Can Selumetinib make advanced thyroid cancer sensitive to radioactive iodine therapy again?

• Register: ISRCTN
• Last refreshed on: 15 November 2021
• Main ID: ISRCTN17468602
• Date of registration: 02/12/2015
• Prospective Registration: Yes
• Primary sponsor: Sheffield Teaching Hospitals NHS Trust
• Public title: Can Selumetinib make advanced thyroid cancer sensitive to radioactive iodine therapy again?
• Scientific title: SEL-I-METRY: Investigating the potential clinical benefit of Selumetinib in resensitising advanced iodine refractory differentiated thyroid cancer to radioiodine therapy
• Date of first enrolment: 01/09/2016
• Target sample size: 60
• Recruitment status: Stopped
• URL: https://www.isrctn.com/ISRCTN17468602
• Study type: Interventional
• Study design: Non-randomised study (Treatment)
• Phase: Not Applicable

Countries of recruitment

England, Scotland, United Kingdom

Contacts

• Name: Jayne Swain

Key inclusion & exclusion criteria

Inclusion criteria:
Current participant inclusion criteria as of 03/11/2021:
1. Diagnosed with locally advanced or metastatic differentiated thyroid cancer (papillary, follicular, Hürthle cell, or poorly differentiated carcinoma) with at least one measurable lesion as measured by computed tomography (CT) or magnetic resonance imaging (MRI)
2. Participants must have iodine refractory disease, defined below:
2.1. One or more measurable lesions that do not demonstrate iodine uptake on a previous radioiodine scan (diagnostic uptake or post therapy)
OR
2.2. One or more measurable lesions that have progressed by RECIST 1.1 criteria within 12 months of I131 therapy, despite demonstrable radioiodine avidity at the time of that treatment
3. Participants must have radiological progression by RECIST 1.1 criteria within the prior 12 months
4. Measurable disease by RECIST 1.1 criteria. Baseline scan must be completed within 4 weeks prior to the start of treatment.
5. ECOG Performance Status = 1 and able to tolerate radioiodine therapy
6. Life expectancy of at least 12 weeks
7. Required laboratory values within 14 days of day 1 of treatment:
7.1. Adequate thyroidstimulating hormone (TSH) suppression < 0.5 mU/L
7.2. Creatinine clearance >50 ml/min,
7.3. Absolute Neutrophil Count =1.5x109/L (1500 per mm3)
7.4. Platelets =100x109/L (100,000 per mm3)
7.5. Haemoglobin >9.0 g/dL
7.6. Serum bilirubin =1.5 x upper limit of normal (ULN)
7.7. Patients with no liver metastasis must have AST or ALT = 2.5 x ULN
7.8. Patients with liver metastasis must have AST or ALT = 5 x ULN. If patients have AST or ALT > 3.5 x ULN and = 5 x ULN they must have an ALP= 6 x ULN
8. Patient’s 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.
9. Able to give informed consent and willing to follow trial protocol.
10. Aged over 18
11. Female participants of childbearing potential must have a negative pregnancy test within 24 hours prior to starting therapy and agree to use dual methods of contraception for the duration of the trial and 6 months after completing treatment. Male participants must agree to use a barrier method of contraception for the duration of the trial and 4 months after completing treatment, if sexually active with a female of childbearing
potential.


Previous participant inclusion criteria:
1. Diagnosed with locally advanced or metastatic differentiated thyroid cancer (papillary, follicular, Hürthle cell, or poorly differentiated carcinoma) with at least one measurable lesion as measured by computed tomography (CT) or magnetic resonance imaging (MRI)
2. Participants must have iodine refractory disease, defined below:
2.1. One or more measurable lesions that do not demonstrate iodine uptake on a previous radioiodine scan (diagnostic uptake or post therapy)
OR
2.2. One or more measurable lesions that have progressed by RECIST 1.1 criteria within 12 months of I131 t
Exclusion criteria:
Current participant exclusion criteria as of 03/11/2021:
1. Foci of anaplastic thyroid cancer identified on histology
2. Able to receive curative surgery or radiation therapy
3. Major surgery with the exception of surgical placement for vascular access, open biopsy, or significant traumatic injury = 30 days prior to registration
4. Previous or concurrent cancer distinct in primary site or histology from thyroid cancer within previous 5 years, except for cervical cancer in situ, treated basal cell carcinoma, squamous cell carcinoma of the skin or superficial bladder tumour
5. Have received or are receiving an IMP or other systemic anticancer treatment within 4 weeks prior to the first dose of study treatment (6 weeks for nitrosoureas, mitomycin, and suramin), or within a period during which the IMP or anticancer treatment has not been cleared from the body (e.g. a period of 5 ‘halflives’), whichever is the most appropriate and as judged by the investigator
6. Any unresolved toxicity =CTCAE Grade 2 from previous anticancer therapy, except for alopecia
7. Prior exposure to Tyrosine Kinase, MEK, RAS or RAF inhibitors
8. Known or suspected allergy to Selumentinib or hypersensitivity to Selumetinib or any excipient agents or history of allergic reactions attributed to compounds of similar chemical or biologic composition to Selumetinib
9. Known or suspected brain metastases or spinal cord compression, unless the condition has been asymptomatic, has been treated with surgery and / or radiation, and has been stable without requiring corticosteroids nor anticonvulsant medications for at least 4 weeks prior to the first dose of study medication
10. Requiring medication with high iodine content (e.g. amiodarone)
11. Participants who have had a iodine contrast enhanced CT scan in previous 2 months
12. Ophthalmological conditions as follows:
12.1 Intra-ocular pressure >21 mmHg, or uncontrolled glaucoma (irrespective of intra-ocular pressure)
12.2 Current or past history of retinal pigment epithelial detachment (REPD)/central serous retinopathy or retinal vein occlusion
13. Any of the following cardiac conditions:
13.1 Uncontrolled hypertension (BP >150/95 mmHg despite medical therapy)
13.2 Acute coronary syndrome within 6 months prior to starting treatment
13.3 Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical therapy)
13.4 Symptomatic heart failure (NYHA grade II-IV), prior or current cardiomyopathy, or severe vascular disease
13.5 Prior or current cardiomyopathy including but not limited to the following:
13.5.1 known hypertrophic cardiomyopathy
13.5.2 known arrhythmogenic right ventricular cardiomyopathy
13.6 Severe valvular heart disease
13.7 Left ventricular ejection fraction <55% measured by echocardiography
13.8 Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest
13.9 QTcF >450ms or other factors that increase the risk of QT prolongation
14. Participants known to be infected with human immunodeficiency virus (HIV) or hepatitis B


Previous

Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Thyroid cancer
Cancer
Malignant neoplasm of thyroid gland

Intervention(s)

Participants will receive an initial I-123 SPECT/CT scan (under rhTSH stimulation) to determine baseline iodine uptake in thyroid cancer lesions. Participants will then receive Selumetinib in a tablet form, which they are to take home and administer according to the dosing schedule (150mg/day, therefore 6 x 25mg tablets, 3 twice per day).

Participants will then undergo another I-123 SPECT/CT after this 28-day period to determine if the iodine uptake in their thyroid cancer lesions has increased. If iodine uptake has increased sufficiently, participants will be referred for further I-131 therapy. Participants will be asked to continue taking Selumetinib from the time that they have the second I-123 scan to the time they receive their I-131. Participants who do not go on the receive I-131 therapy may stop Selumetinib treatment.

The total duration of the treatment will depend on the elapsed time between the second I-123 SPECT/ CT scan, the decision about I-131 therapy being made, and the I-131 therapy being received. The minimum duration of Selumetinib therapy is approximately 28 days. The maximum may be longer (up to 50 days).

Participants who do not go on to receive I-131 will have a single follow-up appointment 30 days after the final dose of Selumetinib. Participants who do go on to receive I-131 will be followed up three-monthly for one year, and then six-monthly until the end of the trial.

Primary Outcome(s)

Progression-free survival is determined at 12 months.

Secondary Outcome(s)

1. Safety is determined based on the occurrence of SAEs, SARs and SUSARs at 48 months
2. Toxicity is determined by the total number of adverse reactions, as graded by CTCAE V4.0, as identified in routine clinical assessments at each centre at 48 months
3. Radiological response rate for patients receiving radioiodine therapy is recorded at 48 months using ongoing CT scans (every 3 months for the first 6 months and then every 6 months thereafter)
4. Overall survival is determined from medical records at 48 months
5. Sufficient iodine uptake is assessed centrally using pre-defined criteria (an increase of 30% from baseline in participants who demonstrated baseline radioiodine uptake, or an increase of any level for participants who have no baseline radioiodine uptake) on an ongoing basis, with a report being collated at 48 months

Secondary ID(s)

2015-002269-47

19937

Source(s) of Monetary Support

Cancer Research UK, AstraZeneca, Senofi-Genzyme

Ethics review

Status:
Approval date:
Contact:

East Midlands – Leicester South Research Ethics Committee, 02/12/2015, ref: 15/EM/0455

Results

• Results available: Yes
• Date Completed: 05/11/2020