Overview
This is a prospective interventional trial that aims to restore iodine incorporation in tumoral lesions of patients with unresectable, radioiodine-refractory thyroid cancer.
Description
This is a prospective interventional study testing the hypothesis that the inhibition of MEK can restore iodine incorporation in BRAF wild type (WT) and a combined inhibition of BRAF and MEK can restore iodine incorporation in BRAFV600E mutant (MUT), radioiodine-refractory (RAIR) thyroid cancer. Patients with proven iodine negative tumor lesion(s) will be included in this study. Patients will then receive Trametinib (WT-group) or Dabrafenib and Trametinib combination-therapy (MUT-group) for approximately 3 weeks, after which a Thyrogen-stimulated 123I SPECT imaging will be performed. For patients whose tumor(s) demonstrate sufficient iodine incorporation in the post drug treatment 123I SPECT imaging, a treatment according to guidelines for iodine positive lesions will be performed. The follow up of the patients will be conducted as standard of care.
Eligibility
Inclusion Criteria:
- Patients must have histologically or cytologically confirmed radioiodine refractory metastatic thyroid carcinoma of follicular origin (including papillary and its respective variants).
- Confirmation of the mutation status of BRAF gene (primary tumor, recurrent tumor, or metastasis) .
- Patients who do not undergo a systemic treatment with sorafenib or lenvatinib or chemotherapy or with other TKIs or other investigational drugs.
- 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 ≥ 15 mm with CT scan, MRI, or calipers by clinical exam. Tumors in previously irradiated fields may be considered measureable if there is evidence of tumor progression after radiation treatment.
- RAI-refractory disease on structural imaging, defined as following:
A metastatic lesion that is not radioiodine-avid on a diagnostic or therapeutic radioiodine
scan performed less than 1 year prior to enrollment in the current study, There are no size
limitations for the index lesion used to satisfy this entry criterion.
- No recent treatment for thyroid cancer as defined as:
1. No prior 131I therapy is allowed < 6 months prior to initiation of therapy on
this protocol. A diagnostic study using < 400 MBq (±100) of 131I is not
considered 131I therapy.
2. 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.)
3. No chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is allowed
< 4 weeks prior to the initiation of therapy on this protocol.
- Age ≥ 18 years
- ECOG performance status ≤ 2.
- 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.
- Patients must have normal organ and bone marrow function as defined below:
- Absolute neutrophil count (ANC) > 1.5x10^9/L
- Hemoglobin ≥ 9 g/dL
- Platelets ≥ 100 x 10^9/L
- Albumin ≥ 2.5 g/dL
- Total bilirubin ≤ 1.5x institutional ULN
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2x institutional
ULN unless it is related to the primary disease
- creatinine ≤ 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) ≥
50 mL/min OR 24-hour urine creatinine clearance ≥ 50 mL/min
- Negative pregnancy test within 7 days prior to starting the study premenopausal women.
Women of non-childbearing potential may be included without pregnancy test if they are
either surgically sterile or have been postmenopausal for ≥ 1 year.
- Fertile men and women must use an effective method of contraception during treatment
and for at least 6 months after completion of treatment as directed by their
physician. Effective methods of contraception are defined as those, which result in a
low failure rate (i.e., less than 1% per year) when used consistently and correctly
(for example implants, injectables, combined oral contraception or intra-uterine
devices). At the discretion of the investigator, acceptable methods of contraception
may include total abstinence in cases where the lifestyle of the patient ensures
compliance. (Periodic abstinence [e.g., calendar, ovulation, symptothermal,
postovulation methods] and withdrawal are not acceptable methods of contraception.)
- Ability to understand and the willingness to sign a written informed consent document.
- Patients must agree to undergo to research biopsy of a malignant lesion if the
mutation status cannot be proven through archival tissue specimen.
- 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 Principal Investigator). This does not apply to patients who undergo a biopsy.
Exclusion Criteria:
- Concomitant malignancies or previous malignancies of life-limiting potential within
the last 3 years.
- Use of other investigational drugs within 28 days preceding the first dose of drug
treatment during this study.
- Known leptomeningeal or brain metastases or spinal metastases.
- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to trametinib and/or to dabrafenib or other known contents of the
two investigational drugs.
- History or evidence of cardiovascular risk including any of the following:
- History or evidence of current, clinically significant uncontrolled arrhythmias
(exception: patients with controlled atrial fibrillation for > 30 days prior to the
initiation of therapy on this protocol are eligible).
- History of acute coronary syndromes (specifically, myocardial infarction and unstable
angina), severe/unstable angina, coronary angioplasty, or stenting within 6 months
prior to the initiation of therapy on this protocol.
- History of symptomatic congestive heart failure within 6 months prior to the
initiation of therapy on this protocol.
- History of cerebrovascular attack or transient ischemic attack within 6 months prior
to the initiation of therapy on this protocol.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situations that would limit compliance with
study requirements.
- Pregnant, lactating, or breast feeding women.
- 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 adequately cleared after the last
intravenous contrast administration.
- Unwillingness or inability to comply with study and follow-up procedures.
- Disorders of eye background as listed in the respective study drug prescribing
information.
- Patients with pancreatitis, prolonged QTc-time on EKG, uncontrolled hypertension,
thrombosis or high risk of bleedings.
- Condition of patient which is critical to participate in this study in the discretion
of the PI.