| Participants |
Baseline characteristics
Oral X‐396 (ensartinib) at 225 mg orally, daily, continously
Median age (range): Female %: Ethnicity Asian %: ECOG 0 to 1 %: Never smoked %: Stage of disease IV at entry %: Adenocarcinoma %: Brain metastases at entry %: Previous chemotherapy %: Previous targeted therapy %:
Oral crizotinib at 250 mg orally, twice daily, continously
Median age (range): Female %: Ethnicity Asian %: ECOG 0 to 1 %: Never smoked %: Stage of disease IV at entry %: Adenocarcinoma %: Brain metastases at entry %: Previous chemotherapy %: Previous targeted therapy %:
Inclusion criteria
Histologically or cytologically confirmed diagnosis of advanced or recurrent (stage IIIB not amenable for multimodality treatment) or metastatic (stage IV) NSCLC that is ALK‐positive by a US Food and Drug Administration (FDA)‐approved assay performed centrally. Patients must be ALK‐positive by local test prior to submitting tissue to the central lab. Randomisation will occur after ALK‐positive confirmation is received from the central lab. Patients may have received up to 1 prior chemotherapy regimen for metastatic disease, which may also have included maintenance therapy. Note that patients that have received adjuvant or neoadjuvant chemotherapy and developed metastatic disease within 6 months from the end of that therapy would be considered to have received 1 prior regimen for metastatic disease. ECOG PS score of 0 to 2 (see Appendix A) Life expectancy of at least 12 weeks Ability to swallow and retain oral medication
Adequate organ system function, defined as follows:
Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L Platelets ≥ 100 x 10^9/L Haemoglobin ≥9 g/dL (≥ 90 g/L) Note that transfusions are allowed to meet the required haemoglobin level. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN if no liver involvement or ≤ 5 x ULN with liver involvement Creatinine < 1.5 x ULN. If > 1.5 x ULN, patient may still be eligible if calculated creatinine clearance > 50 mL/min (0.83 mL/s) as calculated by the Cockcroft‐Gault method Brain metastases allowed if asymptomatic at study baseline. Patients with untreated brain metastases must not be on corticosteroids. If patients have neurological symptoms or signs due to CNS metastases, patients need to complete whole brain radiation or focal treatment at least 14 days before start of study treatment and be asymptomatic on stable or decreasing doses of corticosteroids at baseline. Men with partners of childbearing potential willing to use adequate contraceptive measures during the study and for 90 days after the last dose of study medication Women who are not of childbearing potential, and women of childbearing potential who agree to use adequate contraceptive measures during the study and for 90 days after the last dose of study medication, and who have a negative serum or urine pregnancy test within 1 week prior to initial trial treatment Patients must be > 18 years of age. Patients must have measurable disease per RECIST v. 1.1. Willingness and ability to comply with the trial and follow‐up procedures Ability to understand the nature of this trial and give written informed consent
Note that the following pertains to patients enrolled in France.
Exclusion criteria
Patients that have previously received an ALK TKI or PD‐1/PD‐L1 therapy, and patients currently receiving cancer therapy (i.e. other targeted therapies, chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumour embolisation) Use of an investigational drug within 21 days prior to the first dose of study drug. Note that to be eligible, any drug‐related toxicity should have recovered to Grade 1 or less, with the exception of alopecia. Any chemotherapy within 4 weeks, or major surgery or radiotherapy within the last 14 days Patients with primary CNS tumours and leptomeningeal disease are ineligible. Patients with a previous malignancy within the past 3 years (other than curatively treated basal cell carcinoma of the skin, in situ carcinoma of the cervix, or any cancer that is considered to be cured and have no impact on progression‐free survival (PFS) and overall survival (OS) for the current NSCLC) Concomitant systemic use of anticancer herbal medications. These should be stopped prior to study entry.
Patients receiving the following:
Strong CYP3A inhibitors (including, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, grapefruit, grapefruit juice) Strong CYP3A inducers (including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St John's wort) CYP3A substrates with narrow therapeutic window (including, but not limited to, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) Women who are pregnant or breastfeeding Presence of active gastrointestinal (GI) disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of study medications Patients at risk for GI perforation
Clinically significant cardiovascular disease including:
QTcF interval > 450 ms for men and > 470 ms for women, symptomatic bradycardia <45 beats per minute or other significant electrocardiogram (ECG) abnormalities in the investigator's opinion Clinically uncontrolled hypertension in the investigator's opinion (e.g. blood pressure > 160/100 mmHg; note that isolated elevated readings considered to not be indicative of uncontrolled hypertension are allowed) Congestive heart failure (New York Heart Association class III or IV) Arrhythmia or conduction abnormality requiring medication. Note: patients with atrial fibrillation/flutter controlled by medication and arrhythmias controlled by pacemakers are eligible. Severe/unstable angina, coronary artery/peripheral bypass graft, or myocardial infarction Cerebrovascular accident or transient ischaemia Patients who are immunosuppressed (including known HIV infection), have a serious active infection at the time of treatment, have interstitial lung disease/pneumonitis, or have any serious underlying medical condition that would impair the ability of the patient to receive protocol treatment. Patients with controlled hepatitis C, in the investigator's opinion, are allowed. Patients with known hepatitis B must be hepatitis B e antigen (HBeAg) and hepatitis B (HB) viral DNA negative for enrolment. Note that, because of the high prevalence, all patients in the Asia‐Pacific region (except Australia, New Zealand, and Japan) must be tested, and, if hepatitis B surface antigen (HBsAg) positive, must be HBeAg and HB viral DNA negative for enrolment. Known hypersensitivity to tartrazine, a dye used in the ensartinib 100 mg capsule Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol Concurrent condition that in the investigator's opinion would jeopardise compliance with the protocol or would impart excessive risk associated with study participation that would make it inappropriate for the patient to be enrolled
Inability or unwillingness to comply with study and/or follow‐up procedures outlined in the protocol.
Note that the following pertains to patients enrolled in France.
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