Neoplasms

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Skin and Connective Tissue Diseases

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Neoplasm Metastasis

Melanoma

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Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

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Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

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Antineoplastic Agents

All Drugs and Chemicals

Trametinib

Dabrafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

This will be delivered using Gamma Knife technology. Patients will be fitted with a stereotactic head-frame for stereotactic localization of brain metastases.

Gamma Knife Radiosurgery

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.

Alain Algazi, MD

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.

Dabrafenib and Trametinib With Radiosurgery in Melanoma Brain Mets

A Phase 2 Prospective Trial of Dabrafenib and Trametinib With Stereotactic Radiosurgery in BRAF Mutant Melanoma Brain Metastases

Determine whether dabrafenib combined with stereotactic radiosurgery (SRS) and trametinib 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.

Determine whether dabrafenib combined with SRS and trametinib improves the 6-month local control rate of BRAFV600E melanoma brain metastases compared with historical controls treated with SRS.

Determine the best overall response rate (by RECIST v1.1 ).

Determine median duration of freedom from new brain metastases of BRAFV600E melanoma brain metastases patients treated with SRS, trametinib and dabrafenib. RECIST v1.1 will be used as the primary determinant of disease progression.

Determine the median time to progression in the brain of BRAFV600E melanoma brain metastases patients treated with SRS, trametinib 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.

Determine the systemic best overall response rate of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib 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.

Determine the median progression-free survival of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib and dabrafenib.

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

GlaxoSmithKline

University of California, San Francisco

Assistant Clinical Professor

Dabrafenib: 150mg capsule by mouth twice daily until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity

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.

Dabrafenib With Gamma Knife Radiosurgery

All patients will receive continuous, oral dosing of dabrafenib at a starting dose of 150 mg twice daily until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity

Dabrafenib: 150mg capsule by mouth twice daily

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.

Dabrafenib Given in Combination With Gamma Knife Radiosurgery

Age, Categorical

Sex: Female, Male

United States

Region of Enrollment

1 cycle = 28 days

* Dabrafenib: 150mg capsule by mouth (PO), twice daily, continuous
* Trametinib: 2 mg PO, once daily from beginning of cycle 3 Day 1,until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity.

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) using a stereotactic head frame and MRI imaging in accordance with FDA-approved procedures.

Dabrafenib + Trametinib + Gamma Knife Radiosurgery

Patients Reaching 6 Month Distant Brain Metastasis-free Survival (DBMFS)

Patients Displaying 6-month Local Control Rate

Best Overall Response Rate (by RECIST v1.1 )

Study was terminated due to low accrual. Secondary outcome measure was not accessed.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Dabrafenib and Trametinib With Radiosurgery in Melanoma Brain Mets	NCT01721603	BRAFV600E Melan...	Dabrafenib Gamma Knife Rad... Trametinib	18 Years -	University of California, San Francisco
Dabrafenib and Trametinib With Radiosurgery in Melanoma Brain Mets	NCT01721603	BRAFV600E Melan...	Dabrafenib Gamma Knife Rad... Trametinib	18 Years -	University of California, San Francisco

Spots Global Cancer Trial Database for brafv600e melanoma patients