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
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Determination of whether defrafenib and SRS improves 6 month distant brain metastasis-free survival (DBMFS) rate of BRAFV600E melanoma patients
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.
Up to 6 months
Alain Algazi, MD
University of California, San Francisco
United States: Food and Drug Administration
|University of San Francisco, California||San Francisco, California 94115|