Vemurafenib Neoadjuvant Trial in Locally Advanced Thyroid Cancer
Vemurafenib Neoadjuvant Trial in Locally Advanced Thyroid Cancer
The goal of this clinical research study is to learn about how vemurafenib may affect certain
 biomarkers in patients with PTC. Biomarkers are in the blood/tissue and may be related to
 your reaction to the study drug. The safety of this drug will also be studied.

 Vemurafenib is designed to block the BRAF gene mutation. This mutation causes cancer and
 cancer growth. By blocking this mutation, the drug may kill the cancer cells with the
 mutation and/or stop the tumor from growing.
Study Drug Administration and Groups:

 If you are found to be eligible to take part in this study, you will take 4 tablets of
 vemurafenib by mouth 2 times each day for 56 days. You should take each dose about 12 hours
 apart. If you miss taking the drug at a scheduled time by more than 4 hours, you should skip
 that dose and wait until the next dose.

 After 56 days, the treatment you receive will depend on what group you are assigned to:

 -  If the disease has spread outside the neck, you will be in Group A.

 -  If the disease is able to be entirely removed through surgery, you will be in Group B.

 -  If the disease is unable to be operated on, you will be in Group C.

 Study Visits:

 At all visits, you will be asked about any side effects you may be having and about any other
 drugs you may be taking.

 Before you take the study drug (Baseline):

 -  You will have a procedure called a laryngoscopy, in which a tube with a small camera in
 inserted into the nose to inspect your sinus, throat, and voice box.

 -  You will have a colonoscopy if you have a history of abnormal growth in the bowel
 (polyps or colon cancer). During this procedure a tube with a small camera is inserted
 in the anus to inspect your large bowel.

 At Day 28:

 -  You will have a physical exam, including measurement of your vital signs.

 -  Your performance status will be recorded.

 -  You will have an EKG.

 -  Blood (about 1 tablespoon) will be drawn for routine tests.

 Within 1 week before Day 56, you will have CT scans of the neck, chest, and abdomen to check
 the status of the disease.

 At Day 56, if you are in Group A or B, you will have surgery to remove the tumor. You will
 sign a separate consent form that describes this surgery and its risks. If you are in Group
 C, you will have a core biopsy. During the surgery/biopsy, blood (about 1 teaspoon) will also
 be collected for biomarker testing.

 Follow-Up:

 Your follow-up after the surgery/biopsy will depend on which study group you are in.

 Groups A and C:

 If you are in Group A, you will stop taking the study drug for about 2-4 weeks after you have
 surgery. If you are in Group C, you will not stop taking the study drug. Every 4 weeks (after
 you resume taking the study drug if you are in Group A, and after the biopsy if you are in
 Group C):

 -  You will have a physical exam, including measurement of your vital signs and a skin
 exam.

 -  Your performance status will be recorded.

 -  Blood (about 1 tablespoon) will be drawn for routine tests.

 -  You will be asked about any other drugs you may be taking and about any side effects you
 may be having.

 -  If you are in Group A, these tests will also be performed the day you start taking the
 study drug again. You will also have an EKG.

 Additionally, every 8 weeks (if you are in Group A or C), you will have CT scans of the neck,
 chest, and abdomen to check the status of the disease. Blood (about 1 teaspoon) will also be
 drawn for biomarker testing at the first of these visits.

 About 1 year after your laryngoscopy and colonoscopy, these procedures will be performed
 again to check for side effects related to the study drug. If you did not receive a baseline
 colonoscopy, this procedure will be performed about 1 year after starting vemurafenib. If you
 continue on study drug for more than a year, you will have a laryngoscopy every 12 months.

 At any time the study doctor thinks it is needed, you will have a colonoscopy and
 laryngoscopy.

 About 1 year after the surgery/biopsy, you will return to clinic to check if the disease has
 come back. At this visit, you will have a CT scan or ultrasound of the neck, and blood (about
 1 tablespoon) will be drawn for tests of your thyroid function.

 If after 4 months the study doctor thinks it is in your best interest, you will only need to
 have study visits every 8 weeks. You will still have blood (about 1 tablespoon) drawn for
 routine tests at a local lab and you will be called by the study staff to check on you. Each
 call will last about 5-10 minutes.

 If you are in Group C, and if during follow-up the study doctor decides that the disease can
 be operated on, you will be crossed over to Group A or B. You will have surgery and have the
 follow-up visits described for that study group.

 Group B:

 If you are in Group B, you will have a follow-up visit about 2 weeks after surgery. The
 following tests and procedures will be performed:

 -  You will have a physical exam, including measurement of your vital signs.

 -  Your performance status will be recorded.

 -  Blood (about 1 tablespoon) will be drawn for routine tests.

 -  You will be asked about any other drugs you may be taking and about any side effects you
 may be having.

 You will have a second follow-up visit about 8 weeks after surgery. You will have a CT scan
 of the neck to check the status of the disease. You will have the option of continuing to
 receive vemurafenib if your doctor thinks it is in your best interest. If you do continue on
 vemurafenib, you will follow the Group A follow-up schedule (above).

 About 1 year after your laryngoscopy and colonoscopy, these procedures will be performed
 again to check for side effects related to the study drug. If you did not receive a baseline
 colonoscopy, this procedure will be performed about 1 year after starting vemurafenib.

 At any time the study doctor thinks it is needed, you will have a colonoscopy and
 laryngoscopy.

 About 1 year after the surgery/biopsy, you will return to clinic to check if the disease has
 come back. At this visit, you will have a CT scan or ultrasound of the neck, and blood (about
 1 tablespoon) will be drawn for tests of your thyroid function.

 Length of Study:

 If you are in Group A or C, you will continue to take the study drug for as long as the study
 doctor thinks it is in your best interest. If you are in Group B, you will take the study
 drug for 56 days and will no longer take it after surgery. You will no longer be able to take
 the study drug if the disease gets worse, if intolerable side effects occur, or if you are
 unable to follow study directions.

 Your participation on the study will be over when you have completed the follow-up visits.

 End-of-Study Visit/Call:

 After you stop taking the study drug, you will have an end-of-study visit or phone call. You
 will be asked about any other drugs you may be taking and about any side effects you may have
 had. If you are called, the call will last about 5-10 minutes.

 This is an investigational study. Vemurafenib is FDA approved and commercially available for
 the treatment of late-stage melanoma. It is investigational to use this drug to treat thyroid
 cancer.

 Up to 22 patients will take part in this study. All will be enrolled at MD Anderson.
Inclusion Criteria:

 1. Primary papillary thyroid cancer (PTC), which appears to be stage T3 or T4 on imaging
 or with macroscopic lymph node involvement AND requires surgical resection.

 2. Persistent or locally recurrent PTC with macroscopic lymph node involvement which
 requires surgical resection.

 3. Patients deemed inoperable (no scheduled surgery) are eligible for this trial, as they
 could be surgical candidates after treatment with vemurafenib. Inoperable patients
 must be naïve to therapies targeting the MAPK pathway.

 4. BRAF V600E mutation detected in the primary tumor or the recurrent/persistent tumor.

 5. Total bilirubin </= 1.5 x upper limit of normal (ULN). Patients with Gilbert's
 syndrome are excluded from this requirement. Aspartate transaminase (serum glutamic
 oxaloacetic transaminase) / alanine transaminase (serum glutamic pyruvic transaminase)
 (AST[SGOT]/ALT[SGPT]) </= 2.5 x ULN, (5 x ULN for patients with concurrent liver
 metastases). Serum creatinine </= within 1.5 x ULN. Absolute neutrophil count (ANC)
 >/= 1.0 x 10^9/L; platelets >/= 100 x 10^9/L, HgB>9 mg/dL

 6. Antiangiogenic therapy, specifically vascular endothelial growth factor (VEGF) and
 VEGF receptor (VEGFR) inhibitors, can interfere with wound healing and therefore will
 only be allowed if the agent has been discontinued for at least 14 days prior to day
 1. Group C patients must be naïve to therapies which target mitogen-activated protein
 kinase (MAPK).

 7. Ability to swallow pills.

 8. Eastern Cooperative Oncology Group (ECOG) performance status </= 2

 9. Age >/= 18

 10. Ability to provide consent.

 Exclusion Criteria:

 1. Histological diagnosis other than PTC. Patients with anaplastic tumors are not
 eligible. However, patients whose tumors contain areas of un-differentiated or
 dedifferentiated histology may enroll provided the original diagnosis was clearly PTC,
 and the tumor histology remains predominantly papillary at enrollment.

 2. Refractory nausea and vomiting, malabsorption, or significant bowel resection that
 would preclude adequate absorption.

 3. Known hepatitis B or C virus (HBV or HCV) infection, unless the patient has been
 cleared for chemotherapy from experts on viral hepatitis (infectious disease
 specialists or hepatologists).

 4. Pregnant or lactating women. All pre-menopausal women being screened must have a
 negative serum pregnancy test within 14 days prior to commencement of dosing. Women of
 non-childbearing potential may be included if they are either surgically sterile or
 have been postmenopausal for >/= 1 year

 5. Untreated brain metastases.

 6. Chemotherapy or targeted therapy within 14 days or 5 half-lives (whichever is longer)
 prior to the start of study treatment.

 7. Patients with history of long QT syndrome, uncorrectable electrolyte abnormalities, or
 QTc>500msec.

 8. History of significant cardiac disease or uncontrolled arrhythmias.