ATRIUM: This trial is assessing the safety and effectiveness of ATG-018 treatment in people with advanced cancer, including some types of blood cancerA Phase I, Open-Label, Multi-Center, Dose Finding Study to Investigate the Safety, Pharmacokinetics, and Preliminary Efficacy of ATG-018 (ATR Inhibitor) Treatment in Patients With Advanced Solid Tumors and Hematological Malignancies

Exclusion

• Subjects meeting any of the following exclusion criteria are not eligible to enroll in this study:

  1. Central nervous system (CNS) metastatic disease, leptomeningeal disease, or metastatic cord compression.
  2. Prior treatment with ATR inhibitor.

  3. Subjects with B-NHL in the condition as below:

     1. DLBCL with MALT lymphoma.
     2. Composite lymphoma (Hodgkin's lymphoma + NHL).
     3. Primary mediastinal (thymic) large B-cell lymphoma.
  4. Prior therapy with any other investigational product or anticancer systemic therapy including chemotherapy, immunotherapy, or other anticancer agents within 21 days (or within a period during which the investigational product or systemic anticancer treatment has not been cleared from the body, eg, a period of 5 'half-lives') of the first dose of study treatment, whichever is the most appropriate as judged by the investigator.
  5. Radiotherapy with a wide field of radiation within 28 days, or radiotherapy with a limited field of radiation for palliation within 14 days of the first dose of study treatment. Subject must have recovered from all radiation related toxicity, not requiring corticosteroids.
  6. Prior major surgery (excluding placement of vascular access) within 28 days of the first dose of study treatment or minor surgical procedures ≤7 days. No waiting is required following implantable port and catheter placement.
  7. Subjects receiving unstable or increasing doses of corticosteroids. For patients receiving corticosteroids for endocrine deficiencies or symptoms associated to their disease (excluding central nervous system disease), the dose must have been stabilized (or reducing) for at least 14 days before the first dose of study treatment.
  8. As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension defined as a blood pressure (BP) ≥150/95 mmHg despite medical therapy, unstable or uncompensated respiratory and renal disease, active bleeding diseases, allogeneic stem cell transplantation, or any solid organ transplant.
  9. Have active or previous autoimmune diseases that are likely to recur (such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroid disease, vasculitis, and psoriasis), or are at risk of such diseases.
  10. Poorly controlled of pleural effusion or pericardial effusion (with clinical symptoms, fluctuation of effusion or need for repeated drainage, oral diuretics, etc) at screening. Ascites that can be detected on physical examination, or clinical symptoms caused by ascites, or that require special treatment, such as repeated drainage, intraperitoneal drug infusion, etc, at screening (Subjects with a small amount of ascites that can only be detected by imaging examination can be considered for inclusion).
  11. Active infection including hepatitis B, and/or hepatitis C (HBV-DNA or HCV-RNA detected above lower limit of normal [LLN] by local laboratory, respectively).
  12. Known history of human immunodeficiency virus (HIV) infection.
  13. Active infection requiring parenteral antibiotics, antivirals, or antifungals within 14 days prior to C1D1; however, prophylactic use of these agents is acceptable (including parenteral).
  14. Autologous stem cell transplant < 6 months or CAR-T cell infusion < 6 months prior to C1D1.
  15. History of allogeneic stem cell transplant.

  16. Impaired cardiac function or clinically significant cardiac diseases, including any of the following:

      1. Unstable angina or acute myocardial infarction ≤3 months prior to C1D1.
      2. Clinically significant heart disease (eg, symptomatic congestive heart failure with New York Heart Association Grade 3 or above).
      3. Uncontrolled arrhythmia, or hypertension; history of labile hypertension or poor compliance with an antihypertensive regimen.
      4. Baseline left ventricular ejection fraction (LVEF) below institution's LLN or <50% if assessed by echocardiogram (ECHO), or baseline LVEF below institution's LLN if assessed by multiple gated acquisition scan (MUGA).

  17. Inadequate bone marrow reserve (within 14 days) or organ function as demonstrated by any of the following laboratory values:

      1. Absolute neutrophil count <1.5 × 109/L
      2. Platelet count <100 × 109/L
      3. Hemoglobin <90 g/L Please note that platelet transfusions within 7 days, red blood cell transfusions within 14 days, hematopoietic growth factors within 7 days (G-CSF or erythropoietin) are not permitted prior to obtaining these laboratory values.
      1. Alanine aminotransferase (ALT) >2.5 times the upper limit of normal (ULN)
      2. Aspartate aminotransferase (AST) >2.5 times ULN
      3. Total bilirubin >1.5 times ULN
      4. Creatinine >1.5 times ULN concurrent with creatinine clearance <50 mL/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is >1.5 times ULN
      1. Serum albumin <30 g/L
      2. Coagulation: international normalized ratio (INR) >2.0, prothrombin time (PT) >1.5×ULN
  18. Subject inability or unwillingness to comply with requirement for oral drug administration or presence of a gastro-intestinal condition, eg, refractory nausea and vomiting, any acute or chronic gastrointestinal disease, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of ATG-018.
  19. History of hypersensitivity to any excipient of ATG-018 or these medicinal products or history of allergic reactions attributed to drugs with a similar chemical structure or class to ATG-018.
  20. Any chronic or uncontrolled dermatological condition that will be adversely impacted by the potential skin toxicity of the study treatment(s).
  21. Judgment by the investigator that the subject should not participate in the study if the subject is unlikely to comply with study procedures, restrictions, and requirements.
  22. Other primary malignancies developed within 2 years prior to the first administration of the study drug, except locally curable malignancies after radical treatment (such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast, etc).
  23. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
  24. Subjects was in receipt of any live attenuated vaccination within 30 days prior to the first dose of study treatment.
  25. History or current evidence of any condition or disease that could confound the results of the study or, in the opinion of investigator, is not in the best interest of the subject to participate.