Investigating the potential clinical benefit of Selumetinib in resensitising advanced iodine refractory differentiated thyroid cancer to radioiodine therapy (SEL-I-METRY): protocol for a multicentre UK single arm phase II trial

Abstract

Background Thyroid cancer is the most common endocrine malignancy. Some advanced disease is, or becomes, resistant to radioactive iodine therapy (refractory disease); this holds poor prognosis of 10% 10-year overall survival. Whilst Sorafenib and Lenvatinib are now licenced for the treatment of progressive iodine refractory thyroid cancer, these treatments require continuing treatment and can be associated with significant toxicity. Evidence from a pilot study has demonstrated feasibility of Selumetinib to allow the reintroduction of I-131 therapy; this larger, multicentre study is required to demonstrate the broader clinical impact of this approach before progression to a confirmatory trial. Methods SEL-I-METRY is a UK, single-arm, multi-centre, two-stage phase II trial. Participants with locally advanced or metastatic differentiated thyroid cancer with at least one measureable lesion and iodine refractory disease will be recruited from eight NHS Hospitals and treated with four-weeks of oral Selumetinib and assessed for sufficient I-123 uptake (defined as any uptake in a lesion with no previous uptake or 30% or greater increase in uptake). Those with sufficient uptake will be treated with I-131 and followed for clinical outcomes. Radiation absorbed doses will be predicted from I-123 SPECT/CT and verified from scans following the therapy. Sixty patients will be recruited to assess the primary objective of whether the treatment schedule leads to increased progression-free survival compared to historical control data. Discussion The SEL-I-METRY trial will investigate the effect of Selumetinib followed by I-131 therapy on progression-free survival in radioiodine refractory patients with differentiated thyroid cancer showing increased radioiodine uptake following initial treatment with Selumetinib. In addition, information on toxicity and dosimetry will be collected. This study presents an unprecedented opportunity to investigate the role of lesional dosimetry in molecular radiotherapy, leading to greater personalisation of therapy. To date this has been a neglected area of research. The findings of this trial will be useful to healthcare professionals and patients alike to determine whether further study of this agent is warranted. It is hoped that the development of the infrastructure to deliver a multicentre trial involving molecular radiotherapy dosimetry will lead to further trials in this field. Trial registration SEL-I-METRY is registered under ISRCTN17468602 , 02/12/2015. Electronic supplementary material The online version of this article (10.1186/s12885-019-5541-4) contains supplementary material, which is available to authorized users.

Novel Targeted Therapies for Metastatic Thyroid Cancer—A Comprehensive Review

“…Interestingly, these preliminary data suggest a particularly high efficacy of this therapeutic approach in NRAS -mutated tumors. Given these promising results, there are several ongoing clinical trials utilizing selumetinib as an adjunct to RAI therapy in larger patients populations ( Table 2 ) [ 127 ]. The second-generation MEK inhibitor trametinib is being evaluated in an ongoing phase II trial implementing pretreatment with trametinib, followed by 124I PET/CT-based lesional dosimetry and RAI therapy in patients with sufficiently restored RAI uptake ( identifier NCT02152995) ( Table 2 ).…”

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“…Numerous small molecule compounds have been developed that target the MAPK pathway and based on the role of MAPK signaling in promoting EMP and stemness, inhibition of this pathway presents a logical therapeutic target. In line with this thought, emerging evidence indicates that selumetinib, a MEK1/2 inhibitor which has been used for phase I and II clinic trials in several kinds of malignant diseases (Bodoky et al, 2012;Hayes et al, 2012;Catalanotti et al, 2013;Ho et al, 2013;Jänne et al, 2013;Janne et al, 2015Janne et al, , 2016Carvajal et al, 2014Carvajal et al, , 2015Gupta et al, 2014;Brown et al, 2019), might be a novel therapeutic strategy for breast cancer. For example, Zolkiewska and colleagues found that selumetinib blocked EGF-induced expansion of CD44+/CD24-breast cancer stem cell associated populations (Wise and Zolkiewska, 2017).…”

Current and Future Role of Tyrosine Kinases Inhibition in Thyroid Cancer: From Biology to Therapy

“…Selumetinib, a MEK1/2 inhibitor, is under investigation in a multicenter, phase-II trial with promising results based on the pilot study performed by Ho et al where 12/20 (60%) participants increased radioiodine uptake, with 8/12 being able to receive RAI. 63% achieved partial responses and 37% stable disease as best radiological response [153,154].…”