Ensartinib, Carboplatin, Pemetrexed and Bevacizumab for the Treatment of Stage IIIC or IV or Recurrent ALK-Positive Non-small Cell Lung Cancer

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of stage IV (metastatic) orrecurrent or stage IIIc NSCLC (recurrent or stage IIIC NSCLC must be not a candidatefor definitive multimodality therapy)

• Documented ALK re-arrangement as detected by: (1) fluorescence in situ hybridization (FISH), (2) immunohistochemistry (IHC), (3) tissue next generation sequencing (NGS),or (4) cell free deoxyribonucleic acid (cfDNA) NGS using Clinical LaboratoryImprovement Amendments (CLIA) certified laboratory

• Subjects can be enrolled as (1) treatment naive (2) after progression on any numberof prior ALK tyrosine kinase inhibitors (TKIs). Prior adjuvant platinum-basedchemotherapy and platinum-based chemotherapy for metastatic disease is allowed ifcompleted > 12 months from the study treatment start date with one exception: apatient may be eligible if started on chemotherapy while waiting for ALK testingresults, provided no more than two cycles of chemotherapy were administered and noevidence of disease progression

• Life expectancy of at least 12 weeks

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

• Aged at least 18 years

• Brain metastases allowed if asymptomatic at study baseline. Patients must be not onsteroids, with the maximum size of brain lesion not exceeding 30 millimeters. Ifpatients have neurological symptoms or signs due to central nervous system (CNS)metastases, patients need to complete whole brain radiation or focal treatment atleast 14 days before start of study treatment and be asymptomatic on stable ordecreasing doses of corticosteroids at baseline

• Ability to swallow and retain oral medications

• Absolute neutrophil count (ANC) >= 1500/mm^3 /L

• Platelet count >= 100,000/mm^3

• Hemoglobin (Hb) at least 9 g/dL (or 5.69 mmol/L) at baseline

• Serum creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) >= 60 mL/minute for subjects with creatinine levels > 1.5 x the institutional ULN

• Serum total bilirubin less than or equal to =< 1.5 x ULN or direct bilirubin =< ULNfor subjects with total bilirubin levels > 1.5 x ULN

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULNexcept for subjects with liver metastases (mets) for whom ALT and AST should be =< 5x ULN

• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unlesssubject is receiving anticoagulant therapy as long as PT or partial thromboplastintime (PTT) is within therapeutic range of intended use of anticoagulants

• Activated PTT (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapyif PT or PTT is within therapeutic range of intended use of anticoagulant

• Female patients of childbearing potential must have a negative pregnancy testdocumented at time of screening

• Female patients who:

• Are postmenopausal for at least 1 year before the screening visit, OR

• Are surgically sterile, OR

• If they are of childbearing potential, agree to use a highly effective methodof contraception from the time of signing the informed consent through 4 monthsafter the last dose of study drug, or agree to completely abstain fromheterosexual intercourse

• Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:

• Agree to practice effective barrier contraception during the entire studytreatment period and through 4 months after the last dose of study drug, or

• Agree to completely abstain from heterosexual intercourse

• Voluntary agreement to provide written informed consent and the willingness andability to comply with all aspects of the protocol

Exclusion Criteria:

• 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 2or less, with the exception of alopecia

• Major surgery within the last 4 weeks or radiotherapy within the last 14 days

• Patients with leptomeningeal disease are ineligible

• Patients with a previous malignancy within the past 2 years (other than curativelytreated basal cell carcinoma of the skin, in situ carcinoma of the cervix, or anycancer that is considered to be cured and have no impact on PFS and overall survival [OS] for the current NSCLC)

• Concomitant systemic use of anticancer herbal medications. These should be stoppedprior to study entry

• Patients receiving:

• Strong CYP3A inhibitors (including, but not limited to, atazanavir,clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir,ritonavir, saquinavir, telithromycin, voriconazole, grapefruit, grapefruitjuice)

• 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 willinterfere significantly with the absorption, distribution, metabolism, or excretionof study medications

• Patients at risk for GI perforation

• Clinically significant cardiovascular disease including:

• Corrected QT per Fridericia's formula (QTcF) interval > 450 ms for men and > 470 ms for women, symptomatic bradycardia < 45 beats per minute or othersignificant electrocardiogram (ECG) abnormalities in the investigator's opinion

• Clinically uncontrolled hypertension in the investigator's opinion (e.g., bloodpressure > 160/100 mmHg; note that isolated elevated readings considered to notbe indicative of uncontrolled hypertension are allowed)

• The following within 6 months prior to cycle 1 day 1:

• Congestive heart failure (New York Heart class III or IV)

• Arrhythmia or conduction abnormality requiring medication. Note: patientswith atrial fibrillation/flutter controlled by medication and arrhythmiascontrolled by pacemakers are eligible

• Severe/unstable angina, coronary artery/peripheral bypass graft, ormyocardial infarction

• Cerebrovascular accident or transient ischemia

• Patients who are immunosuppressed (including known human immunodeficiency virus [HIV] infection), have a serious active infection at the time of treatment, haveinterstitial lung disease/pneumonitis, or have any serious underlying medicalcondition that would impair the ability of the patient to receive protocoltreatment. Patients with controlled hepatitis C, in the investigator's opinion, areallowed. Patients with known hepatitis B must be hepatitis B virus e antigen (HBeAg)and HB viral deoxyribonucleic acid (DNA) negative for enrollment. Note that, becauseof 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 enrollment

• Known hypersensitivity to tartrazine, a dye used in the ensartinib 100 mg capsule

• Concurrent condition that in the investigator's opinion would jeopardize compliancewith the protocol or would impart excessive risk associated with study participationthat would make it inappropriate for the patient to be enrolled

• Inability or unwillingness to comply with study and/or follow-up procedures outlinedin the protocol