A Study of XZP-3621 in Chinese Patients With ALK Positive NSCLC

A Phase II, Multi-center, Open-label, Single-Arm Study to Evaluate the Efficacy and Safety of Oral XZP-3621 Treatment for Chinese Patients With ALK-Positive Non-Small Cell Lung Cancer

This was a single-arm, open-label, multicenter, phase II study to evaluate the efficacy and safety of the ALK inhibitor XZP-3621 when used as single agent in patients with ALK-rearranged stage IIIB, IIIC or IV NSCLC previously treated with other ALK inhibitors or non-previously treated.

This is a Phase 2, China only, multi center, open label, three cohorts study, in ALK positive locally advanced or metastatic NSCLC patients will be enrolled to receive XZP-3621 monotherapy.

(in Cohort 1) Treatment-Naive with any ALK inhibitor. (in Cohort 2) Disease progression after crizotinib as the only ALK inhibitor. (in Cohort 3) Disease progression after other ALK inhibitors,including or not including crizotinib previously treated.

The patients will receive XZP-3621 at 500 mg orally once daily (QD), taken with food.Patients will be treated until disease progression, unacceptable toxicity, withdrawal of consent, or death, whichever occurred first. After disease progression (as per RECIST v1.1), patients should discontinue the study medication. After disease progression, patients will be treated at the discretion of the investigator according to local practice. Information regarding the nature and the duration of subsequent therapies will be collected.

Inclusion Criteria:

1. Patients must be 18-75 years-of-age;

2. Patients with Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB and IIIC not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive where ALK status is determined by Ventana immunohistochemistry (IHC) test or FISH or PCR or NGS,Sufficient tumor tissue available to perform ALK status is required if not determined.

3. Subject should have:

   (in Cohort 1) Treatment-Naive with any ALK inhibitor. (in Cohort 2) Disease progression after crizotinib as the only ALK inhibitor. (in Cohort 3) Disease progression after other ALK inhibitors,including or not including crizotinib previously treated.

4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 to 2;

5. All Subjects must have at least 1 measurable extracranial target lesion according to RECIST v1.1 that has not been previously irradiated.

6. CNS metastases are allowed if:

   1. Asymptomatic: either untreated and not currently requiring corticosteroid treatment, or
   2. Previously diagnosed and treatment has been completed with full recovery from the acute effects of radiation therapy or surgery prior to enrollment, and if corticosteroid treatment for these metastases has been withdrawn for at least 4 weeks with neurological stability.
   3. Such cases are not be allowed,such as leptomeningeal disease (LMD) or carcinomatous meningitis (CM) if visualized on magnetic resonance imaging (MRI), or if baseline CSF positive cytology is available .

7. Have recovered from toxicities related to prior anticancer therapy to national cancer institute common terminology criteria for adverse events (NCI CTCAE) v5.0 grade less than or equal to (<=)2. (Note: treatment-related alopecia and AEs that in the investigator's judgment do not constitute a safety risk for the subject are allowed.)

8. Prior chemotherapy and radiotherapy (other than palliative) must be completed at least 4 weeks prior to initial administration; Palliative radiotherapy must be completed 1 week prior to initial administration.

9. Patients treated with any ALK inhibitor must be discontinued for ≥5 half-life or 14 days, whichever is longer, before XZP-3621 tablets are first administered;

10. Life expectancy of at least 12 weeks;

11. Adequate organ system function, defined as follows:

    1. Absolute neutrophil count (ANC) ≥1.5 x 109/L; Platelets ≥100 x 109/L;Hemoglobin ≥9 g/dL (≥90 g/L)
    2. Total bilirubin ≤1.5 times the upper limit of normal (ULN);Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 *ULN if no liver involvement or ≤5 * ULN with liver involvement.
    3. Creatinine < 1.5 *ULN. If >1.5 * ULN, patient may still be eligible if calculated creatinine clearance >50 mL/min (0.83mL/s) as calculated by the Cockcroft-Gault method.

12. Serum pregnancy test (for females of childbearing potential) negative at screening.

13. Ability to understand the nature of this trial and give written informed consent.

Exclusion Criteria:

• Patients who meet any of the following criteria will be excluded from study entry:

  1. Combined with small cell lung cancer;

  2. Uncontrolled malignant pleural/peritoneal effusion and/or pericardial effusion (uncontrolled means that the effusion increases significantly within one week after extraction and has obvious symptoms requiring further puncture or other intervention) ;

  3. Patients with a previous malignancy within the past 5 years are excluded (other than curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by endoscopic resection, in situ carcinoma of the cervix.);

  4. Previous treatment history of organ transplantation, hematopoietic stem cell or bone marrow transplantation;

  5. Patient has had major surgery within 4 weeks prior (2 weeks for resection of brain metastases) to the first dose of study drug or has not recovered from side effects of such procedure;

  6. Active and clinically significant bacterial, fungal, or viral infection including hepatitis B virus (HBV) or hepatitis C virus (HCV) (eg, in case of known HBsAg or HCV antibody positivity);

  7. Known human immunodeficiency virus (HIV);

  8. Clinically active infections affecting the safety of subjects, including active tuberculosis;

  9. Uncontrolled hyperglycemia;

  10. Subject with predisposing characteristics for acute pancreatitis according to investigator judgment, including but not limited to current gallstone disease,history of pancreatitis or history of increased amylase or lipase that was due to pancreatic disease within 28 days of initial administration;

  11. Subject with uncontrolled electrolyte disturbances (e.g., low calcium, low magnesium, or hypokalemia) that are identified by investigator;

  12. Unable to swallow;

  13. History of extensive, disseminated, bilateral or presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis and pulmonary fibrosis;

  14. Clinically significant vascular (both arterial and venous) and non-vascular cardiac conditions, (active or within 3 months prior to enrollment), which may include, but are not limited to:

      1. Arterial disease such as cerebral vascular accident/stroke (including Transient Ischemic Attack -TIA), myocardial infarction, unstable angina;
      2. Venous diseases such as cerebral venous thrombosis, symptomatic pulmonary embolism;
      3. Non-vascular cardiac disease such as congestive heart failure (New York Heart Association Classification Class ≥ II), second-degree or third-degree AV block (unless paced) or any AV block with PR >220 msec; or ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 bpm (unless patient is otherwise healthy such as long-distance runners, etc.), machine-read Electrocardiogram (ECG) with QTc >470 msec, or congenital long QT syndrome;

  15. Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 150 mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 95 mm Hg;

  16. Patient has impairment of GI function or GI disease that may significantly alter the absorption of XZP-3621 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome);

  17. Patient receiving treatment with medications that meet one of the following criteria and that cannot be discontinued at least 14 days prior to the start of treatment with XZP-3621 and for the duration of the study;

      • Strong inhibitors or strong inducers of CYP3A4.
      • Medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes.

  18. Participation in other studies involving investigational drug(s) within 28 days prior to study entry and/or during study participation;

  19. Pregnant female patients; breastfeeding female patients;

  20. History of hypersensitivity to any of the additives in the XZP-3621 or crizotinib drug formulation;

  21. Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior;

  22. laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator and/or the sponsor, would make the subject inappropriate for entry into this study.