A Study of Lorlatinib in ALK Inhibitor-Treated ALK-Positive NSCLC in China

Inclusion Criteria

• Evidence of histologically or cytologically confirmed diagnosis of locally advanced or metastatic ALK positive NSCLC where ALK status has been previously established by the Ventana ALK (D5F3) CDx Assay (Roche Diagnostics), the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular), or the EML4 ALK Fusion Gene Detection Kit (AmoyDx).
• Subject should have:
• (in Cohort 1) Disease progression after crizotinib as the only ALK inhibitor;
• (in Cohort 2) Disease progression after one ALK inhibitor other than crizotinib, with or without prior crizotinib.
• Prior treatment with an ALK inhibitor must have completed 5 half lives prior to study entry.
• All Subjects must have at least 1 measurable extracranial target lesion according to RECIST v1.1 that has not been previously irradiated. CNS metastases are allowed if:
• Asymptomatic: either not currently requiring corticosteroid treatment, or on a stable or decreasing dose of 10 mg QD prednisone or equivalent; or
• 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of radiation therapy or surgery prior to enrollment, and if corticosteroid treatment for these metastases has been withdrawn for at least 4 weeks with neurological stability.
• Eastern Cooperative Oncology Group performance status (ECOG PS) 0, 1, or 2.
• Age 18 years (or 20 years as required by local regulation).
• Adequate bone marrow functions:
• Absolute Neutrophil Count (ANC) 1, 500/mm3 or 1.5 x 109/L;
• Platelets 100,000/mm3 or 100 x 109/L;
• Hemoglobin 9 g/dL.
• Adequate pancreatic function:
• Serum total amylase 1.5 x upper limit of normal (ULN);*
• Serum lipase 1.5 x ULN. *if total amylase >1.5 x ULN, but pancreatic amylase is within the ULN, then subject may be enrolled.
• Adequate renal function:

a. Serum creatinine 1.5 x ULN or estimated creatinine clearance 60 mL/min as calculated using the method standard for the institution.

• Adequate liver function:
• Total serum bilirubin 1.5 x ULN;
• Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) 2.5 x ULN (5.0 x ULN in case of liver metastases).
• Acute effects of prior radiotherapy and chemotherapy resolved to baseline severity or to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 except for AEs that in the investigator's judgment do not constitute a safety risk for the subject.
• Serum or urine pregnancy test (for females of childbearing potential) negative at screening. Female subjects of non childbearing potential must meet at least 1 of the following criteria:
• Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause (which may be confirmed with a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state if appropriate;
• Have undergone a documented hysterectomy and/or bilateral oophorectomy;
• Have medically confirmed ovarian failure. All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.
• Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
• Willing and able to comply with the study scheduled visits, treatment plans, laboratory tests, and other procedures.

Exclusion Criteria

Subjects with any of the following characteristics/conditions will not be included in the study:

• More than 1 prior chemotherapy regimen prior to enrollment in advanced/metastatic setting.

If disease recurred/relapsed within the adjuvant chemotherapy treatment or 220 msec; or

• Ongoing cardiac dysrhythmias of CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, bradycardia defined as 470 msec, or congenital long QT syndrome.
• Subject with predisposing charact