Sorafenib Tosylate With or Without Everolimus in Treating Patients With Advanced, Radioactive Iodine Refractory Hurthle Cell Thyroid Cancer

Study Overview
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Brief Summary
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This randomized phase II trial studies the effects, good and bad, of using everolimus along with sorafenib tosylate versus sorafenib tosylate alone in treating patients with advanced radioactive iodine refractory thyroid cancer. Sorafenib tosylate and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. The addition of everolimus to sorafenib tosylate may cause more shrinkage of thyroid cancer and may prevent it from growing but it could also cause more side effects than sorafenib tosylate alone. It is not yet known whether this treatment with sorafenib tosylate and everolimus is better, the same, or worse than sorafenib tosylate alone.

Detailed Description
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This randomized Phase II trial will compare the progression-free survival (PFS) of sorafenib and everolimus versus sorafenib alone in patients with radioactive iodine refractory hurthle cell thyroid cancer. Prior studies have shown that the median PFS is generally around 4.5 months for sorafenib alone in this disease population. It is hoped that the combination of everolimus and sorafenib can increase the median PFS to at least 9 months. In addition to PFS, this trial will also compare the confirmed response rate, overall survival (OS) and adverse event rates between sorafenib and everolimus vs. sorafenib alone. The primary and secondary objectives for the study are listed below. Primary Objective: To compare the progression free survival between sorafenib and everolimus versus sorafenib alone in patients with radioactive iodine refractory Hurthle cell thyroid cancer Secondary Objective: To compare the confirmed response rate, overall survival and adverse event rates between sorafenib and everolimus versus sorafenib alone. Treatment will continue until disease progression or unacceptable adverse events. Patients will be followed for 5 years after randomization.

Official Title
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Randomized Phase II Study of Sorafenib With or Without Everolimus in Patients With Radioactive Iodine Refractory Hurthle Cell Thyroid Cancer

Conditions
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Refractory Hurthle Cell Thyroid Cancer

Intervention / Treatment
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* Drug: sorafenib
* Drug: everolimus


Participation Criteria
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Eligibility Criteria
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Eligibility Criteria: Central pathology review submission - Patients must have 10 representative hematoxylin and eosin (H&E) stained thyroid tissue slides OR tumor block available for submission to central pathology review. This review is mandatory prior to registration to confirm eligibility. Measurable disease - Patients must have measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) criteria, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral computed tomography (CT) scan. CT must be performed within 28 days of registration. Radioactive iodine (RAI) - refractory disease defined as 1 or more of the following: Patients who have received greater than 600 mCi of radioactive iodine in their lifetime OR RAI-avid metastatic lesion which remained stable in size or progressed despite RAI treatment within 9 months of RAI treatment OR 10% or more increase in serum thyroglobulin (on thyroid-stimulating hormone [TSH]-suppression) within 9 months of RAI treatment OR Index metastatic lesion non-RAI avid on a diagnostic RAI scan OR Presence of fluorodeoxyglucose (FDG) avid metastatic lesions on positron emission tomography (PET)/CT scan (standardized uptake values [SUV]max > 5 of any single lesion) Progressive disease defined by RECIST criteria ≤ 14 months Patients must have metastatic disease or locally advanced unresectable disease Prior treatment Patients may have received prior radiation therapy to index lesions ≥ 28 days prior to registration on this protocol if there has been documented progression by RECIST criteria. Prior radiation therapy to the non-index lesions is allowed if ≥ 28 days prior to registration on this protocol. Prior RAI therapy is allowed if ≥ 90 days prior to registration on this protocol and evidence of progression (as defined above) has been documented in the interim (a diagnostic study using < 10 mCi of RAI is not considered RAI therapy). Prior chemotherapy is allowed if ≥ 28 days prior to registration on this protocol. Patient may have received any number of prior lines of therapy. No prior use of sorafenib or an mammalian target of rapamycin (mTOR) (including phosphoinositide 3-kinase [PI3k] or protein kinase B [AKT]) inhibitor for the treatment of thyroid cancer. No history of major surgery ≤ 28 days of registration No history of intracranial brain metastasis Cardiovascular disease. No history of any of the following ≤ 6 months of registration: Myocardial infarction or unstable angina New York Heart Association grade III or greater congestive heart failure Cerebrovascular accident Grade 3 or 4 peripheral ischemia Grade 3 or 4 thromboembolic event Liver disease: No history of the following: Child Pugh Class B or C liver disease Chronic active hepatitis defined as: Hepatitis B surface antigen (HBsAg) > 6 months Serum hepatitis B virus (HBV) deoxyribonucleic acid (DNA) 20,000 IU/ml (105 copies/ml), lower values 2,000-20,000 IU/ml (104-105 copies/ml) are often seen in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B Persistent or intermittent elevation in alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels Liver biopsy showing chronic hepatitis with moderate or severe necroinﬂammation No history of gastrointestinal fistula or gastrointestinal perforation < 90 days of registration. No known history of prolonged QT syndrome No Grade 3 or 4 hypertension (systolic blood pressure [BP] >160 and or diastolic BP > 100) that cannot be controlled with medication prior to registration. Concomitant medications: Chronic concomitant treatment with strong inhibitors of cytochrome P450 3A4 (CYP3A4) is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study. Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment. Patients requiring anticoagulation must be on stable dose of medication prior to registration. Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative serum pregnancy test done ≤ 7 days prior to registration is required. Age ≥ 18 years Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2 Required Initial Laboratory Values: Absolute neutrophil count (ANC) ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Creatinine ≤ 1.5 mg/dL OR Calculated creatinine clearance ≥ 30 mL/min Total bilirubin ≤ 1.5 x upper limits of normal (ULN) Serum glutamic oxaloacetic transaminase (SGOT) (AST) ≤ 2.5 x ULN Fasting serum cholesterol ≤ 300 mg/dL Documentation of disease: Histologic Documentation - Eligible patients must have histopathologically confirmed Hürthle cell thyroid cancer by central review.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: sorafenib<br>Patients receive sorafenib 400 mg PO twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may cross over and receive everolimus 10 mg PO once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: sorafenib<br>* Given PO<br>* Other names: Nexavar ®, BAY 43-9006;|
| Experimental: sorafenib and everolimus<br>Patients receive sorafenib 400 mg PO twice daily and everolimus 5 mg PO once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: sorafenib<br>* Given PO<br>* Other names: Nexavar ®, BAY 43-9006;Drug: everolimus<br>* Given PO<br>* Other names: RAD001, Afinitor ®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Progression Free Survival (PFS) was defined as the time from randomization to the first of either disease progression or death from any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | 4 years and 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Response Rate | A patient will be classified as a confirmed response per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | 4 years 4 months | 
| Overall Survival |  | 5 years | 
| Number of Participants With Grade 3 or Higher Adverse Events | The maximum grade for each type of adverse event will be summarized using CTCAE version 4.0. The frequency and percentage of grade 3+ adverse events will be compared between the 2 treatment arms. | 4 years 3 months |