Dabrafenib and Lapatinib in Treating Patients With Refractory Thyroid Cancer That Cannot Be Removed by Surgery
Dabrafenib and Lapatinib in Treating Patients With Refractory Thyroid Cancer That Cannot Be Removed by Surgery
This phase I trial studies the side effects and best dose of lapatinib when given together
 with dabrafenib in treating patients with thyroid cancer that cannot be removed by surgery
 and has not responded to previous treatment (refractory). Dabrafenib and lapatinib may stop
 the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVE:

 I. To determine the maximum tolerated dose of lapatinib that can be used in combination of
 dabrafenib.

 SECONDARY OBJECTIVES:

 I. To observe and record anti-tumor activity. II. Evaluate potential mechanisms of primary
 resistance of v-raf murine sarcoma viral oncogene homolog B (BRAF) mutant thyroid cancer to
 dabrafenib by performing pathway profiling of tumor biopsies before and while on therapy.

 III. Obtain preliminary data on the activity of the combination of lapatinib and dabrafenib
 in BRAF mutant thyroid cancer through imaging.

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

 Patients receive dabrafenib orally (PO) twice daily (BID) on days 1-28 and lapatinib PO once
 daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or
 unacceptable toxicity.

 NOTE: Patients also receive dabrafenib PO for 2 weeks prior to beginning treatment with
 lapatinib.

 After completion of study treatment, patients are followed up for 4 weeks and then annually
 thereafter.
Inclusion Criteria:

 -  Patients must have histologically confirmed malignancy that is metastatic or
 unresectable and for which standard curative measures do not exist or are no longer
 effective

 -  Patients must have measurable and histologically or cytologically confirmed thyroid
 cancer with a BRAF V600E or V600K (c. 1799 T to A and c.1799_1800TG>AA) mutation that
 is not considered curable by surgery; confirmation will be done at Memorial Sloan
 Kettering (MSK); only tumors with a BRAFV600E or BRAFV600K mutation will be eligible
 for the clinical study; BRAF status will be assessed in a Clinical Laboratory
 Improvement Amendments (CLIA) certified laboratory; BRAF status may also be tested
 with any Food and Drug Administration (FDA)-approved test (such as Cobas 4800 BRAF
 V600 Mutation Test)

 -  The tumor is considered to be radioactive-iodine refractory by any of the following
 criteria:

 -  Total lifetime dose of radioactive iodine > 600 mCi

 -  Absent or insufficient radioactive iodine uptake in either all lesions or an
 index lesion which has never been resected or received external beam radiation
 therapy as documented on a radioactive iodine scan (insufficient uptake must be
 confirmed by either an endocrinologist or nuclear medicine physician)

 -  Progression of disease (by imaging or thyroglobulin) within 6 months of
 radioactive iodine treatment

 -  Fludeoxyglucose F 18 (FDG)-avid lesion (standard uptake variable maximum [SUVmax]
 >= 3) on a FDG-positron emission tomography (PET) scan

 -  No recent treatment for thyroid cancer as defined as:

 -  No radioactive iodine therapy is allowed if given < 3 months prior to initiation
 of this protocol therapy; a diagnostic study using < 10 mCi of radioactive iodine
 (RAI) is not considered radioactive iodine therapy

 -  No external beam radiation therapy < 4 weeks prior to initiation of therapy on
 this protocol

 -  No chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is allowed
 < 4 weeks prior to the initiation of therapy

 -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or Karnofsky >=
 60%

 -  Life expectancy of greater than 2 months

 -  Able to swallow and retain oral medication and must not have any clinically
 significant gastrointestinal abnormalities that may alter absorption such as
 malabsorption syndrome or major resection of the stomach or bowels

 -  Absolute neutrophil count (ANC) >= 1.2 x 10^9/L, within 2 weeks of the first dose of
 study treatment

 -  Hemoglobin >= 9 g/dL, within 2 weeks of the first dose of study treatment

 -  Platelets >= 100 x 10^9/L, within 2 weeks of the first dose of study treatment

 -  Bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with
 known Gilbert's syndrome, within 2 weeks of the first dose of study treatment

 -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
 institutional ULN, within 2 weeks of the first dose of study treatment

 -  Blood creatinine =< 1.5 mg/dL (if blood creatinine is > 1.5 mg/dL, calculate
 creatinine clearance using standard Cockcroft and Gault method or using a 24 hour
 urine collection for creatinine; creatinine clearance must be > 50 mL/min), within 2
 weeks of the first dose of study treatment

 -  Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
 time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment
 may be allowed to participate with PT/INR/PTT established within the therapeutic range
 prior to randomization; subjects will be eligible if it is determined by a
 hematologist that the cause is not associated with clinical bleeding (e.g., deficiency
 of factor XII), within 2 weeks of the first dose of study treatment

 -  Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by
 echocardiogram (ECHO), within 2 weeks of the first dose of study treatment

 -  Women of childbearing potential must have a negative serum pregnancy test within 7
 days of the first dose of study treatment

 -  The effects of dabrafenib on the developing human fetus are unknown; for this reason
 and because other therapeutic agents used in this trial are known to be teratogenic,
 women of child-bearing potential must agree to use adequate contraception (barrier
 method of birth control, or abstinence; hormonal contraception is not allowed due to
 drug-drug interactions which can render hormonal contraceptives ineffective) for the
 duration of study participation, and for at least 2 weeks after treatment with
 dabrafenib; should a woman become pregnant or suspect she is pregnant while she is
 participating in this study, she should inform her treating physician immediately

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

 -  Patient must agree to allow 3 separate biopsies of any malignant lesion; biopsies do
 not need to be done if:

 -  Tumor is not considered accessible by either the investigator or the person
 performing the biopsy (it is determined the risk is too high due to location near
 vital organs or too great of a risk of an adverse event)

 -  Patient is on anticoagulation and it would be unsafe to temporarily hold the
 anticoagulation

 -  Consent of the principal investigator (PI) not to have a biopsy done

 -  A minimum of 8 subjects must participate in the biopsy part of the study

 Exclusion Criteria:

 -  Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive
 radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the
 last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks
 preceding the first dose of study treatment

 -  Use of other investigational drugs within 28 days (or five half-lives, whichever is
 shorter; with a minimum of 14 days from the last dose) preceding the first dose of
 study treatment and during the study

 -  Current use of a prohibited medication; patients receiving any medications or
 substances that are strong inhibitors or inducers of cytochrome P450, family 3,
 subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8)
 are ineligible; current use of, or intended ongoing treatment with: herbal remedies
 (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or
 breast cancer resistance protein 1 (Bcrp1) should also be excluded; it is important to
 regularly consult a frequently-updated list of these agents; as part of the
 enrollment/informed consent procedures, the patient will be counseled on the risk of
 interactions with other agents, and what to do if new medications need to be
 prescribed or if the patient is considering a new over-the-counter medicine or herbal
 product

 -  Prohibited: strong inducers of CYP3A or CYP2C8, since concentrations of
 dabrafenib may be decreased

 -  Antibiotics: rifamycin class agents (e.g., rifampin, rifabutin, rifapentine)

 -  Anticonvulsant: carbamazepine, oxcarbazepine phenobarbital, phenytoin,
 s-mephenytoin

 -  Miscellaneous: bosentan, St. John's wort

 -  Prohibited: strong inhibitors of CYP3A or CYP2C8, since concentrations of
 dabrafenib may be increased

 -  Antibiotics: clarithromycin, telithromycin, troleandomycin

 -  Antidepressant: nefazodone

 -  Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole

 -  Hyperlipidemia: gemfibrozil

 -  Antiretroviral: ritonavir, saquinavir, atazanavir

 -  Miscellaneous: conivaptan

 -  Unresolved toxicity of National Cancer Institute Common Terminology Criteria for
 Adverse Events, version 4.0 (NCI CTCAE v4.0) grade 2 or higher from previous
 anti-cancer therapy, except alopecia; in specific cases, will be allowed with
 permission from the principal investigator

 -  Human immunodeficiency virus (HIV)-positive patients on antiviral drugs and/or cluster
 of differentiation (CD)4 count is inadequate (< 500); if neither condition exists,
 HIV-positive patients are eligible

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
 arrhythmia, or psychiatric illness/social situations that would limit compliance with
 study requirements

 -  A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the
 exception of cleared HBV and HCV infection, which will be allowed)

 -  Presence of an invasive malignancy other than the study indication under this trial
 within 3 years of study enrollment except for carcinoma in situ CIS, squamous cell
 carcinomas of the skin, or basal cell carcinoma of the skin; a diagnosis of an
 invasive malignancy within 3 years is allowed if both the cure rate is felt to be >
 80% and there has been no evidence of disease in the past year

 -  Patients with a history of RAS mutation-positive tumors are not eligible regardless of
 interval from the current study; Note: prospective RAS testing is not required;
 however if the results of previous RAS testing are known, they must be used in
 assessing eligibility

 -  Brain metastases that are symptomatic or requiring corticosteroids (except inhaled);
 subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks

 -  History or evidence of cardiovascular risks including any of the following:

 -  History of acute coronary syndromes (including myocardial infarction or unstable
 angina), coronary angioplasty, or stenting within the past 24 weeks prior to
 randomization

 -  History or evidence of current class II, III, or IV heart failure as defined by
 the New York Heart Association (NYHA) functional classification system

 -  Intra-cardiac defibrillators

 -  Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with
 grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on
 study); subjects with moderate valvular thickening should not be entered on study

 -  History or evidence of current clinically significant uncontrolled cardiac
 arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30
 days prior to dosing are eligible

 -  Treatment refractory hypertension defined as a blood pressure of systolic > 140
 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive
 therapy

 -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
 chemically related to the study treatments, their excipients, and/or dimethyl
 sulfoxide (DMSO)

 -  Medical or psychiatric illness/social situations that would limit compliance with
 study requirements

 -  Pregnant women are excluded from this study because of the potential for teratogenic
 or abortifacient effects; because there is an unknown but potential risk for adverse
 events in nursing infants secondary to treatment of the mother with dabrafenib,
 breastfeeding should be discontinued if the mother is treated with dabrafenib; these
 potential risks may also apply to other agents used in this study