Dabrafenib and Lapatinib Ditosylate in Treating Patients With Refractory Thyroid Cancer That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of lapatinib (lapatinib ditosylate) 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 ditosylate.

Patients receive dabrafenib orally (PO) twice daily (BID) on days 1-28 and lapatinib
ditosylate PO once daily (QD) on days 1-28. Courses 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 ditosylate.

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

- Women of child-bearing potential must agree to use adequate contraception (barrier
method of birth control, or abstinence; hormonal contraception is not allowed) 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

- 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

- 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; breastfeeding should be discontinued if
the mother is treated with dabrafenib