Sorafenib Tosylate in Treating Patients With Progressive Metastatic Neuroendocrine Tumors

Study Overview
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Brief Summary
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This phase II trial is studying how well sorafenib tosylate works in treating patients with progressive metastatic neuroendocrine tumors. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the objective tumor response rate of BAY 43-9006 (sorafenib tosylate) in patients with advanced neuroendocrine tumors. SECONDARY OBJECTIVES: I. Adverse event rate(s). II. Progression free survival and time to progression. III. Improvement in circulating hormone levels. IV. Overall survival. OUTLINE: This is a multicenter study. Patients are grouped into 2 separate analysis Groups according to tumor type (Group A: Carcinoid; Group B: Islet cell/other well-differentiated tumor). Each Group was independently evaluated for all study endpoints. Patients receive oral sorafenib tosylate twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months until disease progression and then every 6 months for up to 2 years from study entry.

Official Title
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A Phase II Trial of Bay 43-9006 in Progressive Metastatic Neuroendocrine Tumors

Conditions
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Gastrinoma, Glucagonoma, Insulinoma, Metastatic Gastrointestinal Carcinoid Tumor, Neuroendocrine Tumor, Pancreatic Polypeptide Tumor, Recurrent Gastrointestinal Carcinoid Tumor, Recurrent Islet Cell Carcinoma, Somatostatinoma, WDHA Syndrome

Intervention / Treatment
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* Drug: sorafenib tosylate


Participation Criteria
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Eligibility Criteria
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Criteria: Histologically confirmed neuroendocrine tumor: Carcinoid tumor OR islet cell carcinoma/other well-differentiated tumor No anaplastic or high-grade histology Metastatic disease Measurable disease No thyroid carcinoma of any histology, thymoma, or pheochromocytoma/paraganglioma No known brain metastases Performance status: Eastern Cooperative Oncology Group (ECOG) 0-2 Life expectancy: At least 24 weeks Hematopoietic: Absolute neutrophil count >= 1,500/mm3 Platelet count >= 100,000/mm3 No bleeding diathesis Hepatic: Bilirubin =< 2 times upper limit of normal (ULN) Aspartate aminotransferase (AST) =< 3 times ULN (5 times ULN if liver metastases are present) International normalized ratio (INR) normal PTT normal Renal: Creatinine =< 1.5 times ULN Cardiovascular: No poorly controlled hypertension; No symptoms of congestive heart failure; No unstable angina pectoris; No cardiac arrhythmia Gastrointestinal: Able to swallow capsules intact No gastrointestinal tract disease resulting in an inability to take oral medication (e.g., dysphagia) No requirement for IV alimentation No active peptic ulcer disease Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No ongoing or active infection No psychiatric illness or social situation that would preclude study compliance No other invasive malignancy within the past 3 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix No other uncontrolled illness At least 4 weeks since prior interferon No more than 1 prior systemic chemotherapy regimen: Chemoembolization is not considered systemic chemotherapy At least 4 weeks since prior chemoembolization At least 3 weeks since prior radiotherapy No prior procedures adversely affecting intestinal absorption At least 4 weeks since prior hepatic artery embolization No other prior systemic therapy No other concurrent investigational treatment No concurrent combination antiretroviral therapy for HIV-positive patients No concurrent enzyme-inducing anticonvulsants (e.g., carbamazepine, phenobarbital, or phenytoin) No concurrent rifampin No concurrent Hypericum perforatum (St. John's wort) Prior or concurrent octreotide for symptomatic treatment allowed No concurrent therapeutic anticoagulation: Concurrent prophylactic anticoagulation (i.e., low dose warfarin) of venous or arterial access devices allowed provided requirements for INR or PTT are met At least 4 weeks since prior major surgery Recovered from all prior therapy

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A (patients with carcinoid tumors)<br>Patients receive 400 mg oral sorafenib twice daily on days 1-28. | Drug: sorafenib tosylate<br>* 400 mg given orally<br>* Other names: SFN;|
| Experimental: Group B (islet cell and other neuroendocrine tumors)<br>Patients receive 400 mg oral sorafenib twice daily on days 1-28. | Drug: sorafenib tosylate<br>* 400 mg given orally<br>* Other names: SFN;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Response Rate | Confirmed response rate was defined using Response Evaluation Criteria In Solid Tumors (RECIST). A confirmed response is defined as a complete response (CR) or partial response (PR) observed on subsequent scans at least 4 weeks apart. Confirmed response rate was estimated by the number of successes divided by the total number of evaluable patients.> > Complete Response (CR) is defined as the disappearance of all target lesions.> Partial Response (PR) is defined as a 30% decrease in sum of longest diameter of target lesions;> > We report the percentage of patients with a confirmed response and a 95% confidence interval estimated by the Duffy and Santner method. | Duration of Treatment (Up to 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity | For this secondary endpoint, toxicity is defined as a grade 3 or higher adverse events that is classified as either possibly, probably, or definitely related to study treatment. The assignment of attribution to study treatment and grade (or degree of severity) of the adverse event are classified using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The number of participants reporting a grade 3 or higher toxicity are reported. | Up to 2 years | 
| Overall Survival | Overall survival (OS) was defined as the time from registration to death of any cause. Surviving patients were censored at the date of last follow-up. The median OS with 95% CI was estimated using the Kaplan Meier method. | From registration to death (up to 2 years) | 
| Progression Free Survival | Progression was defined using Response Evaluation Criteria In Solid Tumors (RECIST) as a 20% increase in the su of longest diameter of target lesions. Progression free survival (PFS) was defined as the time from registration to progression or death of any cause. Participants who were progression free were censored at the date of their most recent disease assessment. The median PFS with 95% CI was estimated using the Kaplan Meier method. | Time from registration to progression or death (up to 2 years) | 
| Duration of Response | Duration of response (DOR) was defined as the time from attaining a response (PR or CR) to the date of progression. Participants without progression were censored at the date of their most recent disease assessment. The median DOR was estimated using simple summary statistics. | Time from response to progression (up to 2 years) |