Clinical trial NCT00863122: Concentration and Activity of Lapatinib in Vestibular Schwannomas
Official title: Exploration and Estimation of Intratumoral Concentration and Activity of Lapatinib in Vivo in Vestibular Schwannomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Vestibular Schwannoma
NF2
Neurofibromatosis 2
Acoustic Neuroma
Auditory Tumor
Keywords: Lapatinib
Tykerb
EGFR inhibitor
ErbB2 inhibitor
Pharmacokinetics
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: The Children's Tumor Foundation
name: GlaxoSmithKline
name: New York University
name: Ohio State University
name: House Research Institute
name: Washington University School of Medicine
name: Weill Medical College of Cornell University
name: Massachusetts General Hospital
First posted: 2009-03-17
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Meet diagnostic criteria for NF2 including presence of bilateral VS or idiopathic VS without evidence of genetic syndrome.
* VS surgery determined clinically necessary by the treating physician and scheduled within 4 weeks.
* Normal cardiac left ventricular ejection fraction (LVEF) by multiple-gated acquisition (MUGA) scan or transthoracic echocardiogram.
* Karnofsky performance status 60% (i.e. the patient must be able to care for himself/herself with occasional help from others).
* Must have the following hematologic, renal and liver function: Absolute neutrophil count ≥ 1,000/mm³ (unsupported); platelet count ≥ 75,000/mm³ (unsupported); hemoglobin ≥ 8 g/dL (transfusion support allowed); Creatinine ≤ 1.5 times upper limit of normal (ULN) OR glomerular filtration rate ≥ 70 ml/min; Bilirubin ≤ 1.5 times ULN; ALT ≤ 2.5 times ULN.
* Be able to provide written informed consent.
* Any neurologic deficits must be stable for ≥ 1 week.
* Be able to swallow tablets.
* Subjects with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception. Women of childbearing potential must have a negative pregnancy test.
* Suspend the use of P450 inducing or P450 suppressing agents for a minimum of 10 days prior to starting lapatinib.

Exclusion Criteria:

* Serious concurrent infection or medical illness, which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety.
* Pregnant or breast-feeding.
* Receiving concurrent therapy for their tumor (i.e. chemotherapeutics or investigational agents, radiation or immunotherapy) within 4 weeks of the first dose of the study drug.
* Concurrent or prior malignancy, other than curatively treated carcinoma-in-situ or basal cell carcinoma of the skin. Subjects who have been free of disease (any prior malignancy) for five years are eligible for this study.
* Received cytochrome P450-inducing anticonvulsants (EIADs; e.g., phenytoin, carbamazepine, phenobarbital, primidone, oxcarbazepine) or similar agents (e.g., rifampin) or P450 inhibiting agents (Ketoconazole, Itraconazole, Clarithromycin, Atazanavir, Indinavir, Nefazodone, Nelfinavir, Ritonavir, Saquinavir, Telithromycin, Voriconazole) within 10 days prior to starting lapatinib.
* Significant gastrointestinal disorder(s)(e.g., Crohn's disease, ulcerative colitis, extensive gastric resection).
* Neurologic deficits that are rapidly progressing.
* Known cardiac disease (either arrhythmia or congestive heart failure) requiring treatment.

Primary outcomes:
measure: Median Steady-state Lapatinib Plasma Concentrations at the Time of Surgical Resection
timeFrame: At time of surgery, 10-13 days from starting drug.
measure: To Assess Whether Lapatinib Can Reach a Minimum Tumor Concentration Level of >3uM in VS After Oral Dosing.
timeFrame: one year
Secondary outcomes:
measure: Assess the Level of ErbB2 Phosphorylation in VS.
timeFrame: at time of surgery
measure: Assess Markers of Tumor Proliferation and Cell Death in VS After Exposure to Lapatinib.
timeFrame: At time of surgery
measure: Explore the Difference in the Concentration of Lapatinib Achieved in NF2-related Versus Idiopathic VS.
timeFrame: one year
measure: 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.
timeFrame: at time of surgery
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: House Reserach Institute
state: California
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University Medical Center
state: Missouri
city: New York
country: United States
facility: New York University Medical Center
state: New York
city: New York
country: United States
facility: Weil Cornell Medical College, New York Presbyterian Hospital
state: New York
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
Study officials:
affiliation: Johns Hopkins University
name: Jaishri O Blakeley, MD
role: PRINCIPAL_INVESTIGATOR
References: