Phase I/II Trial of Alectinib and Bevacizumab in Patients With Advanced, Anaplastic Lymphoma Kinase (ALK)-Positive, Non-Small Cell Lung Cancer

Inclusion Criteria:

• Histologically or cytologically confirmed advanced, non-squamous, non-small celllung cancer.

• Molecular confirmation of an ALK rearrangement.

• Age ≥ 18 years old.

• Life expectancy > 12 weeks.

• Performance status 0-2.

• Adequate hematologic function:

• Adequate renal function:

• An estimated Glomerular Filtration Rate (eGFR) of at least 45 mL/min/1.73 m2

• International normalized ration (INR)≤ 1.5

• Partial thromboplastin time (PTT) ≤1.5 x upper limit of normal (ULN)

• For all females of childbearing potential, a negative pregnancy test must beobtained within 3 days before starting study treatment.

• Able and willing to provide written informed consent

• Phase II Only:

• Presence of at least one measurable central nervous system (CNS) target lesion (Atleast 5 mm in size)

• Lesions must be untreated or progressive according to Response EvaluationCriteria in Solid Tumors (RECIST) version 1.1 after previous local therapy.

• Participants who are receiving corticosteroids must be on a stable ordecreasing dose

• At least one measurable extra-CNS lesion based upon RECIST version 1.1.

Exclusion Criteria:

• Squamous cell histology or mixed, predominantly squamous adenosquamous carcinoma

• Previous history of haemoptysis

• Tumour infiltrating into large vessels or infiltrating into the proximaltracheobronchial network

• Unstable, symptomatic brain metastases.

• History of hemorrhagic CNS metastases

• History of intracranial hemorrhage (either by clinical history or neuroimaging)

• History of or genetic predisposition to a bleeding diathesis or coagulopathy

• Therapeutic anticoagulation

• Current or recent (within 10 days of first dose of bevacizumab) use of aspirin (> 325 mg/day)

• Clinically significant heart disease (i.e., active), stroke or myocardial infarctionwithin 6 months prior to enrolment, unstable angina pectoris, congestive heartfailure of grade > II according to the New York Heart Association (NYHA), or cardiacarrhythmia requiring specific treatment

• Arterial or venous thromboembolic events within 6 months of study enrollment.

• Poorly controlled arterial hypertension (systolic > 150 mm Hg and/or diastolic > 100mm Hg)

• Invasive surgical intervention within 28 days prior to the start of treatment

• Minor surgical intervention, including placement of a permanent catheter within 24hours prior to the first infusion of bevacizumab.

• Non-healing wound, active peptic ulcer or bone fracture.

• Previous history of abdominal fistula, tracheoesophageal fistula or other fistulawith grade 4 severity, gastrointestinal perforation or intra-abdominal abscesswithin 6 months prior to enrolment.

• Proteinuria at baseline.

• Previous anti-angiogenic treatment

• Patients previously treated with alectinib (Phase II only).

• Radical radiotherapy to the thorax with curative intent within 28 days

• Cytotoxic chemotherapy within 21 days prior to enrolment.

• Treatment with crizotinib within 7 days prior to enrolment. For all other ALKTyrosine kinase inhibitors (TKIs), the washout period should be ≥5 half-lives priorto enrolment.

• Any GI disorder that may affect absorption of oral medications

• Alanine transaminase (ALT) or aspartate transaminase (AST) > 3 × ULN (≥5 × ULN forpatients with concurrent liver metastasis)

• Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function orother conditions of decompensated liver disease such as coagulopathy, hepaticencephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices

• Acute viral or active autoimmune, alcoholic, or other types of hepatitis

• National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy (e.g.radiotherapy) (excluding alopecia),

• History of organ transplant.

• Co-administration of anti-cancer therapies other than those administered in thisstudy.

• QTc > 470 ms or patients with symptomatic bradycardia.

• Administration of strong/potent cytochrome P450 (CYP)3A inhibitors or inducerswithin 14 days

• Administration of agents with potential QT interval prolonging effects within 14days prior to the first administration of study drug and while on treatment.

• History of hypersensitivity to any of the additives in the alectinib drugformulation

• Documented allergy or hypersensitivity to monoclonal antibodies (bevacizumab)

• History of drug-induced pneumonitis or hypersensitivity pneumonitis from prior ALKTKI therapy.

• Pregnant or lactating women.

• Known HIV positivity or AIDS-related illness.

• Any condition or illness that could compromise patient safety or interfere with theevaluation of the study drugs.