A Prospective, Multi-Centre Trial of TKI Redifferentiation Therapy in Patients With RAIR Thyroid Cancer (I-FIRST Study)

Inclusion Criteria:

1. Histologically-confirmed differentiated (including poorly differentiated) thyroid cancer that is either locally advanced or metastatic.
2. Age \> 18 years.
3. Life expectancy \> 12 weeks.
4. Documented radiological progression by RECIST 1.1 in last 12 months.
5. Radioiodine refractory (at least one of):

   1. one measurable lesion without radioiodine uptake on 131I scan,
   2. at least one measurable lesion that had progressed by RECIST criteria within 12 months of 131I therapy despite 131I avidity at time of treatment, or
   3. cumulative treatment with \>24 GBq (600 mCi) of 131I.
6. At least one evaluable lesion as per RECIST v1.1 that has not been treated with local radiation therapy within 3 months prior to the first dose of TKI. Irradiated lesions can only be included as an evaluable lesion if it has shown radiological progression as per RECIST v1.1 on subsequent imaging following irradiation.
7. NRAS or BRAF V600E mutation tested by NGS in a NATA accredited laboratory or by recognised sequencing platform.
8. ECOG 0-1.
9. Informed consent.
10. Adequate haematological and biochemical parameters:

    1. Haemoglobin ≥ 9g/dL
    2. Neutrophils ≥ 1.5 x 109/L
    3. Platelets ≥ 100 x 109/L
    4. INR ≤ 1.4
    5. Serum Creatinine ≤ 1.3 x ULN
    6. Estimated Creatinine Clearance ≥ 30 ml/min (by Cockcroft Gault Formula)
    7. Serum ALT and AST ≤ 2.5 x ULN
    8. Serum Total Bilirubin ≤ 1.5 x ULN.
    9. TSH suppression \<0.1mU/L or otherwise consistent with 2015 ATA Guidelines on Thyroid Cancer

Exclusion Criteria:

1. Anaplastic thyroid cancer.
2. Suitable for curative surgery or radiotherapy.
3. Other anti-cancer (including TKI) therapy in prior 6 weeks.
4. Concurrent malignancy other than non-melanoma skin cancer. Prior malignancies treated with curative intent and no evidence of recurrence in past three years may be allowed upon discussion with the medical monitor.
5. Unstable brain metastasis. Treated or non-treated brain metastasis are allowed if neurologically stable, asymptomatic, on a stable steroid dose for a period of 2 weeks, and not anticipated to require any intervention during the trial treatment period. If treated with radiation or surgery, any related AE's should have recovered to ≤ grade 1 prior to enrolment on trial.
6. Pregnancy, breastfeeding or unwilling to use contraception in those of child-bearing age.
7. Significant medical condition that would prevent compliance with study procedures.
8. History of retinal vein occlusion or retinopathy.
9. Iodine-containing contrast scan within 8 weeks of planned 124I scan.