Meningioma Clinical Trials

• \- 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.

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

• Participants must have a target NF2-related tumor (VS, non-VS, meningioma, or ependymoma) with documented radiographic progression within the preceding 36-months.

• Age between 12 and 25 years on day 1 of treatment.

• Life expectancy of greater than 1 year.

• Participants must meet the following organ and marrow function as defined below:

∙ Leukocytes ≥3000/mcL

‣ Platelets ≥100,000/mcL

‣ Total Bilirubin ≤ 1.5 institutional upper limit of normal (ULN), (\<3.0 × institutional ULN for patients with Gilbert Syndrome)

‣ AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN

‣ Urine Protein:Creatinine Ratio ≤ 1.9

‣ Glomerular Filtration Rate (GFR) ≥30 mL/min/1.73 m2

• Inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. Therefore, 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, defined as ≥12 consecutive months of amenorrhea in the absence of endocrine or anti-endocrine therapy, for a minimum of 1 year prior to 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. Highly effective non-hormonal birth control for women of childbearing potential with male partners may include:

• 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.