Lapatinib Study for Children and Adults With Neurofibromatosis Type 2 (NF2) and NF2-Related Tumors

• Sponsor: NYU Langone Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT00973739
• Collaborator: GlaxoSmithKline (Industry)
• Enrollment: 21
• Location: 1
• Arm: 1
• Duration (Months): 38
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if Lapatinib has any effect on tumors found in patients with Neurofibromatosis Type 2 (NF2). NF2 is a condition that mainly affects the skin and nervous system. It causes non-cancerous tumors (which are known as neuromas) to grow on the nerves around a person's body. Some signs of NF2 include a gradual loss of hearing and tumors growing on the skin, the brain and the spinal cord which can lead to complications.

Lapatinib is an oral drug that is approved by Food and Drug Administration (FDA) for other types of tumors, it is not approved by the FDA for treatment of NF2 related tumors. The investigators know a lot about how well it is tolerated, but the investigators do not know if it is effective in treating your condition, therefore it is considered to be an investigational medication. This study will test whether Lapatinib may shrink tumors commonly found in patients with NF2 or stop them from growing. This will help us to decide if Lapatinib should be used to treat NF2 patients in future. Lapatinib is a drug that has been used for over 10 years to treat various forms of cancer. It has not been studied for the treatment of tumors in NF2 patients.

Condition or Disease	Intervention/Treatment	Phase
Neurofibromatosis 2; Vestibular Schwannoma	Drug: Lapatinib	Phase 2

Detailed Description

In this trial, we propose to assess the objective response rates to Lapatinib in patients with NF2-related tumors. Lapatinib is a commercially available inhibitor of ErbB2 and EGF. 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.

Demonstrating that Lapatinib produces an objective response to reduce tumor volume or stabilize disease will provide additional treatment options for NF patients with multiple tumor growth. For patients with VS we expect to see ≥ 10 dB improvement in PTA and/or improvement in SDS, compared to the audiogram at initiation of treatment. Currently there are no available treatment options for NF2 patients with multiple tumors. Depending on tumor cell type, lapatinib has cytostatic or cytotoxic antitumor effects, and in a recent study assessing the biological effects of Lapatinib on the associated molecular pathways and tumor growth in patients with solid tumors, a correlation was seen between tumor response and pre-treatment levels of (phosphor)-ErbB2 and (phosphor)-ERK1/2.

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Lapatinib in Children and Adults With Neurofibromatosis Type 2(NF2) and NF2-related Tumors
• Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: Oct 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Lapatinib Lapatinib PO dosed according to age: Children/adolescents (less than 18 years of age): 1,800 mg/m2/day PO divided into twice daily doses, to a maximum of 750 mg PO twice daily Adults (18 years of age or older): 1,500 mg PO once daily Lapatinib is available in 250 mg tablets only. For pediatric dosing, the total daily dose will be rounded up or down to the nearest 250 mg increment.

Drug: Lapatinib; Lapatinib is dosed according to age. Lapatinib is available in 250 mg tablets only. For pediatric dosing, the total daily dose will be rounded up or down to the nearest 250 mg increment. Children/adolescents (<18 years of age): 1,800 mg/m2/day PO divided into twice daily doses, to a maximum of 750 mg PO (3 tablets twice daily) Adults (>=18 years of age): 1,500 mg PO (6 tablets once daily) Duration: Up to 12 months, depending on treatment response.; Other Names: Tykerb

Outcome Measures

Primary Outcome Measures

1. Estimated Volumetric Progression Free Survival at 12 Months [Every three months for one year]

   Measurements were taken every three months, up to one year. Estimated volumetric progression free survival (PFS) was measured from date of enrollment to date of volumetric progression. PFS was analyzed using the Kaplan-Meier method in terms of overall PFS (volumetric or hearing progression), volumetric progression, and hearing progression. Point estimates for PFS with 95% confidence intervals (CIs) were calculated from Kaplan-Meier curves.

Secondary Outcome Measures

1. Estimated Volumetric Progression Free Survival for Hearing at 12 Months [Every three months for one year]

   Measurements were taken every three months, up to one year. Estimated volumetric progression free survival (PFS) was measured from date of enrollment to date of hearing progression. PFS was analyzed using the Kaplan-Meier method in terms of overall PFS (volumetric or hearing progression), volumetric progression, and hearing progression. Point estimates for PFS with 95% confidence intervals (CIs) were calculated from Kaplan-Meier curves.

2. Participants Experiencing Grades 1 or 2 Toxicities (CTCAE) [Baseline through one year]

   Toxicity was assessed throughout the study, up to one year.

3. Participants Experiencing Grade 3 Toxicities (CTCAE) [Baseline through one year]

   Toxicity was assessed throughout the study, up to one year.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Patients must be at least 4 years of age.

2. Patients must meet diagnostic criteria for NF2 and at least one volumetrically measured NF2-related brain or spinal tumor with radiographic evidence of progression over the past 12 months, designated as the primary target OR volumetrically measurable VS with ipsilateral progressive hearing loss over the past 12 months, designated as the primary target tumor.

3. Significant hearing loss criteria for enrollment.

4. Karnofsky (PS) OR Lansky 50-100% (>16 years of age)

5. Absolute neutrophil count ≥ 1,000/mm3 g/dL

6. Hemoglobin ≥ 8 g/dL

7. Creatinine ≤ 1.5 times upper limit of normal (ULN) OR corrected glomerular filtration rate ≥ 70 ml/min

8. Bilirubin ≤ 1.5 times ULN

9. ALT ≤ 2.5 times ULN

10. Fully recovered from acute toxic effects of any prior chemotherapy, biological modifiers or radiotherapy.

11. Steroids are allowed for progressive symptoms but patient must be on a stable dose for at least 1 week prior to study entry.

12. Any neurologic deficits must be stable for ≥ 1 week.

13. Patients 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. The anti-proliferative activity of this experimental drug may be harmful to the developing fetus.

14. Normal cardiac left ventricular ejection fraction (LVEF) by transthoracic echocardiogram.

15. Able to provide written informed consent (or consent by parent/legal guardian for minors)

Exclusion Criteria:

1. Patients with serious concurrent infection or medical illness.

2. Neurological deficits that are rapidly progressing.

3. Patients who are pregnant or breast-feeding.

4. Anti-tumor therapy within 4 weeks prior to enrollment.

5. Radiation therapy within 2 months prior to enrollment.

6. Prior therapy with agents targeting EGFR or ErbB2.

7. Any surgery within 4 weeks prior to enrollment.

8. Significant gastrointestinal disorder(s)

9. Known cardiac disease

10. Patients with a concurrent or prior malignancy are ineligible unless they are patients with curatively treated carcinoma-in-situ or basal cell carcinoma of the skin. Patients who have been free of disease (any prior malignancy) for more than five years are eligible for this study.

11. Patients cannot have 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	New York University School of Medicine	New York	New York	United States	10016

Sponsors and Collaborators

• NYU Langone Health
• GlaxoSmithKline

Investigators

• Principal Investigator: Matthias A Karajannis, MD, MS, NYU School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT00973739
• Other Study ID Numbers: 09-0328
• First Posted: Sep 9, 2009
• Last Update Posted: Mar 22, 2016
• Last Verified: Feb 1, 2016

• Keywords provided by NYU Langone Health: NF-2; NF-2 related tumors; Schwannoma, Acoustic, Bilateral; schwannomas; Neurilemmoma of other cranial and peripheral nerves; NF2 related benign intracranial tumors including; NF2 related meningiomas; NF2 related ependymomas; NF2 related spinal neurofibromas; NF2 related gliomas
• Additional relevant MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurilemmoma; Neuroma, Acoustic; Neurofibromatosis 2; Lapatinib

Study Results

Participant Flow

Recruitment Details	Twenty-one patients were enrolled between October 2009 and March 2011 at New York University Medical Center.

Arm/Group Title	Lapatinib
Arm/Group Description	Lapatinib will be administered
Period Title: Overall Study
STARTED	21
COMPLETED	17
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Lapatinib
Arm/Group Description	Lapatinib will be administered
Overall Participants	21
Age (Count of Participants)
<=18 years	4 19%
Between 18 and 65 years	17 81%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28 (5)
Sex: Female, Male (Count of Participants)
Female	8 38.1%
Male	13 61.9%
Region of Enrollment (participants) [Number]
United States	21 100%

Outcome Measures

1. Primary Outcome

Title	Estimated Volumetric Progression Free Survival at 12 Months
Description	Measurements were taken every three months, up to one year. Estimated volumetric progression free survival (PFS) was measured from date of enrollment to date of volumetric progression. PFS was analyzed using the Kaplan-Meier method in terms of overall PFS (volumetric or hearing progression), volumetric progression, and hearing progression. Point estimates for PFS with 95% confidence intervals (CIs) were calculated from Kaplan-Meier curves.
Time Frame	Every three months for one year

Outcome Measure Data

Analysis Population Description

This analysis is based on the 17 evaluable patients.

Arm/Group Title	Lapatinib
Arm/Group Description	Lapatinib PO dosed according to age: Children/adolescents (less than 18 years of age): 1,800 mg/m2/day PO divided into twice daily doses, to a maximum of 750 mg PO twice daily Adults (18 years of age or older): 1,500 mg PO once daily Lapatinib is available in 250 mg tablets only. For pediatric dosing, the total daily dose will be rounded up or down to the nearest 250 mg increment.
Measure Participants	17
Mean (95% Confidence Interval) [Liklihood of PFS at 12 months]	70.6

2. Secondary Outcome

Title	Estimated Volumetric Progression Free Survival for Hearing at 12 Months
Description	Measurements were taken every three months, up to one year. Estimated volumetric progression free survival (PFS) was measured from date of enrollment to date of hearing progression. PFS was analyzed using the Kaplan-Meier method in terms of overall PFS (volumetric or hearing progression), volumetric progression, and hearing progression. Point estimates for PFS with 95% confidence intervals (CIs) were calculated from Kaplan-Meier curves.
Time Frame	Every three months for one year

Outcome Measure Data

Analysis Population Description

This analysis is based on the 17 evaluable patients.

Arm/Group Title	Lapatinib
Arm/Group Description	Lapatinib PO dosed according to age: Children/adolescents (less than 18 years of age): 1,800 mg/m2/day PO divided into twice daily doses, to a maximum of 750 mg PO twice daily Adults (18 years of age or older): 1,500 mg PO once daily Lapatinib is available in 250 mg tablets only. For pediatric dosing, the total daily dose will be rounded up or down to the nearest 250 mg increment.
Measure Participants	17
Mean (95% Confidence Interval) [Liklihood of PFS at 12 months]	88.9

3. Secondary Outcome

Title	Participants Experiencing Grades 1 or 2 Toxicities (CTCAE)
Description	Toxicity was assessed throughout the study, up to one year.
Time Frame	Baseline through one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lapatinib
Arm/Group Description	Lapatinib PO dosed according to age: Children/adolescents (less than 18 years of age): 1,800 mg/m2/day PO divided into twice daily doses, to a maximum of 750 mg PO twice daily Adults (18 years of age or older): 1,500 mg PO once daily Lapatinib is available in 250 mg tablets only. For pediatric dosing, the total daily dose will be rounded up or down to the nearest 250 mg increment.
Measure Participants	21
Number [participants]	21 100%

4. Secondary Outcome

Title	Participants Experiencing Grade 3 Toxicities (CTCAE)
Description	Toxicity was assessed throughout the study, up to one year.
Time Frame	Baseline through one year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lapatinib
Arm/Group Description	Lapatinib PO dosed according to age: Children/adolescents (less than 18 years of age): 1,800 mg/m2/day PO divided into twice daily doses, to a maximum of 750 mg PO twice daily Adults (18 years of age or older): 1,500 mg PO once daily Lapatinib is available in 250 mg tablets only. For pediatric dosing, the total daily dose will be rounded up or down to the nearest 250 mg increment.
Measure Participants	21
Number [participants]	1 4.8%

Adverse Events

Arm/Group Title	Lapatinib
Arm/Group Description	Lapatinib will be administered
All Cause Mortality
	Lapatinib
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Lapatinib
	Affected / at Risk (%)	# Events
Total	0/21 (0%)
Other (Not Including Serious) Adverse Events
	Lapatinib
	Affected / at Risk (%)	# Events
Total	21/21 (100%)
Blood and lymphatic system disorders
Anemia	5/21 (23.8%)	5
Lymphopenia	5/21 (23.8%)	5
Cardiac disorders
Pericardial effusion on echocardiogram	1/21 (4.8%)	1
Possible ectopic atrial bradycardia on EKG	1/21 (4.8%)	1
Premature supraventricular complexes on EKG	1/21 (4.8%)	1
Sinus Bradycardia	2/21 (9.5%)	2
Eye disorders
Keratitis	2/21 (9.5%)	2
Gastrointestinal disorders
Constipation	1/21 (4.8%)	1
Diarrhea	15/21 (71.4%)	15
heartburn	1/21 (4.8%)	1
Hemorrhage - rectum (stools)	1/21 (4.8%)	1
Nausea	4/21 (19%)	4
Vomiting	3/21 (14.3%)	3
General disorders
Fatigue	9/21 (42.9%)	9
Fever	1/21 (4.8%)	1
Pain-Other	8/21 (38.1%)	8
Investigations
Hyperbilirubinemia	2/21 (9.5%)	2
Increased ALT	4/21 (19%)	4
Increased AST	7/21 (33.3%)	7
Increased PTT	1/21 (4.8%)	1
Metabolism and nutrition disorders
Anorexia	2/21 (9.5%)	2
Decreased bicarbonate	5/21 (23.8%)	5
Hyperglycemia	9/21 (42.9%)	9
Hyperkalemia	2/21 (9.5%)	2
Hypernatremia	2/21 (9.5%)	2
Hypocalcemia	2/21 (9.5%)	2
Hypoglycemia	3/21 (14.3%)	3
Hypokalemia	5/21 (23.8%)	5
Hypophosphatemia	4/21 (19%)	4
Nervous system disorders
Vasovagal syncope	1/21 (4.8%)	1
Ataxia	1/21 (4.8%)	1
Memory Impairment	2/21 (9.5%)	2
Numbness L-S area	1/21 (4.8%)	1
Psychiatric disorders
Anxiety	2/21 (9.5%)	2
Insomnia	2/21 (9.5%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/21 (4.8%)	1
Epistaxis	4/21 (19%)	4
Skin and subcutaneous tissue disorders
Dermatology/Skin (Other)	19/21 (90.5%)	19
Stomatitis (oral cavity ulceration)	1/21 (4.8%)	1
Vascular disorders
Hypertension	1/21 (4.8%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.