In this research study the investigators want to learn more about an alternate, local treatment for skin schwannomas. Specifically, local doxycycline intra-tumoral injection will be performed as a potential treatment for NF2-related skin schwannomas, ultimately reducing the risks and costs associated with standard surgical removal of such skin tumors if successful.

Study Design: Interventional Clinical Trial, single-arm, open-label

Estimated Enrollment: Up to 19 participants with NF2-associated cutaneous or subcutaneous schwannomas

Aims: To demonstrate change in peripheral schwannoma size following direct injection into the tumor with doxycycline hyclate.

Nineteen neurofibromatosis type 2-associated peripheral cutaneous or subcutaneous schwannomas between 0.5 cm and 4 cm in greatest diameter will be diagnosed clinically, photographed for documentation of location, and injected with between 0.1 ml to 4 ml of 10mg/ml doxycycline hyclate (Fresenius Kabi, Canton, MA). A maximum of three tumors per patient will be injected. The dose administered will be calculated based on tumor size, not to exceed the estimated volume of the tumor or a maximum of 4 ml. The tumor volume will be estimated by electronic caliper measure of the greatest tumor diameter (D). (V=4/3piR3 where R is the radius (R=D/2) is measured in millimeters and the dose calculated by Vmm3/1000 = injection volume in milliliters). Repeat measures will be made at 6-months and 1-year follow up (+/- 1 month) and documented with electronic calipers and photography. Injection of 1% lidocaine may be given pre-doxycycline to reduce injection pain.

Outcome: The primary outcome will be longitudinal change in tumor maximal diameter measured at 6-months and 1-year compared to baseline defined by a change of 25%. Secondary endpoints include patient reports of paresthesia, pain, skin breakdown or discoloration. Exploratory endpoints will be the change in the sum of maximal diameters.

Inclusion Criteria:

1. Patients must have a confirmed diagnosis of neurofibromatosis 2 by fulfilling National Institute of Health (NIH) criteria or Manchester criteria, or by detection of a causative mutation in the NF2 gene.

   The NIH criteria include presence of:

   • Bilateral vestibular schwannomas, OR
   • First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR
   • Two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity.

   The Manchester criteria include presence of:

   • Bilateral vestibular schwannomas, OR First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR - Two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity OR
   • Unilateral vestibular schwannoma AND any two of: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, OR
   • Multiple meningiomas (two or more) AND unilateral vestibular schwannoma OR
   • Any two of: schwannoma, glioma, neurofibroma, cataract.

2. Patients must have measurable disease, defined as at least one cutaneous/subcutaneous schwannoma with the following qualities:

   • Maximal tumor diameter > 0.5 cm to < 4.0 cm that can be accurately measured by electronic calipers
   • Up to a maximum of 3 tumors/subject may be injected
   • Not located on the face

3. Age ≥ 8 years on day 1 of treatment.

4. Life expectancy of greater than 1 year

5. Lansky/Karnofsky performance status ≥ 60

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

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

8. Patient or parent/legal guardian must be able to provide signed informed consent and assent (as applicable for minors)

Exclusion Criteria:

1. Allergy to doxycycline or tetracycline

2. Tumors located on the face or major motor nerves

3. Patients currently receiving medical anticancer therapies or who have received medical anticancer therapies within 4 weeks of the start of study drug (including chemotherapy and molecular targeted agents), as these may interfere with the study drug

4. Radiation therapy to a study target tumor within 1 year prior to enrollment, or any radiation therapy within 4 weeks prior to enrollment, as these may interfere with our ability to assess response to study drug

5. Prior treatment with any investigational drug within the preceding 4 weeks, as they may interfere with the study drug

6. Unstable or rapidly progressive disease, including patients who require glucocorticoids for symptomatic control of brain or spinal tumors, as this would represent a high risk for inability to comply with the study requirements

7. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

   • symptomatic congestive heart failure of New York heart Association Class III or IV
   • unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
   • severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation that is 90% or less at rest on room air
   • active (acute or chronic) or uncontrolled severe infections liver disease, such as cirrhosis or severe hepatic impairment (Child-Pugh class C)

8. Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Adequate contraception (oral contraceptives, contraceptive implants, vaginal ring, or intrauterine devices (IUDs)) must be used at the time of injection but does not need to be carried out past the 1st month of observation.

9. History of significant noncompliance with follow-up that would jeopardize the study evaluation.

10. Patients unwilling to or unable to comply with the study protocol.