The Effects of Vemurafenib + Cobimetinib on Immunity in Patients With Melanoma

This is multicenter study of vemurafenib and cobimetinib in patients with biopsy-accessible
advanced metastatic melanoma.

The trial will consist of a screening period, a treatment phase, and one post-study follow-up
visit occurring about 30 days after the last dose of drug. Day 1 of the study will be defined
as the first day a subject receives vemurafenib and/or cobitmetinib. During the treatment
phase, all study assessments will be conducted on Day 1 (± 3 days) of each cycle, with the
exception of computed tomography (CT) and/or magnetic resonance imaging (MRI), which should
occur every 6 weeks (+/- 7 days).

All subjects will have biopsies performed of safely accessible tumors before starting
treatment and at 1, 2, and 4 weeks later (days 8, 15, 29). In addition, any patient with
accessible tumor at the time of progression will have a tumor biopsy performed at that time.

Mixed-effects models will be used to study the change in CD8 T cell counts per mm^2 of
tissue, changes in expression of immunoinhibitory proteins (B7-H1/PD-L1, IDO, arginase), and
changes in endothelial homing receptor ligands and tumor associated chemokines at
pre-treatment at pre-treatment and at weeks 1, 2, and 4 after therapy. Subjects will be
treated as random effects to account for individual variability. Potential covariates are
age, gender, and ECOG performance status.

60 ml of blood for lymphocytes will be drawn on days 1, 8, 15, and 29.

- Patients must have histological or cytological confirmed melanoma that is metastatic
or that is unresectable stage III and clearly progressive.

- Melanoma must be documented to contain a BRAFV600 mutation by a FDA approved assay

- Age > 18 years

- ECOG PS 0,1, or 2

- Participants must have measurable melanoma. Measurable disease is defined as at least
one lesion that can be measured accurately in at least one dimension (longest diameter
to be recorded) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT
scan. Cutaneous or subcutaneous lesions may be considered measurable if they can be
measured reliably as ≥ 10 mm by direct physical exam measurement.

In addition, participants must also have separate disease, which may or may not be
measurable as defined by RECIST, but must be readily accessible for core needle biopsy,
excisional biopsy, and/or surgical resection. This disease may include one large tumor
tissue deposit from which biopsies can be harvested multiple times or may include multiple
deposits which can be biopsied, or excised individually, on different dates. Please see
below for suggested minimum size requirements of tumor tissue to be used for biopsy for
research:

- 1 lesion ≥ 5 cm3 or

- 2 lesions ≥ 3 cm3 each

- 3 lesions ≥ 2 cm3each OR

- ≥ 3 skin lesions, such that the surface area is approximately 1 cm^2 each (or in
aggregate for several lesions) and the total volume of tumor I s approximately 260-325
mm^3 or greater for each biopsy time point. These subjects will need ≥ 3 such
epidermal/dermal tumor lesions; excisional tumor tissue biopsies will be performed on
one or more lesions at each time point. It is acceptable to biopsy more than one
lesion, that may be less than 1 cm^2 in surface area, as long as the total tissue
removed has a surface area of approximately 1 cm^2 or greater.

- A combination of these may be acceptable, as long as there appears to be enough tumor
tissue to remove approximately 325 mm^3 or more of tissue at each time point.

Lesion volume can be calculated based on the formula for volume of a sphere (4/3 r3). An
acceptable approximation for lesions approaching spherical shape is to multiply the
diameters in three perpendicular directions and divide by 2. [Volume ~ ½(D1xD2xD3); e.g.:
volume of a 2 x 2 x 3 cm lesion is approximately 6 cm3. Lesion measurements are based on
length X width X depth (height) of sample.]

- Women must not be pregnant due to the fact that the effects of vemurafenib and/or
cobimetinib on the developing human fetus are unknown. For this reason, women of
childbearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry, for the duration of
study participation and for 6 months after completion of study treatment. See Appendix
H for acceptable and unacceptable forms of contraception. Should a woman become
pregnant while participating in this study, she should inform her treating physician
immediately.

- All females of childbearing potential must have a blood test or urine study within 2
weeks prior to registration to rule out pregnancy. A female of childbearing potential
is any woman, regardless of sexual orientation or whether they have undergone tubal
ligation, who meets the following criteria: 1) has not undergone a hysterectomy or
bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive
months).

- Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with vemurafenib and/or cobimetinib,
breastfeeding must be discontinued prior to treatment Day 1 of the study.

- Patients must have measurable disease as defined in Section 9.1. Cutaneous lesions or
lymph nodes measuring at least 1 cm will be considered measurable. Baseline CT or MRI
scans of measurable disease sites must be performed within 4 weeks of study entry.

- Patients may have received any number of prior systemic treatment regimens for distant
metastatic disease or advanced regional disease. The following prior therapy is
permitted in either the adjuvant or metastatic disease setting:

1. No prior therapy

2. Immunotherapy consisting of interferon-alpha, interleukin-2, GM-CSF, ipilimumab,
anti-PD1, cancer vaccines, or other experimental agent.

3. Cytotoxic chemotherapy consisting of dacarbazine, temozolomide, carboplatin, or
paclitaxel alone or in combination.

4. Targeted therapy with temsirolimus, bevacizumab, or sorafenib.

- Patients who have had prior therapy with a MEK inhibitor or an inhibitor of mutant
BRAF are ineligible. Because sorafenib has low efficacy as a BRAF inhibitor, prior
therapy with it is allowed.

- Patients must have discontinued cytotoxic therapy agents at least 4 weeks and cytokine
and immunoregulatory antibody based immunotherapy at least 6 weeks prior to entering
the study and have recovered from adverse events due to those agents.

- Patients must be completed radiation therapy at least 4 week previously

- Patients must have an ECOG performance status of 0, 1 or 2.

- Patients must have the following baseline laboratory values:

1. White Blood Count > 3,000/mm3

2. Absolute Granulocyte Count > 1,500/mm3

3. Platelet Count > 100,000/mm3

4. Hemoglobin > 9 g/dL

5. Serum creatinine < 1.5 x upper limit of normal (ULN) or serum creatinine
clearance (CrCl) > 40ml/min (CrCl= Wt (kg) x (140-age)*/72 x Cr. level, *female x
0.85)

6. AST and ALT < 3 x ULN (< 5 x ULN for patients with documented liver metastases)

7. Alkaline Phosphatase ≤ 2 x ULN (≤ 5x ULN for patients with known liver
involvement and ≤ 7x ULN for patients with known bone involvement)

8. INR < 1.5 and aPTT within 1.1 x ULN. Patients on warfarin therapy are not
eligible due to the requirement for multiple biopsies.

9. Total Bilirubin < 1.5 x ULN

- Patients must not receive any other investigational agents during the period on study
or the four weeks prior to entry.

- Patients will be evaluated with a head CT or MRI within 4 weeks of enrollment.
Patients must have no clinical evidence of active brain metastasis. Patients with a
history of brain metastases must have had them treated greater than 4 weeks previously
with the CNS lesions confirmed to be stable or regressing on imaging since the time of
the last CNS treatment. Patients must have no residual neurologic symptoms while
taking either no steroids or a stable dose of steroids for the 2 weeks prior to
enrollment. Patients are allowed to be on a stable dose of anti-seizure meds.

- Patients who have had brain metastases will be eligible only if all of the following
are true:

- the total number of brain metastases ever is ≤ 3

- all are less than or equal to 2 cm

- they have been resected surgically or have been treated with gamma-knife or
stereotactic radiosurgery

- the patient has not taken any steroids or has not increased the dose of steroids
≤ 14 days prior to registration.

- Patients must not have another cancer diagnosis with a few exceptions- the following
diagnoses will be allowed:

1. squamous cell cancer of the skin without known metastasis. Note, patients with
suspected cuSCCs should have them excised prior to study registration.

2. basal cell cancer of the skin without known metastasis

3. carcinoma in situ of the breast (DCIS or LCIS)

4. carcinoma in situ of the cervix

5. any cancer without distant metastasis that has been treated successfully, without
evidence of recurrence or metastasis for over 3 years

- Patients must not have a serious intercurrent illness including, but not limited to:

- Ongoing or active infection requiring parental antibiotics on Day 1

- History of congenital long QT syndrome or mean corrected QTc interval > 450 msec
at baseline

- Clinically significant cardiovascular disease:

Myocardial infarction within 6 months Unstable angina New York Heart Association grade II
or greater congestive heart failure (see Appendix E) Serious cardiac arrhythmia requiring
medication Uncontrolled hypertension ≥ Grade 2 (patients with a history of hypertension
controlled with anti-hypertensives to ≤ Grade 1 are eligible) Left ventricular ejection
fraction (LVEF) below institutional lower limit of normal or below 50%

- Serious, non-healing wound, active ulcer, or untreated bone fracture

- Psychiatric illness/social situations that would limit compliance with study
requirements.

- Participants must not be known to be HIV positive (testing is not required)

- Participants must be Hepatitis C negative < 6 months prior to screening

- Participants must not have a history of malabsorption or other condition that
would interfere with absorption of vemurafenib or cobimetinib

- Patients must be able to comply with study and follow-up procedures.

- Patients must not have following foods/supplements at least 7 days prior to
initiation of and during study treatment: St. John's wort or hyperforin (potent
cytochrome P450 CYP34A enzyme inducer) or Grapefruit juice (potent cytochrome
P450 CYP34A enzyme inhibitor).

- Patients must not have significant ocular issues including history of or evidence
of retinal pathology on ophthalmologic examination that is considered a risk
factor for neurosensory retinal detachment, RVO, or neovascular macular
degeneration.

The risk factors for RVO are listed below. Patients should be excluded if they have the
following conditions:

1. Uncontrolled glaucoma with intra-ocular pressures > 21mmHg

2. Serum cholesterol ≥ Grade 2

3. Hypertriglyceridemia ≥ Grade 2

4. Hyperglycemia (fasting) ≥ Grade 2

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