Reinducing Radioiodine-Sensitivity in Radioiodine-Refractory Thyroid Cancer Using Lenvatinib (RESET): Study Protocol for a Single-Center, Open Label Phase II Trial

Maaike Dotinga, Dennis Vriens, Floris H P van Velden, Mette K Stam, Jan W T Heemskerk, Petra Dibbets-Schneider, Martin Pool, Daphne D D Rietbergen, Lioe-Fee de Geus-Oei, Ellen Kapiteijn, Maaike Dotinga, Dennis Vriens, Floris H P van Velden, Mette K Stam, Jan W T Heemskerk, Petra Dibbets-Schneider, Martin Pool, Daphne D D Rietbergen, Lioe-Fee de Geus-Oei, Ellen Kapiteijn

Abstract

Background: Management of patients with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) is a challenge as I-131 therapy is deemed ineffective while standard-of-care systemic therapy with tyrosine kinase inhibitor (TKI) lenvatinib is associated with frequent toxicities leading to dose reductions and withdrawal. A potential new treatment approach is to use TKIs as redifferentiation agent to restore RAI uptake to an extent that I-131 therapy is warranted. Prior studies show that short-term treatment with other TKIs restores RAI uptake in 50-60% of radioiodine-refractory DTC patients, but this concept has not been investigated for lenvatinib. Furthermore, the optimal duration of treatment with TKIs for maximal redifferentiation has not been explored. Methods and Design: A total of 12 patients with RAI-refractory DTC with an indication for lenvatinib will undergo I-124 PET/CT to quantify RAI uptake. This process is repeated after 6 and 12 weeks post-initiating lenvatinib after which the prospective dose estimate to target lesions and organs at risk will be determined. Patients will subsequently stop lenvatinib and undergo I-131 treatment if it is deemed effective and safe by predefined norms. The I-124 PET/CT measurements after 6 and 12 weeks of the first six patients are compared and the optimal timepoint will be determined for the remaining patients. In all I-131 treated patients post-therapy SPECT/CT dosimetry verification will be performed. During follow-up, clinical response will be evaluated using serum thyroglobulin levels and F-18 FDG PET/CT imaging for 6 months. It is hypothesized that at least 40% of patients will show meaningful renewed RAI uptake after short-term lenvatinib treatment. Discussion: Shorter treatment duration of lenvatinib treatment is preferred because of frequent toxicity-related dose reductions and drug withdrawals in long-term lenvatinib treatment. Short-term treatment with lenvatinib with subsequent I-131 therapy poses a potential new management approach for these patients. Since treatment duration is reduced and I-131 therapy is more tolerable for most patients, this potentially leads to less toxicity and higher quality of life. Identifying RAI-refractory DTC patients who redifferentiate after lenvatinib therapy is therefore crucial. Trial Registration: ClinicalTrials.gov, NTC04858867.

Keywords: I-124 dosimetry; lenvatinib; radioiodine uptake; radioiodine-refractory DTC; redifferentiation; thyroid cancer.

Conflict of interest statement

E. Kapiteijn: prior thyroid cancer advisory boards Bayer AG, Eisai Co., Ltd. and Eli Lilly and Company. All other authors declare that they have no potential conflict of interest.

Figures

Figure 1
Figure 1
Flowchart of the study for patients in cohort 1, including lenvatinib treatment, dosimetry procedures, I-131 therapy and response evaluation with F-18 FDG PET/CT and serum thyroglobulin levels.

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