Concentration and Activity of Lapatinib in Vestibular Schwannomas
|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.|
|ClinicalTrials.gov Identifier: NCT00863122|
Recruitment Status : Unknown
Verified August 2013 by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.
Recruitment status was: Recruiting
First Posted : March 17, 2009
Last Update Posted : August 7, 2013
Tumors can grow on the auditory nerves and can cause hearing loss. A common type of tumor that does this is a vestibular schwannoma (VS), or acoustic neuroma. These tumors are not cancerous. Most often, people have only one VS. Occasionally, people have more than one VS and may have a condition called neurofibromatosis type 2 (NF2).
Because VS can cause hearing loss, many people with VS will have treatment to preserve their hearing. This treatment usually involves surgery or radiation therapy. There are risks to these procedures, and sometimes they do not work to prevent hearing loss. Because surgery and radiation have risks and are not able to help everyone with VS, other methods of treatment are being explored. One area of exploration is looking to see if there is a drug that can be taken that might prevent the VS from growing larger and causing hearing loss, and might possibly even cause the VS to shrink in size.
This study is exploring whether a drug that is approved by the FDA and is currently used to treat breast cancer might also work to treat VS. This study will measure the amount of drug that travels from the bloodstream and arrives at the tumor. This drug is safe and has few side effects. If this drug is shown to reach the tumor, it might be used in the future to treat VS without needing surgery or radiation.
This study is recruiting people who are having surgery for VS. If you are going to have surgery to treat a VS, you may be eligible to participate.
|Condition or disease||Intervention/treatment||Phase|
|Vestibular Schwannoma NF2 Neurofibromatosis 2 Acoustic Neuroma Auditory Tumor||Drug: lapatinib||Early Phase 1|
Neurofibromatosis type 2 (NF2) is a rare autosomal dominant genetic disorder with an incidence of approximately 1/40,000. The most common tumor type in NF2 is vestibular schwannoma and the majority of NF2 patients develop progressive hearing loss in adolescence or young adulthood due to bilateral vestibular schwannoma (VS). In addition to hearing loss, VS can cause significant morbidity, and in some cases mortality, due to brain stem compression.
Currently, the only accepted modality for treatment of VS in patients with NF2 is surgical resection. Although surgical resection is effective at tumor reduction, it is often associated with morbid complications such as hearing loss, facial palsy, CSF leaks, chronic headache and infection. In addition, the tumors often recur after surgery. Radiation therapy (RT) has been proposed as an alternative, however, its safety in the NF2 population has not been established and there is concern about long term efficacy. For a distinct population of NF2 patients, surgery and RT at not feasible and no additional therapy is currently available. Hence, a systemic therapy is needed.
Sporadic VS are common with roughly 3,000 new cases per year in the United States and a growing incidence in recent years. These tumors cause unilateral hearing loss, tinnitus, and vertigo. The primary treatment modality for these tumors is surgical resection or radiosurgery. Surgery is associated with the same complications listed above for NF2-related VS. Hence, RT is often offered in place of surgery. Although considered safe in sporadic VS, it may not have good long term efficacy and may complicate future procedures. Again, a systemic therapy that could control tumor progression obviating the need for an invasive procedure is needed.
As the understanding of tumor molecular biology continues to advance, there are an increasing number of attractive targets for VS growth inhibition. EGFR and ErbB2 have been identified as important targets for VS. In a study of 21 sporadic and 17 NF2-related VS samples, both EGFR and ErbB2 were found to be upregulated in the majority of tumors. In addition, an anti-ErbB2 monoclonal antibody reduced schwannoma cell proliferation in vitro. Collectively, this data suggests that abnormal signaling via EGFR and ErbB2 is a major contributor to tumor growth and progression in both sporadic and NF2-related VS, and that inhibition of this signaling pathway can result in decreased tumor growth. Although agents targeting these pathways are commercially available, there is little pre-clinical data to assist in prioritizing which agents to advance to clinical trials. Given the relative rarity of the disorder and the enormous patient, financial and time commitments an efficacy study requires, there is a need to carefully select agents for testing that have the best chance of success.
In this trial, we propose to assess the delivery of lapatinib, a commercially available inhibitor of ErbB2 and EGFR, to VS via tissue sampling at the time of clinically indicated surgery. Demonstrating that lapatinib reaches meaningful intratumoral concentrations is important data to recommend this drug above other small molecule inhibitors for efficacy trials for VS. The primary objective is to determine the steady state concentration of lapatinib in VS in patients with NF2 and in patients with sporadic VS. Patient who are planning to have surgical resection of their tumor for clinical indications will be given lapatinib for 15 days prior to resection. At the time of resection, VS tissue will be assessed for drug concentration and molecular markers of drug activity.
Demonstrating that lapatinib reaches meaningful concentrations within VS would support selecting this agent for investigation in efficacy studies for VS, and tissue-based molecular studies will provide corollary information about the behavior of VS in general and about lapatinib specifically in VS tissue. This may further our understanding of the pathophysiology of VS, the similarities and differences between NF2-related and sporadic VS, and inform the design of subsequent efficacy trials.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||26 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||Exploration and Estimation of Intratumoral Concentration and Activity of Lapatinib in Vivo in Vestibular Schwannomas|
|Study Start Date :||June 2009|
|Estimated Primary Completion Date :||December 2013|
Subjects will receive lapatinib for 10 days prior to surgery for vestibular schwannoma resection.
1500 mg lapatinib by mouth per day for 10 days
Other Name: Tykerb
No Intervention: control
Control subjects will not receive any intervention prior to surgery for vestibular schwannoma resection.
- To assess steady-state lapatinib plasma concentrations at the time of surgical resection, 10 (+3) days after oral dosing. [ Time Frame: one year ]
- To assess whether lapatinib can reach a minimum tumor concentration level of >3uM in VS after oral dosing. [ Time Frame: one year ]
- Assess the level of ErbB2 and EGFR phosphorylation and activity of downstream signaling effectors in VS. [ Time Frame: one year ]
- Assess markers of tumor proliferation and cell death in VS after exposure to lapatinib. [ Time Frame: one year ]
- Explore the difference in the concentration of lapatinib achieved in NF2-related versus idiopathic VS. [ Time Frame: one year ]
- Perform NF2 gene mutation analysis via exon scanning and MLPA as well as protein expression in all VS and explore differences between sporadic and NF2 related VS. [ Time Frame: one year ]
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 ClinicalTrials.gov identifier (NCT number): NCT00863122
|Contact: Jaishri Blakeley, MD||(410) email@example.com|
|United States, California|
|House Reserach Institute||Recruiting|
|Los Angeles, California, United States, 90057|
|Contact: Roberta Leyvas 213-273-8025 firstname.lastname@example.org|
|Principal Investigator: William H Slattery, MD|
|Sub-Investigator: Marco Giovannini, MD|
|United States, Maryland|
|Johns Hopkins Hospital||Recruiting|
|Baltimore, Maryland, United States, 21287|
|Contact: Jaishri Blakeley 410-955-8837 email@example.com|
|Principal Investigator: Jaishri O Blakeley, MD|
|Sub-Investigator: John Niparko, MD|
|United States, Massachusetts|
|Massachusetts General Hospital||Recruiting|
|Boston, Massachusetts, United States, 02114|
|Contact: Teresa Alati 617-726-0160 firstname.lastname@example.org|
|Principal Investigator: Scott Plotkin, MD|
|United States, Missouri|
|Washington University Medical Center||Recruiting|
|St. Louis, Missouri, United States, 63110|
|Contact: Lisa Ochsner email@example.com|
|Principal Investigator: David Tran, MD|
|United States, New York|
|New York University Medical Center||Recruiting|
|New York, New York, United States, 10016|
|Contact: Iyore Ayanru 212-263-9945 firstname.lastname@example.org|
|Principal Investigator: Matthias Karajannis, MD|
|Sub-Investigator: Jeffrey Allen, MD|
|Sub-Investigator: J T Roland, MD|
|Sub-Investigator: John Golfinos, MD|
|Sub-Investigator: Pamela Roehm, MD|
|Sub-Investigator: David Zagzag, PhD|
|Weil Cornell Medical College, New York Presbyterian Hospital||Recruiting|
|New York, New York, United States, 10065|
|Contact: Kerry Maleska, RN, CPNP 212-746-3276 Kam9123@NYP.org|
|Principal Investigator: Kaleb Yohay, MD|
|United States, Ohio|
|Ohio State University Medical Center||Recruiting|
|Columbus, Ohio, United States, 43210|
|Contact: Beth Miles-Markley, MS 614-366-9244 email@example.com|
|Principal Investigator: D. Bradley Welling, MD|
|Sub-Investigator: Abraham Jacob, MD|
|Sub-Investigator: Edward E Dodson, MD|
|Principal Investigator:||Jaishri O Blakeley, MD||Johns Hopkins University|