Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAF Mutant Melanoma That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To compare progression-free survival with intermittent dosing and continuous dosing of
dabrafenib and trametinib among patients with metastatic BRAF V600E/K mutant melanoma.

SECONDARY OBJECTIVES:

I. To estimate the frequency and severity of toxicities of the two dosing schedules.

II. To compare the frequency and severity of fever >= grade 1 per Common Terminology Criteria
for Adverse Events (CTCAE) 4.0 of the two dosing schedules.

III. To compare the response rate (complete and partial response, confirmed and unconfirmed),
overall survival, and survival after progression between the two dosing schedules on step 2.

TRANSLATIONAL MEDICINE OBJECTIVES:

I. To evaluate whether acquired molecular events leading to reactivation of the MAPK pathway
are more common among patients on the continuous dosing arm than on the intermittent dosing
arm using circulating tumor deoxyribonucleic acid (DNA) (ctDNA).

II. To assess the prognostic association between baseline biomarkers and early molecular
events with progression free survival (PFS).

III. To explore the potential interaction between treatment arm and baseline biomarkers/early
molecular events with PFS.

IV. To bank tissue and whole blood in anticipation of future studies to evaluate molecular
events associated with clinical benefit and disease progression in patients treated with
continuous versus intermittent dabrafenib and trametinib.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I (CONTINUOUS DOSING): Patients receive dabrafenib orally (PO) twice daily (BID) and
trametinib PO once daily (QD) on days 1-56. Courses repeat every 56 days in the absence of
disease progression or unacceptable toxicity.

ARM II (INTERMITTENT DOSING): Patients receive dabrafenib PO BID and trametinib PO QD on days
1-7 and 29-56. Courses repeat every 56 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 3 years and
then yearly for 2 years.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed stage IV or unresectable
stage III BRAF V600E or BRAF V600K mutant melanoma

- Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical
Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic
techniques include but are not restricted to DNA sequencing, pyrosequencing,
polymerase chain reaction (PCR), melting point assays, and immunohistochemistry

- Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and
pelvis are required; a whole body positron emission tomography (PET)/CT scan with
diagnostic quality images and intravenous iodinated contrast may be used in lieu of a
contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted
if the treating investigator believes that exposure to contrast poses an excessive
risk to the patient; patients must have measurable disease per Response Evaluation
Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within
28 days prior to registration; tests to assess non-measurable disease must be
performed within 42 days prior to registration; all disease must be assessed and
documented on the Baseline Tumor Assessment Form (RECIST 1.1)

- Patients must not have received a prior BRAF or mitogen-activated protein kinase
kinase (MEK) inhibitor

- Patients with a history of brain metastases are eligible if the patient is
asymptomatic with no residual neurological dysfunction and has not received
enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to
registration

- Patients must not have received any anti-cancer drug within 28 days prior to
registration, and must not have received any nitrosoureas or mitomycin C within 42
days prior to registration

- Patients must not have received any major surgery or immunotherapy within 28 days
prior to registration

- Patients must not have any unresolved toxicity greater than National Cancer Institute
(NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia
within 7 days prior to registration

- Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to
registration)

- Platelets >= 100,000/ul (obtained within 28 days prior to registration)

- Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration)

- Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper
limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to
registration)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or
< 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to
registration)

- Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration)

- Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50
mL/min; creatinine measurements must be obtained within 28 days prior to registration

- Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to
registration in order to obtain baseline stratification information

- Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower
limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA)
within 28 days prior to registration

- Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG)
(corrected using the Bazett's formula) within 28 days prior to registration

- Patients with known history or current evidence of retinal vein occlusion (RVO) or
central serous retinopathy (CSR) are not eligible:

- History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled
glaucoma or ocular hypertension, uncontrolled systemic disease such as
hypertension, diabetes mellitus, or history of hyperviscosity or
hypercoagulability syndromes)

- Visible retinal pathology as assessed by ophthalmic exam that is considered a
risk factor for RVO or CSR such as:

- Evidence of new optic disc cupping

- Evidence of new visual field defects

- Intraocular pressure > 21 mmHg

- NOTE: ophthalmic exam is required for all patients; exam must be obtained within
28 days prior to registration

- Patients must be able to take oral medications; patients must not have any impairment
of gastrointestinal function or gastrointestinal disease that may significantly alter
the absorption of protocol treatment (e.g. ulcerative disease, uncontrolled nausea,
vomiting, diarrhea, malabsorption syndrome or small bowel resection)

- Patients receiving anticoagulation treatment are allowed to participate with
international normalized ratio (INR) established within the therapeutic range

- Patients must not have a history of pneumonitis or interstitial lung disease

- Patients must not have any grade II/III/IV cardiac disease as defined by the New York
Heart Association criteria (i.e., patients with cardiac disease resulting in marked
limitation of physical activity or resulting in inability to carry on any physical
activity without discomfort), unstable angina pectoris, myocardial infarction within 6
months, or serious uncontrolled cardiac arrhythmia; abnormal cardiac valve morphology
(>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e.,
mild regurgitation/stenosis]) can be entered on study; patients with a history of
atrial fibrillation must have atrial fibrillation controlled for at least 30 days
prior to registration

- Patients with known hepatitis B or hepatitis C are not eligible, regardless of
concomitant antiretroviral therapy or current viral load

- Patients with known human immunodeficiency virus (HIV) may be eligible providing they
meet the following additional criteria:

- Cluster of differentiation (CD)4 cells >= 500/uL

- Serum HIV viral load of < 25,000 IU/ml

- No current antiretroviral therapy

- Tests must be obtained within 28 days prior to registration; patients who
are HIV positive (+) and do not meet all of these criteria are not eligible
for this study (HIV/hepatitis testing are not required for patients without
known infection)

- Pre-study history and physical must be obtained with 28 days prior to registration

- Patients must have dermatology exam obtained within 28 days prior to registration to
obtain baseline measurement; exam to be performed by treating physician or designated
dermatologist

- Patients must have Zubrod performance status of 0, 1 or 2

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
stage I or II cancer from which the patient is currently in complete remission, or any
other cancer from which the patient has been disease free for three years; exception:
patients with known history of colon cancer, cancer of the pancreas, or any cancer
known to harbor an activating RAS mutation are ineligible regardless of stage or time
since diagnosis

- Patients must not be pregnant or nursing; women/men of reproductive potential must
have agreed to use an effective contraceptive method; a woman is considered to be of
"reproductive potential" if she has had menses at any time in the preceding 12
consecutive months; in addition to routine contraceptive methods, "effective
contraception" also includes heterosexual celibacy and surgery intended to prevent
pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
bilateral oophorectomy or bilateral tubal ligation; however, if at any point a
previously celibate patient chooses to become heterosexually active during the time
period for use of contraceptive measures outlined in the protocol, he/she is
responsible for beginning contraceptive measures; hormonal contraception is not
allowed

- Patients must be offered the opportunity to participate in specimen banking

- Patients with cutaneous or superficial lesions that do not require imaging guidance
for biopsy must be willing to undergo biopsies for tissue submission and blood draws
for translational medicine

- Patients or their legally authorized representative must be informed of the
investigational nature of this study and must sign and give written informed consent
in accordance with institutional and federal guidelines

- As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has been
entered in the system

- STEP 2: RANDOMIZATION

- After completing one cycle of therapy, patients will be registered for randomization
between intermittent and continuous dosing, provided that they were eligible for the
initial step 1 registration and satisfy the following criteria

- Patients must not have unequivocal disease progression (by RECIST v1.1) during the
first cycle; patients must have disease assessed using the same method as baseline
within +/- 5 days of the day 56 scheduled assessment (between days 51-55 of cycle 1,
or days 1-5 of cycle 2); all disease must be assessed and documented on the follow-up
tumor assessment form (RECIST 1.1)

- Patients must be registered to step 2: randomization within +/- 5 days of starting
cycle 2; patients MUST NOT be registered prior to the day 56 disease assessment