Phase II Study of Sunitinib Malate Following Hepatic Artery Embolization

Study Overview
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Brief Summary
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The purpose of this study is to decide if a medicine that slows growth of new blood vessels can be give after the embolization procedure to prevent or delay new growth of blood vessels to tumors.

Detailed Description
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This is a single-center, open-label, non-randomized, prospective phase II trial. Sutent treatment will be continued until disease progression, or excessive toxicity (as determined by treating physician or primary investigator), or until a maximum of eight cycles, whichever duration is shorter.

Official Title
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Phase II Study of Sunitinib Malate Following Hepatic Artery Embolization for Metastatic Gastrointestinal Neuroendocrine Tumors

Conditions
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Neuroendocrine Tumor, Islet Cell Tumor

Intervention / Treatment
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* Drug: Sunitinib malate
* Procedure: Hepatic Artery Embolizations


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Well-differentiated metastatic carcinoid tumors and pancreatic endocrine tumors with measurable liver metastases. Resolution of all acute toxic effects of prior chemotherapy or radiotherapy or surgical procedures to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 grade less than or equal to 1. Adequate organ function as defined by the following criteria: Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) less than or equal to 2.5 x local laboratory upper limit of normal (ULN), or AST and ALT less than or equal to 5 x ULN if liver function abnormalities are due to underlying malignancy Total serum bilirubin less than or equal to 1.5 x ULN Absolute neutrophil count (ANC) greater than or equal to 1500/microL Platelets greater than or equal to 100,000/microL Hemoglobin greater than or equal to 9.0 g/dL Serum calcium less than or equal to 12.0 mg/dL Serum creatinine less than or equal to 1.5 x ULN Prothrombin and activated partial thromboplastin time (PT and aPTT) less than or equal to 1.5 x ULN Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 2 Informed Consent: Patients must be aware of the nature of his/her disease process and must willingly give consent after being informed of the experimental nature of therapy, alternatives, potential benefits, side-effects, risks and discomforts. Exclusion Criteria: Major surgery or radiation therapy within 4 weeks of starting the study treatment. Prior hepatic artery embolization or chemoembolization. Prior treatment with a tyrosine kinase inhibitor or a vascular endothelial growth factor (VEGF) inhibitor. NCI CTCAE grade 3 hemorrhage within 4 weeks of starting the study treatment. History of or known brain metastases, spinal cord compression, or carcinomatous meningitis, or evidence of symptomatic brain or leptomeningeal disease on screening computed tomography (CT) or magnetic Resonance imaging (MRI) scan. Any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism. Ongoing cardiac dysrhythmias of NCI CTCAE grade greater than or equal to 2. Prolonged corrected QT (QTc) interval on baseline electrocardiogram (EKG). Hypertension that cannot be controlled by medications (>150/100 mm Hg despite optimal medical therapy). Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness or other active infection Concurrent treatment on another clinical trial. Supportive care trials or non-treatment trials, e.g. Quality of Life (QOL), are allowed. Concomitant use of ketoconazole and other agents known to induce CYP3A4. Concomitant use of theophylline and phenobarbital and/or other agents metabolized by the cytochrome P450 system. Ongoing treatment with therapeutic doses of Coumadin (low dose Coumadin up to 2 mg by mouth (po) daily for thrombo prophylaxis is allowed). Pregnancy or breastfeeding. Female participants must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of therapy. Female participants with reproductive potential must have a negative pregnancy test (serum or urine) prior to enrollment. Male participants must be surgically sterile or must agree to use effective contraception during the period of therapy. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.

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: Sunitinib Malate and Hepatic Artery Embolizations<br>Sunitinib Malate and Selective Hepatic Artery Embolizations: Sunitinib malate (Sutent) at a dose of 37.5mg. 1-3 selective hepatic artery embolizations. | Drug: Sunitinib malate<br>* Sunitinib malate (Sutent) at a dose of 37.5mg will be administered orally once daily on days 1-28 in a 42-day cycle. Treatment with Sutent will begin no sooner than seven days after the first hepatic artery embolization. Subsequent embolizations (if necessary) will be scheduled during scheduled Sutent treatment breaks. No fewer than seven days shall separate treatment with Sutent and scheduling of hepatic artery embolizations.<br>* Other names: Sutent;Procedure: Hepatic Artery Embolizations<br>* 1-3 selective hepatic artery embolizations will be performed at approximately 5-week intervals, based on the extent of hepatic involvement with tumor.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Progression Free Survival (PFS) at 12 Months | Kaplan-Meier analysis of PFS. Progression-free survival rate at 12 months after first embolization. PFS was defined as time from start of treatment until disease progression or death as a result of any cause. Response and progression endpoints refer specifically to hepatic metastases. Extrahepatic metastases were included for assessment of response and progression by RECIST version 1.0. Progressive Disease (PD): At least a 20% increase in the SLD of target lesions, taking as reference the smallest SLD recorded since the treatment started. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Overall Survival (OS) at One Year | Overall survival at 12 months. OS was defined as time from start of treatment until death as a result of any cause, with patients censored at the date of last follow-up if still alive. | 12 months | 
| Number of Participants With Partial Radiographic Response | Objective radiographic response rate. Response and progression endpoints refer specifically to hepatic metastases. Extrahepatic metastases were included for assessment of response and progression by RECIST version 1.0. Partial Response (PR): At least a 30% decrease in the sum of longest diameter (SLD) of target lesions, taking as reference the baseline SLD. | 12 months | 
| Number of Participants With Biochemical Response | Biochemical response rate (>50% reduction in tumor marker). Response and progression endpoints refer specifically to hepatic metastases. | 12 months | 
| Number of Participants Requiring Dose Reduction | Treatment related toxicity. Participants requiring dose reductions of sunitinib to 25 mg due to side effects. | 12 months | 
| Percentage of Participants With Overall Survival (OS) at 4 Years | Participant overall survival at 48 months. OS was defined as time from start of treatment until death as a result of any cause, with patients censored at the date of last follow-up if still alive. | 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carcinoid, Pancreatic, Metastatic, Neuroendocrine, Tumors, Hepatic, Artery, Embolization, Angiogenesis, Sunitinib, Malate, Sutent, Tyrosine, Kinase, Inhibitor