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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Refractory Hurthle Cell Thyroid Cancer
• Intervention / Treatment: Drug: everolimus; Drug: sorafenib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32224-9980
      • Mayo Clinic in Florida
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Iowa
    • Sioux City, Iowa, United States, 51101
      • Siouxland Regional Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Nebraska Methodist Hospital
  • New Jersey
    • Basking Ridge, New Jersey, United States, 07920
      • Memorial Sloan Kettering Basking Ridge
    • Middletown, New Jersey, United States, 07748
      • Memorial Sloan Kettering Monmouth
    • Montvale, New Jersey, United States, 07645
      • Memorial Sloan Kettering Bergen
  • New York
    • Commack, New York, United States, 11725
      • Memorial Sloan Kettering Commack
    • Harrison, New York, United States, 10604
      • Memorial Sloan Kettering Westchester
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • Sleepy Hollow, New York, United States, 10591
      • Memorial Sloan Kettering Sleepy Hollow
    • Uniondale, New York, United States, 11553
      • Memorial Sloan Kettering Nassau
  • North Carolina
    • Clinton, North Carolina, United States, 28328
      • Southeastern Medical Oncology Center-Clinton
    • Goldsboro, North Carolina, United States, 27534
      • Southeastern Medical Oncology Center-Goldsboro
    • Goldsboro, North Carolina, United States, 27534
      • Wayne Memorial Hospital
    • Jacksonville, North Carolina, United States, 28546
      • Southeastern Medical Oncology Center-Jacksonville
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
  • Wisconsin
    • Janesville, Wisconsin, United States, 53547
      • Mercy Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Eligibility Criteria:

1. 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.
2. 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.

3. 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)
4. Progressive disease defined by RECIST criteria ≤ 14 months
5. Patients must have metastatic disease or locally advanced unresectable disease

6. 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.
7. No history of major surgery ≤ 28 days of registration
8. No history of intracranial brain metastasis

9. 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

10. Liver disease: No history of the following:

    • Child Pugh Class B or C liver disease

    • "Chronic active" hepatitis defined as:

      1. Hepatitis B surface antigen (HBsAg) > 6 months
      2. 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
      3. Persistent or intermittent elevation in alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels
      4. Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation
11. No history of gastrointestinal fistula or gastrointestinal perforation < 90 days of registration.
12. No known history of prolonged QT syndrome
13. 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.

14. 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.
15. 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.
16. Age ≥ 18 years
17. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2

18. 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
19. Documentation of disease: Histologic Documentation - Eligible patients must have histopathologically confirmed Hürthle cell thyroid cancer by central review.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: sorafenib; 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; Given PO; Other Names: Nexavar ®, BAY 43-9006
Experimental: sorafenib and everolimus; 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: everolimus; Given PO; Other Names: RAD001, Afinitor ®; Drug: sorafenib; Given PO; Other Names: Nexavar ®, BAY 43-9006

What is the study measuring?

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
Overall Survival		5 years
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
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

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI); Novartis
• Investigators: Study Chair: Eric Sherman, M.D., Memorial Sloan Kettering Cancer Center

Publications and helpful links

General Publications

• Matsuura D, Yuan A, Wang L, Ranganath R, Adilbay D, Harries V, Patel S, Tuttle M, Xu B, Ghossein R, Ganly I. Follicular and Hurthle Cell Carcinoma: Comparison of Clinicopathological Features and Clinical Outcomes. Thyroid. 2022 Mar;32(3):245-254. doi: 10.1089/thy.2021.0424.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2014
• Primary Completion (Actual): January 28, 2021
• Study Completion (Anticipated): August 6, 2024

Study Registration Dates

• First Submitted: May 19, 2014
• First Submitted That Met QC Criteria: May 19, 2014
• First Posted (Estimate): May 21, 2014

Study Record Updates

• Last Update Posted (Actual): April 4, 2022
• Last Update Submitted That Met QC Criteria: March 11, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Endocrine System Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Thyroid Diseases; Thyroid Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; Sorafenib; Everolimus
• Other Study ID Numbers: A091302; U10CA180821 (U.S. NIH Grant/Contract); NCI-2014-00623 (Registry Identifier: NCI Clinical Trials Reporting Office)