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

A combination of surgery, radioactive iodine (RAI) therapy and long-term thyroid stimulating hormone (TSH) suppression cures many patients with differentiated thyroid cancer, namely papillary and follicular cancers. However around 10% of patients develop advanced disease which will eventually become resistant to therapy. Prognosis for these patients is poor with a 10-year overall survival rate of 10% compared with 56% in patients with RAI avid metastases [2].

Attempts have been made in the past to restore RAI avidity with lithium carbonate [3] and retinoic acid [4], but results have been disappointing and have failed to show clear clinical benefit.

More recently a number of multi-targeted kinase inhibitors have been tested; two phase III trials have shown significant improvements in progression free survival (PFS) with Sorafenib and Lenvatinib when compared with placebo [5, 6]. While these improvements are certainly to be welcomed, both agents cause toxicities, including fatigue, diarrhoea, hand-foot syndrome, weight loss and hypertension. Since they are taken continuously to disease progression this can have a significant impact on patients’ quality of life.

Mutations of RET, RAS or BRAF are present in approximately 70% of papillary thyroid cancers [7]. These oncogenes are part of the mitogen-activated protein kinase (MAPKinase) signalling pathway. Preclinical data suggest that activation of this pathway is critical to tumour initiation and transformation, and also results in reduced expression of genes involved in iodide metabolism, in particular the sodium iodide symporter (NIS) which is responsible for the uptake of iodine by thyroid cells. For example, papillary thyroid cancers with BRAF mutations are associated with reduced expression of key genes involved in iodine metabolism, including NIS [8].

In vitro work with rat thyroid PCCL3 cells with induced BRAF mutations has shown that treating the cells with a MEK inhibitor restores expression of TSH receptors, NIS and thyroglobulin, indicating that the effects of BRAF mutation to reduce NIS expression are potentially reversible [9].

Selumetinib is an oral, potent and highly selective, allosteric MEK1/2 inhibitor. MEK1/2 are critical components of the MAPKinase pathway. This pathway is frequently dysregulated due to activating mutations in various oncogenes, including RAS or RAF. Inhibition of MEK, which lies downstream of these targets, blocks inappropriate signal transduction offering a promising therapeutic strategy. Selumetinib is not currently approved for use in any clinical indications in humans, but phase I and II trials have been conducted in pancreatic cancer [10], melanoma [11‐16], non-small cell lung cancer [17‐19] and differentiated thyroid cancer [20‐22] and it has recently been designated orphan drug status for treatment of differentiated thyroid cancer in the United States. The drug has been found to have an acceptable side effect profile; most frequently reported side effects include diarrhoea, nausea and vomiting, dyspnoea, blurred vision, tiredness and acneiform rash.

A previously reported pilot study [21] tested the use of Selumetinib 75 mg twice daily for four weeks in patients with radioiodine refractory differentiated thyroid cancer. All participants who started therapy were able to complete the full prescribed course of Selumetinib without dose reductions or delays. No toxic effects of Grade 3 or above were noted. Of 20 participants evaluated, Selumetinib increased radioiodine uptake in 12 (60%). Eight of these 12 achieved sufficient increased uptake for further radioiodine therapy to be viable (67%). Of the eight participants treated with radioiodine, five (63%) had partial responses and three (38%) had stable disease. All participants had decreases in serum thyroglobulin level.

Standard practice in the UK, endorsed by recently published guidelines [23] is to prescribe an empirical activity, typically 3.7–7.4GBq iodine-131 (I-131) to patients with metastatic disease. It is well recognised that this leads to a wide range of absorbed dose delivered to tumour targets and organs at risk, and therefore very likely to lead to widely divergent outcomes. This is in stark contrast to modern external-beam radiotherapy practice where absorbed dose delivered to target volumes and to nearby organs at risk is prescribed and can be accurately measured. There have been calls to address this issue [24]. There is evidence that the absorbed dose delivered to thyroid remnants correlates with response for patients undergoing radioiodine ablation [25] and this study will investigate a similar relationship for patients with locally advanced or metastatic disease.

The previously described pilot study [21] used pre-treatment iodine-124 (I-124) positron emission tomography (PET) to estimate absorbed dose to individual lesions. A minimum lesion absorbed dose of 20Gy was chosen as a cut off for proceeding with further I-131 therapy. The choice of cut off used in this pilot does not appear to have been made on the basis of any published data. Additionally the absorbed doses were not verified after treatment, unlike in this study.

The SEL-I-METRY trial has been designed to demonstrate the broader clinical impact of the use of Selumetinib therapy to re-sensitise radioiodine refractory thyroid cancer patients to treatment with radioiodine. The trial will address the dosimetry of I-131 therapy to investigate the relationship between the absorbed dose delivered and the clinical benefit from therapy. In addition the extent to which the therapeutic activity of I-131 can be individualised from the absorbed doses predicted in a pre-therapy tracer study will be analysed using dosimetric calculations. It will also explore possible biomarkers for response to this strategy, including measurement of post I-131 protein bound iodine (PBI) and molecular markers both in tumour tissue and circulating cell-free DNA.

SEL-I-METRY is a UK, single arm, multi-centre, two-stage phase II proof of concept trial investigating the use of Selumetinib to resensitise iodine refractory patients with differentiated thyroid cancer. To ensure at least 38 participants are treated with I-131, approximately 60 participants will be recruited from eight NHS Hospitals. Participants will receive 75 mg of Selumetinib orally twice daily for four weeks (dose may be reduced due to adverse events) and will then be assessed for evidence of an increase in radioiodine uptake via iodine-123 (I-123) single photon emission computed tomography/computed tomography (SPECT/CT); those showing sufficient uptake will then receive I-131 therapy (further details on patient imaging and dosimetry can be found in Additional file 1). A previous pilot study [21] used I-124 sodium iodide (NaI) although there is currently no commercially available source of this isotope in the UK. This trial therefore elected to use I-123 as an alternative to determine changes in radioiodine uptake following Selumetinib therapy, and to predict likely lesional absorbed dose in participants proceeding to I-131 therapy. The use of I-123 as opposed to I-124 is not thought to pose any significant risk to the current trial; whilst theoretically there may be advantages to using I-124, there are no known clinical comparator studies between the two techniques and a pragmatic decision to use I-123 was deemed reasonable by the trial team. An early stopping rule is incorporated in the case where none of the first 10 patients treated with Selumetinib show sufficient iodine uptake to progress to I-131 therapy; should this happen the trial may be discontinued. The study protocol and this manuscript have been written in accordance with Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines [26] (checklist included as an Additional file 2).

The trial has received ethics approval from the NHS National Research Ethics Service (NRES) East Midlands-Leicester South (15/EM/0455).

This trial aims to assess the efficacy of Selumetinib followed by I-131 therapy in iodine refractory patients with differentiated thyroid cancer demonstrating increased iodine uptake following initial treatment with Selumetinib. The primary objective is to assess whether the treatment schedule leads to increased PFS compared to historical control data. PFS has been chosen as the primary endpoint assessing efficacy to allow for proof of concept in this Phase II trial to be obtained in a quick and robust manner and as it is clinically relevant to patients.

Based on previous data, median progression free survival is estimated to be approximately six months, corresponding to 25% of patients alive and progression free at 12 months [5]; a clinically important increase suggesting further investigation of Selumetinib (assuming exponential survival) is deemed to be an increase to 44% (hazard ratio = 0.6). Using a 1-sided 10% significance level, and with 80% power, 38 patients with sufficient radioiodine uptake following Selumetinib therapy are required (allowing for 10% drop out), based on a Case and Morgan two-stage design [27]. Assuming sufficient increase in iodine uptake to warrant I-131 therapy in 60% of patients [21], approximately 60 patients will be recruited in total.

A formal interim analysis will be performed after 21 participants with sufficient iodine uptake following Selumetinib treatment have been recruited and after a minimum of 12 months recruitment. If there is evidence to suggest that 12 month progression free survival is no better than 25% based upon the Nelson-Aalen estimator then the trial may be terminated early for lack of activity.

If none of the first 10 participants treated with Selumetinib has sufficient increase in iodine uptake to progress to I-131 therapy, then the trial may be discontinued. This corresponds to excluding an uptake rate of at least 26% with 95% confidence.

Inclusion and exclusion criteria can be found in Table 1. Patients with Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of evidence of haemolysis or hepatic pathology) will be eligible. Eligibility waivers will not be granted in this trial.

Written informed consent will be obtained prior to the commencement of all trial assessments, tests and procedures by authorised members of the trial team. Screening investigations will be conducted to confirm eligibility following consent and prior to registration. These investigations will include: CT neck, chest, abdomen and pelvis (without iodinated contrast); echocardiogram/multiple gated acquisition (MUGA); single 12-lead electrocardiogram (ECG); vital signs; ophthalmology examinations (best corrected visual acuity; intraocular pressure and slit lamp fundoscopy); full blood count (FBC); urea and electrolytes (U&Es); liver function tests (LFTs) and thyroid function tests (TFTs); serum pregnancy test for premenopausal women. Eligible patients will then be registered to the trial centrally via the University of Leeds automated 24 h system. Whenever possible, a biopsy of an identified iodine refractory lesion will be obtained following registration; archival tissue from initial thyroidectomy will also be requested.

Quality of life will be assessed within 28 days of registration for all participants, and tissue samples will be collected within the same timeframe where applicable. Participants will be asked to observe a low iodine diet from two weeks prior to receiving a baseline I-123 SPECT/CT scan which must be completed within 28 days of registration; 0.9 mg recombinant human TSH (rhTSH) will be given via intramuscular administration two days and one day prior to administration of I-123. Prior to day one of treatment participants will have further assessments including repeat blood tests.

Participants will then be treated with 75 mg of oral Selumetinib twice daily for four weeks; doses will be taken approximately 12 h apart. Repeat assessments including haematology and biochemistry will be conducted on day 14 and day 28; where applicable blood samples for cell-free DNA assessment will also be collected. An I-123 SPECT/CT scan at the end of treatment, day 28 (±1 day), will be reviewed centrally. The increase in uptake will be deemed significant if there is presence of any clinically relevant, targeted uptake in a lesion in which there was previously no uptake or there is an increase of 30% or more in uptake in a lesion with evidence of some uptake on the baseline scan. Participants will be asked to recommence the low iodine diet two weeks prior to the post treatment scan and will again be administered 0.9 mg rhTSH two days and one day prior to the scan. Participants will continue to observe the low iodine diet and take Selumetinib whilst the post treatment scan is undergoing review (for a maximum of 18 days). A further two to three SPECT/CT scans will also be acquired and used to predict the radiation dose that may be achieved with radioiodine treatment.

Participants not deemed to have sufficient increase in iodine uptake will cease treatment with Selumetinib, can return to a usual diet and will continue to be followed up for safety purposes until 30 days after completion of Selumetinib treatment. These individuals will receive no further trial treatment.

Participants with sufficient increase of iodine uptake will go on to receive treatment with I-131 and will continue to take Selumetinib until two days after administration of I-131 (if applicable) when the low iodine diet can be discontinued. rhTSH 0.9 mg will be administered two days and one day prior to I-131 therapy. An activity of 5.5 GBq (±10%) I-131 sodium iodide will be administered orally. In the absence of any strong evidence of benefit from a dosimetric approach, it is felt reasonable to stick to empirical activities as per current standard UK practice. However, following I-131 therapy, dosimetry calculations will be made from three to four SPECT/CT scans. A standardised calibration protocol will be used by sites to optimise and standardise SPECT/CT image data across participants. Therefore an essential element of the this trial is the need to set up, for the first time, a network of UK centres able to perform quantitative I-123 and high activity I-131 imaging.

For participants consenting to blood sample collection for PBI analysis, samples will be collected 24 and 144 h post I-131 therapy.

Upon completion of I-131 therapy, participants will be followed up quarterly for the first 12 months and then 6 monthly for the duration of the trial (i.e. until the last patient recruited reaches 12 months follow up) or until evidence of disease progression is confirmed by CT scan. Follow-up assessments will include measurement of thyroglobulin and antithyroglobulin antibodies; thyroid function test; CT neck, thorax, abdomen and pelvis. Quality of life assessments will be repeated at each follow up for the first 12 months, and where applicable blood sample collection for cell-free DNA assessment will occur at three months and six months.

For all participants, TSH suppression to less than 0.1 units should be maintained throughout treatment and follow-up. Also, for all participants (including those not receiving I-131 therapy), assessments at 30 days post end of Selumetinib treatment will include vital signs, 12-lead ECG, haematology, echocardiogram and repeat quality of life measures.

The participant pathway can be seen schematically in Fig. 1, and Table 2 (SPIRIT diagram) details the assessment schedule.

Statistical analysis for final and interim analyses are fully detailed in separate analysis plans. The full analysis set will include all registered participants receiving at least one dose of Selumetinib and will be equivalent to the safety analysis set. The iodine uptake (IU) cohort will include participants from the full analysis set who were deemed to have sufficient I-123 uptake following treatment with Selumetinib. All other participants in the full analysis set will be the non-IU cohort. All efficacy endpoint analyses will be conducted on the IU cohort only, unless otherwise specified in the analysis plan. Safety analyses will be conducted on the safety analysis set with data summarised for each study cohort and overall during initial therapy.

A Trial Steering Committee will be convened to periodically review safety data; an independent Data Monitoring and Ethics Committee (DMEC) will review safety data to determine patterns and trends of events which would not be apparent on an individual case basis. Following the interim analysis, the DMEC may request that the trial be terminated for lack of activity if there is evidence to suggest that 12 month PFS is no better than 25% based on the Nelson-Aalen estimator.