Innovative Trial for Understanding the Impact of Targeted Therapies in NF2-Related Schwannomatosis (INTUITT-NF2)

• Patients must have a pathogenic variant in the NF2 gene (either in the germline or in two NF2-related tumors) OR a confirmed diagnosis of NF2 by fulfilling National Institute of Health (NIH) criteria or Manchester criteria:

∙ The NIH criteria includes 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 includes 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.

∙ Subjects must have a target NF2-related tumor (VS, non-VS, meningioma, or ependymoma) with documented radiographic progression within the preceding 36 months of Master Study registration defined as either:

• at least 20% increase in volume of enhancing tumor

• at least 2 mm increase in greatest linear dimension of enhancing tumor

∙ Participants must have measurable disease, defined as:

• VS, non-VS, or meningioma target lesions that can be accurately measured as at least 1 ml by volumetric MRI scan or in at least one dimension as ≥10 mm with conventional MRI scan. See protocol for the evaluation of measurable disease

• Ependymoma target lesions measurable linearly.

∙ Participant must have a target NF2-related tumor with the following qualities:

• Not amenable to surgery due to patient refusal or due to high risk for surgical complications (e.g., damage to nerve function). Participant must be ≥ 12 years of age on Day 1 of treatment. Life expectancy of greater than 1 year Karnofsky performance status ≥ 70 or ECOG PS 0 or 1 (see Appendix A). Ability to understand and the willingness to sign written informed consent and assent documents.

• Must have established relationship with primary care physician and provide contact information

• Participants must meet all eligibility criteria outlined in the Master Study

• Participants must be willing and able to provide written informed consent/assent for the brigatinib arm of the INTUITT-NF2 trial.

• Participant is ≥ 12 years of age and has body weight at least 40 kg on Day 1 of treatment.

• Patient must be able to swallow pills.

• Clinical laboratory values as specified below within 28 days before the first dose of study drug, as described in the protocol document:

• Female patients participating in this study should avoid becoming pregnant, and male patients should avoid impregnating a female partner. Non-sterilized female patients of reproductive age group and male patients should use effective methods of contraception through defined periods during and after study treatment as specified below:

∙ Female patients must meet 1 of the following:

• Postmenopausal for at least 1 year before the screening visit, or

• Surgically sterile, or

• If they are of childbearing potential, agree to practice 2 effective methods of contraception from the time of signing of the informed consent form through 4 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse. Brigatinib may decrease effectiveness of hormonal contraceptives, therefore, women are recommended to use non-hormonal methods of contraception. Highly effective non-hormonal birth control for women of child bearing potential with male partners includes:

‣ Sexual abstinence (no sexual intercourse)

⁃ Intrauterine device (IUD) or intrauterine system (IUS)

⁃ Bilateral tubal ligation (both tubes tied)

⁃ Vasectomized partner

∙ Male patients, even if surgically sterilized (i.e., status post-vasectomy) must agree to 1 of the following:

• Practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or completely abstain from heterosexual intercourse.