This phase II trial studies the effect of pembrolizumab, dabrafenib, and trametinib before surgery in treating patients with BRAF V600E-mutated anaplastic thyroid cancer. BRAF V600E is a specific mutation (change) in the BRAF gene, which makes a protein that is involved in sending signals in cells and in cell growth. It may increase the growth and spread of tumor cells. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Pembrolizumab, dabrafenib, and trametinib may help to control BRAF V600E-mutated anaplastic thyroid cancer when given before surgery.
PRIMARY OBJECTIVES: I. Demonstrate the efficacy of upfront treatment with neoadjuvant pembrolizumab in combination dabrafenib and trametinib by comparing the complete gross surgical resection rate (R0 or R1 surgical resection) to historical control of 5%. II. Demonstrate the efficacy of pembrolizumab in combination with dabrafenib and trametinib by comparing the overall survival (OS) to historical OS rate of 9.6 months. SECONDARY OBJECTIVES: I. Assess the efficacy (Response Evaluation Criteria in Solid Tumors \[RECIST\]) of neoadjuvant dabrafenib, trametinib, and pembrolizumab combination (Part 1) and progression-free survival (PFS) for all patients throughout their treatment course. II. Demonstrate the extent to which neoadjuvant dabrafenib, trametinib, and pembrolizumab changes surgical morbidity/complexity. III. Establish surgical safety for neoadjuvant pembrolizumab in combination with BRAF \& MEK inhibitors, dabrafenib and trametinib; as well as safety for concurrent administration of postoperative adjuvant pembrolizumab with intensity modulated radiation therapy (IMRT). VI. Evaluate changes in patient reported outcomes: quality of life assessed by validated questionnaires at initial diagnosis, through the course of therapy, and during the adjuvant targeted therapy phase. VII. Determine whether features of the tumor genomic landscape and tumor immune microenvironment are associated with response to dabrafenib/trametinib/pembrolizumab (DTP). EXPLORATORY OBJECTIVES: I. Determine if changes of cell free deoxyribonucleic acid (DNA) correlate with response to treatment on DTP and overall survival. II. Evaluate the safety of dabrafenib/trametinib/pembrolizumab plus IMRT in a subset of 15 patients. OUTLINE: PART 1 (NEOADJUVANT PHASE): Patients receive dabrafenib orally (PO) twice daily (BID) and trametinib PO once daily (QD) on days 1-21. Starting in week 4, patients also receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive 2 additional cycles of DTP at the discretion of the treating physicians. Patients whose disease is deemed resectable undergo surgery. Patients who are not surgically resectable after 5 cycles of DTP move to Part 3. PART 2 (ADJUVANT PHASE): 2-4 weeks after surgery and at the discretion of the treating physicians, patients may continue to receive pembrolizumab IV over 30 minutes every 3 weeks and concurrently undergo IMRT with or without cisplatin or carboplatin for 6 weeks. Up to 15 patients also receive dabrafenib PO BID and trametinib PO QD concurrently for 6 weeks. PART 3: Patients receive dabrafenib PO BID, trametinib PO QD on days 1-21, and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for 17 cycles in the absence of disease progression or unacceptable toxicity. 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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
30
Undergo surgery
Given PO
Undergo IMRT
Given IV
Ancillary studies
Given PO
Stanford School of Medicine
Stanford, California, United States
University of Michigan Rogel Cancer Center
Ann Arbor, Michigan, United States
Mayo Clinic
Rochester, Minnesota, United States
Cleveland Clinic Taussig Cancer Institute
Cleveland, Ohio, United States
M D Anderson Cancer Center
Houston, Texas, United States
Huntsman Cancer Institute at the University of Utah
Salt Lake City, Utah, United States
Complete gross surgical resection (R0 or R1 resection)
Overall R0/R1 resection rate will be defined by proportion of patients who undergo successful thyroidectomy with clear (R0) or microscopically positive (R1) surgical margins. We will test the hypothesis that the R0/R1 resection rate is greater than historical rate of 5%.
Time frame: Up to 5 cycles (1 cycle = 21 days) Up to 7 cycles
Overall survival (OS)
OS will be measured as the time from the start of any trial treatment to death from any causes. Kaplan-Meier method will be used to estimate the median survival time across all patients and its 95% confidence intervals (CI).
Time frame: Up to 72 months
Tumor response
Objective tumor response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Time frame: Up to 42 months
Progression free survival (PFS)
PFS will be measured as the time from the start of the treatment to the first occurrence of disease progression or death from any cause, whichever occurs first, as determined by RECIST version 1.1.
Time frame: Up to 42 months
Surgical morbidity/complexity
Surgical morbidity/complexity will be measured at enrollment, prior to surgery and at surgery. The Thyroid Neck Group Morbidity Complexity Scoring and MGH/MEE-MSK-MD Anderson (MMM) Surgical Morbidity Complexity Score are incorporated, specifying on a scale with 5 levels of complexity and morbidity of the surgery \[mild (level 0), moderate (level 1), severe (level 2), very severe (level 3), and unresectable (level 4)\].
Time frame: Up to 5 cycles (1 cycle = 21 days) Up to 7 cycles
Number of patients with adverse events as a measure of safety of neoadjuvant dabrafenib, trametinib, and pembrolizumab
Frequency and severity of adverse events as a measure of safety profile for neoadjuvant concurrent administration of dabrafenib, trametinib, and pembrolizumab (DTP) will be assessed using Common Terminology Criteria for Adverse Events version 5.0.
Time frame: Up to 5 cycles (1 cycle = 21 days)
Number of patients with adverse events as a measure of safety of postoperative pembrolizumab plus IMRT
Frequency and severity of adverse events as a measure of safety profile for concurrent administration of postoperative pembrolizumab with IMRT will be assessed using Common Terminology Criteria for Adverse Events version 5.0.
Time frame: Over the course of adjuvant IMRT plus 2 weeks of safety follow-up, assessed up to 2 months
Locoregional control
Locoregional control will be measured as the time from the start of any trial treatment to the first locoregional recurrence/progression event.
Time frame: Up to 42 months
Health related quality of life
Changes of health-related quality of life will be measured by the European Quality of Life 5 Dimension Questionnaire (EQ-5D). The EQ-5D consists of health state description and evaluation. The health state description consists of five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), with each dimension specifying five levels of severity \[best (1)-worst (5)\]. The health state evaluation is assessed using the visual analogue scale (\[worse (0)-best (100)\].
Time frame: Up to 42 months
Patient-reported symptoms
Symptom burden experienced by patients will be measured by the M.D. Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN) instrument.
Time frame: Up to 42 months
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