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Phase 2 Study of Neoadjuvant Vemurafenib in Melanoma Patients With Untreated Brain Metastases

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2013 by Yale University
Genentech, Inc.
Information provided by (Responsible Party):
Harriet Kluger, Yale University Identifier:
First received: January 29, 2013
Last updated: May 2, 2013
Last verified: May 2013

The purpose of this trial is to study the activity of vemurafenib in untreated melanoma brain metastases harboring BRAF mutations that are not amenable to stereotactic radiosurgery based on size, number of lesions or location, to measure cerebrospinal fluid (CSF) levels of vemurafenib as an indicator of central nervous system penetrance and to measure levels of vemurafenib in normal brain tissue and brain metastases in those in whom surgical management is feasible.

Condition Intervention Phase
Melanoma [C04.557.465.625.650.510]
Drug: Vemurafenib
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Neoadjuvant Vemurafenib in Melanoma Patients With Untreated Brain Metastases, Whose Tumors Harbor B-raf Mutations

Resource links provided by NLM:

Further study details as provided by Yale University:

Primary Outcome Measures:
  • To determine the activity of vemurafenib in untreated brain metastases [ Time Frame: March 2014 ] [ Designated as safety issue: Yes ]
    After the first 10 patients are entered onto the trial, an interim assessment will be conducted.

Estimated Enrollment: 34
Study Start Date: April 2013
Estimated Study Completion Date: March 2016
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: This is a single arm trial
Experimental. Vemurafenib 960 mg p.o. bid
Drug: Vemurafenib
Single arm trial
Other Name: Zelboraf / RO5185426

Detailed Description:

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.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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 allowed
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01781026

Contact: Harriet Kluger, MD 203-737-5127
Contact: Mario Sznol, MD 203-737-2572

United States, Connecticut
Smilow Cancer Hospital at Yale New Haven Recruiting
New Haven, Connecticut, United States, 06510
Principal Investigator: Harriet Kluger, MD         
Sponsors and Collaborators
Yale University
Genentech, Inc.
Principal Investigator: Harriet M Kluger, M.D. Yale University
  More Information

No publications provided

Responsible Party: Harriet Kluger, Associate Professor of Internal Medicine, Oncology, Yale University Identifier: NCT01781026     History of Changes
Other Study ID Numbers: 1208010666
Study First Received: January 29, 2013
Last Updated: May 2, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Yale University:
B-raf V600E
V600K mutation
metastatic melanoma

Additional relevant MeSH terms:
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Neuroendocrine Tumors
Nevi and Melanomas processed this record on November 25, 2014