A Phase 2 Prospective Trial of Dabrafenib With Stereotactic Radiosurgery in BRAFV600E Melanoma Brain Metastases

• Determination of whether dabrafenib combined with SRS improves the 6-month local control rate of BRAFV600E melanoma brain metastases [ Time Frame: Up to 6 months ] [ Designated as safety issue: No ]
  Determination of whether dabrafenib combined with SRS improves the 6-month local control rate of BRAFV600E melanoma brain metastases compared with historical controls treated with SRS.
• Tumor Assessment- Determination of the best overall response rate (by RECIST v1.1 ) [ Time Frame: Up to 12 months ] [ Designated as safety issue: No ]
  Determine the best overall response rate (by RECIST v1.1) of BRAFV600E melanoma brain metastases patients treated with SRS and dabrafenib. RECIST v1.1 will be used as the primary determinant of disease progression. Disease response will be assessed at scheduled visits by MRI of the brain and clinical exam every two months thereafter. The proportion of patients that progression free at 6 months will be calculated.
• Tumor Assessment- Determination of the median duration of freedom from new brain metastases( by RECIST v1.1 ) [ Time Frame: Up to 12 months ] [ Designated as safety issue: No ]
  Determine the median duration of freedom from new brain metastases of BRAFV600E melanoma brain metastases patients treated with SRS and dabrafenib. RECIST v1.1 will be used as the primary determinant of disease progression. Disease response will be assessed at scheduled visits by MRI of the brain and clinical exam every two months thereafter. The proportion of patients that progression free at 6 months will be calculated.
• Tumor Assessment- Determination of the median time to progression (by RECIST v1.1 ) [ Time Frame: Up to 12 months ] [ Designated as safety issue: No ]
  Determine the median time to progression in the brain of BRAFV600E melanoma brain metastases patients treated with SRS and dabrafenib. RECIST v1.1 will be used as the primary determinant of disease progression. Disease response will be assessed at scheduled visits by MRI of the brain and clinical exam every two months thereafter. The proportion of patients that progression free at 6 months will be calculated.
• Determination of the systemic best overall response rate [ Time Frame: Up to 12 months ] [ Designated as safety issue: No ]

  Determine the systemic best overall response rate and median progression-free survival of BRAFV600E melanoma brain metastasis patients treated with SRS and dabrafenib.

  The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).

  The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.

• Determination of the median progression-free survival [ Time Frame: Up to 12 months ] [ Designated as safety issue: No ]
  Determine the systemic best overall response rate and median progression-free survival of BRAFV600E melanoma brain metastasis patients treated with SRS and dabrafenib.
• Determination of the median overall survival of BRAFV600E melanoma brain metastasis patients [ Time Frame: Up to 12 months ] [ Designated as safety issue: No ]

  Determine the median overall survival of BRAFV600E melanoma brain metastasis patients treated with SRS and dabrafenib

  As secondary efficacy endpoints, 6-month local control rate, the time to progression in the CNS as well as the median PFS and OS will be estimated using exact binomial distribution; time to progression will be estimated using Kaplan-Meier methods. The 6-month PFS and 95% confidence intervals will be reported. ORR will be reported as frequencies and proportions with exact 95% confidence intervals from the Binomial distribution.

• Number of reported Adverse Events [ Time Frame: Up to 12 months ] [ Designated as safety issue: Yes ]
  Assessment of treatment-related toxicities of the combination of dabrafenib and gamma knife radiosurgery. Treatment-associated adverse events will be assessed based on clinical and laboratory findings using the Common Toxicity Criteria for Adverse Events, version 4.0. Adverse event assessments will be performed every 2 weeks though cycle 3 day 1 and then every 4 weeks thereafter.

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).

This is a single arm Phase II clinical trial. All patients will receive continuous dosing of dabrafenib at 150 mg PO bid 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 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.

• Drug: Dabrafenib
  150mg capsule by mouth twice daily
  Other Name: GSK2118436
• Procedure: Gamma Knife Radiosurgery
  This will be delivered using Gamma Knife technology. Patients will be fitted with a stereotactic head-frame for stereotactic localization of brain metastases.
  Other Names:

  • SRS
  • Stereotactic Radiosurgery

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.
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

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. Any prior radiation therapy to the brain including stereotactic radiosurgery or whole brain irradiation.
5. 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.
6. History of known cardiac arrhythmias or acute coronary syndromes within the past 24 weeks.
7. 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
8. 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.
9. 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.
10. Patients with metastases in the brainstem.
11. Contraindication to MRI (such as cardiac pacemaker).

12. 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.
13. 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.
14. 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 GSK medical monitor for permission to enroll the subject. PI has final decision regarding which subjects will be enrolled.
15. 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.
16. A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency.
17. 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.
18. Uncontrolled medical conditions (i.e, diabetes mellitus, hypertension, etc), 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.