Pain, Chronic, Schwannomas, Schwannomatosis
Conditions
Keywords
Schwannomatosis, Schwannomas, Pain, chronic Pain, Severe Pain
Brief summary
This is a placebo-controlled, multi-arm phase II platform screening trial designed to test the safety, pain responses, and pharmacodynamic activity of multiple experimental therapies simultaneously in participants with moderate-to-severe pain due to schwannomatosis (SWN). This Master Study is being conducted as a platform that may allow participants with pain associated with schwannomatosis to receive a novel intervention throughout this study. Embedded within the Master Study are individual drug sub-studies: * Investigational Drug Sub-Study A: Siltuximab * Investigation Drug Sub-Study B: Erenumab-Aooe
Detailed description
This is a placebo-controlled, multi-arm phase II platform screening trial designed to test the safety, pain responses, and pharmacodynamic activity of multiple experimental therapies simultaneously in participants with moderate-to-severe pain due to schwannomatosis (SWN). The MASTER STUDY has no study drug or intervention. It is intended to enroll participants who will be placed into different treatment arms (SUB-STUDIES), which will each have an additional consent and enrollment process. MASTER STUDY * The research study procedures include screening for eligibility, randomization to an experimental treatment sub-study, if qualified, and observation for up to 10 years. * Subjects who complete treatment on one experimental arm will be permitted to enroll in a different experimental treatment arm if they meet eligibility criteria. * Participants who are not eligible for enrollment in a different treatment sub-study will be permitted to remain under observation on this Master Study to understand the natural history of schwannomatosis-related pain and tumor growth pattern. * Participants will be eligible to remain on this Master Study for up to 10 years. * It is expected that about 40 people will take part in the Master Study. * The study will randomize a maximum of 20 participants to each of the experimental arms. The overall size of the trial is not fixed by design because it includes arm-dropping rules for futility and allow for the possibility of arm addition by amendment. * Upon meeting Master Study qualifications, participant will be randomly assigned to a treatment sub-study. SUB-STUDY A - SILTUXIMAB * The purpose of this study is to find out what effects, good and/or bad, siltuximab has on schwannomatosis-associated pain. * The U.S. Food and Drug Administration (FDA) has not approved Siltuximab for schwannomatosis but it has been approved for the treatment of people with multicentric Castleman's disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. * Siltuximab was identified as a potential treatment for schwannomatosis tumors in a screen of compounds in a laboratory. Siltuximab is believed to work by blocking the growth signals and inflammation in tumor cells. * Upon meeting sub-study qualifications, participant will be randomly assigned to either the early-start group or the delayed-start group. * Twenty (20) people will take part in the siltuximab Sub-study. * Participants in the early-start group will receive siltuximab every 3 weeks over 168 days. Participants in the delayed-start group will receive placebo every 3 weeks for the first 84 days followed by siltuximab every 3 weeks over the subsequent 84 days (for a total of 168 days). SUB-STUDY B - ERENUMAB-AOOE * The purpose of this study is to find out what effects, good and/or bad, erenumabaooe has on schwannomatosis-associated pain. * The U.S. Food and Drug Administration (FDA) has not approved Erenumab-Aooe for schwannomatosis but has approved it for treatment of migraines headaches in adults. * Erenumab-Aooe was identified as a potential treatment for schwannomatosis pain. Erenumab-aooe acts by blocking pain signals in the body. By blocking pain signals, erenumabaooe may reduce pain associated with schwannomatosis. * Upon meeting sub-study qualifications, participant will be randomly assigned to either the early-start group or the delayed-start group. * Twenty (20) people will take part in the ERENUMAB-AOOE Sub-study. * Participants in the early-start group will receive erenumab-aooe every 4 weeks over 168 days. Participants in the delayed-start group will receive placebo every 4 weeks for the first 84 days followed by erenumab-aooe every 4 weeks over the subsequent 84 days (for a total of 168 days).
Interventions
DRUGSiltuximab
A chimeric immunoglobulin G mAb, via intravenous infusion.
DRUGErenumab-Aooe
Human monoclonal antibody, single-dose prefilled SureClick® autoinjector, via subcutaneous injection.
DRUGSiltuximab Matching Placebo
Dextrose 5% in water, via intravenous infusion.
DRUGErenumab-Aooe Matching Placebo
0.9% saline, 1 mL single-dose prefilled syringe, via subcutaneous injection.
Sponsors
Massachusetts General Hospital
United States Department of Defense
RECORDATI GROUP
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
(1) Double-Blind period for Siltuximab or Placebo Arm; and (2) Single-Blind period for Erenumab-Aooe or Placebo Arm
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in worst pain intensity for each drug sub-study | Baseline to week 12 | Defined as the change in the worst pain intensity between baseline and day 85. Worst pain is measured using the 11-point Pain Intensity Numerical Rating Scale (NRS), where scores range from 0 (no pain) to 10 (worst pain ever) of the maximum SWN-related pain experienced over the past week |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants with Adverse Events in each drug sub-study | Randomization/1st treatment to 4 weeks post final treatment | Graded according to NCI CTCAE v5.0. All participants will be evaluable for toxicity from the time of first treatment. |
Countries
United States
Contacts
CONTACTScott Plotkin, MD, PhD
CONTACTLei Xu, PhD
PRINCIPAL_INVESTIGATORScott Plotkin, MD
Massachusetts General Hospital
Outcome results
None listed