NCT04632758.

Study name	Study comparing WX‐0593 to crizotinib in ALK positive non‐small cell lung cancer (NSCLC) patients
Methods	Study design: randomised controlled trial Study grouping: parallel group
Participants	Included criteria: ≥ 18 years female or male patient has an ECOG PS ≤ 2. Life expectancy of at least 12 weeks. At least 1 measurable lesion (according to RECIST v1.1). Histologically or cytologically confirmed diagnosis of advanced or recurrent or metastatic NSCLC that is ALK‐positive by an Abbott FISH assay in the central lab. Randomisation will occur after ALK‐positive confirmation is received from the central lab or local test using a method including Abbott FISH, reverse transcription‐polymerase chain reaction (RT‐PCR), or Ventana IHC. No brain metastasis, or asymptomatic brain metastasis, or symptomatic brain metastasis but stable for more than 4 weeks after treatment, and has stopped systemic hormone treatment (prednisone of > 10 mg/day or equivalent hormone) for more than 2 weeks. Patients must have normal function defined as follows: Absolute neutrophil count (ANC) ≥ 1.5*10^9/L Platelets ≥ 90*10^9/L Haemoglobin ≥ 90 g/L Total bilirubin (TBIL) ≤ 1.5*upper limit of normal (ULN) (Gilbert's syndrome TBIL ≤ 3.0*ULN and direct bilirubin (DBIL) ≤ 1.5*ULN) Alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤ 2.5*ULN. For liver metastasis patients, ALT and AST ≤ 5*ULN Serum creatinine ≤ 1.5*ULN Left ventricular ejection fraction (LVEF) ≥ 50% Any surgery or prior radiation (expect for palliative radiation)/operations must have been completed at least 4 weeks prior to first dosing. Palliative radiation must have been completed at least 48 hours prior to first dosing. Patients must be able to understand and volunteer to sign the informed consent. Exclusion criteria Patients that have previously received cancer therapy (i.e. other targeted therapies, chemotherapy, immunotherapy, biologic therapy, hormonal therapy). Patients with tumour meningeal metastasis. Clinically significant cardiovascular disease within 6 months prior to first dosing. 2 consecutive corrected QT interval (QTc) > 480 ms through electrocardiogram (ECG) examination during screening, ≥2 arrhythmias, ≥ 2 heart failure (according to Common Terminology Criteria for Adverse Events (CTCAE) 4.03), atrial fibrillation and ventricular fibrillation of any grade, or clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention. Patients needing medications that may prolong QT interval or induce torsades de pointes within 14 days prior to the first dosing or during the study. Continuous use of corticosteroids for more than 30 days, or require chronic use of corticosteroids or other immunosuppressants. Past history of a large area of diffuse/interstitial pulmonary fibrosis, or known history of Grade 3 or 4 interstitial pulmonary fibrosis or interstitial lung disease. Patients with Grade > 1 nausea, vomiting, or diarrhoea (CTCAE 4.03), other gastrointestinal (GI) dysfunction or GI disease that may potentially affect drug absorption. Patients at risk for GI perforation or intestinal obstruction. Patient has received other investigational drug within 1 month prior to first dosing. Patient received other clinical trial treatment within 1 month prior to the first dose of the investigational drug. Patients who are hepatitis B surface antigen (HBsAg)‐positive and/or hepatitis B core antibody (HBcAB)‐positive and hepatitis B virus (HBV) DNA > 10^3 copies/mL, or hepatitis C virus (HCV) antibody‐positive, or syphilis antibody‐positive or known HIV infected. Patients who cannot suspend the use of a strong CYP3A4 inducer or inhibitor at least 1 week prior to this study and during the study. Patients who cannot suspend the use of a CYP3A4 substrate at least 1 week prior to this study and during the study, and the therapeutic index is low. Females who are pregnant or breastfeeding. Pregnant or lactating female patients or a positive pregnancy test at baseline for females of childbearing potential. Female patients who are unwilling to use effective contraceptive measures during the entire course of the study and within 6 months after the end of the study, or male patients who plan to have children. Concurrent diseases that may seriously affect patient safety or impact patient completion of the study as determined by the investigator (such as clinically uncontrolled hypertension (blood pressure > 160/110 mmHg), severe diabetes, or thyroid disease). Drug abusers and alcoholics. Drug or alcohol abuse. Alcohol abuse refers to drinking 14 units of alcohol per week: 1 unit = 285 mL of beer, or 25 mL of spirits, or 100 mL of wine; history of definitive neurological or mental disorder, including epilepsy or dementia. Patients with other malignant tumours within 5 years prior to screening (except for cured basal cell carcinoma of the skin, cervical carcinoma in situ, thyroid carcinoma in situ, and papillary thyroid carcinoma). Patients with added risks associated with the study or may interfere with the interpretation of study results as determined by the investigator, or deemed unsuitable by the investigator and/or sponsor
Interventions	WX‐0593 60 mg orally, daily for 7 days, then 180 mg orally, daily 28‐day cycle continuously Type: TKI Crizotinib 250 mg orally, twice daily, continuously Type: TKI
Outcomes	Primary outcome Progression‐free survival (PFS) [ Time Frame: from randomisation until firstly recorded disease progression or death (whichever occurs earlier), or to the date that the last participants observed for 12 months ]. PFS as assessed by independent radiology review based on RECIST v. 1.1 criteria Secondary outcomes PFS [ Time Frame: from randomisation until firstly recorded disease progression or death (whichever occurs earlier), or to the date that the last participants observed for 12 months ]. PFS based on investigator assessment Overall survival (OS) [ Time Frame: from randomisation until death due to any cause, withdraws informed consent, is lost to follow‐up, or refuses phone visits, or study completion (up to 2.5 years) ] Confirmed objective response rate (ORR) assessed by independent radiology review [ Time Frame: from first administration to the date that the last participants observed for 12 months ]. ORR is defined as the percentage of participants who have achieved complete response (CR) or partial response (PR) per independent radiology review using RECIST version 1.1 after the initiation of study treatment. Confirmed objective response rate (ORR) assessed by investigators [ Time Frame: from first administration to the date that the last participants observed for 12 months ]. ORR is defined as the percentage of the participants who have achieved complete response (CR) or partial response (PR) per investigators using RECIST version 1.1 after the initiation of study treatment. Time to response (TTR) assessed by independent radiology [ Time Frame: from first administration to the date that the last participants observed for 12 months ]. Assessed from date of the first dose until the date of progression per independent radiology review Time to response (TTR) assessed by investigators [ Time Frame: from first administration to the date that the last participants observed for 12 months ]. Assessed from date of the first dose until the date of progression per investigator Duration of response (DOR) assessed by independent radiology [ Time Frame: from first administration to the date that the last participants observed for 12 months ]. The DOR is defined as the time from the date of the first response CR/PR (whichever is first recorded) to the date on which progressive disease (PD) is first noted or date of death. Duration of response (DOR) assessed by investigators [ Time Frame: from first administration to the date that the last participants observed for 12 months ]. The DOR is defined as the time from the date of the first response CR/PR (whichever is first recorded) to the date on which PD is first noted or date of death. CNS response rate based on independent radiology review [ Time Frame: from first administration to the date that the last participants observed for 12 months ]. CNS response rate based on independent radiology review. CNS response rate based on investigator assessment [ Time Frame: from first administration to the date that the last participants observed for 12 months ]. CNS response rate based on investigator assessment. Time to CNS progression [ Time Frame: from first administration to the date that the last participants observed for 12 months ]. Time to CNS progression Percentage of participants with adverse events [ Time Frame: from the signing of the informed consent form until at least 28 days after the last dose of study drug was administered ]. The incidence of adverse events, including adverse events (AEs), serious adverse events (SAEs), and treatment‐emergent adverse events (TEAEs). Causality is determined by the investigator. Plasma concentrations (Cssmin) [ Time Frame: Cssmin before dosing on Cycle 1 Day 1, Cycle 1 Day 7, Cycle 1 Day 21, Cycle 2 Day 21, and Cycle 4 Day 21 ]. Minimum value of steady plasma‐drug concentration for WX‐0593 at participating sites Patient‐reported time to deterioration (TTD) [ Time Frame: from first administration to the date that the last participants observed for 12 months ]. Patient‐reported TTD as measured by EORTC QLQ‐C30/LC13 Patient‐reported TTD [ Time Frame: from first administration to the date that the last participants observed for 12 months ]. Patient‐reported TTD as measured by Lung Cancer Symptom Scale (LCSS) questionnaire Patient‐reported health‐related quality of life (HRQoL) [ Time Frame: from first administration to the date that the last participants observed for 12 months ]. Patient‐reported HRQoL as measured by EORTC QLQ‐C30/LC13 Patient‐reported HRQoL [ Time Frame: from first administration to the date that the last participants observed for 12 months ]. Patient‐reported HRQoL as measured by LCSS questionnaire
Starting date	June 2019
Contact information	Shunjiang Yu, CMO: shunjiang.yu@qilu‐pharma.com Yuankai Shi, MD; syuankaipumc@126.com
Notes	Qilu Pharmaceutical Co., Ltd  clinicaltrials.gov/ct2/show/NCT04632758