Reinducing Radioiodine-sensitivity in Radioiodine-refractory DTC Using Lenvatinib (RESET)

Inclusion Criteria:

• Age ≥ 18 years at the time of informed consent
• Histologically or cytologically confirmed DTC (including papillary, follicular orHürthle Cell carcinoma)
• Progressive (biochemical or anatomic) disease for which lenvatinib is started asstandard treatment at the discretion of the treating physician
• Measurable disease at baseline imaging (F-18 FDG PET) according to the definition ofthe Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 1.0 withat least one lesion ≥1.0 cm in the longest diameter for a non-lymph node or ≥1.5 cm inthe short axis for a lymph node.
• RAI-R disease on structural imaging, defined as any one of the following:
• Metastatic lesions that are not RAI-avid on a diagnostic or intra-therapeutic RAIscanperformed prior to enrolment in the current study
• RAI-avid metastatic lesions which remained stable in size or progressed accordingto RECIST 1.1 criteria despite RAI treatment. Absence of response is observedduring 6-9 months after high dose I-131 therapy.
• No recent treatment for thyroid cancer:
• No prior I-131 therapy is allowed <6 months prior to initiation of therapy onthis protocol (a diagnostic study using <400 MBq of I-131 is not considered 131Itherapy)
• No external beam radiation therapy is allowed <4 weeks prior to initiation oftherapy on this protocol. (Previous treatment with radiation for any indicationis allowed if the investigator judges that the previous radiation does notsignificantly compromise patient safety on this protocol)
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (or Karnofsky ≥60%)
• Life expectancy ≥3 months
• Ability to swallow and retain orally-administered medication and no clinicallysignificant gastrointestinal abnormalities that may alter absorption
• Creatinine ≤1.5 mg/dL (≤133 µmol/L) or estimated glomerular filtration rate (eGFR) (using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula) ≥50mL/min/1.73m2 or 24-hour urine creatinine clearance ≥50 mL/min/1.73m2
• Adequate blood coagulation function as evidenced by an international normalized ratio (INR) ≤1.5
• Adequate bone marrow function with:
• Absolute neutrophil count ≥1.5*10^9 /L
• Hemoglobin ≥9 g/dL (5.6 mmol/L)
• Platelets ≥100*10^9 /L
• Adequate liver function with
• Albumin ≥25 g/L
• Total bilirubin <1.5x institutional upper limit of normal (ULN) with an exceptionfor patients with Gilbert's syndrome
• Aspartate aminotransferase and alanine aminotransferase ≤3x institutional ULN (≤5x ULN if subject has liver metastases)
• Negative pregnancy test within 7 days prior to starting the study for premenopausalwomen. Women can be included without pregnancy test if they are either surgicallysterile or have been postmenopausal for ≥1 year.
• Sexually active women of childbearing potential must agree to use a highly effectivemethod of contraception during the study and for at least 6 months after the laststudy treatment administration.Sexually active males patients must agree to use condomduring the study and for at least 6 months after the last study treatmentadministration. Also, it is recommended their women of childbearing potential partneruse a highly effective method of contraception. Effective methods of contraception aredefined 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 oralcontraception or intrauterine devices). At the discretion of the investigator,acceptable methods of contraception may include total abstinence in cases where thelifestyle of the patient ensures compliance. (Periodic abstinence [e.g., calendar,ovulation, symptothermal, postovulation methods] and withdrawal are not acceptablemethods of contraception.)
• Voluntary agreement to provide written informed consent and the willingness andability to comply with all aspects of the protocol

Exclusion Criteria:

• Concomitant or previous malignancies within the last 3 years. Patients are eligiblefor this study if they have been disease-free of the previous malignancy for at least 3 years, have a history of completely resected non-melanoma skin cancer and/or haveindolent secondary malignancies.
• Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression
• Evidence of cardiovascular risk including any of the following:
• Clinically relevant arrhythmias
• Acute coronary syndromes, severe/unstable angina
• Symptomatic congestive heart failure
• Use of other investigational drugs within 28 days preceding the first dose oftreatment in this study or during the study
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugschemically related to lenvatinib and/or to Thyrotropin alfa (human recombinantthyrotropin) or other known contents of the two drugs.
• Inability to follow a low iodine diet or requiring medication with high content iniodide (e.g. amiodarone)
• Patients who received iodinated intravenous contrast as part of a radiographicprocedure within 6-8 weeks of study registration. Patients are eligible for this studyif urinary iodine analysis reveals that the excess iodine has been adequately clearedafter the last intravenous contrast administration
• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection or psychiatric illness/social situations that would limit compliance withstudy requirements.
• Pregnant, lactating or breast feeding women
• Any medical or other condition that in the opinion of the investigator(s) wouldpreclude the participation in a clinical study
• Unwillingness or inability to comply with study and follow-up procedures