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

Study Overview
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Brief Summary
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This is a single-centre open label phase II study evaluating the effect of lenvatinib treatment for restoring radioiodine uptake and retention in radioiodine-refractory (RAI-R) thyroid cancer to warrant I-131 therapy.

Detailed Description
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RAI-R DTC patients starting standard-of-care lenvatinib treatment will be included in this study. Prior to lenvatinib treatment, patients will undergo I-124 PET/CT to quantify RAI uptake and retention at baseline. The first half of the intended sample size (cohort 1) will be treated with lenvatinib for a total of 12 weeks. After 6- and 12-week treatment, patients will undergo I-124 PET/CT dosimetry to evaluate the redifferentiation effect, assess expected absorbed lesion doses and maximum tolerable activity. Results between 6- and 12-week lenvatinib treatment will be compared to select the lenvatinib treatment duration that leads to highest extent of redifferentiation. The next patients (cohort 2) will then receive lenvatinib for either 6 or 12 weeks. Patients will undergo subsequent I-131 therapy if a clinically meaningful lesion dose is expected and toxicity is deemed acceptable. For all patients eligible for I-131 therapy, lenvatinib is discontinued prior to administration of I-131 and intra-therapeutic I-131 SPECT dosimetry will be performed for dose verification. Patients who are not eligible for I-131 therapy, will continue lenvatinib treatment at the discretion of the treating physician. Biopsies are performed at baseline and after 6-week lenvatinib treatment to evaluate alterations at the transcriptional and translational level in biopted tumor lesions. Patients will be followed up according to current guidelines for a total of 9 months after initiating lenvatinib treatment. Metabolic and biochemical response will be assessed using F-18 FDG PET/CT and Tg levels, respectively.

Official Title
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Reinducing Radioiodine-sensitivity in Radioiodine-refractory Differentiated Thyroid Cancer Using Lenvatinib (RESET)

Conditions
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Differentiated Thyroid Cancer

Intervention / Treatment
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* Radiation: rhTSH-stimulated I-124 dosimetry
* Radiation: Intra-therapeutic I-131 dosimetry


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years at the time of informed consent Histologically or cytologically confirmed DTC (including papillary, follicular or Hürthle Cell carcinoma) Progressive (biochemical or anatomic) disease for which lenvatinib is started as standard treatment at the discretion of the treating physician Measurable disease at baseline imaging (F-18 FDG PET) according to the definition of the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 1.0 with at least one lesion ≥1.0 cm in the longest diameter for a non-lymph node or ≥1.5 cm in the 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 RAI scanperformed prior to enrolment in the current study RAI-avid metastatic lesions which remained stable in size or progressed according to RECIST 1.1 criteria despite RAI treatment. Absence of response is observed during 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 on this protocol (a diagnostic study using <400 MBq of I-131 is not considered 131I therapy) No external beam radiation therapy is allowed <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) 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 clinically significant 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) ≥50 mL/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 exception for 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 premenopausal women. Women can be included without pregnancy test if they are either surgically sterile or have been postmenopausal for ≥1 year. Sexually active women of childbearing potential must agree to use a highly effective method of contraception during the study and for at least 6 months after the last study treatment administration.Sexually active males patients must agree to use condom during the study and for at least 6 months after the last study treatment administration. Also, it is recommended their women of childbearing potential partner use a highly effective method of contraception. 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 intrauterine 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.) Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol Exclusion Criteria: Concomitant or previous malignancies within the last 3 years. Patients are eligible for 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 have indolent 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 of treatment in this study or during the study Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to lenvatinib and/or to Thyrotropin alfa (human recombinant thyrotropin) or other known contents of the two drugs. Inability to follow a low iodine diet or requiring medication with high content in iodide (e.g. amiodarone) Patients who received iodinated intravenous contrast as part of a radiographic procedure within 6-8 weeks of study registration. Patients are eligible for this study if urinary iodine analysis reveals that the excess iodine has been adequately cleared after the last intravenous contrast administration 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 Any medical or other condition that in the opinion of the investigator(s) would preclude the participation in a clinical study Unwillingness or inability to comply with study and follow-up procedures

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Cohort 1<br>Study procedures Lenvatinib during week 1-12 rhTSH-stimulated I-124 dosimetry at week 0, 6 and 12 rhTSH-stimulated I-131 therapy at week 13 (if eligible) Intra-therapeutic I-131 dosimetry at week 13 (if eligible) Biopsy at week 0 and 6 F-18 FDG PET/CT at week 0, 6, 12, 24 and 36 Tg levels at week 0, 6, 12, 24 and 36 QoL assessment at week 0, 6, 12, 24 and 36 | Radiation: rhTSH-stimulated I-124 dosimetry<br>* Preparation: Low iodine diet 7 days prior to I-124 ingestion until 24 hours post-ingestion Thyrogen injections 24 and 48h prior to I-124 ingestion Procedures following Jentzen et al: Ingestion of capsule with 37±10% MBq I-124 I-124 PET/CT at 24 and 96h post-ingestion Blood draws at 2, 24 and 96h post-ingestion Whole body counting at 2, 24 and 96h post-ingestion<br>Radiation: Intra-therapeutic I-131 dosimetry<br>* Procedures following EANM guidelines: I-131 SPECT/CT at 2, 6, 24, 96 and 144h post-ingestion Blood draws at 2, 6, 24, 96 and 144h post-ingestion Whole body counting at 2, 6, 24, 96 and 144h post-ingestion<br>|
| Other: Cohort 2<br>Study procedures (in case of 12-wk lenvatinib): Lenvatinib during week 1-12 rhTSH-stimulated I-124 dosimetry at week 0 and 12 rhTSH-stimulated I-131 therapy at week 13 (if eligible) Intra-therapeutic I-131 dosimetry at week 13 (if eligible) Biopsy at week 0 and 6 F-18 FDG PET/CT at week 0, 12, 24 and 36 Tg levels at week 0, 6, 12, 24 and 36 QoL assessment at week 0, 6, 12, 24 and 36 Study procedures (in case of 6-wk lenvatinib) Lenvatinib during week 1-6 rhTSH-stimulated I-124 dosimetry at week 0 and 6 rhTSH-stimulated I-131 therapy at week 13 (if eligible) Intra-therapeutic I-131 dosimetry at week 13 (if eligible) Biopsy at week 0 and 6 F-18 FDG PET/CT at week 0, 6, 12, 24, 30 and 36 Tg levels at week 0, 6, 12, 24, 30 and 36 QoL assessment at week 0, 6, 12, 24, 30 and 36 | Radiation: rhTSH-stimulated I-124 dosimetry<br>* Preparation: Low iodine diet 7 days prior to I-124 ingestion until 24 hours post-ingestion Thyrogen injections 24 and 48h prior to I-124 ingestion Procedures following Jentzen et al: Ingestion of capsule with 37±10% MBq I-124 I-124 PET/CT at 24 and 96h post-ingestion Blood draws at 2, 24 and 96h post-ingestion Whole body counting at 2, 24 and 96h post-ingestion<br>Radiation: Intra-therapeutic I-131 dosimetry<br>* Procedures following EANM guidelines: I-131 SPECT/CT at 2, 6, 24, 96 and 144h post-ingestion Blood draws at 2, 6, 24, 96 and 144h post-ingestion Whole body counting at 2, 6, 24, 96 and 144h post-ingestion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fraction of RAI-R thyroid cancer patients who are eligible for I-131 therapy after 6- or 12-week lenvatinib treatment | Patients are deemed eligible for I-131 therapy if the therapeutic activity (max. 7.4 GBq) will lead to (1) an expected absorbed dose >20 Gy in at least one lesion, (2) a blood dose <2 Gy and (3) whole body retention <3.0 or 4.4 GBq at 48h post-ingestion in presence or absence of diffuse pulmonary metastases, respectively. | 2-3 months after completed inclusion of all study participants | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extent of RAI uptake at baseline and after 6- or 12-week lenvatinib | Assessing expected absorbed dose [Gy] per lesion or critical organ using I-124 PET/CT, whole body counting and blood sampling | 0, 6, 12 weeks after inclusion | 
| Optimal duration of lenvatinib treatment for maximum redifferentiation to occur | Either 6 of 12 weeks after comparing (1) fraction of patients eligible for I-131 therapy, (2) expected absorbed dose [Gy] per lesion or critical organ and (3) toxicity incidence and severity | 3 months after completed inclusion of cohort 1 | 
| Extent of RAI uptake after I-131 therapy | Assessing expected absorbed dose [Gy] per lesion or critical organ using intra-therapeutic I-131 SPECT/CT, whole body counting and blood sampling | 7 or 12 weeks after inclusion | 
| Metabolic treatment response using F-18 FDG PET | Metabolic response will be assessed using PERCIST v1.0. Tumor response is defined as complete response, partial response, stable response or progressive disease. | 0, 6, 12, 24, 30, 36 weeks after inclusion | 
| Unstimulated (TSH suppressed) thyroglobulin levels | Assessment of biochemical treatment response | 0, 6, 12, 24, 30, 36 weeks after inclusion | 
| Overall survival at 36 weeks after initation of lenvatinib |  | 9 months after inclusion | 
| Best objective response at 36 weeks after initation of lenvatinib |  | 9 months after inclusion | 
| Progression free survival at 36 weeks after initation of lenvatinib |  | 9 months after inclusion | 
| Incidence and severity of toxicities according to CTCAE 5.0 |  | during 0-9 months after inclusion | 
| Quality of life using standardized questionnaire ThycaQoL |  | 0, 6, 12, 24, 30, 36 weeks after inclusion | 
| Quality of life using standardized questionnaire RAND36 |  | 0, 6, 12, 24, 30, 36 weeks after inclusion | 
| Quality of life using standardized questionnaire EQ5D5L |  | 0, 6, 12, 24, 30, 36 weeks after inclusion | 
| Quality of life using standardized questionnaire Distress thermometer |  | 0, 6, 12, 24, 30, 36 weeks after inclusion |