Vemurafenib Combined With Whole Brain Radiation Therapy or Radiosurgery in Patients With BRAF Mutation-Positive Melanoma and Brain Metastases

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of vemurafenib when combined with WBRT or
SRS and determine a recommended phase II dose of vemurafenib to be used with WBRT or SRS in
patients with brain metastases from melanoma.

SECONDARY OBJECTIVES:

I. To determine local control rates of the brain metastases in each arm. II. To determine
the rates of developing of new brain metastases in each arm. III. To determine the response
of extracranial disease. IV. To determine the overall survival rate and progression free
survival rate. V. To determine the safety and tolerability of each arm.

OUTLINE: This is a dose-escalation study of vemurafenib. Patients are assigned to 1 of 2
arms based on the number and size of brain metastasis.

All patients receive vemurafenib orally (PO) twice daily (BID) beginning 3-5 days before the
start of radiation therapy and continuing in the absence of disease progression or
unacceptable toxicity.

ARM A: Patients undergo WBRT once daily (QD) for 10 doses.

ARM B: Patients undergo SRS (gamma knife, tomotherapy, cyberknife, or megavoltage linear
accelerator [LINAC] radiation therapy) on day 1.

After completion of study therapy, patients are followed up on weeks 5 or 7, 9 and 13, and
then on months 4, 6, 9, and 12.

Inclusion Criteria:

1. Age ≥ 18 years

2. Histological confirmed melanoma (prior diagnosis okay)

3. BRAFV600 mutation positive (cobas 4800 BRAFV600 mutation test)

4. ECOG performance status 0 or 1

5. Craniotomy resection is allowed (a minimum 2 weeks recovery time from surgery to
initiation of protocol therapy)

6. Radiographic evidence of brain metastasis

7. Ability to understand and the willingness to sign a written informed consent. A
signed informed consent must be obtained prior to any study specific procedures.

8. Adequate organ function:

1. WBC ≥ 2000/uL

2. ANC ≥ 1000/uL

3. Platelets ≥ 75 x 103/uL

4. Hemoglobin ≥ 9 g/dL (≥ 80 g/L; may be transfused)

5. Creatinine ≤ 2.0 x ULN OR 24-hour creatinine clearance >= 50 ml/min

6. AST/ALT ≤ 2.5 x ULN for patients without liver metastasis, ≤ 5 times for liver
metastases

7. Bilirubin ≤ 2.0 x ULN, (except patients with Gilbert's Syndrome, who must have a
total bilirubin less than 3.0 mg/dL)

8. Total serum calcium (corrected for serum albumin) or ionized calcium ≥ lower
limit of normal (LLN)

9. Serum potassium ≥ LLN

10. Serum sodium ≥ LLN

11. Serum albumin ≥ LLN or 3g/dl

12. Patients with any elevated Alkaline Phosphatase due to bone metastases can be
enrolled

9. Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for up to 26 weeks after
the last dose of investigational product, in such a manner that the risk of pregnancy
is minimized. Women of potential child bearing potential include any female who has
experienced menarche and who has not undergone successful surgical sterilization
(hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not
post-menopausal. Post-menopause is defined as:

1. Amenorrhea ≥ 12 consecutive months without another cause, or

2. For women with irregular menstrual periods and taking hormone replacement
therapy (HRT), a documented serum follicle stimulating hormone (FSH) level ≥ 35
mIU/mL.

3. Women who are using oral contraceptives, other hormonal contraceptives (vaginal
products, skin patches, or implanted or injectable products), or mechanical
products such as an intrauterine device or barrier methods (diaphragm, condoms,
spermicides) to prevent pregnancy, or are practicing abstinence or where their
partner is sterile (eg, vasectomy) should be considered to be of childbearing
potential.

4. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25
IU/L or equivalent units of HCG) within 72 hours before the start of radiation.

Men of fathering potential must be using an adequate method of contraception to avoid
conception throughout the study [and for up to 26 weeks after the last dose of
investigational product] in such a manner that the risk of pregnancy is minimized.

10. Specific eligibility criteria for the two arms:

1. Arm A (WBRT and Vemurafenib):

- Patients have 5 or more brain metastases, or patients have any brain
metastases exceeding the limit for SRS (maximum diameter is > 4 cm).

- OR Patient has only one brain metastasis and completely resected, the
resection cavity is > 5 cm in diameter.

2. Arm B (SRS and Vemurafenib):

- Patients have 4 or fewer brain metastases. All the brain metastases are ≤ 4
cm in diameter.

- Patients have only one brain metastasis and completely resected, the
resection cavity is ≤ 5 cm in diameter.

- OR If a patient is found to have progression of brain metastases that
exceed 4 cm in diameter based on the MRI scan on the day of SRS procedure,
the patient should be re-assigned to WBRT arm or withdrawn from the study.
The study PI should be notified.

- OR If a patient is found to have progression of brain metastases that
exceed 4 lesions based on the MRI scan on the day of the SRS procedure, the
patient can either receive SRS to all the lesions (up to 10 lesions), be
re-assigned to WBRT arm, or be withdrawn from the study per the treating
physician. The study PI should be notified.

Exclusion Criteria:

1. Leptomeningeal involvement

2. Cardiac disease: Congestive heart failure > class II. Patients must not have unstable
angina (anginal symptoms at rest) or new onset angina (began within the last 3
months) or myocardial infarction within the past 6 months.

3. Pregnancy or breastfeeding

4. Documented history of cranial hemorrhage

5. Concurrent administration of any anticancer therapies other than those administered
in the study

6. Treatment with any cytotoxic, investigational drug, or targeted therapy within 2
weeks prior to the protocol treatment.

7. Craniotomy within 2 weeks of protocol treatment.

8. Prior treatment with other BRAF or MEK inhibitors

9. Patients who had prior brain radiation. However, prior WBRT is allowed in Arm B.

10. QTc > 450 ms

11. Patients have a history of any other malignancy from which the patient has been
disease-free for less than 2 years, with the exception of adequately treated basal or
squamous cell carcinoma of skin, superficial bladder cancer or carcinoma in situ of
cervix, AJCC (version 7.0) stage 0 or I breast cancer, AJCC (version 7.0) stage I, or
II prostate cancer.