Dabrafenib and Trametinib With Radiosurgery in Melanoma Brain Mets
Condition: BRAFV600E Melanoma Patients
MeSH terms: Melanoma
Intervention: Dabrafenib; Gamma Knife Radiosurgery; Trametinib
Intervention description: 150 mg capsule by mouth twice daily; This will be delivered using Gamma Knife technology. Patients will be fitted with a stereotactic head-frame for stereotactic localization of brain metastases.; 2 mg by mouth once daily from beginning at Cycle 3 Day 1, until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity.
Intervention MeSH terms: Trametinib; Dabrafenib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: BRAFV600E melanoma patients; melanoma; stereotactic radiosurgery; BRAFV600E melanoma brain metastases; dabrafenib; SRS

Summary:

      The purpose of this study is to test the safety and find out what effects, good and/or bad,
      dabrafenib (a BRAF inhibitor) alone or dabrafenib when given in combination with gamma knife
      radiosurgery has on participants with a certain type of skin cancer (BRAFV600E melanoma) and
      brain metastases (tumors that have spread to the brain).
    

Eligibility criteria:

        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.