Screening Trial for Pain Relief in Schwannomatosis, STARFISH Trial

Inclusion Criteria

• MASTER: Patients must have a confirmed diagnosis of schwannomatosis by fulfilling diagnostic criteria
• MASTER: A diagnosis of SMARCB1-SWN can be made when an individual meets one of the following criteria: * At least one pathologically confirmed schwannoma or hybrid nerve sheath tumor AND a SMARCB1 pathogenic variant in an unaffected tissue such as blood. * A shared SMARCB1 pathogenic variant in two schwannomas or hybrid nerve sheath tumors.
• MASTER: A diagnosis of LZTR1-SWN can be made when an individual meets one of the following criteria: * At least one pathologically confirmed schwannoma or hybrid nerve sheath tumor AND an LZTR1 pathogenic variant in an unaffected tissue such as blood. * A shared LZTR1 pathogenic variant in two schwannomas or hybrid nerve sheath tumors.
• MASTER: A diagnosis of 22q-related schwannomatosis can be made when an individual does not meet criteria for NF2-related schwannomatosis, SMARCB1-related schwannomatosis, or LTZR1-related schwannomatosis, does not have a germline DGCR8 pathogenic variant and has both of the following molecular features: * Loss of heterozygosity (LOH) of the same chromosome 22q markers in two anatomically distinct schwannomas or hybrid nerve sheath tumors AND. * A different NF2 pathogenic variant in each tumor which cannot be detected in unaffected tissue.
• MASTER: A clinical diagnosis of schwannomatosis-not elsewhere classified (SWN-NOS) is confirmed if the following criteria are met: * Presence of two or more lesions on appropriate imaging consistent with non-intradermal schwannomas, AND * Pathologic confirmation of at least one schwannoma or hybrid nerve sheath tumor.
• MASTER: A clinical diagnosis of schwannomatosis-not elsewhere classified (SWN-NEC) is made if a person fulfills criteria for SWN-NOS AND genetic testing of unaffected tissue and at least 2 anatomically distinct tumors does not reveal a pathogenic variant (PV) in known schwannomatosis-related genes.
• MASTER: Participant must be ≥ 18 years of age on day 1 of treatment
• MASTER: Karnofsky performance status ≥ 70 or Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
• MASTER: 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 within the screening period
• MASTER: Ability to understand and the willingness to sign written informed consent and assent documents
• MASTER: Must have established relationship with primary care physician and provide contact information
• SILTUXIMAB ARM: Participants must be willing and able to provide written informed consent/assent for the siltuximab arm of the STARFISH trial
• SILTUXIMAB ARM: 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
• SILTUXIMAB ARM: Subject must have insufficient response to, intolerance of, be unwilling to try, or contraindication to medical therapies for SWN-related pain, such as nonsteroidal anti-inflammatory drugs (NSAID) therapy, opioid treatment, or neuropathic pain medications
• SILTUXIMAB ARM: Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 2.5 × institutional upper limit of normal (ULN) (within 28 days before the first dose of study drug)
• SILTUXIMAB ARM: Total serum bilirubin ≤ 1.5 × institutional ULN (< 3.0 × institutional ULN for patients with Gilbert syndrome) (within 28 days before the first dose of study drug)
• SILTUXIMAB ARM: Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m^2, using the modification of diet in renal disease (MDRD) equation (within 28 days before the first dose of study drug)
• SILTUXIMAB ARM: Serum lipase ≤ 1.5 × institutional ULN (within 28 days before the first dose of study drug)
• SILTUXIMAB ARM: Absolute neutrophil count ≥ 1.5 × 10^9/L (within 28 days before the first dose of study drug)
• SILTUXIMAB ARM: Platelet count ≥ 75 × 10^9/L (within 28 days before the first dose of study drug)
• SILTUXIMAB ARM: Hemoglobin ≥ 9 g/dL and < 17 g/dL (within 28 days before the first dose of study drug)
• SILTUXIMAB ARM: 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
• ERENUMAB-AOOE ARM: Participants must be willing and able to provide written informed consent/assent for the erenumab-aooe arm of the STARFISH trial
• ERENUMAB-AOOE ARM: Subject must have moderate to severe pain secondary to schwannomatosis, defined as a median NRS-11 score ≥ 5 within the screening period
• ERENUMAB-AOOE ARM: 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
• ERENUMAB-AOOE ARM: ALT/aspartate aminotransferase (AST) ≤ 2.5 × institutional upper limit of normal (ULN) (within 28 days before the first dose of study drug)
• ERENUMAB-AOOE ARM: Total serum bilirubin ≤ 1.5 × institutional ULN (< 3.0 × institutional ULN for patients with Gilbert syndrome) (within 28 days before the first dose of study drug)
• ERENUMAB-AOOE ARM: Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m^2, using the modification of diet in renal disease (MDRD) equation (within 28 days before the first dose of study drug)
• ERENUMAB-AOOE ARM: Serum lipase ≤ 1.5 × institutional ULN (within 28 days before the first dose of study drug)
• ERENUMAB-AOOE ARM: Absolute neutrophil count >= 1.5 x 10^9/L (within 28 days before the first dose of study drug)
• ERENUMAB-AOOE ARM: Platelet count ≥ 75 × 10^9/L (within 28 days before the first dose of study drug)
• ERENUMAB-AOOE ARM: Hemoglobin ≥ 9 g/dL (within 28 days before the first dose of study drug)
• ERENUMAB-AOOE ARM: 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

• MASTER: 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: Participants who are receiving any other investigational agents
• MASTER: 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
• MASTER: 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
• MASTER: 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
• SILTUXIMAB ARM: Subject has a history of allergic or anaphylactic reaction to a therapeutic or diagnostic monoclonal antibody or IgG fusion protein
• SILTUXIMAB ARM: 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
• SILTUXIMAB ARM: Subjects at increased risk for gastrointestinal (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)
• SILTUXIMAB 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
• SILTUXIMAB ARM: Treatment with any investigational products within 1 month or 5 half-lives (whichever is shorter) before the first dose of study drug
• SILTUXIMAB ARM: 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
• SILTUXIMAB ARM: 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
• SILTUXIMAB ARM: 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
• SILTUXIMAB ARM: 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 principal investigator (PI), are uncomplicated are not considered exclusion criteria
• SILTUXIMAB ARM: 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
• SILTUXIMAB ARM: Have a known history of human immunodeficiency virus (HIV) infection. Testing is not required in the absence of history
• SILTUXIMAB ARM: Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of siltuximab
• ERENUMAB-AOOE ARM: Subject has a history of allergic or anaphylactic reaction to a therapeutic or diagnostic monoclonal antibody or IgG fusion protein
• ERENUMAB-AOOE ARM: Have chronic constipation limiting instrumental activities of daily living (e.g., laundry, dressing, shopping, running errands, and transportation)
• ERENUMAB-AOOE ARM: Have uncontrolled hypertension (defined as an average systolic blood pressure > 140 or an average diastolic blood pressure > 90). Patients with pre-existing hypertension should be under treatment on study entry to control blood pressure
• ERENUMAB-AOOE ARM: 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
• ERENUMAB-AOOE 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
• ERENUMAB-AOOE ARM: Treatment with any investigational products within 1 month or 5 half-lives (whichever is shorter) before the first dose of study drug
• ERENUMAB-AOOE ARM: 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
• ERENUMAB-AOOE ARM: 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
• ERENUMAB-AOOE ARM: 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
• ERENUMAB-AOOE ARM: Have a known history of HIV infection. Testing is not required in the absence of history
• ERENUMAB-AOOE ARM: Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of erenumab-aooe
• ERENUMAB-AOOE ARM: 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