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.
- - 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.
