Treatment of a Resistant Disease Using Decitabine Combined With Vemurafenib Plus Cobimetinib

The primary objective of the Phase I portion of this study is to evaluate the safety and
tolerability of the proposed schedule of decitabine and Vemurafenib plus Cobimetinib in the
treatment of metastatic melanoma.

Inclusion criteria:

Male or female >/= 18 years old ECOG Performance Status of
Meet the following lab criteria:

Hematology Neutrophil count >1500/mm3 Platelet count >100,000/mm3 Hemoglobin >/= 9 g/dL
Biochemistry AST/ALT transaminase elevation is due to disease involvement Serum bilirubin creatinine /= 50 ml/min by Cockcroft-Gault
equation Total serum calcium (corrected for serum albumin) >/= 8.5 mg/dL or ionized calcium
>/= 3.8 mg/dL Serum potassium >/= LLN Serum sodium >/= LLN Serum albumin >/= 3g/dl Baseline
MUGA or ECHO must demonstrate LVEF >/= the lower limit of the institutional normal.

TSH and free T4 within normal limits, may be on thyroid hormone replacement Women of
childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of
the first dose of study drug. Willing to use 2 methods of contraception, one being a
barrier method during the study and for 3 months after last study drug dose.

Any patient with metastatic melanoma (any site) whose tumor is V600EBRAF positive,
regardless of prior treatment.

Prior treatment with Vemurafenib will be allowed Must not have taken a hypomethylating
agent. Must have had disease progression on or following most recent treatment regimen or
on presentation for the first time with metastatic disease.

Patients with CNS disease are eligible for treatment only after their CNS disease has been
directly addressed with radiation therapy.

Exclusion criteria:

Prior Decitabine for the treatment of cancer

Impaired cardiac function including any one of the following:

Screening ECG with a QTc > 460 msec confirmed by central lab prior to enrollment;
congenital long QT syndrome; History of sustained ventricular tachycardia; History of
ventricular fibrillation/torsades de pointes; Bradycardia defined as heart rate (hr) < 50
beats per minute; Patients with a pacemaker and hr >/= 50 beats per minute are eligible;
Patients with a myocardial infarction or unstable angina within 6 mos of study entry; CHF
(NYHA class III or IV); Right bundle branch block and left anterior hemiblock; Uncontrolled
hypertension Concomitant use of drugs with a risk of causing torsades de pointes
Concomitant use of CYP3A4, CYP1A2, or CYP2D6 substrates Unresolved diarrhea > CTCAE grade 1
Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the
absorption of Vemurafenib Other concurrent severe or uncontrolled medical conditions
Patients who have received prior therapies will be allowed to enroll after a wash-out
period: Chemotherapy - 3 week (wk) wash-out; Oral agents - 2 wk wash-out (Except
Vemurafenib, no wash-out period); Investigational agents - 3 wk wash-out; Immunotherapy - 4
wk wash-out; Palliative radiation therapy to bone/brain - 2 wk wash-out; Major radiation or
surgical procedure - 3 wk wash-out Concomitant use of any anti-cancer or radiation therapy.
No measurable disease Pregnant, breast-feeding women or WOCBP not willing to use a double
barrier method of contraception during the study and 3 months after the end of treatment.
One method of contraception must be a barrier method. WOCBP are defined as sexually mature
women who have not undergone a hysterectomy or have not been naturally postmenopausal for
at least 12 consecutive months (who has had menses any time in the preceding 12 consecutive
months).

Male patients whose sexual partners are WOCBP not using a double method of contraception
during the study and 3 months after the end of treatment. One of these methods must be a
condom History of another primary malignancy within 5 years other than curatively treated
CIS of the cervix, or basal or squamous cell carcinoma of the skin Known positivity for HIV
or hepatitis C Any significant history of non-compliance to medical regimens or with
inability to grant a reliable informed consent