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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01781026
Recruitment Status : Completed
First Posted : January 31, 2013
Results First Posted : April 2, 2015
Last Update Posted : March 10, 2017
Genentech, Inc.
Information provided by (Responsible Party):
Yale University

Brief Summary:
The purpose of this trial is to study the activity of vemurafenib in untreated melanoma brain metastases harboring B-Raf proto-oncogene, serine/threonine kinase (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 or disease Intervention/treatment Phase
Melanoma Drug: Vemurafenib Phase 2

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, Laser Induced Thermal Therapy (LITT), Stereotactic Radiosurgery (SRS) or Whole Brain Radiation Therapy (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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (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
Study Start Date : April 2013
Actual Primary Completion Date : June 2014
Actual Study Completion Date : June 2014

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma
Drug Information available for: Vemurafenib

Arm Intervention/treatment
Experimental: Vemurafenib Administration
Vemurafenib 960 mg orally, twice per day
Drug: Vemurafenib
Single arm trial
Other Name: Zelboraf / RO5185426

Primary Outcome Measures :
  1. Activity of Vemurafenib in Untreated Brain Metastases [ Time Frame: 1 year ]
    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
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.

Information from the National Library of Medicine

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 identifier (NCT number): NCT01781026

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United States, Connecticut
Smilow Cancer Hospital at Yale New Haven
New Haven, Connecticut, United States, 06510
Sponsors and Collaborators
Yale University
Genentech, Inc.
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Principal Investigator: Harriet M Kluger, M.D. Yale University
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Responsible Party: Yale University Identifier: NCT01781026    
Other Study ID Numbers: 1208010666
First Posted: January 31, 2013    Key Record Dates
Results First Posted: April 2, 2015
Last Update Posted: March 10, 2017
Last Verified: January 2017
Keywords provided by Yale University:
B-raf V600E
V600K mutation
metastatic melanoma
Additional relevant MeSH terms:
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Brain Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action