Dabrafenib, Trametinib, and IMRT in Treating Patients With BRAF Mutated Anaplastic Thyroid Cancer
Dabrafenib, Trametinib, and IMRT in Treating Patients With BRAF Mutated Anaplastic Thyroid Cancer
This trial studies how well dabrafenib, trametinib, and intensity modulated radiation therapy
 (IMRT) work together in treating patients with BRAF mutated anaplastic thyroid cancer.
 Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes
 needed for cell growth. Radiation therapy uses high energy beams to kill tumor cells and
 shrink tumors. Giving dabrafenib, trametinib, and IMRT together may kill more tumor cells.
PRIMARY OBJECTIVES:

 I. To assess the safety and tolerability (maximum tolerated dose [MTD]) of concurrent
 intensity modulated radiation therapy (IMRT) and BRAF-MEK inhibitors dabrafenib and
 trametinib in patients with BRAF-mutated anaplastic thyroid cancer.

 SECONDARY OBJECTIVES:

 I. To assess overall objective response rate, time to progression of local recurrence,
 progression free survival and overall survival.

 II. To assess pharmacokinetics during concurrent IMRT and dabrafenib plus trametinib therapy.

 III. To assess pharmacodynamics of dabrafenib plus trametinib induction therapy.

 IV. To assess mechanism of resistance to dabrafenib plus trametinib and radiation therapy.

 OUTLINE: This is a dose-escalation study of dabrafenib.

 INDUCTION: Patients receive dabrafenib orally (PO) twice daily (BID) and trametinib PO once
 daily (QD) for 7-28 days in the absence of disease progression and unacceptable toxicity.

 OPTIONAL SURGERY: Patients with resectable disease may undergo surgery 3 days after stop
 treatment of dabrafenib/trametinib, and move to Concurrent Radiation 14 days after surgery
 provided that surgical wound has healed. All other patients continue to receive dabrafenib PO
 BID and trametinib PO QD in the absence of disease progression and unacceptable toxicity.

 CONCURRENT RADIATION: Patients receive dabrafenib PO BID and trametinib PO QD at weeks 6-7.
 Within 2.5 hours of morning doses of dabrafenib/trametinib administration, patients undergo
 intensity modulated radiation therapy (IMRT) on Monday-Friday delivered over 6.5 weeks in the
 absence of disease progression or unacceptable toxicity.

 POST-RADIATION: Patients receive dabrafenib PO BID and trametinib PO QD for 4 weeks in the
 absence of disease progression and unacceptable toxicity.

 MAINTENANCE: Patients with residual disease receive dabrafenib PO BID and trametinib PO QD in
 the absence of disease progression and unacceptable toxicity. Patients stop dabrafenib and
 trametinib 8 weeks after achieving complete response. Patients with no residual disease stop
 dabrafenib and trametinib, with the option of restarting dabrafenib and trametinib at time of
 disease recurrence.

 After completion of study treatment, patients are followed up every 2 months for 1 year.
Inclusion Criteria:

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

 -  Note: Tissue collection for central review is mandatory, but central review is
 not 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 to achieve
 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?s
 disease).

 -  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 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. Should a woman become pregnant or suspect she is
 pregnant while she or her partner is participating in this study, she should inform
 her treating physician immediately. Men treated or 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 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.

 -  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).

 -  Ability to understand and the willingness to sign a written informed consent document.

 Exclusion Criteria:

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

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

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

 -  Patients who have had oral multikinase inhibitors within 1 week prior to study
 treatment initiation.

 -  Patients that have not recovered from adverse events related to prior therapy for
 cancer to Common Terminology Criteria for Adverse Events (CTCAE) 4.03 grade 2 or less
 except for alopecia.

 -  Patients previously treated with potent BRAF inhibitor or MEK inhibitor. Previous
 treatment 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 of
 corticosteroids for more than 1 week or off corticosteroids for 2 weeks prior to study
 enrollment can be enrolled. Enzyme-inducing anti-epileptic drugs are not permitted.

 -  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.

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

 -  Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
 or active infection requiring intravenous (IV) antibiotics, 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 embroyfetal 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.