Molecularly Targeted Therapy in Treating Patients With BRAF Wild-type Melanoma That is Metastatic

PRIMARY OBJECTIVES:

I. To determine the difference in best overall response rate (BORR) between patients treated
with MEK162 following personalized molecularly guided assignment vs. a historical BORR of 7%
in this patient population.

SECONDARY OBJECTIVES:

I. To evaluate the safety of performing individualized drug therapy (including novel agents
and commercially-available agents) in the context of a personalized medicine clinical trial.

II. To define the difference in progression free survival (PFS) between patients treated with
MEK162 following personalized molecularly guided assignment vs. a historical PFS rate of 2
months in this patient population.

III. To continually assess data in real time so as to iteratively refine and standardize a
set of statistical and informatics methodologies for matching treatments to the patient's
tumor, based on the molecular profile.

OUTLINE:

Patients undergo collection of tissue and blood samples for deoxyribonucleic acid (DNA) and
ribonucleic acid (RNA) analysis via sequencing. Based on the results of the DNA and RNA
analysis, patients receive molecularly targeted therapy. Treatment continues in the absence
of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Patient with metastatic or locally advanced and unresectable BRAF wild-type melanoma
who have either progressed following previous treatment of immunotherapy, or are not
eligible for immunotherapy; pts. are defined as "BRAF wild-type" if they test negative
for V600 mutations based on a Clinical Laboratory Improvement Amendments (CLIA)
certified assay

- Patients must have tumor accessible by interventional radiology or surgical
intervention and suitable for biopsy (BX) with 5-6 passes of a 16 or 18 gauge needle
for core BX (defined as at least 1 cm^3 tumor/50 mg accessible for BX), and must agree
to undergo up to two surgical resections/biopsies to collect tumor for research
purposes; the first of these biopsies will occur at the beginning of the study, prior
to genetic analysis and Rx; the second BX will be performed at the time of DZ
progression/end of study should funding be available

- Patients must have measurable DZ (per Response Evaluation Criteria in Solid Tumors
[RECIST] version 1.1 [v1.1] criteria), defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional
techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic
resonance imaging (MRI), or a subcutaneous or superficial lesion that can be measured
with calipers by clinical exam; for lymph nodes, the short axis must be >= 15 mm

- Previous therapies: prior radiation therapies, immunotherapies, and investigational
therapies are allowed as follows.

- Radiation: prior radiation therapy (RT) is allowed with the following conditions:

- Patients who have received minimal RT (=< 5% of their total marrow volume)
must have completed it >= 2 weeks prior to the initiation of study Rx

- Patients who have received RT that constituted > 5% but < 50% of their total
marrow volume must have completed it >= 4 weeks prior to the initiation of
study treatment

- Patients who have received prior radiation to 50% or more of their total
marrow volume will be excluded

- Patients may be biopsied while undergoing RT as long as BX site is not in
the radiation portal; however, they still have to wait the required amount
of time from radiation to treatment even though the tumor board may have
already occurred and a treatment plan assigned

- Other therapies: prior investigational or targeted therapies and immunotherapies
may be allowed following discussion with the PI (PI); if the PI deems the prior
treatment acceptable, patients must not have received these therapies for 28 days
or five half-lives of the drug (whichever is lesser) prior to the initiation of
study treatment and must have full recovery from any acute effects of these
therapies; prior therapy with mitogen-activated protein kinase (MEK) inhibitors
will not be allowed

- Patients with chronic grade 2 toxicity may be eligible at the discretion of the PI if
the condition has been stable, and not worsening, for at least 30 days; pts. with
ongoing alopecia of any grade will be eligible

- Patient must have a life expectancy of >= 3 months, as estimated by the treating
oncologist

- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Hemoglobin >= 9 g/dL

- Leukocytes >= 3,000/microliter (mcL)

- Absolute neutrophil count (ANC) >= 1,500/mcL

- Platelets (PLT) >= 100,000/mcL

- Aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN); if liver
metastases are present, =< 5 x ULN

- Alanine aminotransferase (ALT) =< 2.5 x ULN; if liver metastases are present, =< 5 x
ULN

- Bilirubin =< 1.5 x ULN

- Creatinine =< 1.5 x ULN OR calculated or measured creatinine clearance >= 50
mL/min/1.73 m^2 for pts. with creatinine above institutional normal

- If available, pt. must agree to provide archival tissue for research purposes (either
archival paraffin tissue block or 10 unstained slides of a primary or metastatic
melanoma lesion) prior to enrollment; samples should be shipped within 1 month after
enrollment

- Patient agrees to having a blood sample (a minimum of 10 mL, with 20 mL preferred)
drawn and analyzed to compare their normal genetic profile to that of their tumor
sample

- Patient must be able to tolerate oral medication

- Women of child-bearing potential and men must agree to use 2 forms of adequate
contraception (hormonal or barrier method of birth control; abstinence) for the
duration of study participation, and for four months following completion of study
therapy; should a woman become pregnant or suspect she is pregnant while participating
in this study, she should inform her treating physician immediately; women who become
pregnant must immediately discontinue Rx with any study therapy; male pts. should
avoid impregnating a female partner; male pts., even if surgically sterilized, (i.e.
post-vasectomy) must agree to one of the following: practice effective barrier
contraception during the entire study Rx period and through 4 months after the last
dose of study drug, or completely abstain from sexual intercourse

- Patient must have the ability to understand and the willingness to sign a written
informed consent document

- Patient must be willing and able to comply with the protocol for the duration of the
study, including attending scheduled visits, examinations, the BX procedure, and
having their tumor and blood molecularly characterized

- Patient understands they must meet all inclusion and exclusion criteria in the drug
specific appendix for which they were assigned.

Exclusion Criteria:

- Patients with peripheral neuropathy >= grade 2 are not permitted unless discussed with
the PI and only in unique circumstances (i.e. unilateral neuropathy due to trauma)

- Patient has DZ that tests positive for BRAF V600 mutations based on the results of a
CLIA certified assay

- Patients with active infection at time of BX

- Patients with any evidence of severe or uncontrolled systemic DZ(s) including known
cases of hepatitis B or C or human immunodeficiency virus (HIV); screening for chronic
conditions is not required, although pts. known to have such conditions at screening
should not be included

- Any patient requiring chronic maintenance of red blood cell, white blood cell or
granulocyte counts through the use of blood transfusions or growth factor support
(e.g. Neulasta®, Neupogen®)

- Patients with a prior history of seizures within the past year unrelated to brain
metastases

- Patients with known active progressive brain metastases; pts. with prior treated brain
metastases are allowed, providing that they were not accompanied by seizures within
the past year and that a baseline brain MRI scan prior to study entry demonstrates no
current evidence of active brain metastases; all pts. with prior treated brain
metastases must be stable for > 1 months after treatment and off steroid treatment
prior to study enrollment

- Patients receiving any other anti-cancer therapy (cytotoxic, biologic, radiation, or
hormonal other than for replacement) except for medications that are prescribed for
supportive care but may potentially have an anti-cancer effect (i.e. megestrol
acetate, bisphosphonates); these medications must have been started >= month prior to
enrollment on this study; pts. may be on low molecular weight heparin or direct factor
Xa inhibitors

- Patients with any clinically significant medical condition which, in the opinion of
the investigator, makes it undesirable for the pt. to participate in the study or
which could jeopardize compliance with protocol requirements including, but not
limited to: ongoing or active infection, significant uncontrolled hypertension, or
severe psychiatric illness/social situations

- Patients with preexisting cardiac conditions, including uncontrolled or symptomatic
angina, arrhythmias, or congestive heart failure will not be eligible

- Patients with left ventricular ejection fraction (LVEF) < 45% will not be eligible

- Patients with either of the following within 6 months before the first dose of study
treatment:

- Stroke (including transient ischemic attack [TIA], or other ischemic event)

- Myocardial infarction

- Patients with acute gastrointestinal bleeding within 1 month of study entry

- Patients who have, at screening, corrected QT interval using Fridericia's formula
(QTcF) >= 450 msec for males and QTcF >= 470 for females

- Patients with a co-morbid condition(s) that, in the opinion of the investigator,
prevents safe surgery/BX procedure

- Patients with malabsorption syndrome or other condition that would interfere with
intestinal absorption or ability to swallow oral medication

- Pregnant or nursing women; breastfeeding must be discontinued prior to Rx

- Patients who have received organ transplant

- Patients who have had major surgery within 14 days of study enrollment

- Patients diagnosed or treated for another malignancy within 3 years of enrollment,
with the exception of complete resection of basal cell carcinoma or squamous cell
carcinoma of the skin, or an in situ malignancy. Patients with a low grade prostate
cancer, not on hormonal therapy, for which the disease is confined to the prostate may
be considered eligible by the overall Principal Investigator on a case by case basis.