Concentration and Activity of Lapatinib in Vestibular Schwannomas

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Completed
• CT.gov ID: NCT00863122
• Collaborator: The Children's Tumor Foundation (Other), GlaxoSmithKline (Industry), New York University (Other), Ohio State University (Other), House Research Institute (Other), Washington University School of Medicine (Other), Weill Medical College of Cornell University (Other), Massachusetts General Hospital (Other)
• Enrollment: 26
• Locations: 7
• Arms: 2
• Duration (Months): 62
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Vestibular Schwannoma; NF2; Neurofibromatosis 2; Acoustic Neuroma; Auditory Tumor	Drug: lapatinib	Early Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: Non-Randomized
• 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: Jun 1, 2009
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: lapatinib Subjects will receive lapatinib for 10 days prior to surgery for vestibular schwannoma resection.	Drug: lapatinib; 1500 mg lapatinib by mouth per day for 10 days; Other Names: Tykerb
No Intervention: control Control subjects will not receive any intervention prior to surgery for vestibular schwannoma resection.

Outcome Measures

Primary Outcome Measures

1. Median Steady-state Lapatinib Plasma Concentrations at the Time of Surgical Resection [At time of surgery, 10-13 days from starting drug.]

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

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

   Count of tissue samples with lapatinib concentration >3uM

Secondary Outcome Measures

1. Assess the Level of ErbB2 Phosphorylation in VS. [at time of surgery]

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

2. Assess Markers of Tumor Proliferation and Cell Death in VS After Exposure to Lapatinib. [At time of surgery]

3. Explore the Difference in the Concentration of Lapatinib Achieved in NF2-related Versus Idiopathic VS. [one year]

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

4. 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. [at time of surgery]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	House Reserach Institute	Los Angeles	California	United States	90057
2	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
3	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
4	Washington University Medical Center	Saint Louis	Missouri	United States	63110
5	New York University Medical Center	New York	New York	United States	10016
6	Weil Cornell Medical College, New York Presbyterian Hospital	New York	New York	United States	10065
7	Ohio State University Medical Center	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• 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

Investigators

• Principal Investigator: Jaishri O Blakeley, MD, Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT00863122
• Other Study ID Numbers: J0867; NA_00020841
• First Posted: Mar 17, 2009
• Last Update Posted: Jan 12, 2021
• Last Verified: Dec 1, 2020

• Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: Lapatinib; Tykerb; EGFR inhibitor; ErbB2 inhibitor; Pharmacokinetics
• Additional relevant MeSH terms: Neurofibromatoses; Neurilemmoma; Neuroma; Neuroma, Acoustic; Neurofibromatosis 2; Lapatinib

Study Results

Participant Flow

Recruitment Details	All patients undergoing surgery for vestibular schwannoma resection who met eligibility criteria were invited to participate
Pre-assignment Detail	Patients could enroll on control (no drug) or lapatinib arms. 20 people were consented for the the lapatinib arm, but one patient withdrew consent prior to completion of eligibility screening and enrollment. So 19 patients enrolled on the lapatinib arm.

Arm/Group Title	Lapatinib	Control
Arm/Group Description	Subjects received lapatinib 1500 mg by mouth for 10 days prior to surgery for vestibular schwannoma resection.	Control subjects did not receive any intervention prior to surgery for vestibular schwannoma resection.
Period Title: Overall Study
STARTED	19	7
COMPLETED	19	7
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Lapatinib	Control	Total
Arm/Group Description	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 of all reporting groups
Overall Participants	19	7	26
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	19 100%	7 100%	26 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	44	40	43.5
Sex: Female, Male (Count of Participants)
Female	15 78.9%	6 85.7%	21 80.8%
Male	4 21.1%	1 14.3%	5 19.2%
Region of Enrollment (participants) [Number]
United States	19 100%	7 100%	26 100%
Karnofsky Performance Status (KPS) (units on a scale (percent)) [Median (Full Range) ]
Median (Full Range) [units on a scale (percent)]	90	90
Patients with a diagnosis of NF2 (participants) [Number]
Number [participants]	9 47.4%	0 0%	9 34.6%

Outcome Measures

1. Primary Outcome

Title	Median Steady-state Lapatinib Plasma Concentrations at the Time of Surgical Resection
Description	Steady-state plasma concentrations of lapatinib (ng/mL) at time of surgery, 10-13 days from starting drug.
Time Frame	At time of surgery, 10-13 days from starting drug.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Lapatinib
Arm/Group Description	Subjects received lapatinib 1500 mg by mouth for 10 days prior to surgery for vestibular schwannoma resection
Measure Participants	8
Median (Full Range) [ng/mL]	3149

2. Primary Outcome

Title	To Assess Whether Lapatinib Can Reach a Minimum Tumor Concentration Level of >3uM in VS After Oral Dosing.
Description	Count of tissue samples with lapatinib concentration >3uM
Time Frame	one year

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Lapatinib
Arm/Group Description	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
Measure Participants	9
Count of Participants [Participants]	7 36.8%

3. Secondary Outcome

Title	Assess the Level of ErbB2 Phosphorylation in VS.
Description	Assessed number of samples with high expression of phospho-ErbB2 in tissue at time of surgery
Time Frame	at time of surgery

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Lapatinib	Control
Arm/Group Description	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	Control subjects will not receive any intervention prior to surgery for vestibular schwannoma resection. Control subjects donate tissue at the time of surgery.
Measure Participants	9	4
Count of Participants [Participants]	5 26.3%	2 28.6%

4. Secondary Outcome

Title	Assess Markers of Tumor Proliferation and Cell Death in VS After Exposure to Lapatinib.
Time Frame	At time of surgery

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Lapatinib
Arm/Group Description	Subjects received lapatinib 1500 mg by mouth for 10 days prior to surgery for vestibular schwannoma resection
Measure Participants	0

5. Secondary Outcome

Title	Explore the Difference in the Concentration of Lapatinib Achieved in NF2-related Versus Idiopathic VS.
Description	A comparison in the median lapatinib concentration (ng/g) in vestibular schwannomas associated with neurofibromatosis type 2 and sporadic vestibular schwannomas
Time Frame	one year

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NF2 Associated VS	Sporadic VS
Arm/Group Description	Participants with vestibular schwannomas associated with a diagnosis of neurofibromatosis type 2	Participants with sporadic vestibular schwannomas (i.e. not associated with a diagnosis of neurofibromatosis type 2)
Measure Participants	4	5
Median (Full Range) [ng/g]	8367	4502

6. Secondary Outcome

Title	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.
Description	Due to the sample sizes, a comparison between sporadic and NF2-related vestibular schwannomas could not be made. Instead we report the mutational status.
Time Frame	at time of surgery

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Participants With Tissue Available for Gene Mutation Analysis
Arm/Group Description	Seven participants had successful NF2 gene mutation analysis via exon scanning and MLPA.
Measure Participants	7
Hemizygous deletion in NF2 gene	4 21.1%
Homozygous deletion in NF2 gene	1 5.3%
No deletion in NF2 gene	2 10.5%

Adverse Events

Adverse Event Reporting Description	Zero participants were At Risk from the Control arm since they did not receive any intervention.
Arm/Group Title	Lapatinib		Control
Arm/Group Description	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).
All Cause Mortality
	Lapatinib		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Lapatinib		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Lapatinib		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/19 (63.2%)		0/0 (NaN)
Gastrointestinal disorders
Diarrhea	7/19 (36.8%)	7	0/0 (NaN)	0
Nausea	4/19 (21.1%)	4	0/0 (NaN)	0
General disorders
Fatigue	4/19 (21.1%)	4	0/0 (NaN)	0
Skin and subcutaneous tissue disorders
Rash	6/19 (31.6%)	6	0/0 (NaN)	0
Acne	2/19 (10.5%)	2	0/0 (NaN)	0

Limitations/Caveats

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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.