Study of the Rechallenge Concept in Patients With BRAF-positive Anaplastic Thyroid Cancer After Progression on Anti-BRAF Therapy

This pilot phase 2 study evaluates the effectiveness and safety of the Rechallenge concept in patients with BRAF-positive anaplastic thyroid cancer after progression on anti-BRAF therapy. Patients with BRAF-positive anaplastic thyroid cancer who were previously treated with dabrafenib and trametinib (with a clinical or objective response at the start of treatment) and later with tumor progression during anti-BRAF therapy and subsequent lines of chemotherapy are scheduled to undergo targeted therapy (repeated administration of dabrafenib and trametinib in standard doses) and evaluate the outcomes according to the primary and secondary endpoints.

The aim of the study was to demonstrate the efficacy and safety of the rechallenge concept in patients with BRAF-positive anaplastic thyroid cancer after progression on anti-BRAF therapy.

Scientific hypothesis: rechallenge in patients with BRAF-positive anaplastic thyroid cancer after progression on anti-BRAF therapy is effective and safe.

Trial design, materials and methods: this study is a pilot phase 2 study. This study is prospective and open-label.

Patients with BRAF-positive anaplastic thyroid cancer who were previously treated with dabrafenib and trametinib (with a clinical or objective response at the start of treatment) and later with tumor progression during anti-BRAF treatment with the transition to at least one line of chemotherapy (treatment with taxane-containing regimens is mandatory) followed by progression on it. Patients who meet the criteria and with no initial resistance to anti-BRAF therapy are scheduled to undergo targeted therapy (repeated administration of dabrafenib and trametinib in standard doses) and evaluate outcomes according to primary and secondary endpoints.

The control will be carried out by monitoring the initial state in dynamics. Before starting investigational therapy, data will be recorded for each patient in an individual registration card.

Before starting investigational therapy, clinical and laboratory parameters will be evaluated and computed tomography of the brain, neck, thoracic and abdominal cavities with intravenous contrast (baseline) will be performed.

Mutations in the BRAF V600 gene, microsatellite instability (MSI) and PD-L1 expression will be determined in the tumor material (first of all), and the following molecular genetic variants will be determined in the second place (planned): RET, NTRK, ALK, ROS1.

Investigational therapy includes dabrafenib 150 mg 2 times a day daily, trametinib 2 mg 1 time a day daily.

Duration of treatment: until progression or intolerable toxicity.

Follow-up period of patients:

* duration of the initial follow-up period: taking drugs for 10 days, followed by an assessment of the effect using tumor imaging methods;
* follow-up during active treatment in the framework of the study with tumor reduction after day 10 - continuation of targeted therapy until progression or intolerable toxicity;
* patient survival monitoring - documenting subsequent lines of antitumor treatment before the patient's death or loss of contact with him;
* patient safety monitoring is the period of research therapy, 30 and 90 days from the date of the final dose (provided there is no next line of antitumor treatment, during the next line, safety monitoring is discontinued).

Assessment of the response to treatment (assessment of clinical and laboratory parameters, computed tomography of the brain, neck, chest and abdominal cavity with intravenous contrast) will be carried out after 10 days, then - according to the decision of the research team. Based on the results of the control study, the response to treatment will be evaluated according to the RECIST 1.1 criteria. Patients who meet the criteria for progression will be excluded from the study.

When converting a tumor to resectability and planning surgical treatment, it is recommended to suspend taking the drug trametinib 5 days before surgery and resume taking it 3-5 days after. There is no correlation between dabrafenib and complications associated with surgical treatment, and no interruptions in treatment are required.

Eligibility Criteria:
Inclusion Criteria:

* immunohistochemically verified anaplastic thyroid cancer;
* presence of a mutation in the BRAF V600 gene;
* documented progression during targeted therapy with dabrafenib + trametinib;
* documented progression during at least one line of chemotherapy (use of taxane-containing chemotherapy is mandatory);
* age ≥ 18 years;
* ECOG performance status 0-2;
* adequate function of internal organs and bone marrow;
* ability to give written informed consent.

Exclusion Criteria:

* primary resistance (absence of initial clinical and radiological response to therapy with dabrafenib and trametinib (response criteria - primary objective response according to RECIST 1.1 criteria and duration of response of at least 3 months);
* absence of taxane-containing chemotherapy as second or third line;
* contraindication to taking any of the study drugs (including severe toxicity that occurred during a previous dose, which led to discontinuation of treatment);
* patients with unsatisfactory functional status (ECOG 3-4);
* pregnancy and breastfeeding.