Trametinib in Increasing Tumoral Iodine Incorporation in Patients With Recurrent or Metastatic Thyroid Cancer
Trametinib in Increasing Tumoral Iodine Incorporation in Patients With Recurrent or Metastatic Thyroid Cancer
This phase II trial studies how well trametinib works in increasing tumoral iodine
 incorporation in patients with thyroid cancer that has come back or spread to another place
 in the body. Trametinib may stop the growth of tumor cells by blocking some of the enzymes
 needed for cell growth and may help make treatment with iodine I-131 more effective.
PRIMARY OBJECTIVES:

 I. To evaluate the effect of trametinib on enhancing radioiodine (RAI) activity by
 determining the proportion of patients alive at 6 months without disease progression by
 Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST version [v]1.1) criteria
 following treatment with RAI in co-administration with trametinib. (Cohort A) II. To evaluate
 the effect of trametinib on enhancing RAI activity by determining the objective response rate
 (ORR) at 6 months following treatment with radioiodine (RAI) in co-administration with
 trametinib. (Cohort A) III. To determine the proportion of patients following trametinib
 therapy with increased tumoral iodine incorporation as quantified by iodine iodine-124
 (I-124) positron emission tomography (PET)/computed tomography (CT) lesional dosimetry.
 (Cohort B)

 SECONDARY OBJECTIVES:

 I. To determine the proportion of patients following trametinib therapy with increased
 tumoral iodine incorporation as quantified with I-124 PET/CT lesional dosimetry. (Cohort A)
 II. To evaluate the safety/tolerability of trametinib with or without RAI. (Cohort A) III. To
 evaluate changes in thyroglobulin levels in patients treated with RAI. (Cohort A) IV. To
 explore potential correlations between genomic alterations present in the tumor and/or
 tumoral pharmacodynamic changes induced by trametinib to clinical outcomes. (Exploratory)
 (Cohort A) V. To evaluate the effect of trametinib on enhancing RAI activity by determining
 the ORR at 6 months following treatment with RAI in co-administration with trametinib.
 (Cohort B) VI. To evaluate the effect of trametinib on enhancing RAI activity by determining
 the proportion of patients alive at 6 months without disease progression by RECIST v 1.1
 criteria following treatment with RAI in co-administration with trametinib. (Cohort B) VII.
 To evaluate the safety/tolerability of trametinib with or without RAI. (Cohort B) VIII. To
 evaluate changes in thyroglobulin levels in patients treated with RAI. (Cohort B) IX. To
 explore potential correlations between genomic alterations present in the tumor and/or
 tumoral pharmacodynamic changes induced by trametinib to clinical outcomes. (Exploratory)
 (Cohort B) X. Preliminary evaluation of best objective response (BOR) rate for patients
 treated with trametinib alone. (Exploratory) (Cohort C) XI. Preliminary evaluation of the
 proportion of patients following treatment with trametinib alive at 6 months without disease
 progression by RECIST v 1.1 criteria. (exploratory) (Cohort C) XII. To evaluate the
 safety/tolerability of trametinib. (Cohort C) XIII. To evaluate changes in thyroglobulin
 levels in patients treated with trametinib. (Cohort C) XIV. To explore potential correlations
 between genomic alterations present in the tumor and/or tumoral pharmacodynamic changes
 induced by trametinib to clinical outcomes. (Exploratory) (Cohort C) XV. To explore the
 impact of continued trametinib upon RAI avidity and efficacy. (Exploratory) (Cohort C)

 OUTLINE:

 Patients undergo iodine I-124 PET/CT on day 5 of week 1. Beginning day 6, patients receive
 trametinib orally (PO) daily for 4 weeks in the absence of disease progression or
 unacceptable toxicity. Patients undergo second iodine I-124 PET/CT on week 5. If I-124 PET/CT
 shows enough iodine absorption, patients may receive iodine I-131 PO and continue receiving
 trametinib for another 2 days. If I-124 shows that the thyroid is not absorbing iodine,
 patients may continue trametinib at the doctor's discretion and do not receive iodine I-131.

 After completion of study treatment, patients are followed up for 30 days.
Inclusion Criteria:

 -  Patients must have histologically or cytologically confirmed thyroid carcinoma of
 follicular origin (including papillary, follicular, or poorly differentiated subtypes
 and their respective variants); confirmation of thyroid carcinoma will be done at
 Memorial Sloan-Kettering (MSK)

 -  Patients must have measurable disease, defined as at least one lesion that can be
 accurately measured in at least one dimension (longest diameter to be recorded for
 non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional
 techniques or as >= 10 mm with spiral CT scan, magnetic resonance imaging (MRI), or
 calipers by clinical exam; tumors in previously irradiated fields may be considered
 measurable if there is evidence of tumor progression after radiation treatment

 -  RAI-refractory disease on structural imaging, defined as any one of the following:

 -  A metastatic lesion that is not radioiodine-avid on a diagnostic radioiodine scan
 performed prior to enrollment in the current study, or

 -  A radioiodine-avid metastatic lesion which remained stable in size or progressed
 despite radioiodine treatment 6 months or more prior to entry in the study; there
 are no size limitations for the index lesion used to satisfy this entry criterion

 -  The presence of at least one fluorodeoxyglucose (FDG) avid lesion

 -  No recent treatment for thyroid cancer as defined as:

 -  No prior RAI therapy is allowed < 6 months prior to initiation of therapy on this
 protocol; a diagnostic study using < 10 millicurie (mCi) of RAI is not considered
 RAI therapy

 -  No external beam radiation therapy < 4 weeks prior to initiation of therapy on
 this protocol; (previous treatment with radiation for any indication is allowed
 if the investigator judges that the previous radiation does not significantly
 compromise patient safety on this protocol)

 -  No chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is allowed
 < 4 weeks prior to the initiation of therapy on this protocol

 -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

 -  Life expectancy of greater than 3 months

 -  Able to swallow and retain orally-administered medication and does not have any
 clinically significant gastrointestinal abnormalities that may alter absorption such
 as malabsorption syndrome or major resection of the stomach or bowels

 -  All prior treatment-related toxicities must be Common Terminology Criteria for Adverse
 Events version 4.0 (CTCAE v 4.0) grade =< 1 (except alopecia); grade 2 prior treatment
 related toxicities may be allowed after discussion with the principal investigator

 -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

 -  Hemoglobin >= 9 g/dL

 -  Platelets >= 100 x 10^9/L

 -  Albumin >= 2.5 g/dL

 -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

 -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
 institutional ULN

 -  Creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula)
 >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min

 -  Prothrombin time (PT) or international normalized ratio (INR) and partial
 thromboplastin time (PTT) =< 1.5 x institutional ULN

 -  Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by
 echocardiogram (ECHO) or multi gated acquisition scan (MUGA)

 -  The effects of trametinib on the developing human fetus are unknown; since MEK
 inhibitors and RAI may be teratogenic, women of child-bearing potential and men must
 agree to use adequate contraception (hormonal or barrier method of birth control;
 abstinence) prior to study entry, for the duration of study, and 4 months after study
 completion; women of child-bearing potential must have a negative pregnancy test
 within 2 weeks prior study registration; should a woman become pregnant or suspect she
 is pregnant while she or her partner is participating in this study, she should inform
 the treating physician immediately; men treated or enrolled on this protocol must also
 agree to use adequate contraception prior to the study, for the duration of study
 participation, and 4 months after completion of trametinib administration

 -  Ability to understand and the willingness to sign a written informed consent document

 -  Patients must agree to undergo two separate biopsies of a malignant lesion; biopsies
 do not need to be done if one of the following apply:

 -  If either the site investigator or person performing the biopsy judges that no
 tumor is accessible for biopsy or that biopsy poses too great of a risk to the
 patient (if the only tumor accessible for biopsy is also the only lesion that can
 be used for RECIST v1.1 response evaluation, then the patient may be exempt from
 biopsy after discussion with the MSK principal investigator)

 -  The goal will be to have a minimum of 6 patients from Cohort A and 3 patients
 from Cohort B attempt to have one or both of these research biopsies done (for a
 total of 9 patients total); accrual may be limited only to subjects for whom
 tumor is accessible for biopsy and attempt at biopsy is considered safe if
 continued enrollment of those who are not candidates for biopsy make it
 impossible to reach the accrual goals for research biopsies described above
 (e.g., if 19 [of 25] patients are accrued to Cohort A without any biopsies having
 been obtained within the cohort, then all further subjects who are registered to
 that cohort must qualify for attempted research biopsy in order to be enrolled
 into the study [i.e., subjects who would have been excluded from having biopsies
 done due to the above reasons would be excluded from participating in the study;
 these conditions also apply to Cohort B])

 -  Availability of archival tumor tissue from the thyroid cancer primary or metastasis (a
 tissue block or a minimum of 30 unstained slides would be required; patients with less
 archival tissue available may still be eligible for the study after discussion with
 the MSK principal investigator)

 -  COHORT A: Confirmation in a Clinical Laboratory Improvement Amendments (CLIA)
 certified laboratory that one of the patient's thyroid tumors (primary tumor,
 recurrent tumor, or metastasis) has an neuroblastoma RAS viral (v-ras) oncogene
 homolog (NRAS) or Kirsten rat sarcoma viral oncogene homolog (KRAS) or Harvey rat
 sarcoma viral oncogene homolog (HRAS) mutation at G12, G13, or Q61; this group of
 patients will also be referred to as "RAS MUT"

 -  COHORT A: Patients must have progressive disease, defined as the presence of new or
 growing lesion(s) on radiologic imaging within 14 months of study enrollment and/or
 new/worsening disease related symptoms within 14 months of study enrollment;
 (progression according to RECIST v 1.1 criteria is not required)

 -  COHORT B: Confirmation in a CLIA certified laboratory that one of the patient's
 thyroid tumors (primary tumor, recurrent tumor, or metastasis) does not have any of
 the following mutations:

 -  Mutation at V600 of the v-raf murine sarcoma viral oncogene homolog B (BRAF) gene

 -  Mutation in NRAS or KRAS or HRAS at G12, G13, or Q61

 -  These patients will be designated "BRAF/RAS wild type (WT)"

 Exclusion Criteria:

 -  History of another malignancy; exception: patients who have been disease-free for 3
 years, patients with a history of completely resected non-melanoma skin cancer, and/or
 patients with indolent secondary malignancies, are eligible; MSK can consult the
 Cancer Therapy Evaluation Program (CTEP) Medical Monitor if unsure whether second
 malignancies meet the requirements specified above

 -  History of interstitial lung disease or pneumonitis

 -  Use of other investigational drugs within 28 days (or five half-lives, whichever is
 shorter; with a minimum of 14 days from the last dose) preceding the first dose of
 trametinib and during the study

 -  Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression

 -  Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
 chemically related to trametinib, or excipients or to dimethyl sulfoxide (DMSO) or to
 thyrotropin alpha (Thyrogen)

 -  Current use of a prohibited medication; the following medications or non-drug
 therapies are prohibited:

 -  Other anti-cancer therapy while on study; (note: megestrol [Megace] if used as an
 appetite stimulant is allowed; thyroid-stimulating hormone [TSH] suppressive
 therapy is also allowed; palliative radiation therapy to non-target lesions is
 also allowed)

 -  Concurrent treatment with bisphosphonates is permitted; prophylactic use of
 bisphosphonates in patients without bone disease is not permitted, except for the
 treatment of osteoporosis

 -  Because the composition, pharmacokinetics (PK), and metabolism of many herbal
 supplements are unknown, the concurrent use of all herbal supplements is
 prohibited during the study (including, but not limited to, St. John's wort,
 kava, ephedra [ma huang], gingko biloba, dehydroepiandrosterone [DHEA], yohimbe,
 saw palmetto, or ginseng)

 -  Patients with the following ophthalmological findings/conditions:

 -  Intraocular pressure > 21 mmHg, or uncontrolled glaucoma (irrespective of
 intraocular pressure)

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

 -  History or evidence of cardiovascular risk including any of the following:

 -  Left ventricular ejection fraction (LVEF) < LLN

 -  A QT interval corrected for heart rate using the Bazett's formula (QTcB) >= 480
 msec

 -  History or evidence of current clinically significant uncontrolled arrhythmias
 (exception: patients with controlled atrial fibrillation for > 30 days prior to
 randomization are eligible)

 -  History of acute coronary syndromes (including myocardial infarction and unstable
 angina), coronary angioplasty, or stenting within 6 months prior to randomization

 -  History or evidence of current >= class II congestive heart failure as defined by
 the New York Heart Association (NYHA) functional classification system

 -  Treatment-refractory hypertension defined as a blood pressure of systolic > 140
 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive
 therapy

 -  Patients with intra-cardiac defibrillators

 -  Known cardiac metastases

 -  Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C
 virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection,
 which will be allowed); patients with human immunodeficiency virus (HIV) are not
 eligible if on anti-retroviral medications

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

 -  Animal reproductive studies have not been conducted with trametinib; therefore, the
 study drug must not be administered to pregnant women or nursing mothers; these
 potential risks may also apply to RAI and Thyrogen

 -  HIV-positive patients on combination antiretroviral therapy are ineligible because of
 the potential for pharmacokinetic interactions with trametinib; in addition, these
 patients are at increased risk of lethal infections when treated with
 marrow-suppressive therapy

 -  Patients unable to follow a low iodine diet or requiring medication with high content
 in iodide (amiodarone)

 -  Patients who received iodinated intravenous contrast as part of a radiographic
 procedure within 3 months of study registration; those that have had iodinated
 intravenous contrast within this time frame may still be eligible if a urinary iodine
 analysis reveals that the excess iodine has been cleared after the last intravenous
 contrast administration