Screening Trial for Pain Relief in Schwannomatosis (STARFISH)

Inclusion Criteria for Master Study: * Patients must have a confirmed diagnosis schwannomatosis by fulfilling either clinical or molecular diagnosis. * Clinical diagnosis: A clinical diagnosis of schwannomatosis is confirmed by either of the two following criteria: * Two or more non-intradermal schwannomas, one with pathological confirmation, without evidence of bilateral vestibular schwannoma (see exclusion criteria 3.2.3) OR * one pathologically confirmed schwannoma or intracranial meningioma and * An affected first-degree relative. Molecular diagnosis * A molecular diagnosis of schwannomatosis is confirmed by either (1) two or more pathologically proven schwannomas or meningiomas AND genetic studies of at least two tumors with loss of heterozygosity (LOH) for chromosome 22 and two different NF2 mutations; or (2) one pathologically proven schwannoma or meningioma and a germline SMARCB1 or LZTR1 pathogenic mutation. * Participant must be ≥ 18 years of age on Day 1 of treatment. * Karnofsky performance status ≥ 70 or ECOG PS 0 or 1 (see Appendix A). * Subject must have moderate-to-severe pain secondary to SWN, defined as Score ≥5 on the Numeric Rating Scale-11 (NRS-11) as the maximum pain intensity in the previous 7 days. * 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. Inclusion Criteria for Sub-study A - Siltuximab or Placebo Arm: * Participants must be willing and able to provide written informed consent/assent for the siltuximab arm of the STARFISH trial. * Subject must have moderate to severe pain secondary to schwannomatosis, defined as having a median Numeric Rating Scale-11 (NRS-11) score ≥5 during screening. * Subject must have insufficient response to, intolerance of, be unwilling to try, or contraindication to medical therapies for SWN-related pain, such as NSAID therapy, opioid treatment, or neuropathic pain medications. * Clinical laboratory values as specified below within 28 days before the first dose of study drug: * ALT/aspartate aminotransferase (AST) ≤ 2.5 × institutional upper limit of normal (ULN); * Total serum bilirubin ≤ 1.5 × institutional ULN (\<3.0 × institutional ULN for patients with Gilbert syndrome) * Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, using the modification of diet in renal disease (MDRD) equation * Serum lipase ≤1.5 × institutional ULN * Absolute neutrophil count ≥1.5 × 109/L * Platelet count ≥75 × 109/L * Hemoglobin ≥9 g/dL and \<17 g/dL * Female subjects of childbearing potential and at risk for pregnancy (e.g., not abstinent) must agree to use 2 highly effective methods of contraception throughout the study and for 100 days (15 weeks) after the last dose of assigned study medication. * Female subjects of non-childbearing potential must meet at least 1 of the following criteria: * Have undergone documented total hysterectomy or bilateral oophorectomy * Have medically confirmed ovarian failure * Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; \[status may be confirmed with/and have\] a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state; In the event of indeterminate or anomalous results on pregnancy/FSH testing or issues surrounding contraceptive requirements, the study clinician should be contacted and will make the final decision as to the adequacy/need for contraception. Inclusion Criteria for Sub-study B - Erenumab-Aooe or Placebo Arm: * Participants must be willing and able to provide written informed consent/assent for the erenumab-aooe arm of the STARFISH trial. * Subject must have moderate to severe pain secondary to schwannomatosis, defined as a median NRS-11 Score ≥5 during Screening. * Subject must have insufficient response to, unwillingness to take, intolerance of, or contraindication to at least one medical therapies for SWN-related pain, such as NSAID therapy, opioid treatment, or neuropathic pain medications. * Clinical laboratory values as specified below within 28 days before the first dose of study drug: * ALT/aspartate aminotransferase (AST) ≤ 2.5 × institutional upper limit of normal (ULN); * Total serum bilirubin ≤ 1.5 × institutional ULN (\<3.0 × institutional ULN for patients with Gilbert syndrome) * Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, using the modification of diet in renal disease (MDRD) equation * Serum lipase ≤1.5 × institutional ULN * Absolute neutrophil count ≥1.5 × 109/L * Platelet count ≥75 × 109/L * Hemoglobin ≥9 g/dL * Female subjects of childbearing potential and at risk for pregnancy (e.g., not abstinent) must agree to use 2 highly effective methods of contraception throughout the study and for 60 days after the last dose of assigned study medication. * Female subjects of non-childbearing potential must meet at least 1 of the following criteria: * Have undergone documented total hysterectomy or bilateral oophorectomy * Have medically confirmed ovarian failure * Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; \[status may be confirmed with/and have\] a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state; In the event of indeterminate or anomalous results on pregnancy/FSH testing or issues surrounding contraceptive requirements, the study clinician should be contacted and will make the final decision as to the adequacy/need for contraception. Exclusion Criteria for 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). * Participants who are receiving any other investigational agents. * Participants with 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. * History of a malignancy in the last 3 years, unless (a) have been disease-free for at least 2 years or (b) are deemed by the treating investigator to be at low risk for progression or recurrence of that malignancy (e.g., carcinoma in situ, basal cell carcinoma, Gleason 6 prostate cancer) in the next 2 years * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Exclusion Criteria for Sub-study A - Siltuximab or Placebo Arm: * Subject has a history of allergic or anaphylactic reaction to a therapeutic or diagnostic monoclonal antibody or IgG fusion protein. * The subject's pain is related to a non-schwannomatosis cause such as prior cancer therapy, infection, bowel obstruction/perforation, spinal cord compression, or fracture or impending fracture of weight bearing bone. * Subjects at increased risk for GI perforation including documented history of GI perforation, mesenteric ischemia, or intestinal volvulus; or chronic use of high dose glucocorticoids (particularly in combination with NSAIDs) * Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol. * Treatment with any investigational products within 1 month or 5 half-lives (whichever is longer) before the first dose of study drug * Had major surgery within 30 days of the first dose of siltuximab. Minor surgical procedures such as catheter placement or minimally invasive biopsies are allowed. * Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: * Myocardial infarction within 6 months before the first dose of siltuximab. * Unstable angina within 6 months before first dose of siltuximab. * Congestive heart failure within 6 months before first dose of siltuximab. * 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 siltuximab. * Have uncontrolled hypertension (defined as an average systolic blood pressure \> 160 or an average diastolic blood pressure \> 100 for adults) despite adequate treatment with medications. Patients with hypertension should be under treatment on study entry to control blood pressure. * Have an ongoing or active clinically significant 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 PI, are uncomplicated are not considered exclusion criteria. * History of a malignancy in the last 3 years, unless (a) have been disease-free for at least 2 years or (b) are deemed by the treating investigator to be at low risk for progression or recurrence of that malignancy (e.g., carcinoma in situ, basal cell carcinoma, Gleason 6 prostate cancer) in the next 2 years. * Have a known history of HIV infection. Testing is not required in the absence of history. * Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of siltuximab. Exclusion Criteria for Sub-study B - Erenumab-Aooe or Placebo Arm: * Subject has a history of allergic or anaphylactic reaction to a therapeutic or diagnostic monoclonal antibody or IgG fusion protein * Have chronic constipation limiting instrumental activities of daily living (e.g., laundry, dressing, shopping, running errands, and transportation). * Have uncontrolled hypertension (defined as an average systolic blood pressure \> 160 or an average diastolic blood pressure \> 100) despite adequate treatment with medications. Patients with hypertension should be under treatment on study entry to control blood pressure * The subject's pain is related to a non-schwannomatosis cause such as prior cancer therapy, infection, bowel obstruction/perforation, spinal cord compression, or fracture or impending fracture of weight bearing bone. * Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol * Treatment with any investigational products within 1 month or 5 half-lives (whichever is longer) before the first dose of study drug * Had major surgery within 30 days of the first dose of erenumab-aooe. Minor surgical procedures such as catheter placement or minimally invasive biopsies are allowed. * Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: * Myocardial infarction within 6 months before the first dose of erenumab-aooe. * Unstable angina within 6 months before first dose of erenumab-aooe. * Congestive heart failure within 6 months before first dose of erenumab-aooe. * 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 erenumab-aooe. * History of a malignancy in the last 3 years, unless (a) have been disease-free for at least 2 years or (b) are deemed by the treating investigator to be at low risk for progression or recurrence of that malignancy (e.g., carcinoma in situ, basal cell carcinoma, Gleason 6 prostate cancer) in the next 2 years. * Have a known history of HIV infection. Testing is not required in the absence of history. * Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of erenumab-aooe. * Participants who are lactating women are excluded from this study because there are no data on the presence of erenumab-aooe in human milk, the effects on the breastfed infant, or the effects on milk production.