Clinical Trial Finder

Inclusion Criteria:

• - Must have histologically confirmed unresectable locally advanced or metastatic MTC and be a candidate for systemic therapy with SOC MKI.

• - Must have received no prior systemic anticancer treatment with MKI therapies for advanced or metastatic MTC.

• - Must have radiologically confirmed progressive disease within the last 14 months and at least one of the following: 1.

A MTC-associated symptom and. 2. CLN (Calcitonin) and CEA (carcinoembryonic antigen) level doubling time of less than 24 months.

• - Confirmed RET mutation.

• - Must be able to swallow an oral medication.

• - Must have an ECOG (Eastern Cooperative Oncology Group) Performance Status of 0-2.

• - For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use appropriate contraception during the treatment period and for the respective period of time after final dose of study drug.

• - For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use appropriate contraception during the treatment period and for the respective period of time after final dose of study drug and to refrain from donating sperm.

Exclusion Criteria:

• - Participants who are pregnant or breastfeeding, or intending to become pregnant during the study within 14 days after the final dose of pralsetinib or within 4 months after the final dose of vandetanib or cabozantinib.

• - Have disease that is suitable for surgery or radiotherapy administered with curative intent.

• - Have been previously treated with any systemic kinase inhibitor therapy regimens, including a selective RET inhibitor, given for recurrent and/or metastatic disease.

• - Have received any radiation therapy within 14 days prior to Day 1 of Cycle 1 and any related toxicity must be resolved to Grade 1 or better.

• - Participant's tumor has any additional known primary driver alterations other than RET.

• - Have known hypersensitivity to pralsetinib, vandetanib, or cabozantinib, or any of their ingredients.

• - Have a history of pneumonitis of non-infectious etiology within the last 12 months.

• - Have ongoing treatment with chronic immunosuppressants or systemic steroids >10 mg/day.

• - Have any history of hereditary bleeding disorder or any evidence of hematemesis.

• - Have had major surgery or invasive dental procedure within 3 weeks prior to Day 1 of Cycle 1.

• - Have central nervous system (CNS) metastases that are associated with progressive neurologic symptoms, untreated spinal cord compression or requires increasing doses of corticosteroids to control the CNS disease.

• - Have clinically significant, uncontrolled, cardiovascular disease.

• - Have required treatment with a prohibited medication or herbal remedy.

• - Have received hematopoietic growth factor support or transfusion within 14 days of the first dose of study drug.

• - Had a major surgical procedure within 14 days of the first dose of study drug.

• - Have a history of another primary malignancy that has been diagnosed or required therapy within the past 2 years before randomisation.

• - Have a serious infection requiring intravenous (IV) antibiotics within 7 days prior to initiation of study treatment.

• - Have an active, uncontrolled infection (viral, bacterial, or fungal) or is positive for Hepatitis B/C infections (HBV/HCV) or HIV.

• - Have received organ or allogenic bone marrow or peripheral blood stem cell transplant.

• - Is a female who is unwilling to abstain from sexual intercourse or employ highly effective contraception from the time of informed consent and for at least 4 months after the last dose of study drug.

• - Is a male who is unwilling to abstain from sexual intercourse or employ highly effective contraception from the time of informed consent and for at least 120 days after the final dose of study drug.

• - Have prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator's or Sponsor's opinion, could affect the safety of the patient or impair the assessment of study results.

Arms

Experimental: Arm A (Pralsetinib)

Participants will receive pralsetinib at a dose of 400 milligrams (mg) orally once daily (PO QD) in 28-day cycles.

Active Comparator: Arm B (SOC: Cabozantinib/Vandetanib)

Adult participants will receive investigator's choice of SOC MKI therapy with either 140 mg cabozantinib PO QD or 300 mg vandetanib PO QD in 28-day cycles. Adolescents participants (≥ 12 and < 18 years of age) will receive vandetanib, PO QD or every other day, in 28-day cycles depending on the body surface area (BSA), at a dose determined according to the dosing nomogram available in the E.U. Vandetanib SmPC.

Interventions

Drug: - Pralsetinib

Participants will receive pralsetinib at a dose of 400 mg, as per the dosing schedule described above.

Drug: - Cabozantinib

Adult participants will receive cabozantinib at a dose of 140 mg, as per the dosing schedule described above.

Drug: - Vandetanib

Adult participants will receive vandetanib at a dose of 300 mg and adolescent participants will receive vandetanib as per the dosing schedule described above.