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

Anaplastic Thyroid Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06362694
• Other study ID #: 34
• Status: Recruiting
• Phase: Phase 2
• Start date: March 25, 2024
• Est. completion date: June 25, 2026

Study information

• Verified date: April 2024
• Source: Saint Petersburg State University, Russia
• Contact: Ilya Sleptsov, MD
• Phone: +7(921)951-70-88
• Email: newsurgery[@]yandex.ru
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 10
• Est. completion date: June 25, 2026
• Est. primary completion date: March 25, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Anaplastic Thyroid Cancer
• Thyroid Carcinoma, Anaplastic
• Thyroid Diseases
• Thyroid Neoplasms

Intervention

Drug:
• Dabrafenib + Trametinib
Dabrafenib is an inhibitor of some mutated forms of BRAF kinases. Trametinib is a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. Dabrafenib and trametinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Use of dabrafenib 623 and trametinib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive tumors.

Locations

Country	Name	City	State
Russian Federation	Saint Petersburg State University Hospital	Saint Petersburg

Sponsors (1)

Lead Sponsor	Collaborator
Saint Petersburg State University, Russia

Country where clinical trial is conducted

Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective response rate	The proportion of participants with a partial or complete response to the therapy. It is determined according to the RECIST criteria.	10 days, then each month from date of treatment initiation until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months
Primary	Progression-Free Survival	The time from the date of initiation of treatment to the radiological progression or death of the patient for any reason.	6-month, 1-year, 2-year
Primary	Safety and Tolerability assessment (Incidence of Treatment-Emergent Adverse Events)	Safety assessment will be assessed on the basis of adverse events (according to CTCAE 5.0)	Each visit (every 21 days) assessed up to 48 months
Secondary	Overall survival	The time from the start date of treatment to the death of the patient for any reason.	6-month, 1-year, 2-year
Secondary	The assessment of conversion to resectability	The proportion of participants with an initially unresectable or potentially resectable tumor who have moved to a resectable during treatment.	Each month from date of treatment initiation until the date of first documented progression or date of death from any cause, whichever came first , assessed up to 48 months