Innovative Trial for Understanding the Impact of Targeted Therapies in Neurofibromatosis Type 2 - Related Schwannomatosis, The INTUITT-NF2 Trial

Inclusion Criteria

• MASTER STUDY: Patients must fulfill diagnostic criteria for NF2-SWN * A diagnosis of NF2-related schwannomatosis (previously termed neurofibromatosis 2, NF2) can be made when an individual has one of the following: ** Bilateral vestibular schwannomas (VS) ** An identical NF2 pathogenic variant in at least 2 anatomically distinct NF2-related tumors (schwannoma, meningioma, and/or ependymoma) ** Either 2 major or 1 major and 2 minor criteria as described in the following: *** Major criteria: **** Unilateral VS **** First-degree relative other than sibling with NF2-related schwannomatosis **** 2 or more meningiomas (Note: single meningioma qualifies as minor criteria). **** NF2 pathogenic variant in an unaffected tissue such as blood *** Minor criteria: Can count > 1 of a type (eg, 2 distinct schwannomas would count as 2 minor criteria) **** Ependymoma, meningioma, schwannoma Can count only once (eg, bilateral cortical cataracts count as a single minor criterion) **** Juvenile subcapsular or cortical cataract, retinal hamartoma, epiretinal membrane in a person aged < 40 years, meningioma
• MASTER STUDY: Participants 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: * >= 20% increase in volume of enhancing tumor * >= 2 mm increase in greatest linear dimension of enhancing tumor
• MASTER STUDY: Participants must have measurable disease, defined as: * VS, non-VS, or meningioma target lesions that can be accurately measured as >= 1 ml by volumetric MRI scan or in at least one dimension as >=10 mm with conventional MRI scan * Ependymoma target lesions measurable linearly
• MASTER STUDY: 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)
• MASTER STUDY: Participant must be >= 12 years of age on day 1 of treatment
• MASTER STUDY: Life expectancy of greater than 1 year
• MASTER STUDY: For participants 16 or older: Karnofsky performance status >= 70 or Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1; for participants age 12 to < 16: Lansky scale >= 70
• MASTER STUDY: Ability to understand and the willingness to sign written informed consent and assent documents
• MASTER STUDY: Must have established relationship with primary care physician and provide contact information
• BRIGATINIB ARM: Participants must meet all eligibility criteria outlined in the Master Study and complete initial registration
• BRIGATINIB ARM: 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 >= 40 kg on Day 1 of treatment
• BRIGATINIB ARM: Participants must have a target NF2-related tumor (VS, non-VS, meningioma, or ependymoma) with documented radiographic progression within the preceding 36 months of brigatinib sub-study registration defined as either: * ≥ 20% increase in volume of enhancing tumor * ≥ 2 mm increase in greatest linear dimension of enhancing tumor
• BRIGATINIB ARM: Participant is >= 12 years of age and has body weight >= 40 kg on day 1 of treatment
• BRIGATINIB ARM: Patient must be able to swallow pills
• BRIGATINIB ARM: Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 2.5 x institutional upper limit of normal (ULN) (within 14 days before the first dose of study drug)
• BRIGATINIB ARM: Total serum bilirubin =< 1.5 x institutional ULN (< 3.0 x institutional ULN for patients with Gilbert syndrome) (within 14 days before the first dose of study drug)
• BRIGATINIB ARM: Estimated glomerular filtration rate (eGFR) >= 30 mL/min/1.73 m^2, using the modification of diet in renal disease (MDRD) equation (within 14 days before the first dose of study drug)
• BRIGATINIB ARM: Serum lipase =< 1.5 x institutional ULN (within 14 days before the first dose of study drug)
• BRIGATINIB ARM: Absolute neutrophil count >= 1.5 x 10^9/L (within 14 days before the first dose of study drug)
• BRIGATINIB ARM: Platelet count >= 75 x 10^9/L (within 14 days before the first dose of study drug)
• BRIGATINIB ARM: Hemoglobin >= 9 g/dL (within 14 days before the first dose of study drug)
• BRIGATINIB ARM: It is not known what effects brigatinib has on human pregnancy or development of the embryo or fetus. 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 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. 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
• NERATINIB ARM: Participants must meet all eligibility criteria outlined in the Master Study and complete initial registration
• NERATINIB ARM: Participants must be willing and able to provide written informed consent/assent for the neratinib arm of the INTUITT-NF2 trial
• NERATINIB ARM: Participants must have a target NF2-related tumor (VS, non-VS, meningioma, or ependymoma) with documented radiographic progression within the preceding 36 months of neratinib sub-study registration defined as either: * ≥ 20% increase in volume of enhancing tumor * ≥ 2 mm increase in greatest linear dimension of enhancing tumor
• NERATINIB ARM: Participant must be >= 12 years of age and have body weight >= 40 kg on Day 1 of treatment
• NERATINIB ARM: Patient must be able to swallow pills
• NERATINIB ARM: Recovery (i.e., to grade 1 or baseline) from all clinically significant AEs related to prior therapies (excluding alopecia, neuropathy, and nail changes)
• NERATINIB ARM: ALT/aspartate aminotransferase (AST) =< 2.5 x institutional upper limit of normal (ULN) (within 14 days before the first dose of study drug)
• NERATINIB ARM: Total serum bilirubin =< 1.5 x institutional ULN (< 3.0 x institutional ULN for patients with Gilbert syndrome) (within 14 days before the first dose of study drug)
• NERATINIB ARM: Estimated glomerular filtration rate (eGFR) >= 30 mL/min/1.73 m^2, using the modification of diet in renal disease (MDRD) equation (within 14 days before the first dose of study drug)
• NERATINIB ARM: Serum lipase =< 1.5 x institutional ULN (within 14 days before the first dose of study drug)
• NERATINIB ARM: Absolute neutrophil count >= 1.5 x 10^9/L (within 14 days before the first dose of study drug)
• NERATINIB ARM: Platelet count >= 75 x 10^9/L (within 14 days before the first dose of study drug)
• NERATINIB ARM: Hemoglobin >= 9 g/dL (within 14 days before the first dose of study drug)
• NERATINIB ARM: Left ventricular ejection fraction (LVEF) >= 50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO)
• NERATINIB ARM: It is not known what effects neratinib has on human pregnancy or development of the embryo or fetus. 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 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. Neratinib 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 *** Effective barrier contraception * 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
• NERATINIB ARM: Female patients must have negative beta-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after menopause. (Women are considered postmenopausal if they are >= 12 months without menses, in the absence of endocrine or anti-endocrine therapies.)

Exclusion Criteria

• MASTER STUDY: Participants who have had chemotherapy within a minimum of 4 weeks prior to Master Study registration (or a minimum of 5 half-lives and resolution to baseline of toxicities unless there are irreversible toxicities from prior drug that do not influence risk of next drug)
• MASTER STUDY: Participants who have received radiation to the target tumor within the last 3 years prior to Master study registration
• MASTER STUDY: Participants who are receiving any other investigational agents
• MASTER STUDY: Participants with target or non-target nervous system tumors that, in the opinion of the treating investigator, are likely to require active treatment (including surgery) within 6 months of registration to the Master Study
• MASTER STUDY: History of a different malignancy, unless (a) have been disease-free for at least 2 years and are deemed by the treating investigator to be at low risk for recurrence of that malignancy, and/or (b) malignancy was breast or cervical cancer in situ, superficial bladder cancer or basal cell or squamous cell carcinoma of the skin, and malignancy has been treated. Patients who meet the above listed criteria and are only on preventative treatment will be deemed eligible
• MASTER STUDY: Pregnant women are excluded from this study because the experimental agents may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these experimental agents, breastfeeding should be discontinued if the mother is treated
• BRIGATINIB ARM: Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug (if applicable)
• BRIGATINIB ARM: Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
• BRIGATINIB ARM: Treatment with any investigational products within 28 days or 5 half-lives (whichever is longer) before the first dose of study drug
• BRIGATINIB ARM: Had major surgery within 30 days of the first dose of brigatinib. Minor surgical procedures such as catheter placement or minimally invasive biopsies are allowed
• BRIGATINIB ARM: Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: * Myocardial infarction within 6 months before the first dose of brigatinib * Unstable angina within 6 months before first dose of brigatinib * Congestive heart failure within 6 months before first dose of brigatinib * History of clinically significant atrial arrhythmia (including clinically significant bradyarrhythmia), as determined by the treating physician * Any history of clinically significant ventricular arrhythmia * Had a cerebrovascular accident or transient ischemic attack within 6 months before first dose of brigatinib
• BRIGATINIB ARM: Have uncontrolled hypertension (defined as an average systolic blood pressure > 160 or an average diastolic blood pressure > 100 for adult patients >= 21 years and as an average systolic blood pressure (BP) > 130 or an average diastolic blood pressure > 80 for pediatric patients 12-21 years despite adequate treatment with medications. Patients with hypertension should be under treatment on study entry to control blood pressure
• BRIGATINIB ARM: Have a history or the presence at baseline of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis
• BRIGATINIB ARM: Have an ongoing or active infection, including, but not limited to, the requirement for intravenous antibiotics. Note: superficial infections that are treated with topical medications or other infections that, in the opinion of the site principal investigator (PI), are uncomplicated are not considered exclusion criteria.
• BRIGATINIB ARM: Have a known history of human immunodeficiency virus (HIV) infection. Testing is not required in the absence of history
• BRIGATINIB ARM: Have malabsorption syndrome or other gastrointestinal (GI) illness that could affect oral absorption of brigatinib
• BRIGATINIB ARM: Have a known or suspected hypersensitivity to brigatinib or its excipients
• BRIGATINIB ARM: Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of brigatinib
• BRIGATINIB ARM: Received systemic treatment with strong cytochrome P-450 (CYP)3a inhibitors, strong CYP3a inducers, or moderate cyp3a inducers within 14 days before enrollment
• NERATINIB ARM: Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug (if applicable)
• NERATINIB ARM: Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
• NERATINIB ARM: Treatment with any investigational products within 28 days or 5 half-lives (whichever is longer) before the first dose of study drug
• NERATINIB ARM: Had major surgery within 30 days of the first dose of neratinib. Minor surgical procedures such as catheter placement or minimally invasive biopsies are allowed
• NERATINIB ARM: Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: * Myocardial infarction within 6 months before the first dose of neratinib * Unstable angina within 6 months before first dose of neratinib * Congestive heart failure within 6 months before first dose of neratinib * History of clinically significant atrial arrhythmia (including clinically significant bradyarrhythmia), as determined by the treating physician * Any history of clinically significant ventricular arrhythmia * Had a cerebrovascular accident or transient ischemic attack within 6 months before first dose of neratinib. * QTc interval > 0.450 seconds (males) or > 0.470 (females), or known history of QTc prolongation or Torsade de Pointes (TdP)
• NERATINIB ARM: Have a known history of HIV infection. Testing is not required in the absence of history
• NERATINIB ARM: Have malabsorption syndrome or other GI illness that could affect oral absorption of neratinib. Note: This includes any predisposing chronic condition resulting in baseline grade 2 or higher diarrhea
• NERATINIB ARM: History of severe allergic reactions or intolerability attributed to compounds of similar chemical or biologic composition to neratinib
• NERATINIB ARM: Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of neratinib
• NERATINIB ARM: Concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs), including phenytoin, carbamazepine, oxcarbazepine, fosphenytoin, phenobarbital, pentobarbital, or primidone
• NERATINIB ARM: Received systemic treatment with cytochrome P-450 inhibitors or inducers within 14 days before enrollment