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

A Phase I/II Trial to Evaluate the Safety and Tolerability of Alectinib and Bevacizumab in Patients With Advanced, ALK-Positive, Non-Small Cell Lung Cancer

This research study is evaluating two drugs, alectinib and bevacizumab, as possible treatments for Advanced Non-Small Cell Lung Cancer (NSCLC).

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.

In the phase I portion of the study, a 3 + 3 dose de-escalation design was to determine the recommended phase II dose (RP2D) of alectinib and bevacizumab. Three patients will be treated per cohort for one cycle (21 days per cycle) beginning with dose level 1 cohort.

• Dose level 1 (starting dose) = Alectinib 600mg twice daily orally (PO), and Bevacizumab 15 mg/kg administered intravenously (IV) every 3 weeks.

  -- Dose level 1 was selected based on the individual RP2Ds for each medication and anticipation for minimal overlapping toxicities.

• Dose level -1 = Alectinib 600mg twice daily orally (PO),and Bevacizumab 7.5 mg/kg administered intravenously (IV) every 3 weeks.

• Dose level -2 = Alectinib 450mg twice daily orally (PO), and Bevacizumab 7.5 mg/kg administered intravenously (IV) every 3 weeks.

DLTs were defined as adverse events (AEs) occurring within the first cycle of treatment (21 days) attributed to the study drugs, and grade 3 or higher according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. If no DLTs are observed with dose level 1 cohort, we will enroll an additional 3 participants (6 total) to the same cohort and proceed with the phase II portion of the study if one or less experience a DLT. In any other dose level cohort, if one of three patients experiences a DLT, another 3 patients will be treated at the same dose level for one cycle. If no additional DLTs are observed, we will proceed with the phase II portion of the trial. If more than one of 3 patients develops a DLT in any cohort, another 3 patients will be treated in the next lowest dose cohort.

The RP2D for the combination of alectinib and bevacizumab was defined as either (i) the highest dosage cohort in which less than a third of patients experienced a DLT, or (ii) alectinib at the previously defined RP2D as a single agent (600 mg twice daily) plus bevacizumab at the highest tolerated dose investigated for the indication (15 mg/kg every 21 days), whichever was the lower dose.

In the phase II portion of the study, all patients received alectinib plus bevacizumab at the RP2D determined in the phase I portion. Cycles were 21 days long. Treatment was continued until there was evidence of progressive disease, death, or unacceptable toxicity. Patients were allowed to continue study drugs beyond progression if deemed clinically beneficial at the investigator's discretion. Intra-patient dose modification of bevacizumab was not permitted.

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.