An Open-Label, Multi-Center Phase II Study of the BRAF Inhibitor Vemurafenib in Patients with Metastatic or Unresectable Papillary Thyroid Cancer (PTC) positive for the BRAF V600 Mutation and Resistant to Radioactive Iodine.

1. Male or female patients >= 18 years of age
2. Histologically confirmed papillary thyroid cancer that is metastatic or unresectable
and for which standard curative or palliative measures do not exist or are no longer
effective.Patients whose tumors exhibit areas of *other histology* may be
enrolled, provided the tumor histology remains predominantly papillary.
Patients whose tumors exhibit *mixed* histology may be discussed with the
Medical Monitor if there are questions about eligibility.
3. BRAFV600-positive thyroid cancer tissue, as determined by the Roche-designated
Central Reference Laboratory using the cobas® 4800 BRAF V600 Mutation Test.
Testing requires a formalin-fixed paraffin-embedded (FFPE) tumor tissue block or
unstained sections from such a block. Samples may be either archival or new. Fine
needle and core needle biopsies will not be accepted.
4. Must have radioactive iodine resistant disease, defined by any one of the following:
o lack of RAI uptake on either a low-dose diagnostic or a post-therapy RAI scan in
the measurable lesion (or lesions) demonstrated previously (without time
limitation), or
o radiographic progression of disease within 18 months of last course of RAI
therapy despite the presence of RAI uptake on the scans performed with that prior
therapy, or
o Patient that has exceeded a cumulative activity of at least 600 mCi of radioiodine
therapy
5. Thyroid carcinoma tissue, either archival or recent biopsy must be available for
submission and review by a central pathology laboratory.
6. Allowed Prior therapy:
- Cohort 1: may have received surgery, RAI, and/or standard of care chemotherapy
(e.g. doxorubicin) [Note: Acceptable prior chemotherapy can be discussed with
the Sponsor.]
Cohort 2: may have received surgery, RAI, and standard of care chemotherapy
(e.g. doxorubicin), and must also have received prior treatment with investigational
or commercial tyrosine kinase inhibitor with activity against VEGFR2 provided the
drug is not a specific/selective BRAF or MEK pathway inhibitor. [Note: Acceptable
prior chemotherapy can be discussed with the Sponsor.]
7. Must have fully recovered from the effects of any previous therapies.
8. Radiologic (CT or MRI) evidence of clinically relevant disease progression (as per
RECIST 1.1) within the preceding 14 months prior to planned first treatment.
9. Measurable disease (by RECIST Version 1.1 criteria)
10. ECOG performance status of 0 or 1
11. Life expectancy > 3 months
12. Be able to swallow pills
13. Must have a head CT/MRI to evaluate for CNS metastasis within 28 days prior to
study drug treatment (Cycle 1 Day 1). Patients with radiographically stable,
asymptomatic previously treated lesions are eligible provided:
o Patient has received prior treatment (including radiation), stereotactic radiosurgery, surgical resection) to the
site(s) of CNS metastatic disease >= 28 days prior to starting study treatment
o Patient has no requirement for glucocorticoids, and discontinued >= 21 days prior
to starting study treatment)
o Patient is not taking anticonvulsants (discontinued at least 3 weeks prior to
treatment)
o Patient has no overt evidence of neurological deficit
14. Prior Surgery (excluding tumor biopsy at baseline for biomarker analysis) must have
occurred at least 14 days prior to first dose of study treatment, and patients must have
recovered from any effects from surgery and have adequate wound healing prior to
first dose of study treatment.
15. External beam radiotherapy for the treatment of a symptomatic (e.g. bone) metastasis
as clinically indicated must be at least 14 days prior to first dose of study treatment
16. Completed baseline skin exam by a dermatologist or other qualified physician for cutaneous squamous cell
carcinoma. Exam must be negative or if, suspected cuSCC, basal cell carcinoma
(BCC), or other suspicious lesions are identified they must be excised, and there must
be adequate wound healing prior to study treatment.
17. Thyroid stimulating hormone (TSH) level <0.5 mIU/L
18. Adequate hematologic, renal and liver function
o Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
o Platelet count >= 100 x 10^9/L
o Hemoglobin >= 9 g/dL
o Serum creatinine <=1.5 X ULN or CrCl > 40 ml/hr by Cockcroft-Gault formula
o AST and ALT <= 2.5 times upper limit of normal (ULN) (<= 5 times ULN for
patients with concurrent liver metastases)
o Bilirubin <= 1.5 times ULN
o Alkaline phosphatase <= 2.5 times ULN (<= 5 times ULN for patients with
concurrent liver metastases)
19. Negative serum pregnancy test within 7 days prior to commencement of dosing in
pre-menopausal women. Women of non-childbearing (see Appendix 6) potential may
be included if they are either surgically sterile or have been postmenopausal for >= 1
year
20. Fertile men and women must use an effective method of contraception during
treatment and for at least 6 months after completion of treatment as directed by their
physician (in accordance with local requirements)
21. Absence of any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up schedule;
those conditions should be discussed with the patient before trial entry
22. Before study entry, signed informed consent must be obtained from patient prior to
performing any study-related procedures

1. Histological diagnosis other than papillary thyroid carcinoma (PTC), including
squamous cell variants of PTC or PTC with areas of squamous metaplasia.Patients with anaplastic tumors are not eligible. However, patients whose tumors contain areas of *un-differentiated* or *de-differentiated* histology may enroll provided the original diagnosis was clearly PTC, and the tumor histology remains predominantly papillary at enrollment. Patients whose tumors exhibit mixed histology may be discussed with the Medical Monitor.
2. Active or untreated CNS metastases 3. History of or known carcinomatous meningitis
4. Anticipated or ongoing administration of any anti-cancer therapies other than those
administered in this study
5. Active squamous cell skin cancer that has not been excised or has not yet adequately
healed post excision
6. Pregnant or lactating women
7. Previous treatments with any commercial or investigational targeted agents that
specifically and selectively targets the MEK or BRAF pathway
8. Received any investigational treatment within 28 days prior to start of study treatment
9. Prior radioactive iodine therapy within 28 days prior to start of study treatment
10. Chemotherapy or targeted therapy (in case of cohort 2) within 28 days prior to start of
study treatment
11. Prior radiotherapy to the only measurable lesion
12. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant
bowel resection that would preclude adequate absorption
13. QTc >450 msec on screening ECG or history of congenital long QT
syndrome or uncorrectable electrolytes abnormalities.At least one QTc measurement using Fridericia*s correction (QTcF)
must be <= 450 msec. Additionally, cases of patients with stable asymptomatic
conduction delays (e.g., right bundle branch block) with QTc >450 msec may
be discussed with the Medical Monitor for potential inclusion.
14. NCI CTCAE Version 4.0 grade 3 hemorrhage within 28 days of starting the study
treatment
15. Any of the following within the 6 months prior to study drug administration:
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft,
symptomatic congestive heart failure, cerebrovascular accident or transient ischemic
attack, or active pulmonary embolism
16. Known clinically significant active infection at the time of study treatment start
17. History of allogeneic bone marrow transplantation or organ transplantation
18. Other severe, acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration, or may interfere with the interpretation of study results, which in
the judgment of the investigator would make the patient inappropriate for entry into
this study
19. Patients with a previous malignancy are excluded except for patients with adequately
treated basal cell or squamous cell skin cancer, in situ cervical cancer and/or
curatively treated cancer, from which the patient is currently disease-free, or any
malignancy from which the patient has been continuously disease-free for at least 5
years. Also, isolated elevation in PSA in the absence of prostate cancer is allowed
20. Known HIV positivity or AIDS-related illness, HBV, and active HCV