Dabrafenib and Trametinib With Radiosurgery in Melanoma Brain Mets

This is a single arm Phase II clinical trial. All patients will receive continuous dosing of
dabrafenib at 150 mg PO bid and trametinib beginning at Cycle 3 Day 1, at a starting dose of
2 mg PO once daily until progression of disease, withdrawal of consent, or the development of
intolerable treatment associated toxicity. An MRI will be performed after 28 days of
treatment with dabrafenib. Patients who have unequivocal disease progression in the brain at
that time will be deemed to have disease progression at 4 weeks. Patients with a complete
response of all lesions in the brain will continue to receive dabrafenib and trametinib on
study but they will not undergo SRS. For patients with stable disease or partial tumor
responses in the brain, Gamma Knife radiosurgery will be performed on treatment cycle 2, day
1 (+/- 3 days, 28 day cycle) using a stereotactic head frame and MRI imaging in accordance
with FDA-approved procedures.

Melanoma brain metastases

Cutaneous melanoma is the most aggressive form of all skin cancers. Worldwide, it is
currently expected that approximately 132,000 people will be diagnosed with melanoma each
year and some 37,000 people are expected to die of the disease annually. Brain metastases are
a major source of morbidity and mortality in patients with metastatic melanoma and
approximately 3 out of 4 develop brain metastases at some point in their disease course. The
prognosis of metastatic melanoma with CNS involvement is dismal1, and, until recently, no
medical therapy demonstrated clear evidence of activity against melanoma in the brain. For
patients with fewer than 4 brain lesions and no brain lesion greater than 3 cm in diameter,
stereotactic radiosurgery (SRS) is the standard-of-care. By delivering highly focal
irradiation to melanoma brain metastases, SRS confers local control rates exceeding 80% for
lesions under 2 cm in diameter. However, SRS does not treat micrometastatic disease in the
brain, and new brain metastases develop in approximately half of patients treated.

Furthermore, local control rates are lower for lesions larger than 2 cm in diameter. As a
result, the median overall survival for melanoma patient treated with SRS is only 7 months.

BRAF mutant melanoma

The RAS/RAF/MEK/ERK pathway is a critical proliferation pathway in many human cancers. This
pathway can be constitutively activated by alterations in specific proteins, including BRAF,
which phosphorylates MEK1 and MEK2 on two regulatory serine residues. Approximately 90% of
all identified BRAF mutations that occur in human result in a V600 E/D/Kamino acid
substitution. This mutation appears to mimic regulatory phophorylation and increases BRAF
activity approximately 10-fold compared to wild type. BRAF mutations have been identified at
a high frequency in specific cancers, including approximately 40-60% of melanoma. The
frequency of this activating mutation and the pathway addiction to which it leads makes
mutated BRAF an extremely attractive target.

Inclusion Criteria:

1. Histologically-confirmed BRAFV600E melanoma

2. Up to 4 untreated brain metastases (at least 1 > 0.5 cm) with no metastasis larger
than 3 cm as assessed by a gadolinium-enhanced MRI of the brain. Detection of
additional lesions at time of Gamma Knife radiosurgery MRI scan will not be considered
exclusionary if the detection of these lesions are thought to be due solely to
difference in imaging techniques (i. e. higher sensitivity, double gadolinium contrast
MRI utilized at the time of Gamma Knife radiosurgery compared with conventional MRI
imaging).

3. ECOG PS 0-2

4. 14 days elapsed from last treatment with surgery.

5. At least 28 days or five half-lives (whichever is longer) have elapsed from last dose
of any approved or investigational therapy for metastatic melanoma.

6. Appropriate birth control for men and women with childbearing potential

7. Corticosteroid dose stable for at least 14 days

8. Adequate end-organ function:

- ANC ≥ 1.5x109/L

- Hemoglobin ≥ 9 g/dL

- Platelets ≥100 x109/L

- Total bilirubin ≤ 1.5x ULN

- AST and ALT ≤ 2.5x ULN

- Creatinine ≤ 1.5 mg/dL

- PT/PTT ≤ 1.5x ULN

- LVEF ≥ 50%

9. Age ≥ 18 years

10. Recipients of prior radiation therapy to the brain including stereotactic radiosurgery
or whole brain irradiation may be included if there are 1-4 untreated or progressing
brain lesions. At his discretion, the Study Chair may review any enrollment decision
regarding which subjects will be enrolled prior to the initiation of treatment on
trial.

Exclusion Criteria:

1. Neurological symptoms from melanoma brain metastases

2. Patients may not have received prior therapy with dabrafenib, vemurafenib, or other
potent, highly effective BRAF inhibitors. Prior therapy with sorafenib is permitted.

3. Any indication for urgent or emergent neurosurgery. Patient may enroll after
neurosurgery at least 14 days after neurosurgery as long as they meet all other study
qualifications.

4. Pregnant or lactating women. The effects of dabrafenib on the developing human fetus
are unknown. For this reason, women of child-bearing potential and men must agree to
use a highly effective method of contraception including: hormonal contraceptives
(oral contraceptives, Nuvaring, Depo Provera) an intrauterine device, true abstinence
or two barrier methods of birth control including condoms with cervical cap or
diaphragm. Baseline pregnancy testing is required for all women of child-bearing
potential. Should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, she should inform her treating physician
immediately. Men treated or enrolled on this protocol who are sexually active with
women of child bearing potential must also agree to use adequate contraception prior
to and during the study as outlined above, and for, and four months after completion
of study drug administration.

5. History of known cardiac arrhythmias or acute coronary syndromes within the past 24
weeks.

6. History of a second malignancy with evidence of active disease within the past 3 years
except non-melanoma skin cancer, indolent prostate cancer, and stable CLL without
lymphadenopathy

7. Complete resection of a single brain metastasis or of all known brain metastases.
Patients who have undergone subtotal resection are eligible providing residual disease
is < 2.0 cm in maximum diameter.

8. Patients with metastases within 2 mm of the optic nerve or optic chiasm so that some
portion of the optic nerve or chiasm would receive > 9 Gy from radiosurgery.

9. Patients with metastases in the brainstem.

10. Contraindication to MRI (such as cardiac pacemaker).

11. The following medications or non-drug therapies are prohibited:

- Other anti-cancer therapy while on treatment in this study.

- Use of other investigational drugs within 28 days preceding the first dose of
dabrafenib.

- Antiretroviral drugs. Subjects with known HIV are ineligible for study
participation.

- Herbal remedies (i.e., St. John's wort).

- Drugs that are strong inhibitors or inducers of CYP3A or CYP2C8, p-glycoprotein
(Pgp) or Bcrp transporter because they may alter dabrafenib concentrations. The
list may be modified based on emerging data. These include but are not limited to
those listed in Appendix 2; consider therapeutic substitutions for these
medications.

12. Unresolved toxicity of National Cancer Institute Common Terminology Criteria for
Adverse Events, version 4.0. Grade 2 or higher from previous anti-cancer therapy,
except alopecia.

13. Presence of active gastrointestinal disease or other condition that will interfere
significantly with the absorption of drugs. If clarification is needed as to whether a
condition will significantly affect absorption of drugs, contact the Study Chair for
permission to enroll the subject. Study Chair has final decision regarding which
subjects will be enrolled.

14. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or
Hepatitis C Virus (HCV) infection. Subjects with laboratory evidence of HBV clearance
may be enrolled with permission of the GSK medical monitor.

15. A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency.

16. Corrected QT (QTc) interval ≥480 msecs; history of acute coronary syndromes (including
unstable angina), coronary angioplasty, or stenting within the past 24 weeks; Class
II, III, or IV heart failure as defined by the New York Heart Association (NYHA)
functional classification system; abnormal cardiac valve morphology documented by
echocardiogram (subjects with minimal abnormalities including mild
regurgitation/stenosis can be entered on study with approval from the GSK medical
monitor); or history of known cardiac arrhythmias.

17. Treatment refractory hypertension defined as a blood pressure of systolic> 140 mmHg
and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy.

18. History of RVO or CSR, or predisposing factors to RVO or CSR(e.g. uncontrolled
glaucoma or ocular hypertension, uncontrolled systemic disease such as diabetes
mellitus, hypertension, or history of hyperviscosity or hypercoagulability syndromes)

19. Visible retinal pathology as assessed by ophthalmic exam that is considered a risk
factor for RVO or CSR such as:

- Evidence of new optic disc cupping

- Evidence of new visual field defects

- Intraocular pressure > 21 mm Hg as measured by tonography

20. Psychological, familial, sociological, or geographical conditions that do not permit
compliance with the protocol; or unwillingness or inability to follow the procedures
required in the protocol.