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 cell lung 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 be obtained 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 (At least 5 mm in size)

  * Lesions must be untreated or progressive according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 after previous local therapy.
  * Participants who are receiving corticosteroids must be on a stable or decreasing 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 proximal tracheobronchial 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 infarction within 6 months prior to enrolment, unstable angina pectoris, congestive heart failure of grade \> II according to the New York Heart Association (NYHA), or cardiac arrhythmia 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 \> 100 mm Hg)
* Invasive surgical intervention within 28 days prior to the start of treatment
* Minor surgical intervention, including placement of a permanent catheter within 24 hours 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 fistula with grade 4 severity, gastrointestinal perforation or intra-abdominal abscess within 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 ALK Tyrosine kinase inhibitors (TKIs), the washout period should be ≥5 half-lives prior to enrolment.
* Any GI disorder that may affect absorption of oral medications
* Alanine transaminase (ALT) or aspartate transaminase (AST) \> 3 × ULN (≥5 × ULN for patients with concurrent liver metastasis)
* Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or other conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, 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 this study.
* QTc \> 470 ms or patients with symptomatic bradycardia.
* Administration of strong/potent cytochrome P450 (CYP)3A inhibitors or inducers within 14 days
* Administration of agents with potential QT interval prolonging effects within 14 days prior to the first administration of study drug and while on treatment.
* History of hypersensitivity to any of the additives in the alectinib drug formulation
* Documented allergy or hypersensitivity to monoclonal antibodies (bevacizumab)
* History of drug-induced pneumonitis or hypersensitivity pneumonitis from prior ALK TKI therapy.
* Pregnant or lactating women.
* Known HIV positivity or AIDS-related illness.
* Any condition or illness that could compromise patient safety or interfere with the evaluation of the study drugs.