Phase 2 Study of Selumetinib Hydrogen Sulfate in Iodine-131 Refractory Papillary Thyroid Carcinoma and Papillary Thyroid Carcinoma With Follicular Elements

• Histologically or cytologically confirmed papillary thyroid cancer or papillary thyroid cancer with follicular elements

• No longer amenable to radioactive iodine therapy or curative surgical resection

‣ Tumor is no longer iodine avid

⁃ Tumor did not respond to the most recent radioactive iodine treatment

⁃ Patient is ineligible for further radioactive iodine therapy due to medical contraindications (e.g., lung toxicity)

• Measurable disease, 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 CT scan

• Evidence of disease progression (objective growth of existing tumors)

‣ New or enlarging measurable lesions within the past 12 months

⁃ If the most recent imaging study is older than 12 months, patients will still be eligible if objectively measurable disease progression is associated with clinical symptoms

• Archival tumor tissue available for mutational analysis

• No known brain metastases

• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%

• Life expectancy \> 12 weeks

• WBC ≥ 3,000/µL

• ANC ≥ 1,500/µL

• Platelet count ≥ 100,000/µL

• Total bilirubin normal

• AST and ALT \< 2.5 times upper limit of normal

• Creatinine normal OR creatinine clearance ≥ 60 mL/min

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception prior to, during, and for 4 weeks after completion of study treatment

• Able to understand and willing to sign a written informed consent document

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib (AZD6244) or its excipient Captisol®

• QTc interval \> 450 msec or other factors that increase the risk of QT prolongation

• Arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome), including heart failure that meets NYHA class III and IV definition

• Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption

• Concurrent uncontrolled illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements

• At least 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C)

• Prior treatment with tyrosine kinase inhibitors that target RET or RAF

• Prior treatment with MEK inhibitors

• Concurrent combination antiretroviral therapy for HIV-positive patients

• Concurrent medication that can prolong the QT interval

• Other concurrent investigational agents