Clinical trial NCT02143726: Sorafenib Tosylate With or Without Everolimus in Treating Patients With Advanced, Radioactive Iodine Refractory Hurthle Cell Thyroid Cancer
Official title: Randomized Phase II Study of Sorafenib With or Without Everolimus in Patients With Radioactive Iodine Refractory Hurthle Cell Thyroid Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Refractory Hurthle Cell Thyroid Cancer
Lead sponsor: Alliance for Clinical Trials in Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
name: Novartis
First posted: 2014-05-21
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Progression Free Survival
timeFrame: 4 years and 4 months
Secondary outcomes:
measure: Confirmed Response Rate
timeFrame: 4 years 4 months
measure: Overall Survival
timeFrame: 5 years
measure: Number of Participants With Grade 3 or Higher Adverse Events
timeFrame: 4 years 3 months
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: Mayo Clinic in Florida
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Sioux City
country: United States
facility: Siouxland Regional Cancer Center
state: Iowa
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: Basking Ridge
country: United States
facility: Memorial Sloan Kettering Basking Ridge
state: New Jersey
city: Middletown
country: United States
facility: Memorial Sloan Kettering Monmouth
state: New Jersey
city: Montvale
country: United States
facility: Memorial Sloan Kettering Bergen
state: New Jersey
city: Commack
country: United States
facility: Memorial Sloan Kettering Commack
state: New York
city: Harrison
country: United States
facility: Memorial Sloan Kettering Westchester
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Sleepy Hollow
country: United States
facility: Memorial Sloan Kettering Sleepy Hollow
state: New York
city: Uniondale
country: United States
facility: Memorial Sloan Kettering Nassau
state: New York
city: Clinton
country: United States
facility: Southeastern Medical Oncology Center-Clinton
state: North Carolina
city: Goldsboro
country: United States
facility: Southeastern Medical Oncology Center-Goldsboro
state: North Carolina
city: Goldsboro
country: United States
facility: Wayne Memorial Hospital
state: North Carolina
city: Jacksonville
country: United States
facility: Southeastern Medical Oncology Center-Jacksonville
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Janesville
country: United States
facility: Mercy Health System
state: Wisconsin
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Eric Sherman, M.D.
role: STUDY_CHAIR
References:
citation: 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.