Trametinib in Increasing Tumoral Iodine Incorporation in Patients With Recurrent or Metastatic Thyroid Cancer

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Brief Title

Trametinib in Increasing Tumoral Iodine Incorporation in Patients With Recurrent or Metastatic Thyroid Cancer

Official Title

A Phase 2 Study of Trametinib in Combination With Radioiodine (RAI) for RAS Mutant or RAS/RAF Wild-Type, RAI-Refractory Recurrent and/or Metastatic Thyroid Cancers

Brief Summary

      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.
    

Detailed Description

      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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Proportion of patients alive following treatment with trametinib and I-124 (Cohort A)

Secondary Outcome

 Adequate increase in iodine corporation (Cohort A)

Condition

Metastatic Thyroid Gland Carcinoma

Intervention

Computed Tomography

Study Arms / Comparison Groups

 Treatment (iodine I-124 PET/CT, trametinib, iodine I-131)
Description:  Patients undergo iodine I-124 PET/CT on day 5 of week 1. Beginning day 6, patients receive trametinib 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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Procedure

Estimated Enrollment

35

Start Date

August 14, 2014


Primary Completion Date

June 30, 2021

Eligibility Criteria

        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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Alan L Ho, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02152995

Organization ID

NCI-2014-01106

Secondary IDs

NCI-2014-01106

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Alan L Ho, Principal Investigator, Memorial Sloan Kettering Cancer Center


Verification Date

February 2021