A Phase I Study of XZP-3621 in Chinese Patients With ALK or ROS1 Rearrangement Non-small Cell Lung Cancer

Inclusion Criteria:

1. Male or female subjects aged 18-75 years (including 18 and 75 years);

2. Stage IV NSCLC or Stage IIIB and IIIC NSCLC that cannot be treated with radicalradiotherapy(IASLC); Dose escalation: ALK rearrangement or ROS1 rearrangementpositive, the test specimen and method is not limited;Patients were required to haveexperienced treatment failure or disease progression after prior ALK inhibitortherapy or were unable to afford ALK inhibitors, regardless of other previousanti-tumor therapies. Dose expansion: ALK rearrangement or ROS1 rearrangement was confirmed by nationallyapproved Ventana immunohistochemistry or FISH or RT-PCR. There is no restriction onthe number and type of antitumor therapy previously received; There is no limit totest time, test unit/kit and test specimen; Prior treatment was not limited,regardless of prior treatment with or without other antitumor therapy.

3. Dose escalation: ECOG score 0-1; Dose expansion: ECOG score 0-2;

4. Dose expansion: Subjects must have at least one measurable target lesion as definedby RECIST V1.1 and the lesion has not previously been treated with radiation or hashad significant disease progression after radiation therapy;

5. All acute toxicities from prior anti-cancer treatment or complications/sequelae fromsurgical procedures are resolved to baseline or ≤ grade 1 (CTCAE V5.0, hair loss orother toxicities deemed by the investigator to pose no safety risk to the subject);

6. All previous antitumor therapies (including chemotherapy, radiotherapy andimmunotherapy) have been stopped for at least 4 weeks before the firstadministration of XZP-3621 (in which nitrosoreas or mitomycin should be stopped for≥ 6 weeks, and oral small molecule targeted therapy drugs and Chinese medicine (including decoction or Chinese patent medicine) should be stopped for at least 2weeks);Palliative radiation therapy (irradiation of non-target lesions, localadministration of non-target lesions) for the purpose of relieving local symptomswas allowed to be completed one week before study enrollment;

7. The expected survival was determined by the investigator to be 12 weeks or more;

8. At the time of enrollment, the subject's organ function at baseline was good, andthe laboratory data met the following criteria:

9. Blood routine: Absolute Neutrophils Count≥1.5109/L、PLT≥90109/L、HGB≥90g/L;

≤1.5 * ULN；ALT and AST≤3 * ULN；ALT andAST ≤5*ULN (Liver metastases subjects);

3. Renal function: CrCl≥50 mL/min /1.73 m2（≥0.835mL/s, according toCockcroft-Gault formula;

4. AMS≤ULN (If AMS is elevated, between 1 and 2 times of ULN, but there are noother signs and clinical evidence of pancreatic disease, the subject can beincluded);

5. HbA1c≤ 7.0%;

6. The fertile male or female subject must agree to use an effective contraceptivemethod, such as a double-screen contraceptive method, a condom, oral or injectablecontraceptive, an intrauterine device, etc. during the study period and within 90days of the last dose of XZP-3621.

7. The subject has fully understood the study and signed the informed consentvoluntarily.

Exclusion Criteria:

1. Subjects with primary CNS tumors or symptoms of brain metastases (except those withtreated or untreated asymptomatic CNS metastases who had not been treated withcorticosteroids for 2 weeks prior to enrollment, stereotactic radiotherapy for 1week, and whole brain radiotherapy for 2 weeks prior to enrollment);

2. subject with small cell lung cancer;

3. Malignant thoracic cavity/peritoneal cavity effusion and/or pericardial effusionthat cannot be controlled in the dose extension study;

4. Prior diagnosis of any other malignancy within 3 years prior to enrollment exceptfor adequately treated and stable basal cell carcinoma or squamous skin cellcarcinoma or carcinoma in situ of the cervix;

5. Subject has history of hematopoietic stem cell or bone marrow transplantation;

6. Subject has history of pancreatitis;

7. A history of cerebrovascular accident, including transient ischemic attack orstroke, within 6 months prior to enrollment;

8. Major surgery (defined as surgery under general anesthesia or surgery withsignificant incisions) or unresolved postoperative complications prior toadministration of XZP-3621 within 4 weeks prior to enrollment;

9. Chronic Hepatitis B(HBV), or/and HBV DNA>500 IU/ml, Hepatitis C(HCV);

10. known human immunodeficiency virus (HIV);

11. Body temperature is above 37.5℃ or significant active infections that can influencethe clinical study, including active tuberculosis;

12. Uncontrollable electrolyte disturbances, such as low calcium, low magnesium, and lowkalemia, may affect the elongation of QTc;

13. Unable to swallow;

14. History of large area diffusion/double pulmonary fibrosis, or known grade 3 or 4pulmonary fibrosis, or current with clinically significant active pulmonarydiseases, including pneumonia, allergic pneumonia, interstitial pneumonia and otherinterstitial lung diseases, and bronchiolitis oblationus, currently suffering fromradiation pneumonia requiring hormone therapy, but not includ a history of previousradiation pneumonia;

15. Subjects with impaired heart function or clinically significant heart disease;

16. Clinically significant gastrointestinal abnormalities, including active ulcerativecolitis, chronic diarrhea due to intestinal malabsorption, Crohn's disease, and/orprior surgery affecting absorption;

17. Any serious and/or uncontrolled comordities that the investigator believes mayinterfere with the study assessment, such as uncontrolled hypertension (defined assystolic blood pressure ≥140mmHg and/or diastolic blood pressure ≥90mmHg at rest)and clinically significant neurological disorders;

18. Subjects are receiving drugs known to strongly inhibit or induce CYP3A4 and shouldnot stop taking them one week before administration XZP-3621 and during the studyperiod (or within the five half-lives of the drug, whichever is longer);

19. The subject is scheduled for surgery, or the investigator determines that thesubject needs surgery;

20. Participation in any other clinical trial within 1 month prior to enrollment (exceptthose who had been removed from other clinical studies and only had survivalfollow-up);

21. Allergic constitution or a history of severe allergies;

22. Pregnant women and breastfeeding women;

23. Other conditions that the investigator considered unsuitable for inclusion.