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.
