Iodine I-131 With or Without Selumetinib in Treating Patients With Recurrent or Metastatic Thyroid Cancer
Iodine I-131 With or Without Selumetinib in Treating Patients With Recurrent or Metastatic Thyroid Cancer
This phase II trial studies how well iodine I-131 works with or without selumetinib in
 treating patients with thyroid cancer that has returned (recurrent) or has spread from where
 it started to other places in the body (metastatic). Many thyroid cancers absorb iodine. Due
 to this, doctors often give radioactive iodine (iodine I-131) alone to treat thyroid cancer
 as part of standard practice. It is thought that the more thyroid tumors are able to absorb
 radioactive iodine, the more likely it is that the radioactive iodine will cause those tumors
 to shrink. Selumetinib may help radioactive iodine work better in patients whose tumors still
 absorb radioactive iodine. It is not yet known whether iodine I-131 is more effective with or
 without selumetinib in treating thyroid cancer.
PRIMARY OBJECTIVE:

 I. To determine the response rate at 6 months following treatment with 131I (iodine I-131) in
 combination with placebo or selumetinib for radioactive iodine-avid (RAIA) recurrent and/or
 metastatic thyroid cancer.

 SECONDARY OBJECTIVES:

 I. To determine the best overall response following treatment with 131I in combination with
 placebo or selumetinib for RAIA recurrent and/or metastatic thyroid cancer.

 II. To compare the progression-free survival of patients with RAIA recurrent and/or
 metastatic thyroid cancer treated with 131I in combination with placebo or selumetinib.

 III. To compare serum thyroglobulin changes for patients with RAIA recurrent and/or
 metastatic thyroid cancer treated with 131I in combination with placebo or selumetinib.

 IV. To evaluate the safety and tolerability of 131I in combination with placebo or
 selumetinib for patients with RAI-avid recurrent and/or metastatic thyroid cancer.

 CORRELATIVE OBJECTIVE:

 I. To explore the genomic and transcriptomic landscape of RAIA tumors for signatures that
 correlate to therapeutic benefit achieved with 131I in combination with placebo or
 selumetinib.

 OUTLINE: Patients are randomized to 1 of 2 treatment arms.

 ARM I: Patients receive selumetinib orally (PO) twice daily (BID) starting on week 1, day 1
 and continuing through 2 days after iodine I-131 therapy has been administered. Approximately
 3 weeks after beginning treatment with selumetinib, patients receive iodine I-131 PO.

 ARM II: Patients receive placebo PO BID starting on week 1, day 1 and continuing through 2
 days after iodine I-131 therapy has been administered. Approximately 3 weeks after beginning
 treatment with placebo, patients receive iodine I-131 PO.

 After completion of study treatment, patients are followed up at 1 and 3 months, every 3
 months for 12 months, and then every 6 months for 2 years.
Inclusion Criteria:

 -  Diagnosis of recurrent and/or metastatic thyroid cancer

 -  Histological or cytological confirmation of thyroid carcinoma of follicular origin
 (including papillary, follicular, or poorly differentiated subtypes and their
 respective variants); NOTE: medullary and anaplastic thyroid cancers are excluded;
 Hurthle cell carcinomas are excluded (defined as having an invasive tumor composed of
 > 75% oncocytic [Hurthle] cells lacking the nuclear features of papillary carcinoma,
 tumor necrosis, and marked mitotic activity); patients with oncocytic (Hurthle cell)
 variants of papillary thyroid carcinoma (defined as a tumor composed of a majority of
 oncocytic [Hurthle] cells having the nuclear features of papillary carcinoma) are
 eligible to participate

 -  RAI-avid lesion on a radioiodine scan (a diagnostic, post-therapy, or post-ablation
 scans) performed =< 24 months prior to registration, which suggests that therapy with
 131I is justifiable in the judgment of the investigator

 -  Clinically or radiographically evident structural disease; patients with measurable
 disease and those with only non-measurable ("non-target") structural disease
 (according to modified Response Evaluation Criteria in Solid Tumors [RECIST] version
 [v] 1.1 criteria) are eligible;

 NOTE 1: Modification of the RECIST v1.1 measurable disease criteria includes a change in
 the definition of what is considered a measurable malignant lymph node; a malignant lymph
 node is considered measurable if any of the following apply:

 -  It is noted to be RAI-avid on radioactive iodine imaging (diagnostic or post-therapy
 whole body scans acceptable) and it measures >= 1 cm in the long axis,

 -  It is pathologically proven to be involved with thyroid cancer (by cytology or
 pathology) and it measures >= 1 cm in the long axis, or

 -  Its short axis is >= 1.5 cm when assessed by computed tomography (CT) scan NOTE 2:
 Patients only with biochemical evidence of disease without structural evidence of
 cancer are not eligible for this study

 -  For patients with non-measurable, structural disease the following must apply:

 -  Undetectable thyroglobulin antibody AND

 -  A serum thyroglobulin of 10 ng/ml or greater in the context of suppressed
 thyroid-stimulating hormone (TSH) (TSH =< 0.4 mcU/ml) =< 28 days prior to study
 registration; use of any thyroglobulin assay is allowed, though all serum
 thyroglobulin measurements for study purposes must be conducted with the same
 thyroglobulin assay

 -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

 -  Able to swallow and retain orally-administered medication with no clinically
 significant gastrointestinal abnormalities that may alter absorption

 -  Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 28 days prior to
 randomization)

 -  Platelet count >= 100,000/mm^3 (obtained =< 28 days prior to randomization)

 -  Hemoglobin > 9.0 g/dL (obtained =< 28 days prior to randomization)

 -  Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 28 days prior
 to randomization)

 -  Aspartate transaminase (AST) =< 2.5 x ULN (or =< 5 x ULN in presence of liver
 metastases) (obtained =< 28 days prior to randomization)

 -  Creatinine =< 1.5 mg/dL OR calculated creatinine clearance of >= 50 ml/min by
 either the Cockcroft-Gault formula or 24-hours urine collection analysis
 (obtained =< 28 days prior to randomization)

 -  Negative pregnancy test performed =< 7 days prior to registration for women of
 childbearing potential only

 -  Provide informed written consent

 -  Willing to return to enrolling institution for follow-up (during the Active
 Monitoring Phase of the study)

 -  Note: during the Active Monitoring Phase of a study (i.e., active treatment and
 observation), participants must be willing to return to the consenting institution for
 follow-up

 -  Willing to provide mandatory archival tumor tissue (block or minimum of 30
 unstained slides from a primary or recurrent/metastatic thyroid cancer) for
 correlative research purposes; NOTE: patients with less archival tumor tissue
 available may still be eligible for the study after discussion with Academic and
 Community Cancer Research United (ACCRU); receipt of archival tumor tissue is not
 required for study registration and initiation of therapy

 -  Willing to provide mandatory blood samples for correlative research purposes

 Exclusion Criteria:

 -  131I therapy =< 6 months prior to registration; Note: 131I administered solely for
 diagnostic purposes is not considered 131I therapy

 -  External beam radiation therapy =< 28 days prior to registration; note: previous
 treatment with radiation is allowed if the investigator judges it will not compromise
 patient safety on the study

 -  Having been treated with a total cumulative (lifetime) 131I therapeutic activity > 800
 mCi (excluding 131I activity administered for diagnostic scans)

 -  Treatment with chemotherapy or targeted therapy (e.g. tyrosine kinase inhibitor) =< 28
 days prior to registration

 -  Prior exposure to mitogen-activated protein kinase kinase (MEK), RAS, or RAF
 inhibitors (note: previous exposure to sorafenib is allowed) OR history of
 hypersensitivity to selumetinib, thyrotropin alpha (Thyrogen), or any excipient agents

 -  Unresolved toxicity > Common Terminology Criteria for Adverse Events (CTCAE) grade 2
 from previous anti-cancer therapy, except for alopecia

 -  Cardiac conditions as follows:

 -  Uncontrolled hypertension (blood pressure [BP] >=150/95 mmHg despite medical
 therapy)

 -  Left ventricular ejection fraction < 55% measured by echocardiography

 -  Atrial fibrillation with a ventricular rate > 100 beats per minute (bpm) on
 electrocardiogram (ECG) at rest

 -  Symptomatic heart failure (New York Heart Association [NYHA] grade II-IV)

 -  Prior or current cardiomyopathy

 -  Severe valvular heart disease

 -  Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical
 therapy)

 -  Acute coronary syndrome =< 6 months prior to registration

 -  Ophthalmological conditions as follows:

 -  Intra-ocular pressure > 21 mmHg, or uncontrolled glaucoma (irrespective of
 intra-ocular pressure)

 -  Current or past history of central serous retinopathy or retinal vein occlusion

 -  Symptomatic or untreated leptomeningeal disease, brain metastasis, or spinal cord
 compression

 -  Unable to follow a low iodine diet or requiring medication with high content in iodide
 (e.g., amiodarone)

 -  Received iodinated intravenous contrast within =< 2 months of registration; avoidance
 of iodinated oral contrast is also preferred but not strictly required for study
 enrollment; NOTE: those who have had iodinated intravenous contrast within this time
 frame may still be eligible if a urinary iodine analysis reveals that excess iodine
 has been cleared (defined as urinary iodine documented to be < 300 mcg/day by either a
 spot urinary iodine or 24-hour urinary iodine measurement)

 -  Any of the following:

 -  Pregnant women

 -  Nursing women

 -  Men or women of childbearing potential who are unwilling to employ adequate
 contraception

 -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
 of the investigator, would make the patient inappropriate for entry into this study or
 interfere significantly with the proper assessment of safety and toxicity of the
 prescribed regimens

 -  Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
 positive and currently receiving antiretroviral therapy; NOTE: patients known to be
 HIV positive, but without clinical evidence of an immunocompromised state, are
 eligible for this trial

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, hepatitis B infection, hepatitis C infection, symptomatic congestive heart
 failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
 situations that would limit compliance with study requirements

 -  Receiving any other investigational agent which would be considered as a treatment for
 the primary neoplasm. (NOTE: Performance of investigational 124I PET/CT scans is
 allowed prior to and during conduct of this study)

 -  Other active malignancy =< 2 years prior to registration that will interfere with
 conduct of this trial; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of
 the cervix; NOTE: if there is a history of prior malignancy, patients must not be
 receiving other specific treatment (chemotherapy, hormonal therapy, radiation) for
 their cancer

 -  Not willing to discontinue use of supplemental vitamin E