Inclusion Criteria:

• Are of an acceptable age to provide informed consent according to local regulations and are at least 18 years of age (patients as young as 12 years of age will be allowed if permitted by local regulatory authorities and institutional review boards).
  • All patients of 12 years of age and older, after giving assent / legally designated representative/ participant written consent.
• Histologically or cytologically confirmed, unresectable, locally advanced and/or metastatic MTC and no prior history of treatment with kinase inhibitors for advanced/metastatic disease. Patients with mixed histology (e.g., incidental papillary thyroid cancer identified at the time of resection) are eligible if MTC is the dominant histology. Prior systemic or radiation therapy in the adjuvant setting may be allowed with discussion and approval by the Lilly medical team.
• Radiographic progressive disease per RECIST 1.1 (Eisenhauer et al. 2009) at screening compared with a previous image taken within the prior 14 months as assessed by the BICR. Patients with measurable or non-measurable but evaluable disease are eligible; however, patients with non-measurable disease may not have disease limited to bone sites only.
• A RET gene alteration identified in a tumor, germline DNA or blood sample (e.g., cfDNA). The RET alteration result should be generated from a laboratory with CLIA, ISO/IEC, CAP, or other similar certification. Lilly should be contacted to discuss test results from labs where such certification is not clearly demonstrated to determine eligibility; if certification is not required in the patient’s country, the Sponsor may allow enrollment using a result from a non-certified lab if sufficient evidence can be provided as to the accuracy of the result. A positive germline test for a RET mutation is acceptable given the test was determined by internal institutional quality standards and performed for clinical evaluation. In all cases, a redacted Molecular Pathology Report or other report(s) describing RET (and any co-occurring findings, if applicable) alteration analysis should be submitted to Lilly or designee during/prior to eligibility.
  • Mandatory provision of an unstained, archived tumor tissue sample in a quantity sufficient to allow for retrospective central analysis of RET mutation status (for confirmation). 
• Eastern Cooperative Oncology Group (ECOG) performance status score (Oken et al. 1982) of zero to two.
• Ability to swallow capsules and comply with treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
• Patients must have discontinued from previous treatments as shown below and fully recovered.  Consult with the Lilly medical team for the appropriate length of time prior to the first dose of study treatment on additional therapies not mentioned.
• Patients must have normal serum potassium, calcium, and magnesium levels (may be receiving supplements.
• Men with partners of childbearing potential or women of childbearing potential must agree to use a highly effective contraceptive method (for example, intrauterine device [IUD], birth control pill, or barrier method) during treatment with study drug and for 4 months following the last dose of study drug.
  • Note: Unless not allowed by local regulations, women of childbearing potential who are abstinent (if this is complete abstinence, as their preferred and usual lifestyle) or in a same-sex relationship (as part of their preferred and usual lifestyle) must agree to either remain abstinent or stay in a same-sex relationship without sexual relationships with males unless they agree to use contraceptive method known to be highly effective. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), declaration of abstinence just for the duration of a trial, and withdrawal are not acceptable methods of contraception.
• 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;
  • not be breast-feeding during treatment and for at least 4 months after the last dose of study drug.
• Capable of giving signed informed assent/consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria:

• An additional validated oncogenic driver in MTC if known that could cause resistance to selpercatinib treatment. Examples include, but are not limited to RAS or BRAF gene mutations and NTRK gene fusions.
• Symptomatic CNS metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression. Patients are eligible if neurologically stable and without increase in steroid dose for 14 days prior to the first dose of study treatment and no CNS surgery or radiation has been performed for 28 days, 14 days if stereotactic radiosurgery (SRS).
• Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of study treatment, history of Torsades de pointes, or prolongation of the QT interval corrected for heart rate using Fridericia’s formula (QTcF) > 470 msec on more than one ECG during Screening. Correction of suspected drug-induced QTcF prolongation may be attempted at the investigator’s discretion if clinically safe to do so.  Patients who are intended to receive vandetanib if randomized to the control arm ineligible if QTcF is > 450 msec.
  • Note: Patients with implanted pacemakers may enter study without meeting QTc criteria due to nonevaluable measurement if QT changes are considered monitorable;
  • Note:  Patients with bundle branch block may be considered for study entry if QTc is appropriate by a formula other than Fridericia’s and if QT changes are considered monitorable.
• Active uncontrolled systemic bacterial, viral, or fungal infection or serious ongoing intercurrent illness, such as hypertension or diabetes, despite optimal treatment, a clinical diagnosis or symptoms of interstitial lung disease, or other serious medical conditions which in the medical judgment of the investigator would prevent the patient from safely participating (screening for chronic conditions is not required).
• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug.
• Uncontrolled symptomatic hyperthyroidism or hypothyroidism
• Uncontrolled symptomatic hypercalcemia or hypocalcemia
• Active hemorrhage or at significant risk for hemorrhage.
• Other malignancy unless nonmelanoma skin cancer, carcinoma in situ or malignancy diagnosed ≥ 2 years previously and not currently active.  Patients receiving adjuvant hormone therapy for breast or prostate cancer with no evidence of disease are eligible. Participants with MEN2-associated pheochromocytoma are eligible if the pheochromocytoma is, in the opinion of the investigator, documented to be stable or has been resected (and patient has fully recovered from surgery).
• Prior systemic treatment with kinase inhibitor(s)
• Are taking a concomitant medication that is known to cause QTc prolongation.
• Have participated, within the last 30 days (4 months for studies conducted in Japan; 3 months for studies conducted in the UK), in a clinical study involving an investigational product.  If the previous investigational product has a long half-life, 5 half-lives or 30 days (4 months for studies conducted in Japan; 3 months for studies conducted in the UK) (whichever is longer) should have passed.  Exceptions will be considered on a case by case basis by the Lilly medical team.
• Life expectancy ≤ 3 months
• Have a known hypersensitivity to any of the excipients of selpercatinib, cabozantinib, or vandetanib.

Eligibility last updated 10/27/21.  Questions regarding updates should be directed to the study team contact.