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A Phase 2 Study of Neoadjuvant Vemurafenib in Melanoma Patients With Untreated Brain Metastases, Whose Tumors Harbor B-raf Mutations

Phase 2
18 Years
Open (Enrolling)
Melanoma [C04.557.465.625.650.510]

Thank you

Trial Information

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
for surgery.

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.

Inclusion Criteria:

- Biopsy proven metastatic melanoma with the B-raf V600E or V600K mutations.

- Untreated brain metastases

- At least one cerebral metastasis that is not amenable to stereotactic radiosurgery
(SRS) or surgical resection based on size or location OR four or more lesions

- Patients may be symptomatic at the time of enrollment, but after any necessary local
therapy and/or corticosteroids, the patient should be asymptomatic when vemurafenib
is initiated.

- Age >18

- Adequate organ function

- ECOG performance status < 3

- No prior therapies with selective inhibitors of mutated BRAF; other prior therapies
must have been administered at least 4 weeks before administration of vemurafenib

- Life expectancy of at least 3 months

- Understanding and willingness to consent

- The use of corticosteroids to control cerebral edema or treat symptoms will be

- A history of whole brain radiotherapy for brain metastases is allowed, but any stable
lesion that was present at the time of WBRT will NOT be considered evaluable. A
minimum of 1 week break will be required between prior WBRT and initiation of
vemurafenib therapy.

Exclusion Criteria:

- Presence of leptomeningeal disease based on positive CSF cytology.

- History or presence of clinically significant ventricular or atrial dysrhythmias ≥
Grade 2 (NCI CTCAE, v4.0), Corrected QT (QTc) interval >450 ms at baseline or history
of congenital long QT syndrome

- Uncontrolled medical illness, such as uncontrolled infection, congestive heart
failure and MI within 2 months.

- Second active, untreated malignancy, which is likely to result in the patient's
demise prior to death from uncontrolled melanoma CNS metastases. This will be
determined on a case by case basis by the PIs.

- Unwillingness to undergo monitoring for a secondary malignancy including clinical
dermatologic examinations and head and neck examinations and serial CT scans.

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the activity of vemurafenib in untreated brain metastases

Outcome Description:

After the first 10 patients are entered onto the trial, an interim assessment will be conducted.

Outcome Time Frame:

March 2014

Safety Issue:


Principal Investigator

Harriet M Kluger, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Yale University


United States: Food and Drug Administration

Study ID:




Start Date:

April 2013

Completion Date:

March 2016

Related Keywords:

  • Melanoma [C04.557.465.625.650.510]
  • B-raf V600E
  • V600K mutation
  • metastatic melanoma
  • Melanoma
  • Neoplasm Metastasis



Smilow Cancer Hospital at Yale New Haven New Haven, Connecticut  06510