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

This is an interventional treatment trial for Non-Small Cell Lung Cancer (NSCLC) focused on measuring Non-Small Cell Lung Cancer (NSCLC), Anaplastic lymphoma kinase, ALK, Brain metastases Read More

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.