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

This is a Phase I/II clinical trial.

- A Phase I clinical trial tests the safety of an investigational intervention and also
tries to define the appropriate dose(s) of the investigational intervention to use for
further studies.

- Phase II clinical trials test the safety and effectiveness of an investigational
intervention to learn whether the intervention works in treating a specific disease.

- "Investigational" means that the intervention is being studied.

- In this research study, the investigators are investigating the combination of two
study drugs: alectinib and bevacizumab. The FDA (the U.S. Food and Drug
Administration) has not approved alectinib as a treatment for any disease.

It has been found that some people with NSCLC have a change (mutation) in a certain gene
called the anaplastic lymphoma receptor tyrosine kinase (ALK) gene. This mutated gene helps
cancer cells grow.

-- Alectinib belongs to a class of drugs designed to inhibit ALK. This drug has been used in
other research studies. Information from those other research studies suggests that alectinib
may be effective in killing cancer cells that have changes in ALK. Only participants with
changes in the ALK gene will be allowed to participate in this study.

In this research study, Alectinib will be combined with Bevacizumab.

-- Bevacizumab (also called Avastin) works by slowing or stopping the growth of cells in
cancer tumors by decreasing the blood supply of the tumors. If blood supply is decreased,
oxygen and nutrients that are needed for tumor growth are decreased. The FDA has approved
Bevacizumab as a treatment option for your disease

The purpose of this study is to test the safety of Alectinib and Bevacizumab. The
investigators will also determine how effective this combination is in participants with
advanced, ALK-positive NSCLC with a focus on participants with brain metastases.

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.