Dabrafenib, Trametinib, and IMRT in Treating Patients With BRAF Mutated Anaplastic Thyroid Cancer

Inclusion Criteria:

• Pathologic (histologic or cytologic) diagnosis of anaplastic thyroid cancer (adiagnosis that is noted to be ?consistent with anaplastic thyroid cancer? with thepresence of a thyroid mass is acceptable; pathology showing additional types ofthyroid cancer is allowed)

• Note: Tissue collection for central review is mandatory, but central review isnot required for eligibility. Due to the aggressiveness of this disease,treatment will be started prior to central review.

• Presence of BRAF mutation (V600E or V600K) in tumor tissue.

• Eastern Cooperative Oncology Group (ECOG) performance status < 2.

• Absolute neutrophil count > 1,000/mcL.

• Hemoglobin >= 9.0 g/dl (Note: The use of transfusion or other intervention toachieve hemoglobin [Hgb] >= 9.0 g/dl is acceptable).

• Platelets > 75,000/mcL.

• Total bilirubin < 1.5 x institutional upper limit of normal (unless due to Gilbert?sdisease).

• Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x institutional upper limit of normal.

• Serum creatinine < 1.5 x institutional upper limit of normal.

• Female patients of childbearing potential are required to have a negative serumpregnancy 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 ofnegative serum pregnancy test, throughout the study duration, and for 4 months afterthe last dose of study medication. Should a woman become pregnant or suspect she ispregnant while she or her partner is participating in this study, she should informher treating physician immediately. Men treated or enrolled on this protocol mustalso agree to use adequate contraception prior to study enrollment, for the durationof study participation, and for 16 weeks after completion of the last dose of studydrug.

• Specific contraception requirements for females: Female subjects of childbearingpotential must not become pregnant and are required to be sexually inactive byabstinence or use contraceptive methods with a failure rate of < 1%. Sexualinactivity by abstinence must be consistent with the preferred and usual lifestyleof the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation 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) priorto the female subject's entry into the study, and this male is patient?s solesexual partner. For this definition, ?documented? refers to the outcome of theinvestigator's/qualified physician designee?s medical examination of thesubject or review of the subject's medical history for study eligibility, asobtained via a verbal interview with the subject or from the subject?s medicalrecords.

• Double barrier method: condom and occlusive cap (diaphragm or cervical/vaultcaps) plus spermicidal agent (foam, gel, film, cream, suppository) Theseallowed methods of contraception are only effective when used consistently,correctly and in accordance with the product label. The investigator isresponsible for ensuring subjects understand how to properly use these methodsof contraception.

• Specific contraception requirements for males: To prevent pregnancy in a femalepartner or to prevent exposure of any partner to the investigational product from amale subject?s semen, male subjects must use one of the following contraceptivemethods during the study and for a total of 16 weeks following the last dose ofstudy drug (based upon the lifecycle of sperm):

• Abstinence, defined as sexual inactivity consistent with the preferred andusual 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 ofstudy drug. Periodic abstinence (e.g. calendar, ovulation, symptothermal,post-ovulation methods) and withdrawal are not acceptable methods ofcontraception.

• Condom (during non-vaginal intercourse with any partner - male or female) OR

• Condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidalagent (foam/gel/film/cream/suppository) (during sexual intercourse with afemale).

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

• Patients with resectable stage IVA anaplastic thyroid cancer who are candidates forsurgery and wish to proceed with surgery.

• Patients who have had external beam radiotherapy to neck or chest for cancer thatwould result in overlap of radiation therapy fields.

• Patients who have had cytotoxic chemotherapy, stereotactic brain radiation orexternal beam radiation within 2 weeks prior to study treatment initiation.

• Patients who have had oral multikinase inhibitors within 1 week prior to studytreatment initiation.

• Patients that have not recovered from adverse events related to prior therapy forcancer to Common Terminology Criteria for Adverse Events (CTCAE) 4.03 grade 2 orless except for alopecia.

• Patients previously treated with potent BRAF inhibitor or MEK inhibitor. Previoustreatment with sorafenib is permitted.

• Patients that are receiving any other investigational agent.

• Patients that are currently taking any prohibitive medication.

• Patients with a history of other active malignancy requiring cancer treatment.

• Patients with uncontrolled brain metastases. Patients who are on a stable dose ofcorticosteroids for more than 1 week or off corticosteroids for 2 weeks prior tostudy enrollment can be enrolled. Enzyme-inducing anti-epileptic drugs are notpermitted.

• Patients with a known history of retinal vein occlusion (RVO), central serousretinopathy (CSR), uncontrolled glaucoma or ocular hypertension.

• Patients with class II, III, or IV heart failure as defined by the New York HeartAssociation (NYHA) functional classification system.

• Corrected QT (QTc) interval greater than or equal to 480 msecs (>= 500 msec forsubjects with Bundle Branch Block).

• Patients with uncontrolled intercurrent illness including, but not limited to,ongoing or active infection requiring intravenous (IV) antibiotics, symptomaticcongestive heart failure, unstable angina pectoris, cardiac arrhythmia, orpsychiatric illness/social situations that would limit compliance with studyrequirements.

• Pregnant women and nursing women are excluded from this study because dabrafenib hasthe potential for teratogenic or abortifacient effects. In embroyfetal developmentalstudies in rats, developmental toxicities including reduced fetal body weight,embryo-lethality, cardiac ventricular septal defect malformations, delayed skeletaldevelopment and variation in thymic shape have been observed.

• Known human immunodeficiency virus (HIV)-positive patients or those on combinationantiretroviral therapy are ineligible because of the potential for pharmacokineticinteractions with study drugs.