BRAFV600E Melanoma Patients Clinical Trial
Official title:
A Phase 2 Prospective Trial of Dabrafenib and Trametinib With Stereotactic Radiosurgery in BRAF Mutant Melanoma Brain Metastases
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 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.
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