malignancies within 3 years (subjects with localized tumors that have been cured, such as basal cell carcinoma of skin, squamous cell carcinoma of skin, superficial bladder cancer, carcinoma in situ of prostate, carcinoma in situ of cervix, carcinoma in situ of breast, etc., could be enrolled); 2. Subjects with bleeding tendency; those with active bleeding, hemoptysis, or history of major bleeding within the past 6 months; those who have imaging (CT or MRI) results showed that the tumor had invaded important blood vessels or were judged by the investigator to be highly likely to invade important blood vessels during the subsequent study, resulting in fatal major hemorrhage; 3. Subjects with active leptomeningeal lesions or uncontrolled brain metastases. (Subjects with suspected or confirmed brain metastases may be enrolled as long as they are asymptomatic and do not require treatment (eg, radiotherapy, surgery, or corticosteroid therapy) to control symptoms of brain metastases. For subjects with brain metastases requiring treatment, subjects with stable symptoms after treatment (no hormone maintenance therapy, no symptoms of brain metastases) for 2 weeks may be enrolled); 4. Subjects with conditions that, as judged by the investigator, seriously affect the absorption, distribution, metabolism and excretion of drugs (e.g., inability to swallow drugs orally, active inflammatory bowel disease, chronic diarrhea with intestinal malabsorption, refractory nausea and vomiting, intestinal obstruction, need for long-term parenteral nutrition treatment, etc.); 5. Subjects had previously received MAT2A inhibitors (e.g. AG-270, IDE397, S095033, etc.); 6. Adverse events of prior anti-tumor therapy have not recovered to ≤ Grade 1 as assessed by CTCAE V5.0 (except for toxicities judged by the investigator as no safety risk such as alopecia); 7. Subjects received any anti-tumor therapy (including chemotherapy, targeted therapy, immunotherapy, etc.) within 4 weeks or 5 half-lives (whichever is shorter) before the first dose of the investigational medicinal product, or any traditional Chinese medicinal products with anticancer activity approved by NMPA (regardless of cancer type) within 2 weeks prior to the first dose of the investigational medicinal product; 8. Subjects who are participating in another clinical study, except for observational (non-interventional) clinical studies, or in the follow-up period of an interventional clinical study; 9. Subjects who have undergone major surgery or invasive intervention within 4 weeks prior to the first dose, or have planned to undergo systematic or local tumor resection during the study; 10. Known severe allergic reactions to the study drug or other ingredients or excipients in the formulation; 11. Subjects with active microbial, fungal, or viral infection (defined as requiring intravenous antimicrobial, antifungal, or antiviral drug therapy) prior to the first dose. Subjects who have no clinical manifestations of active infection before the first dose and are given prophylactic treatment for infection may be considered for enrollment; 12. As judged by the investigator,subjects with uncontrolled serous effusion (e.g., pleural effusion, ascites, pericardial effusion, etc.); 13. History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation; 14. History of immunodeficiency, including positive HIV antibody test; 15. Subjects with active hepatitis B (hepatitis B surface antigen (HBsAg) or HBcAb test positive and active hepatitis B (HBV-DNA ≥ 10\^4 cps/mL or ≥ 2000 IU/mL) at screening); hepatitis C (subjects with a positive hepatitis C antibody (Anti-HCV) test and a positive PCR test for HCV RNA); 16. History of severe cardiovascular diseases, including but not limited to:

  1. Severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmia requiring clinical intervention, degree II-III atrioventricular block, etc.;
  2. Subjects with electrocardiogram QT/QTc interval prolongation at screening (QTcF \> 480 ms, Fridericia formula: QTcF = QT/(RR \^ 0.33), RR = 60/heart rate), using any concomitant medication known to prolong the QT interval;
  3. Subjects with acute coronary syndrome, congestive heart failure, stroke, or other Grade 3 or higher cardiovascular events within 6 months prior to the first dose;
  4. New York Heart Association (NYHA) functional class ≥ III or left ventricular ejection fraction (LVEF) \< 50%;
  5. Subjects with uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg at screening); 17. Subjects who have received strong inducers or strong inhibitors of CYP3A4 and CYP1A2 enzymes, moderate inhibitors or moderate inducers of CYP3A4 enzymes within 2 weeks prior to the first dose; Subjecrs who have continously received systemic corticosteroids dosage (\> 10 mg/day prednisone or equivalent within 2 weeks before the first time of dosing; Low doses of corticosteroids, such as prednisone ≤10mg per day or equivalent, were allowed if doses were stable for 4 weeks); 18. Presence of alcohol or drug abuse or dependence and other conditions that interfere with the interpretation of the study results, or the presence of psychotic disorders and other conditions that affect study compliance; 19. Pregnant or lactating women; 20. Subjects that are considered ineligible for this study by the investigator for other reasons.