This is a phase Ib trial that studies personalized network pharmacology-based drug repurposing in patients with advanced thyroid cancer who have no other treatment options. The main objective is to study if it is feasible to give patients individualized drug combinations selected based on their tumor genetic profile. The secondary objective is to find out whether these treatments are safe and can help control the growth of the patient tumors or stop them from getting worse.

Patients with advanced thyroid cancer often have very few treatment options, and standard therapies usually cannot cure the disease. Some types grow and spread quickly and do not respond to surgery and radioactive iodine. For patients with other types, existing drugs may slow the disease but can cause strong side effects, limiting their usefulness.

This study is testing a new personalized approach called network pharmacology-based drug repurposing. This concept uses genetic tumor information to identify combinations of existing approved drugs that may work better together. The idea is that targeting several connected networks in the tumor at the same time may be more effective than standard treatments that focus on a single target.

The main objective is to study if it is feasible to give patients individualized drug combinations selected based on their tumor genetic profile. The secondary objective is to find out whether these treatments are safe and can help control the growth of the patient tumors or stop them from getting worse.

This is an exploratory, single-arm phase Ib trial. Each patient receives a personalized treatment based on the genetic profile of their tumor. The study focuses on understanding feasibility and safety. Each participant will be in the study for approximately 4 months. The first month is used to examine the tumor of the patient and select the best personalized treatment. Once the treatment is chosen and both the patient and their doctor agree, the patient will receive the treatment for three months. During treatment, patients will have regular check-ups, blood tests, scans, and questionnaires to monitor safety and see how well the treatment is controlling the tumor.

This study is funded by the EU horizon project Precision drug REPurpOsing For EUrope and the world (REPO4EU) under grant agreement No. 101057619

Inclusion Criteria:

• Patients with locally advanced or metastatic TC (such as ATC, PDTC, and RAI refractory DTC progressive under treatment with multikinase inhibitors) for whom no approved conventional treatments are available.
• Prior anticancer treatment-related toxicities resolved to Grade ≤1 (CTCAE v5.0).
• Measurable disease per RECIST 1.1
• ECOG performance status ≤ 2
• Negative pregnancy test within 7 days prior to starting the study in women of childbearing potential and adequate use of contraception.

Exclusion Criteria:

• Inability to provide informed consent
• Inability to obtain a (new) biopsy for molecular profiling
• Pregnancy or breastfeeding.
• Other active malignancies requiring therapy.
• Neutropenia (ANC < 1.5 × 10⁹/L).
• Severe uncontrolled medical conditions (renal, cardiac, liver, respiratory).