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

 1. Objective Response Ratio (ORR) Evaluate the effectiveness of the combination of
 dabrafenib and trametinib using an objective 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.

 2. 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%. 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.

 Secondary endpoints

 1. Safety Profile (Number / Severity of Serious Adverse Events, SAEs) Number of serious
 adverse events classified by severity as assessed by CTCAE v 5.0

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

 3. Health-related quality of life Changes in health-related quality of life will be
 measured using the European Quality of Life Assessment Questionnaire (EQ-5D). The EQ-5D
 consists of a description and a health assessment. The health description consists of
 five dimensions (mobility, self-care, normal activities, pain/discomfort, and
 anxiety/depression), with each dimension identifying five levels of severity [best (1) -
 worst (5)]. Health assessment is assessed using a visual analog scale ([worse (0) -
 better (100)].

 4. Progression-Free Survival (PFS) Median progression-free survival (mPFS) is defined as
 the time from the date of inclusion to the date of the first documented progression of
 disease or death from any cause, whichever occurs first. PFS will be determined based on
 the tumor score (RECIST criteria version 1.1).

 5. Overall Survival (OS) Median overall survival (mOS) at 12, 24, 36, 48, and 60 months are
 calculated as the time from the date of inclusion to the date of death for any reason at
 the specific time points.

 OUTLINE:

 Patients receive dabrafenib orally (PO) twice daily (BID) and trametinib PO once daily (QD)
 for 3 months in the absence of disease progression or unacceptable toxicity. Patients then
 undergo surgery.

 After completion of study treatment, patients are followed up every 3 months during years
 1-2, every 6 months during years 3-4, and then annually thereafter.
Inclusion Criteria:

 1. Male or female subjects ≥ 18 years of age.

 2. 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.

 3. ECOG status 0 or 1 or 2. The ECOG assessment must be completed within 7 days prior to
 the distribution date.

 4. Measurable disease according to RECIST 1.1, as defined by the investigator.

 5. 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.

 6. Weight over 30 kg.

 7. Ability to swallow tablets/capsules or gastrostomy.

 8. The absence of metastases in the brain.

 9. 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.

 -  Measured creatinine clearance (CL)> 40 ml/min or Estimated creatinine clearance>
 40 ml/min using the Cockcroft-Gault formula (Cockcroft and Gault, 1976) or
 24-hour urine collection to determine creatinine clearance.

 -  Albumin> = 2.5 mg / dL (received = <30 days prior to registration)

 -  International normalized ratio (INR) or prothrombin time (PT) = <1.5 X ULN if the
 subject is not receiving anticoagulant therapy while PT or partial thromboplastin
 time (PTT) is within the therapeutic range of the intended use of anticoagulants

 -  Activated partial thromboplastin time (APTT) = <1.5 x ULN if the subject is not
 receiving anticoagulant therapy while the PT or PTT is within the therapeutic
 range of the intended use of anticoagulants

 10. Adequately controlled blood pressure with or without antihypertensive drugs, defined
 as blood pressure (BP) <150/90 mm Hg. Art.

 11. Subjects should be prepared to undergo tumor biopsy before and after
 dabrafenib/trametinib therapy if a biopsy is impractical or not safe in the judgment
 of the treating physician. Subjects should be prepared for surgery if their tumor
 becomes surgically resectable. Research Subjects reserve the right to refuse any
 research intervention.

 12. Female subjects of childbearing age (not surgically sterile or at least 2 years
 postmenopausal) must present a negative pregnancy test at screening and use a
 medically accepted double-barrier method of contraception (such as a spermicide condom
 + IUD or cervical caps) ... In addition, they must agree to continue using this
 double-barrier method for the duration of the study and for 4 months after the end of
 study participation. Women will be considered postmenopausal if they have had
 amenorrhea within 12 months without an alternative medical cause. The following age
 requirements apply:

 1. Women younger than 50 are considered postmenopausal if they have had amenorrhea
 for 12 months or more after stopping treatment with exogenous hormones, and if
 they have postmenopausal levels of luteinizing hormone and follicle-stimulating
 hormone or have undergone surgical sterilization (bilateral oophorectomy or
 hysterectomy).

 2. Women over 50 years of age will be considered postmenopausal if they have had
 amenorrhea for 12 months or more after stopping all exogenous hormonal drugs with
 last menstrual period> 1 year ago, had menopause caused by chemotherapy with last
 menstrual period> 1 year ago, or have undergone surgery sterilization (bilateral
 oophorectomy, bilateral salpingectomy or hysterectomy).

 13. Men must agree to abstain from sexual intercourse with a female partner or agree to
 use a double-barrier method of contraception (for example, a spermicide condom, in
 addition to the fact that their female partner is using some form of contraception,
 such as an intrauterine device (IUD) or cervical caps), at the time of the study and
 for 4 months after the end of participation in the study, and refrain from donating
 sperm during this period.

 14. Patient willingness and ability to adhere to protocol throughout the study, including
 undergoing treatment, and availability for scheduled visits and examinations,
 including follow-up.

 Exclusion Criteria:

 1. 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.

 2. 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.

 3. Receiving any type of anticancer drugs (including investigational) or systemic
 chemotherapy within 2 weeks before starting treatment.

 4. The presence of distant metastases (for example, to the brain, lungs).

 5. 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

 -  Stroke, including transient ischemic attack (TIA), myocardial infarction, other
 ischemic event or thromboembolic events such as deep vein thrombosis (DVT) and
 pulmonary embolism) within 6 months prior to inclusion. Subjects with a later
 diagnosis of DVT are eligible if they are stable, asymptomatic, and have received
 LMWH for at least 6 weeks prior to study treatment.

 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.

 -  Abdominal fistula, gastrointestinal perforation, bowel obstruction, or
 intra-abdominal abscess within 6 months prior to inclusion. Note: Complete
 healing of the intra-abdominal abscess must be confirmed before starting
 treatment.

 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.

 -  Serious non-healing wound / ulcer / bone fracture.

 -  Moderate or severe liver failure (Child-Pugh B or C).

 -  The need for hemodialysis or peritoneal dialysis.

 -  Uncontrolled diabetes mellitus.

 -  History of solid organ transplantation.

 6. Major surgery (such as gastrointestinal surgery and removal or biopsy of brain
 metastases) within 8 weeks prior to inclusion. Complete wound healing following major
 surgery should occur 4 weeks before the study treatment, and after minor surgery (eg,
 simple excision, tooth extraction) at least 10 days before the study treatment.
 Patients with clinically significant ongoing complications from prior surgery are not
 eligible.

 7. Adjusted QT interval calculated by Fridericia formula (QTcf)> 500 ms for 28 days prior
 to study treatment.

 Note: If a single ECG displays a QTCf with an absolute value> 500 ms, two additional
 ECGs at approximately 3 min intervals must be performed within 30 minutes of the
 initial ECG, and the average of these three consecutive results will be used to assess
 eligibility for study participation.

 8. Pregnant (test must be done no later than 7 days before the start of the study) or
 nursing mothers.

 9. Received any live vaccine = <30 days prior to study initiation.

 10. Inability to swallow tablets/capsules and lack of gastrostomy.

 11. Previously identified allergy or hypersensitivity to the components of the
 investigational dosage forms.

 12. Presence of previously diagnosed retinal vein occlusion, central serous retinopathy,
 uncontrolled glaucoma, or ocular hypertension.

 13. Diagnosis of another malignant neoplasm within 3 years prior to study treatment, with
 the exception of superficial skin cancer or localized low-grade tumors that are
 considered cured and untreated by systemic therapy.