AP-L1898 Capsule in Patients With Non-small Cell Lung Cancer

"Inclusion criteria:

1. Age≥18 years, male or female;
2. Patients with histologically or cytologically confirmed locally advanced (stageIIIB/IIIC) or metastatic (stage IV) NSCLC that can not undergo radicalchemoradiotherapy;
3. Dose-escalation and dose-extension periods: failure of standard of care or intoleranceof standard of care, having received at least one or more systemic therapeuticregimens for locally advanced or metastatic disease;
4. There is clear evidence showing carrying EGFR exon 20 insertion and other rare EGFRmutations (only applicable for dose-extension and efficacy-extension periods). Thetest method can use: ARMS method for tissue or cell specimen (need to be tested innational certified laboratory), NGS method for tissue or blood specimen (need to betested in CLIA or CAP certified laboratory). Note: enrollment of patients does notneed to be confirmed by central laboratory;
5. At least one measurable lesion meeting RECIST v1.1 definition, no history of puncturebiopsy for the target lesion within the previous two weeks;
6. United States Eastern Cooperative Oncology Group (ECOG) Performance Status score 0~1;
7. Life expectancy >12 weeks;
8. Having adequate function of important organs at screening (requiring no bloodtransfusion, no use of hematopoietic stimulating factor or human albumin preparationwithin 14 days prior to screening):
9. Absolute neutrophil count (ANC) ≥1.5x109/L;
10. Platelets ≥100×109/L;
11. Haemoglobin > 90 g/L;
12. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5×upperlimit of normal (ULN) (for known liver metastasis, ≤ 5×ULN);
13. Total bilirubin ≤1.5×ULN;
14. Coagulation function INR≤1.5 ULN;
15. Serum creatinine ≤ 1.5×ULN or creatinine clearance (Ccr, calculated usingCockcroft-Gault formula) ≥45 mL/min;
16. Serum lipase and amylase ≤ 1.5 × ULN;
17. Serum pregnancy test must be confirmed as negative for women of childbearing potentialwithin 7 days prior to enrollment, who agree upon use of effective contraceptivemeasures during use of the study drug and within 6 months after the last dose. Womenof childbearing potential in this protocol is defined as sexually mature women: 1) nohysterectomy or bilateral ovariectomy, 2) uncontinuous natural menopause for 24 months (i.e., menses occurred at any time in the previous consecutive 24 months; fertilitycan not be excluded in case of amenorrhoea following cancer therapy). Male subjectswhose partners are women of childbearing potential must agree to take effectivecontraceptive measures during the use of study drug and within 6 months after the lastdose;
18. Being voluntary to participate in this study after sufficient informed consent andsign the informed consent form.

Exclusion criteria:

1. Use of any chemotherapeutic agen within 14 days prior to the first dose of AP-L1898;or the time from discontinuation of other investigational product to the use ofanticancer drug less than 5 half-lives or 28 days, whichever is shorter;
2. EGFR exon 20 insertion cohort in efficacy-extension stage: once used the drugstargeting EGFR exon 20 insertion mutation (e.g., AZD9291, TAK-788, Poziotinib,CLN-081, JNJ-372, etc.); the patients previously receiving AZD9291 for treatment ofEGFR sensitive mutation are allowed to be enrolled;
3. Ongoing use of CYP3A potent inhibitor or inducer, or discontinuation of potentinhibitor less than 5 half-lives of the drug, or discontinuation of potent inducerless than 5 half-lives of the drug or 14 days (whichever is longer) at the first doseof AP-L1898;
4. Not recovered from the adverse event induced by previous antitumor therapy atscreening (recovered to ≤ grade 1) (except alopecia);
5. Having other malignant tumors within 5 years prior to the start of treatment orsimultaneously (except radically treated non-melanoma without evidence on recurrenceof disease, including skin basal cell carcinoma or squamous cell carcinoma,breast/cervical carcinoma in situ, superficial bladder cancer and other carcinomas insitu);
6. Presence of active gastrointestinal disease or other conditions that may obviouslyaffect absorption, metabolism or excretion of drugs;
7. Patients who known to have received organ transplantation;
8. Major surgery performed within 28 days prior to the first dose. Small surgerypermitted, e.g., minimally invasive biopsy;
9. Patents with carcinomatous meningitis, spinal cord compression at present;
10. At rested state, mean corrected QT interval QTc, using Fridericia's correctionformula>450 ms in man or >470 ms in woman on electrocardiography (ECG) (repeated forthree times). A variety of clinically significant abnormalities in cardiac rhythm,conduction or morphology of resting ECG, e.g., complete left bundle branch block,degree III heart block, degree II heart block, PR interval>250 ms. Any factors thatmay increase the risk of prolonged QTc interval or risk of arrhythmic events, e.g.,heart failure, hypokalaemia, congenital long QT syndrome, family history of long QTsyndrome or unexplained sudden death under 40 years of age in lineal relatives, orongoing use of any drug known to prolong QT interval;
11. History of poorly controlled hypertension;
12. Previous history of the following diseases: interstitial lung disease, drug-inducedinterstitial lung disease, radiation pneumonitis requiring steroid therapy, activeinterstitial lung disease with clinical evidence;
13. Patients with active brain metastasis, if the CNS metastasis is only limited tosupratentorial area or cerebellum that has been adequately treated (surgery orradiotherapy) and radiologically stable for at least 4 weeks, and no corticosteroid isneeded to control symptoms, the patients will be allowed to be enrolled;
14. In acute infection phase and requiring pharmacotherapy;
15. HBV DNA≥103 copies/mL or ≥200 IU/mL when the hepatitis B surface antigen is positiveor hepatitis B core antibody is positive;
16. HCV-RNA > the upper limit of reference at the site when hepatitis C antibody ispositive;
17. Human immunodeficiency virus (HIV) antibody positive;
18. Patient with a previous history of clear mental disorder and taking drugs fortreatment;
19. Patient with a history of drug abuse or drug taking;
20. Pregnant or lactating women;
21. Presence of other factors that may possibly affect the study results, interfere withtheir participation in the entire study, including previous or current physicalcondition (e.g., ocular disease, including corneal ulcer, conjunctivitis, etc.),treatment or laboratory examination abnormality, unwillingness to comply with eachprocedure, restriction and requirement in the study, as considered by investigators. A limited list of criteria for selection of participants in the clinical study, provided interms of inclusion and exclusion criteria and suitable for assisting potential participantsin identifying clinical studies of interest. Use a bulleted list for each criterion belowthe headers ""Inclusion Criteria"" and ""Exclusion Criteria"". (Limit: 15,000 characters.)"