Dabrafenib and Trametinib Combination as a Neoadjuvant Strategy in BRAF-positive Anaplastic Thyroid Cancer

NCT04739566 | Withdrawn Phase 2

• 1 other identifier: 2
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The aim of the study was to evaluate the effectiveness of combination therapy with dabrafenib and trametinib (anti-BRAF and anti-MEK inhibitors) in the neoadjuvant treatment of BRAF-positive anaplastic thyroid cancer. The prognosis in patients with ATC is poor due to the rapid and invasive tumor growth and the rapid development of metastases. Dabrafenib is an antineoplastic agent, a selective RAF kinase inhibitor that competes with ATP. Oncogenic substitutions of the amino acid valine at position 600 (V600) BRAF lead to constitutive activation of the RAS / RAF / MEK / ERK pathway and stimulation of tumor cell growth. Trametinib is a reversible, highly selective, allosteric inhibitor of the activation of mitogen-activated, extracellular signal-regulated kinases 1 (MEK1) and 2 (MEK2). Dabrafenib and trametinib inhibit two kinases in the signaling pathway, BRAF, and MEK. The combination of the two drugs provides effective inhibition of proliferative signal conduction. The investigators hypothesize that the combination treatment with these two drugs - dabrafenib and trametinib - can improve the response rate in the neoadjuvant mode in ATC without significant regimen-limiting toxicity and with better follow-up locoregional control.

Conditions

Thyroid Gland Anaplastic Carcinoma

Outcome Measures

Primary Outcomes (2)

• Overall response rate (ORR)

  Evaluate the effectiveness of the combination of dabrafenib and trametinib using an overall response rate (ORR) for BRAF-mutated anaplastic thyroid cancer in neoadjuvant mode 7, 14, 28 days, 12 and 24 weeks after the start of treatment. Includes patients with a confirmed partial (PR) and complete response (CR) as the best response according to RECIST v 1.1. ORR will be calculated as the number of patients with an observed response divided by the number of patients included in the study. A two-sided confidence interval will be calculated at 80% (in accordance with the specified α) and 95% (for comparison with the literature).

  Prior to study completion, average 3 years

• Number of R0 resections after 3 months of neoadjuvant combination therapy with anti-BRAF and MEK inhibitors.

  Comparison of the proportion of complete surgical resection (surgical resection R0 or R1) with historical controls of 5 percent. The R0 / R1 ratio will be determined by the proportion of patients who successfully undergo thyroidectomy with clear (R0) or microscopically positive (R1) resection margins.

  3 months

Secondary Outcomes (5)

• Safety Profile (Number / Severity of Serious Adverse Events, SAEs)

  SAEs will be reported in the clinical trial within 6 months of the end of the study.

• Percentage of patients who received a complete response 3 months after the first dose of treatment.

  3 months

• Health-related quality of life

  up to 60 months

• Progression-Free Survival (PFS)

  from date of enrollment to date of first documented progression, date of death from any cause, or patient failure, whichever is earlier, up to 60 months

• Overall Survival (OS)

  from date of enrollment to date of death from any cause or patient failure, whichever comes first, estimated up to 60 months

Study Arms (1)

Treatment (dabrafenib, trametinib)

EXPERIMENTAL

Patients receive dabrafenib 150 mg orally (PO) twice daily, trametinib 2mg PO once daily for 3 months

Drug: Dabrafenib; Drug: Trametinib

Interventions

Dabrafenib DRUG

Given PO twice daily

Also known as: BRAF Inhibitor GSK2118436, GSK-2118436, GSK-2118436A, GSK2118436

Treatment (dabrafenib, trametinib)

Trametinib DRUG

Given PO once daily

Also known as: GSK1120212, JTP-74057, MEK Inhibitor GSK1120212, Mekinist

Treatment (dabrafenib, trametinib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female subjects ≥ 18 years of age.
• Willingness to participate in the study by signing an informed consent form approved by the ethics committee of the KVMT named after N.I. Pirogov St. Petersburg State University.
• ECOG status 0 or 1 or 2. The ECOG assessment must be completed within 7 days prior to the distribution date.
• Measurable disease according to RECIST 1.1, as defined by the investigator.
• Patients with a histologically confirmed disease (according to the pathologist's report) that meets one of the following criteria (according to 2010 WHO classification):
• BRAF - positive anaplastic thyroid cancer, determined by immunohistochemistry for the presence of the BRAF V600E mutation in tumor tissue, genetic/molecular testing of the tumor, or by liquid biopsy of circulating DNA to determine the presence of the BRAF V600E mutation (if the histological examination is not possible). The primary tumor may or may not be resectable, but the risk of aerodigestive compression or bleeding should be excluded.
• Weight over 30 kg.
• Ability to swallow tablets/capsules or gastrostomy.
• The absence of metastases in the brain.
• Normal organ and bone marrow function as defined below (obtained = \<30 days prior to study entry):
• Hemoglobin ≥ 9.0 g / dL.
• Absolute neutrophil count (ANC)\> 1500 per mm.
• Platelet count ≥ 100,000 per mm.
• Serum bilirubin ≤ 1.5 times the upper limit of normal (ULN) if liver metastases are absent, in which case it should be ≤ 2X ULN. This does not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia, which is predominantly unconjugated in the absence of hemolysis or liver pathology); however, they will only be admitted after consulting their doctor.
• Aspartate transaminase (AST) (SGOT) / alanine aminotransferase (ALT) (SGPT) ≤ 2.5x the institutional upper limit of normal, unless liver metastases are present, in which case it should be ≤ 5x ULN.

You may not qualify if:

• Concurrent participation in another clinical trial unless it is an observational (non-interventional) clinical trial or during the follow-up period of an interventional trial.
• Taking any type of low molecular weight kinase inhibitor (including the investigational kinase inhibitor) for 2 weeks or 5 half-lives of the agent, whichever is greater.
• Receiving any type of anticancer drugs (including investigational) or systemic chemotherapy within 2 weeks before starting treatment.
• The presence of distant metastases (for example, to the brain, lungs).
• Subject has an uncontrolled, serious underlying medical condition or recent illness, including but not limited to the following conditions:
• A) Cardiovascular diseases:
• Congestive heart failure, grade 3 or 4 as defined by the New York Heart Association, unstable angina, and severe cardiac arrhythmias.
• Uncontrolled hypertension, defined as sustained blood pressure\> 150 mm Hg. Systolic or diastolic\> 100 mmHg
• B) Gastrointestinal disorders (eg malabsorption syndrome or gastric outlet obstruction), including those associated with a high risk of perforation or fistula formation:
• Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreas or bile ducts, or obstruction of the gastric outlet.
• C) Clinically significant vomiting or hemoptysis\> 0.5 teaspoons (\> 2.5 ml) of red blood or another significant bleeding in history within 3 months prior to treatment.
• D) Interstitial lung lesions or known manifestations of the endobronchial disease.
• F) Lesions invading the main pulmonary blood vessels.
• F) Other clinically significant disorders such as:
• An active infection requiring systemic treatment, infection with human immunodeficiency virus or disease associated with acquired immunodeficiency syndrome, or chronic infection with hepatitis B or C.

Sponsors & Collaborators

• Saint Petersburg State University, Russia: lead

Study Sites (1)

Saint-Petersburg State University (SPSU) N.I.Pirogov Clinic of High Medical Technologies

Saint Petersburg, Russia

Location

MeSH Terms

Conditions

Thyroid Carcinoma, Anaplastic

Interventions

dabrafenib; trametinib

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Study Officials

• Yuliya Mikheeva, M.D., Ph.D.

  Saint-Petersburg State University (SPSU) N.I.Pirogov Clinic of High Medical Technologies

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: January 29, 2021
• First Posted: February 4, 2021
• Study Start: January 22, 2021
• Primary Completion: December 22, 2023
• Study Completion: December 22, 2023
• Last Updated: March 25, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

RU (1)