Dabrafenib, Trametinib, and IMRT in Treating Patients with BRAF Mutated Anaplastic or Poorly Differentiated Thyroid Cancer

Inclusion Criteria

• Documented informed consent of the participant and/or legally authorized representative * Assent, when appropriate, will be obtained per institutional guidelines
• Agreement to allow the use of archival tissue from diagnostic tumor biopsies * If unavailable, exceptions may be granted with study principal investigator (PI) approval
• Ability to understand and the willingness to sign a written informed consent document
• Age: >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status =< 3. Since dabrafenib/trametinib can be quite effective rapidly, patients with ECOG performance status (PS) of 2-3 will be included
• Patients who have been recommended to undergo external beam radiation therapy to the neck with pathologic (histologic or cytologic) diagnosis of poorly differentiated thyroid carcinoma or anaplastic thyroid cancer (a diagnosis that is noted to be “consistent with anaplastic or poorly differentiated thyroid cancer” with or without the presence of a thyroid mass is acceptable; pathology showing additional types of aggressive thyroid cancer is allowed; in addition, other pathological variants of anaplastic or poorly differentiated thyroid cancer that are clinically behaving like ATC or PDTC are allowed, such as squamoid or undifferentiated thyroid cancer)
• Presence of BRAF mutation (V600E or V600K) in tumor tissue or peripheral blood tumor deoxyribonucleic acid (DNA). BRAF mutation testing must be performed in a Clinical Laboratory Improvement Act (CLIA) certified laboratory
• Absolute neutrophil count > 1,000/mcL
• Hemoglobin >= 9.0 g/dl (Note: The use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 9.0 g/dl is acceptable)
• Total bilirubin < 1.5 x upper limit of normal (ULN) (unless due to Gilbert’s disease)
• Platelets > 75,000/mcL
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) < 2.5 x ULN
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x ULN
• Serum creatinine < 1.5 x institutional ULN
• Women of childbearing potential (WOCBP): negative serum pregnancy test within 14 days prior to the first dose of study medication
• Females are required to use an effective method of contraception from the time of negative serum pregnancy test, throughout the study duration, and for 4 months after the last dose of study medication. If a subject becomes pregnant during the treatment period, study treatment should be stopped immediately, and they should inform their treating physician immediately. * Specific contraception and nursing requirements for females: Female subjects of childbearing potential must not become pregnant and are required to be sexually inactive by abstinence or use contraceptive methods with a failure rate of < 1%. Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not acceptable methods of contraception. Contraceptive methods with a failure rate of < 1% include the following: ** Intrauterine device (IUD) or intrauterine system (IUS) that meets the < 1% failure rate as stated in the product label, ** Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is patient’s sole sexual partner. For this definition, “documented” refers to the outcome of the investigator's/qualified physician designee’s medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject’s medical records ** Double barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam, gel, film, cream, suppository) These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring subjects understand how to properly use these methods of contraception. Hormonal-based methods (e.g., oral contraceptives) are not permitted due to potential drug-drug interactions with DRB. Female subjects who are lactating must discontinue nursing prior to first dose of study treatment and must refrain from nursing throughout the treatment period and for 4 months following last dose of study treatment
• Men treated of enrolled on this protocol must also agree to use adequate contraception prior to study enrollment, for the duration of study participation, and for 16 weeks after completion of the last dose of study drug. * Specific contraception requirements for males: To prevent pregnancy in a female partner or to prevent exposure of any partner to the investigational product from a male subject’s semen, male subjects must use one of the following contraceptive methods during the study and for a total of 16 weeks following the last dose of study drug (based upon the lifecycle of sperm): ** Abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject for 14 days prior to first dose of study drug, through the dosing period, and for at least 16 weeks after the last dose of study drug. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception ** Condom (during non-vaginal intercourse with any partner - male or female) OR ** Condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) (during sexual intercourse with a female)

Exclusion Criteria

• Patients with resectable stage IVA anaplastic thyroid cancer who are candidates for surgery and wish to proceed with surgery. However, trial participation and therapy in post-operative setting is allowed
• Patients who have had external beam radiotherapy to neck or chest for cancer that would result in overlap of radiation therapy fields
• Any other condition that would, in the Investigator’s judgment, contraindicate the patient’s participation in the clinical study due to safety concerns with clinical study procedures
• Patients who have had oral multikinase inhibitor, cytotoxic chemotherapy, stereotactic brain radiation or external beam radiation within 7 days prior to study treatment initiation. Immunotherapy, biologics, or vaccine therapy within 2 weeks. Patients who are actively on BRAF and MEK inhibitor treatment for ATC/PDTC are allowed onto the trial without needing to stop therapy, as long as the number of weeks and dosing is recorded
• Patients that have not recovered from adverse events related to prior therapy for cancer to Common Terminology Criteria for Adverse Events (CTCAE) 5.0 grade 2 or less except for alopecia
• Patients that are receiving any other investigational agent (exceptions may be granted with Study PI approval)
• Patients that are currently taking any prohibitive medication
• Patients with a history of other active malignancy requiring cancer treatment. (Exceptions may be granted by Study PI if the natural history of treatment is unlikely to interfere with the safety assessment of the investigational regimen on this trial: for example, patients taking tamoxifen and/or aromatase inhibitors are able to be enrolled in this study)
• Patients with a known history of retinal vein occlusion (RVO), central serous retinopathy (CSR), uncontrolled glaucoma or ocular hypertension
• Patients with class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
• History of acute coronary syndromes (including myocardial infarction [MI] or unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization
• Patients with cardiac defibrillators
• Treatment refractory hypertension defined as blood pressure (BP) of systolic > 140 mm Hg or diastolic > 90 mm Hg not controlled by anti-hypertensive therapy
• Corrected QT (QTc) interval greater than or equal to 480 msecs using Bazett’s formula (>= 500 msec for subjects with Bundle Branch Block)
• Patients with a history or evidence of current clinically significant uncontrolled arrhythmias; (Subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible)
• Patients with uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women and nursing women are excluded from this study because dabrafenib has the potential for teratogenic or abortifacient effects. In embryofetal developmental studies in rats, developmental toxicities including reduced fetal body weight, embryo-lethality, cardiac ventricular septal defect malformations, delayed skeletal development and variation in thymic shape have been observed
• Known human immunodeficiency virus (HIV)-positive patients or those on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with study drugs
• Patients with a history of hepatitis B virus (HBV) or hepatitis C (HCV) infection (subjects with laboratory evidence of cleared HBV and/or HCV will be permitted)
• Patients with interstitial lung disease or pneumonitis
• Patients with known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO)
• Any serious or unstable pre-existing medical conditions, psychiatric disorders, or other conditions that could interfere with subject’s safety, obtaining informed consent form (ICF) or compliance with study procedures