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

Summary

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.