Summary

This phase I trial studies how well dabrafenib, trametinib, and intensity modulated radiation therapy (IMRT) work together in treating patients with BRAF mutated anaplastic or poorly differentiated 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.

Objectives

PRIMARY OBJECTIVE:
I. To assess the safety and tolerability (maximum tolerated dose [MTD] and recommended phase II dose [RP2D]) of concurrent intensity modulated radiation therapy (IMRT) and BRAF-MEK inhibitors dabrafenib and trametinib in patients with BRAF-mutated anaplastic thyroid cancer or poorly differentiated 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 pathologic response rate in those patients who undergo surgery after dabrafenib plus trametinib.
III. To assess mechanism of resistance to dabrafenib plus trametinib and radiation therapy.

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

INDUCTION: Patients may receive dabrafenib orally (PO) twice daily (BID) and trametinib PO once daily (QD) for 7-56 days in the absence of disease progression and unacceptable toxicity.

OPTIONAL SURGERY: Patients with resectable disease may undergo surgery 2-5 days after stop treatment of dabrafenib/trametinib, and move to Concurrent Radiation 14-28 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 to 3 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 (unless the treating physician recommends continuing dabrafenib and trametinib). Patients with no residual disease can either stop dabrafenib and trametinib, with the option of restarting dabrafenib and trametinib at time of disease recurrence, or continuing treatment at the discretion of the treating physician.

Patients also undergo echocardiogram (ECHO) or multigated acquisition (MUGA) scans, computed tomography (CT) scans, positron emission tomography (PET)-CT scans, and collection of blood samples throughout the trial. Patients may also undergo brain CT or brain magnetic resonance imaging (MRI) scans as clinically indicated. In addition, patients may undergo optional biopsies throughout the trial.

Patients are followed every 2 months for 1 year after completion of radiation therapy.

Eligibility

1. Documented informed consent of the participant and/or legally authorized representative * Assent, when appropriate, will be obtained per institutional guidelines
2. Agreement to allow the use of archival tissue from diagnostic tumor biopsies * If unavailable, exceptions may be granted with study principal investigator (PI) approval
3. Ability to understand and the willingness to sign a written informed consent document
4. Age: >= 18 years
5. 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
6. 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)
7. 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
8. Absolute neutrophil count > 1,000/mcL
9. Hemoglobin >= 9.0 g/dl (Note: The use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 9.0 g/dl is acceptable)
10. Total bilirubin < 1.5 x upper limit of normal (ULN) (unless due to Gilbert’s disease)
11. Platelets > 75,000/mcL
12. Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) < 2.5 x ULN
13. Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x ULN
14. Serum creatinine < 1.5 x institutional ULN
15. Women of childbearing potential (WOCBP): negative serum pregnancy test within 14 days prior to the first dose of study medication
16. 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
17. 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)

Treatment Sites in Georgia