AZD6244 in Treating Patients With Papillary Thyroid Cancer That Did Not Respond to Radioactive Iodine

PRIMARY OBJECTIVES:

I. Ascertain the objective response rate (complete response and partial response) in
patients with iodine I 131-refractory papillary thyroid cancer treated with AZD6244.

SECONDARY OBJECTIVES:

I. Determine the toxicity of this treatment in these patients. II. Determine the
pharmacokinetic profile of this treatment in these patients. III. Determine the
progression-free and overall survival of these patients. IV. Assess proxy measures of
treatment response (thyroglobulin and PET scan) in patients treated with AZD6244.

IV. Compare relevant laboratory correlates between responders and non-responders.

OUTLINE: This is a multicenter study.

Patients receive oral AZD6244 twice daily on days 1-28. Treatment repeats every 28 days in
the absence of unacceptable toxicity or disease progression.

Archived tissue is examined for gene mutations, including RET, BRAF, NTRK, and RAS, by
fluorescence in situ hybridization and/or polymerase chain reaction and fluorescence melting
curve analysis. Protein expression of ERK and phosphorylated ERK is assessed by
immunohistochemical staining.

Blood samples are collected periodically for pharmacokinetic analysis and biomarker
assessment (thyroglobulin and antithyroglobulin autoantibodies).

After completion of study therapy, patients are followed periodically for up to 2 years.

Inclusion Criteria:

- 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 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