Neoplasms

All Conditions

Nervous System Diseases

Diseases and Abnormalities at or Before Birth

Ear, Nose, and Throat Diseases

Symptoms and General Pathology

Skin and Connective Tissue Diseases

Rare Diseases

Neurilemmoma

Neurofibromatoses

Neurofibromatosis 1

Neurofibroma

Neuroma

Neuroma, Acoustic

Neurofibromatosis 2

Nerve Sheath Neoplasms

Neoplasms, Nerve Tissue

Neoplasms by Histologic Type

Syndrome

Neoplastic Syndromes, Hereditary

Neurocutaneous Syndromes

Heredodegenerative Disorders, Nervous System

Neurodegenerative Diseases

Genetic Diseases, Inborn

Nervous System Neoplasms

Peripheral Nervous System Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Vestibulocochlear Nerve Diseases

Retrocochlear Diseases

Ear Diseases

Otorhinolaryngologic Diseases

Otorhinolaryngologic Neoplasms

Cranial Nerve Diseases

Schwannoma

Neurofibromatosis

Neurofibromatosis Type 1

Acoustic Neuroma

Neurofibromatosis Type 2

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Lapatinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Subjects will receive lapatinib for 10 days prior to surgery for vestibular schwannoma resection.

Control subjects will not receive any intervention prior to surgery for vestibular schwannoma resection.

1500 mg lapatinib by mouth per day for 10 days

lapatinib

Jaishri O Blakeley, MD

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.

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.

Concentration and Activity of Lapatinib in Vestibular Schwannomas

Exploration and Estimation of Intratumoral Concentration and Activity of Lapatinib in Vivo in Vestibular Schwannomas

Steady-state plasma concentrations of lapatinib (ng/mL) at time of surgery, 10-13 days from starting drug.

Count of tissue samples with lapatinib concentration \>3uM

Assessed number of samples with high expression of phospho-ErbB2 in tissue at time of surgery

A comparison in the median lapatinib concentration (ng/g) in vestibular schwannomas associated with neurofibromatosis type 2 and sporadic vestibular schwannomas

Due to the sample sizes, a comparison between sporadic and NF2-related vestibular schwannomas could not be made. Instead we report the mutational status.

The Children's Tumor Foundation

GlaxoSmithKline

New York University

Ohio State University

House Research Institute

Washington University School of Medicine

Weill Medical College of Cornell University

Massachusetts General Hospital

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Zero participants were At Risk from the Control arm since they did not receive any intervention.

Subjects received lapatinib 1500 mg by mouth for 10 days prior to surgery for vestibular schwannoma resection.

Control subjects will not receive any intervention prior to surgery for vestibular schwannoma resection. Control subjects donate tissue at the time of surgery. AEs were not collected in this group as there was no study intervention (i.e. they did not take the drug).

Control

Subjects received lapatinib for 1500 mg by mouth daily for 10 days prior to surgery for vestibular schwannoma resection

Control subjects did not receive any intervention prior to surgery for vestibular schwannoma resection

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

KPS is a physician-reported outcome measuring an individual's functional impairment. Scores range from 0% (death) to 100% (normal no complaints; no evidence of disease).

Specific to these results, 70% represents an ability to care for self; unable to carry on normal activity or to do active work, and 90% represents an ability to carry on normal activity; minor signs or symptoms of disease.

Per protocol, KPS was not recorded for control participants. Control participants agreed to donate tissue only. No clinical data was collected.

Karnofsky Performance Status (KPS)

Patients with a diagnosis of NF2

A total of 10 tissue and 11 plasma samples donated by participants receiving lapatinib and 2 tissue samples from control participants were lost from analysis due to freezer failure denaturing the samples. This substantially reduced the sample size.

Jaishri Blakeley

Subjects received lapatinib 1500 mg by mouth for 10 days prior to surgery for vestibular schwannoma resection

In the lapatinib group, 10 tissue and plasma samples were lost from analysis due to a freezer failure during a natural disaster denaturing the samples. 1 blood sample was contaminated, but tissue was available. Control group did not get any drug. A total of 8 participants of 19 given drug had data for analysis.

Median Steady-state Lapatinib Plasma Concentrations at the Time of Surgical Resection

Subjects will receive lapatinib for 10 days prior to surgery for vestibular schwannoma resection.

lapatinib: 1500 mg lapatinib by mouth per day for 10 days

In the lapatinib group, 10 tissue and plasma samples were lost from analysis due to a freezer failure during a natural disaster denaturing the samples. Nine samples were available for tissue concentration assessment.

To Assess Whether Lapatinib Can Reach a Minimum Tumor Concentration Level of >3uM in VS After Oral Dosing.

Control subjects will not receive any intervention prior to surgery for vestibular schwannoma resection. Control subjects donate tissue at the time of surgery.

10 lapatinib participants and 3 control participants did not have adequate tissue for analysis.

Assess the Level of ErbB2 Phosphorylation in VS.

The experiment to assess this outcome measure failed and no interpretable data could be collected.

Assess Markers of Tumor Proliferation and Cell Death in VS After Exposure to Lapatinib.

Participants with vestibular schwannomas associated with a diagnosis of neurofibromatosis type 2

NF2 Associated VS

Participants with sporadic vestibular schwannomas (i.e. not associated with a diagnosis of neurofibromatosis type 2)

Sporadic VS

Of the nine participants in the lapatinib who had tumor available for analysis, four had a vestibular schwnannoma associated with a diagnosis of neurofibromatosis type 2 (NF2); five had sporadic vestibular schwannomas.

Explore the Difference in the Concentration of Lapatinib Achieved in NF2-related Versus Idiopathic VS.

Hemizygous deletion in NF2 gene

Homozygous deletion in NF2 gene

No deletion in NF2 gene

Seven participants had successful NF2 gene mutation analysis via exon scanning and MLPA.

Participants With Tissue Available for Gene Mutation Analysis

6 of the 7 participants had sporadic VS; 1 of 7 had NF2-associated VS. As such, we were unable to explore differences between the groups.

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.

Control subjects did not receive any intervention prior to surgery for vestibular schwannoma resection.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Concentration and Activity of Lapatinib in Vestibular Schwannomas	NCT00863122	Vestibular Schw... NF2 Neurofibromatos... Acoustic Neurom... Auditory Tumor	lapatinib	18 Years -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Concentration and Activity of Lapatinib in Vestibular Schwannomas	NCT00863122	Vestibular Schw... NF2 Neurofibromatos... Acoustic Neurom... Auditory Tumor	lapatinib	18 Years -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Concentration and Activity of Lapatinib in Vestibular Schwannomas	NCT00863122	Vestibular Schw... NF2 Neurofibromatos... Acoustic Neurom... Auditory Tumor	lapatinib	18 Years -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Spots Global Cancer Trial Database for auditory tumor