A Phase 2 Study of Neoadjuvant Vemurafenib in Melanoma Patients With Untreated Brain Metastases, Whose Tumors Harbor B-raf Mutations
This is a phase II single arm study. After establishing eligibility, including at least one
lesion that is not amenable to immediate stereotactic radiosurgery (SRS) or surgical
resection based on size or location OR more than four lesions, patients will begin therapy
with vemurafenib at 960 mg PO BID continuous dosing. Any lesions deemed in need of and
amenable to urgent local therapy will be treated prior to initiation of vemurafenib,
provided that patients have at least one untreated evaluable lesion.
An MRI of the brain will be obtained after 4 weeks of vemurafenib therapy. If the CNS index
lesion(s) are stable or shrinking, an additional 4 weeks of vemurafenib will be given with
the goal of providing definitive local therapy at 8 weeks. If any lesion is growing after 4
weeks, depending on the size and concern for symptom evolution, the PIs can either continue
vemurafenib for 4 additional weeks or provide definitive local or regional therapy at the 4
week mark in the form of surgery, LITT, SRS or WBRT. If a lesion becomes symptomatic at any
time, local therapy can be administered, and the patient can remain on study provided that
there is an additional untreated brain metastasis. If the patient receives LITT or has
surgical resection, biopsy samples will be sent to the sponsor for measurement of
vemurafenib levels in tumor and normal brain parenchyma. Levels of pERK, as a surrogate for
vemurafenib activity, will be measured in tumor samples. Vemurafenib will be held on the
morning of radiation and restarted the following day. Vemurafenib dosing will not be held
All patients will be asked to have a lumbar puncture after 4 weeks of vemurafenib therapy.
The next MRI of the brain will be obtained at week 8 and then every 8 weeks, along with body
CT or PET/CT scans.
If a patient is having overall shrinkage or stable disease in most CNS lesion(s), but if an
individual cerebral metastases enlarges, local therapy can be done on study at any time if
necessary. Patients will continue on vemurafenib until they have overall disease progression
in either their CNS lesion(s) or in their systemic metastases as determined by modified
MacDonald criteria (for cerebral lesion(s)) or RECIST criteria (for systemic disease),
toxicities that preclude continuing the study drug, withdrawal from study, development of
other severe illness, neurologic or systemic complications following local therapy to any
lesion, termination of study, or death. Dose reductions for toxicities will be allowed.
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the activity of vemurafenib in untreated brain metastases
After the first 10 patients are entered onto the trial, an interim assessment will be conducted.
Harriet M Kluger, M.D.
United States: Food and Drug Administration
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