Trial of Vemurafenib/Cobimetinib With or Without Bevacizumab in Patients With Stage IV BRAFV600 Mutant Melanoma

In this study, the drugs being used are vemurafenib, cobimetinib, and bevacizumab.
Vemurafenib has been approved by the FDA for treatment of patients with advanced melanoma
that harbors a BRAF mutation. However, vemurafenib in combination with cobimetinib has not
been approved by the FDA for the treatment of cancer. Bevacizumab has been approved by the
FDA for use in combination with first line chemotherapies for treatment of patients with
colorectal, breast and lung cancer. Bevacizumab has not been approved for use in patients
with metastatic melanoma.

Vemurafenib and cobimetinib attack different proteins that cause cancer cells to grow.
Vemurafenib works by blocking a protein called B-RAF. Researchers have found that a large
number of melanomas have mutations (changes) in the BRAF gene. The BRAF gene codes for a
protein called B-RAF, which is involved in sending signals in cells that can lead to cell
growth. Research has determined that mutations in the BRAF gene at the V600 position cause a
change in the B-RAF protein that can drive the growth and spread of melanoma cells.
Vemurafenib works by preventing these altered B-RAF proteins from working, and thereby may
block the growth and spread of cancer cells in patients with melanoma. Cobimetinib works by
blocking a protein called MEK. MEK has been known to promote growth in cancer that carries
either a mutation in the BRAF or KRAS genes. The vemurafenib/cobimetinib combination has been
used in prior clinical studies. Information from those other research studies suggests that
these drugs can shrink melanoma tumors in the majority of patients and slow tumor growth as
compared to standard chemotherapy. Another drug to block the BRAF and MEK proteins was
recently approved by the FDA in the treatment of patients with B-RAFV600 mutant melanoma. The
researchers want to see if using vemurafenib and cobimetinib together will work in a similar
way to treat malignant melanoma.

Bevacizumab is a humanized monoclonal antibody (a type of protein that is normally made by
the immune system to help defend the body from infection and cancer) produced by using
recombinant DNA technology. Bevacizumab is an antibody directed against vascular endothelial
growth factor or VEGF. VEGF is a potent, specific growth factor with a well-defined role in
normal and abnormal blood vessel formation. It is present in a wide variety of normal
tissues, but is produced in excess by most solid cancers (tumors). In the setting of cancer,
VEGF promotes the growth of blood vessels that bring nutrients to tumor cells. Its expression
by the tumor has been associated with worse outcome in patients with a number of tumors types
including melanoma. In laboratory experiments, bevacizumab inhibits the growth of several
different types of human cancer cells by blocking the effects of VEGF.

The purpose of this research study is to determine the effectiveness of using the study drugs
vemurafenib, cobimetinib, and bevacizumab together relative to vemurafenib and cobimetinib
alone. This study will investigate whether using both study drugs lengthens the amount of
time before participants' melanoma worsens, increases the number of people whose melanoma
responds to treatment and what the side effects are of using the drugs together rather than
separately.

Inclusion Criteria:

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

2. Patients must have melanoma that is documented to contain a BRAFV600E or BRAFV600K
mutation by a FDA-approved test.

3. Age >= 18 years.

4. Women must not be pregnant due to the fact that the effects of vemurafenib,
cobimetinib, and/or bevacizumab on the developing human fetus are unknown. For this
reason and because antiangiogenic agents as well as other therapeutic agents used in
this trial are known to be teratogenic, women of child-bearing potential and men must
agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence; defined in Appendix G) prior to study entry and for the duration of study
participation. Should a woman become pregnant while participating in this study, she
should inform her treating physician immediately.

5. 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).

6. Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with bevacizumab, cobimetinib, and vemurafenib,
female participants who are breastfeeding must agree to discontinue nursing prior to
Day 1 of the study.

7. Patients must have measurable disease as defined in Section 10.1 (cutaneous lesions
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.

8. Patients must have discontinued immunotherapy or other systemic therapy including
investigational agents at least 4 weeks prior to entering the study and have recovered
from adverse events due to those agents. Patients must agree to not receive any other
investigational agents during study participation.

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

10. Patients must have the following baseline laboratory values:

1. White Blood Count > 3,000/mm3

2. Absolute Neutrophil Count > 1,500/mm3

3. Platelet Count > 100,000/mm3

4. 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)

5. Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) < 3 x ULN (< 5
x ULN for patients with documented liver metastases)

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

7. International Normalized Ratio (INR) < 1.5 and aPTT within 1.1 x ULN

8. Total Bilirubin < 1.5 x ULN

9. UPC ratio < 1.0 at screening or 24 hours urine protein < 1 gm (Appendix D)

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

Exclusion Criteria:

1. Patients may not have received more than 2 prior systemic treatment regimens for
distant metastatic disease. The following prior therapy is permitted in either the
adjuvant or metastatic disease setting, provided treatment is discontinued at least 4
weeks prior to initiating study treatment:

1. Immunotherapy, such as interferon, interleukin-2, GM-CSF, ipilimumab, anti-PD1 or
other experimental agent.

2. Cytotoxic chemotherapy, such as dacarbazine, temozolomide, carboplatin
+/-paclitaxel.

2. Patients may not have had radiation therapy within the last 4 weeks prior to
initiation of study treatment.

3. Patients who have had prior VEGF pathway inhibitor, BRAF or MEK inhibitor therapy are
ineligible.

4. Patients must have no clinical evidence of active brain metastasis. Patients with a
history of brain metastases must meet all of the following criteria:

1. Have completed treatment greater than 4 weeks prior to enrollment.

2. Have CNS lesions that are confirmed to be stable or regressing on imaging since
the time of the last CNS treatment including the pre-treatment CT or MRI scan for
this trial.

3. Patients must have no residual neurologic symptoms while taking no steroids, a
stable or decreasing dose of steroids, or a stable dose of anti-seizure
medication for the 2 weeks prior to enrollment.

5. Patients must not have other concurrent uncontrolled malignancies, defined as a
malignancy that currently requires therapy or other intervention. Patients with
suspected cuSCCs should have them excised prior to study registration. Surgical
resection should not be performed within 7 days of starting protocol therapy.

6. Patients may not have had a major surgical procedure, open biopsy (excluding skin
cancer resection, cutaneous/subcutaneous melanoma metastasis resection or biopsy or
vascular access device insertion), or significant traumatic injury within 28 days
prior to Day 1, or have an anticipated need for major surgical procedure or a planned
elective surgical procedure during the course of the study.

7. Patients may not have had a core biopsy, skin cancer resection, or other minor
surgical procedure, including placement of a vascular access device, within 7 days
prior to Day 1 of the protocol.

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

1. Ongoing or active infection requiring parental antibiotics on Day 1

2. A history of malabsorption or other condition that would interfere with
absorption of vemurafenib or cobimetinib.

3. History of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) within 1
month prior to Day 1

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

5. Clinically significant cardiovascular disease, defined as any of the following
conditions:

i. Uncontrolled hypertension (defined as systolic blood pressure > 150 mmHg and/or
diastolic blood pressure > 100 mmHg) ii. Prior history of hypertensive crisis or
hypertensive encephalopathy iii. Myocardial infarction within 6 months iv. Unstable
angina v. New York heart association grade II or greater congestive heart failure
(Appendix C) vi. Serious cardiac arrhythmia requiring medication vii. LVEF < 50% or
below institutional limit of normal f) History of stroke of TIAs within 6 months prior
to Day 1 g) Grade II or greater peripheral vascular disease within 1 year prior to
study entry or other significant vascular disease (e.g., aortic aneurysm, requiring
surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day
1 h) Serious, non-healing wound, active ulcer, or untreated bone fracture i) History
of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1 j)
Known hypersensitivity to any component of bevacizumab k) Known CNS disease, except
for stable or regressing brain metastases. l) Evidence of bleeding diathesis or
significant coagulopathy (in the absence of therapeutic anticoagulation) m)
Psychiatric illness/social situations that would limit compliance with study
requirements.

n) Significant ocular issues including history of or evidence of retinal pathology on
ophthalmologic examination that is considered a risk factor for neurosensory retinal
detachment, retinal vein occlusion (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 >21mm Hg

2. Serum cholesterol >= Grade 2

3. Hypertriglyceridemia >= Grade 2

4. Hyperglycemia (fasting) >= Grade 2

9. Patients must not have the following foods/ supplements at least 7 days prior to
initiation of and during study treatment:

1. St. John's wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer)

2. Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor).

10. Because patients with immune deficiency are at increased risk of lethal infections
when treated with bone marrow-suppressive therapy, HIV-positive patients receiving
combination anti-retroviral therapy are excluded from the study because of possible
pharmacokinetic interactions with bevacizumab, vemurafenib and cobimetinib.