A Study of HMPL-295S1 in Patients With Advanced Malignant Solid Tumors

Exclusion Criteria

• •The patients can not participate in this study if any of the following conditions is met:
• •1. Previous antitumor therapy meeting any of the following:
• •1. Previous treatment with a ERK inhibitor and having PD;
• •2. Receiving approved systematic antitumor therapy within 4 weeks prior to the first dose, including chemotherapy, targeted therapy, immunotherapy, biotherapy, etc. (elution for two weeks for hormone therapy or treatment with traditional Chinese medicine and Chinese patent drug with clear antitumor indication);
• •3. In the treatment period of other interventional clinical study (including small molecular chemical drug and macromolecular antibody) within 4 weeks prior to the first dose. Patients can be enrolled in this study if they are involved in non-interventional clinical study (e.g., epidemiological study); and can also be enrolled if they stay in the survival follow-up period of one interventional clinical study.
• •4. Having received major surgery or radical radiotherapy (except for the palliative radiotherapy for bone metastasis) within 4 weeks prior to the first dose.
• •2. Toxicity associated with previous antitumor therapy (including surgery, chemotherapy, radiotherapy, targeted therapy and immunotherapy) not recovered to ≤ CTCAE grade 1, except for alopecia and peripheral neuropathy. The peripheral neurotoxicity needs to be recovered to ≤ CTCAE grade 2 in the patients who have been previously treated with platinum;
• •3. Patients with central nervous system (CNS) malignant tumor or malignant solid tumor with known CNS metastasis;
• •4. Combined with other malignant tumor or having a history of other malignant tumor within 2 years prior to study screening (not including the basal or squamous cell carcinoma of skin, non-melanoma skin cancer, papillary thyroid carcinoma that have been appropriately treated, or radically resected cervical carcinoma in situ and ductal carcinoma in situ);
• •5. Known history of clinically significant liver disease, including viral or other hepatitis, except the following patients:
• •* HBsAg positive patients can be enrolled if the polymerase chain reaction (PCR) test of hepatitis B virus (HBV) DNA is negative. The investigator can provide preventive or therapeutic antiviral therapy based on patient's condition and diagnostic routines during study treatment;
• •* Patients with positive hepatitis C virus (HCV) antibody can be enrolled if the PCR test of HCV RNA is negative.
• •6. Patients infected by human immunodeficiency virus (HIV);
• •7. Presence of active bacterial, fungal or viral infection requiring systematic treatment within one week prior to the first dose;
• •8. Use of CYP3A potent inducer within 2 week or 5 half-lives (whichever is longer, 3 weeks needed for St. John's wort) prior to the first dose, see (Appendix 5);
• •9. Use of CYP3A, P-gp potent inhibitor or sensitive substrate of P-gp, BCRP, MATE 2-K, CYP3A, CYP2C8/OATP1B1 and CYP2D6/CYP3A within one week or three half-lives (whichever is longer) prior to the first dose, this exclusion criterion will be adjusted in accordance with the actual dose of HMPL-295S1 and determined plasma concentration during the clinical study (see Appendix 5);
• •10. Meeting any of the following criteria for cardiac examination:
• •* Hereditary long QT syndrome or QTcF\>480 msec (the formula is seen in Appendix 10), or currently taking the drugs that are known to prolong QT interval or lead to torsade de pointe arrhythmia (Appendix 6);
• •* Serious arrhythmia or conduction abnormality requiring clinical intervention;
• •* Impaired cardiac function or clinically significant cardiac disease, including but not limited to the acute myocardial infarction, unstable angina pectoris, coronary artery bypass grafting, New York Heart Association (NYHA, see Appendix 9) evaluated Grade III/IV congestive heart failure, left ventricular ejection fraction (LVEF) \<50%, or uncontrollable hypertension within 6 months prior to enrollment.
• •11. Pregnant or lactating women;
• •12. Having multiple factors affecting absorption, distribution, metabolism or excretion of oral drugs, e.g., inability to swallow, frequent vomiting, chronic diarrhea, etc.;
• •13. Currently known or previous retinopathy;
• •14. Any other disease, metabolic abnormality, physical examination abnormality or clinically significant laboratory examination abnormality, one disease or state that may affect patient's compliance or provides a reason to suspect that the patient is not suitable to use the study drug, or will affect interpretation of the study results, or bring the patient at a high risk, according to investigator's judgment.