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

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

Detailed Description
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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.

Official Title
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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

Conditions
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Non-Small Cell Lung Cancer (NSCLC)

Intervention / Treatment
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* Drug: Alectinib
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alectinib and Bevacizumab.<br>Phase 1 Dose escalation will occur using a standard 3+3 dose escalation approach, beginning in dose level I with dose cohorts and rules for escalation and de-escalation. Alectinib, orally, twice a day, per cycle Bevacizumab, iv, once per cycle Phase II In the phase II portion of this study, the investigators will evaluate the combination of alectinib plus bevacizumab in ALK-positive patients with untreated or progressive, asymptomatic brain metastases. Eligible participants will receive alectinib plus bevacizumab at the recommended phase II doses determined in the phase I portion of the study. | Drug: Alectinib<br> <br> * Other names: Alecensa;Drug: Bevacizumab<br> <br> * Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended phase II dose of the combination of Alectinib and Bevacizumab | Phase I Primary Endpoint: To determine the recommended phase II dose of the combination of alectinib and bevacizumab. | 21 Days | 
| Number of participants treated with the combination of alectinib and bevacizumab with adverse events | Phase II Primary Endpoint: Safety and tolerability of alectinib and bevacizumab as assessed by Common Terminology Criteria for Adverse Events version 4.0 | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Central nervous system objective response rate | Number of subjects with intracranial complete or partial responses | 2 years | 
| Central nervous system disease control rate | Number of subjects with intracranial complete responses, partial responses, or stable disease | 2 years | 
| Central nervous system progression-free survival | Time from initiation of alectinib/bevacizumab to central nervous system progression or death. | 2 years | 
| Overall objective response rate | Number of subjects with partial or complete responses | 2 years | 
| Overall disease control rate | Number of subjects with partial/complete responses or stable disease | 2 years | 
| Progression-free survival | Time from initiation of alectinib/bevacizumab to progression or death. | 2 years | 
| Quality of life: change from baseline to on-treatment, measured by the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 | Questionnaire | 2 years | 
| Quality of life: change from baseline and on-treatment, measured by the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-BN20 | Questionnaire | 2 years | 
| Number of patients with an ALK resistance mutation | Determination of the number of patients who develop an ALK resistance mutation as a mechanism of resistance to alectinib and bevacizumab | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALK, Non-Small Cell Lung Cancer (NSCLC), Anaplastic lymphoma kinase, Brain metastases