Phase 2 Study of Neoadjuvant Vemurafenib in Melanoma Patients With Untreated Brain Metastases
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.
|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|
- 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.
|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)|
Experimental: This is a single arm trial
Experimental. Vemurafenib 960 mg p.o. bid
Single arm trial
Other Name: Zelboraf / RO5185426
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01781026
|Contact: Harriet Kluger, MDfirstname.lastname@example.org|
|Contact: Mario Sznol, MDemail@example.com|
|United States, Connecticut|
|Smilow Cancer Hospital at Yale New Haven||Recruiting|
|New Haven, Connecticut, United States, 06510|
|Principal Investigator: Harriet Kluger, MD|
|Principal Investigator:||Harriet M Kluger, M.D.||Yale University|