Dabrafenib and Trametinib With Radiosurgery in Melanoma Brain Mets
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|ClinicalTrials.gov Identifier: NCT01721603|
Recruitment Status : Terminated (Low accrual)
First Posted : November 6, 2012
Results First Posted : January 23, 2018
Last Update Posted : January 23, 2018
|Condition or disease||Intervention/treatment||Phase|
|BRAFV600E Melanoma Patients||Drug: Dabrafenib Procedure: Gamma Knife Radiosurgery Drug: Trametinib||Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||2 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 2 Prospective Trial of Dabrafenib and Trametinib With Stereotactic Radiosurgery in BRAF Mutant Melanoma Brain Metastases|
|Study Start Date :||April 2013|
|Actual Primary Completion Date :||January 2016|
|Actual Study Completion Date :||January 2016|
|Experimental: Dabrafenib + Trametinib + gamma knife radiosurgery||
150 mg 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.
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.
Other Name: GSK1120212
- Patients Reaching 6 Month Distant Brain Metastasis-free Survival (DBMFS) [ Time Frame: Up to 6 months after surgery ]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.
- Patients Displaying 6-month Local Control Rate [ Time Frame: From surgery up to 6 months ]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.
- Best Overall Response Rate (by RECIST v1.1 ) [ Time Frame: From surgery up to 12 months ]Determine the best overall response rate (by RECIST v1.1 ).
- Median Duration of Freedom From New Brain Metastases( by RECIST v1.1 ) [ Time Frame: From surgery up to 12 months ]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.
- Median Time to Progression [ Time Frame: From surgery up to 12 months ]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.
- Systemic Overall Response Rate [ Time Frame: From surgery up to 12 months ]
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.
- Median Progression-free Survival [ Time Frame: From surgery up to 12 months ]Determine the median progression-free survival of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib and dabrafenib.
- Median Overall Survival [ Time Frame: From surgery up to 12 months ]Determine the median overall survival of BRAFV600E melanoma brain metastasis patients treated with SRS, trametinib and dabrafenib.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01721603
|United States, California|
|University of San Francisco, California|
|San Francisco, California, United States, 94115|
|Study Chair:||Alain Algazi, MD||University of California, San Francisco|