Papillary thyroid cancer (PTC) is the most common form of differentiated thyroid cancer (DTC). The traditional first line treatment for patients with advanced DTC after surgical resection is radioactive iodine (RAI) therapy. However, less than a quarter of patients with lung metastases will achieve a complete response to RAI therapy, and this therapy carries the risk of pulmonary fibrosis and an increasingly recognized risk of secondary malignancies.

This will be an open label, non-randomized study to evaluate the efficacy and safety of the combination of selpercatinib followed by 131I therapy for patients with RET fusion differentiated thyroid cancer. The primary Phase II objective will be to evaluate the pulmonary structural response rate at 18 months to the combination of selpercatinib given for 6-months followed by 131I therapy. This is exempt from Investigational New Drug requirements per the FDA.

Inclusion Criteria:

1. Age 2-25 years, inclusive

2. Histologic diagnosis of a differentiated thyroid cancer, status post thyroidectomy and adequate local therapy (e.g., lymph node dissection as per standard of care) for metastatic disease in the neck in the opinion of the treating investigator

3. Anatomically evaluable disease on chest CT (Computed Tomography) meeting one of the following criteria (obtained within 90 days of enrollment):

   A. multiple (> 10) noncalcified solid pulmonary nodules visible on CT and/or B. enlarging, discrete pulmonary nodules visible on CT of any number consistent with metastatic disease

4. Identification of an activating RET gene alteration (fusion or mutation). The RET alteration result should be generated from a laboratory with specific certifications (depending on country requirement) that clearly denotes the presence of a RET alteration without known kinase domain resistance mutation

5. Lansky/Karnofsky performance status >50%

6. Adequate Organ Function

   A. Bone Marrow Function:

   • Peripheral absolute neutrophil count (ANC) ≥1500/µL
   • Platelet count ≥ 100,000/µL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
   • Hemoglobin ≥ 9.0 g/dL at baseline (may receive Red Blood Cell transfusions).

   B. Adequate Renal Function: Creatinine clearance or radioisotope Glomerular Filtration Rate (GFR) ≥ 70 mL/min/1.73 m2 or a maximum serum creatinine based on age/gender.

   C. Adequate Liver Function

   • Bilirubin (sum of conjugated + unconjugated) < / = 1.5 x upper limit of normal (ULN) for age. Except participants with a documented history of Gilbert syndrome who must have a total bilirubin level of <3.0X ULN
   • Alanine aminotransferase (ALT) <2.5X ULN OR <5x ULN if the liver has tumor involvement. For the purpose of this study, the ULN for ALT is 45 U/L.
   • Serum albumin ≥ 2 g/dL

7. Patient must have normal serum potassium, calcium, and magnesium levels (may be receiving supplements)

8. Men with partners of childbearing potential or women of childbearing potential must agree to use a highly effective contraceptive method during treatment with study drug and for 6 months following the last dose of study drug. Selpercatinib could impair fertility in males and females. Advise women not to breastfeed during treatment with selpercatinib and for 1 week following the final dose

9. Women of childbearing potential must have a negative pregnancy test (serum or urine, consistent with local regulations) documented within 24 hours prior to treatment with study drug and at least monthly while on study treatment

Exclusion Criteria:

1. No prior systemic therapy for thyroid cancer, including RET inhibitors. Note: prior 131I is allowed.
2. Females who are pregnant or breastfeeding are excluded due to the potential risks of selpercatinib and radioactive iodine to the fetus/neonate.
3. Concurrent therapy: Patients currently receiving a strong CYP3A4 inducer or inhibitor are not eligible. Strong inducers or inhibitors of CYP3A4 should be avoided 14 days prior to treatment to the end of the study treatment.
4. Patients with clinically significant active cardiovascular disease, Torsades de pointes, or history of myocardial infarction within 6 months prior to planned start of study treatment or prolongation of the QT interval corrected for heart rate using Fridericia's formula (QTcF) >470 msec.
5. Have clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the drug.
6. Are taking a concomitant medication that is known to cause QTc prolongation.
7. Active hemorrhage or at significant risk for hemorrhage.
8. Uncontrolled hypertension (blood pressure greater than 140/90 in adults or greater than the 95% for height and gender in children). Use of anti-hypertensives to control blood pressure is permitted.