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

Phase 2
18 Years
Open (Enrolling)
BRAFV600E Melanoma Patients

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Trial Information

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

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.

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

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

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

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

- 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

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.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Determination of whether defrafenib and SRS improves 6 month distant brain metastasis-free survival (DBMFS) rate of BRAFV600E melanoma patients

Outcome Description:

Determination of whether dabrafenib combined with SRS improves the 6 month DBMFS rate of BRAFV600E melanoma patients for whom the standard of care is stereotactic radiosurgery (≤4 brain lesions and no lesion > 3 cm) in comparison with similar historical controls treated with radiosurgery alone.

Outcome Time Frame:

Up to 6 months

Safety Issue:


Principal Investigator

Alain Algazi, MD

Investigator Role:

Study Chair

Investigator Affiliation:

University of California, San Francisco


United States: Food and Drug Administration

Study ID:




Start Date:

April 2013

Completion Date:

October 2015

Related Keywords:

  • BRAFV600E Melanoma Patients
  • BRAFV600E melanoma patients
  • melanoma
  • stereotactic radiosurgery
  • BRAFV600E melanoma brain metastases
  • dabrafenib
  • SRS
  • Melanoma
  • Neoplasm Metastasis
  • Brain Neoplasms



University of San Francisco, California San Francisco, California  94115