Trial Summary
What is the purpose of this trial?This trial is testing two drugs, Siltuximab and Erenumab-Aooe, to see if they can help people with severe pain from schwannomatosis. Siltuximab blocks tumor growth signals, and Erenumab-Aooe blocks pain signals. The trial aims to find out if these drugs can make a difference for people whose pain is hard to treat. Erenumab has been shown to be safe and effective for chronic migraine treatment.
Is the drug Erenumab-Aooe, Siltuximab a promising treatment for Schwannomatosis Pain?The information provided does not directly address the effectiveness of Erenumab-Aooe, Siltuximab for Schwannomatosis Pain, so we cannot determine if it is promising based on this data.4561012
What safety data exists for Erenumab and Siltuximab in treating Schwannomatosis pain?The provided research does not contain specific safety data for Erenumab (Aimovig) or Siltuximab (Sylvant) in the context of treating Schwannomatosis pain. The studies focus on other drugs and conditions, such as multiple sclerosis and neuromyelitis optica spectrum disorder, without mentioning Erenumab or Siltuximab. Therefore, further research specifically targeting these drugs and their use in Schwannomatosis pain is needed to determine their safety profile.278915
What data supports the idea that Erenumab + Siltuximab for Schwannomatosis Pain is an effective drug?The available research does not provide specific data on the effectiveness of Erenumab + Siltuximab for Schwannomatosis Pain. However, it mentions that blocking IL-6, a protein involved in inflammation, can significantly reduce pain in Schwannomatosis, and combining IL-6 and EGFR blockade can control both pain and tumor growth. This suggests that targeting similar pathways might be effective, but direct evidence for Erenumab + Siltuximab is not provided.13111314
Do I need to stop my current medications to join the trial?The trial protocol does not specify if you need to stop your current medications. However, you must have an insufficient response to, intolerance of, or be unwilling to try certain pain medications like NSAIDs, opioids, or neuropathic pain medications. It's best to discuss your current medications with the trial team.
Eligibility Criteria
This trial is for people with schwannomatosis, a condition causing chronic pain due to tumors on nerves. Participants must have at least two non-skin surface tumors, one confirmed by pathology, and no signs of certain other nerve-related tumors.Inclusion Criteria
I have been diagnosed with schwannomatosis.
I have two or more schwannomas, one confirmed by a doctor, and no bilateral vestibular schwannoma.
Treatment Details
The STARFISH trial is testing the safety and pain relief effectiveness of Erenumab-Aooe and Siltuximab against placebos in individuals with schwannomatosis. It's a phase II study where patients are randomly assigned to receive either an experimental therapy or a placebo.
2Treatment groups
Experimental Treatment
Group I: Sub-study B: Erenumab-AooeExperimental Treatment2 Interventions
The treatment period includes a single-blind treatment period (days 1-84) and an open-label treatment period (days 85-168).
All participants will receive erenumab-aooe during this drug sub-study. Twenty (20) participants will receive a randomization assignment to receive either Erenumab-Aooe or matching placebo during the single-blind treatment period. All participants will receive erenumab-aooe during the open-label treatment period. Participants will complete study procedures as outlined:
* Single-Blind treatment period (days 1 - 84): Administration of Erenumab-Aooe versus matching placebo in pre-determined dose once every 28 days (for 3 cycles).
* Open-Label Treatment period (days 85-168): Administration of Erenumab-Aooe in pre-determined dose once every 28 days (for 3 cycles).
Group II: Sub-study A: SiltuximabExperimental Treatment2 Interventions
The treatment period includes a double-blind treatment period (days 1-84) and an open-label treatment period (days 85-168).
All participants will receive siltuximab during this drug sub-study. Twenty (20) participants will be randomized to receive either Siltuximab or matching placebo during the double-blind treatment period. All participants will receive siltuximab during the open-label treatment period. Participants will complete study procedures as outlined:
* Double-Blind Treatment period: Administration of Siltuximab versus matching placebo in pre-determined dose once every 21 days (for 4 cycles).
* Open-Label Treatment period: Administration of Siltuximab in pre-determined dose once every 21 days (for 4 cycles).
Erenumab-Aooe is already approved in United States, European Union, Canada, Japan for the following indications:
🇺🇸 Approved in United States as Aimovig for:
- Migraine prevention
🇪🇺 Approved in European Union as Aimovig for:
- Migraine prevention
🇨🇦 Approved in Canada as Aimovig for:
- Migraine prevention
🇯🇵 Approved in Japan as Aimovig for:
- Migraine prevention
Find a clinic near you
Research locations nearbySelect from list below to view details:
Massachusetts General Hospital Cancer CenterBoston, MA
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Who is running the clinical trial?
Massachusetts General HospitalLead Sponsor
United States Department of DefenseCollaborator
Recordati Rare DiseasesIndustry Sponsor
References
Multiple schwannomas: schwannomatosis or neurofibromatosis type 2? [2015]The aim of this study was to clarify the clinical outcome of schwannomatosis, a rare condition characterized by multiple nonvestibular schwannomas in the absence of meningiomas, intraspinal ependymomas, and other clinical signs of neurofibromatosis type 2 (NF2).
Safety and tolerability of fingolimod in patients with relapsing-remitting multiple sclerosis: results of an open-label clinical trial in Italy. [2019]The safety profile of fingolimod is well established in clinical trials and post-marketing studies. This study aimed to evaluate the safety and tolerability of fingolimod in a cohort of Italian patients with relapsing-remitting multiple sclerosis (RRMS). This is a non-comparative, open-label, multicentre, interventional study conducted in patients with RRMS with no suitable alternative treatment option. Safety and tolerability of fingolimod 0.5 mg were assessed by recording adverse events (AEs) and serious AEs (SAEs). Of the 906 patients enrolled in the study, 91 % of the patients completed the study. AEs and SAEs were reported in 35.4 and 2.9 % of the patients, respectively. Most common AEs reported were headache (4.1 %), influenza (2.1 %), lymphopenia (1.8 %), asthenia (1.8 %) and pyrexia (1.8 %). Increased alanine aminotransferase levels and hypertension were reported as AE in 1.0 and 1.4 % of the patients, respectively. Macular oedema was reported in three patients. These results emphasize the safety of fingolimod in patients representing the real-world clinical practice in the Italian population. Fingolimod was safe and well tolerated in this population, which, compared to those enrolled in pivotal trials in terms of concomitant diseases and used medications, is broader.
Sporadic Schwannomatosis: A Systematic Review Following the 2005 Consensus Statement. [2019]To identify the frequency of reports of sporadic schwannomatosis, the types of patients affected, and the nerves affected.
Beneficial Effect of Bendamustine in a Patient with Anti-MAG/SGPG Neuropathy and Bing-Neel Syndrome Associated with Waldenström Macroglobulinemia: A Case Report. [2020]A 71-year-old man with Waldenström macroglobulinemia (WM) presented with a slowly progressive sensory disturbance and mild weakness predominantly affecting the distal portion of the limbs over the course of 6 months. Cervical magnetic resonance imaging (MRI) showed a long hyperintense lesion at the C1-C4 level. Nerve conduction studies (NCS) revealed prolongation of distal latency, slowed conduction velocity, and conduction block. His serum IgM level was increased, and he was positive for anti-myelin-associated glycoprotein (MAG) and anti-sulfoglucuronyl paragloboside (SGPG) IgM antibodies. Based on the presence of anti-MAG/SGPG antibodies and a single atypical cell with lymphoplasmacytic character in the cerebral spinal fluid, he was diagnosed as having anti-MAG/SGPG neuropathy and Bing-Neel syndrome (BNS) associated with WM. Following 6 cycles of bendamustine monotherapy, the patient's neurological impairment improved; and the serum IgM level became normalized. Furthermore, NCS findings indicated improvement; and the hyperintense lesion on MRI had almost completely disappeared. The present findings suggest that bendamustine monotherapy is effective not only for WM but also for its associated MAG/SGPG neuropathy and BNS.
Axonal sensorimotor polyneuropathy after starting guselkumab. [2022]Guselkumab is an IL-23 inhibitor that binds to the p19 subunit of IL-23 that is highly efficacious and well tolerated for the treatment of moderate-to-severe plaque psoriasis. We report a 20-year-old male who developed sensorimotor axonal polyneuropathy starting treatment with guselkumab, confirmed by neurological examination and serial neurophysiologic studies. His symptoms improved within 5 months of stopping the treatment. The neurophysiologic studies also showed improvement but with continued neuropathy and re-innervation changes on electromyography after about 10 months of stopping treatment. The time line of symptoms and a positive de-challenge are strong but not definitive evidence of guselkumab as a cause.
Successful treatment with tirabrutinib for relapsed lymphoplasmacytic lymphoma complicated by Bing-Neel syndrome. [2022]A 53-year-old woman was diagnosed with lymphoplasmacytic lymphoma (LPL)/Waldenström's macroglobulinemia (WM) in 2008. Six courses of R-COP (rituximab, cyclophosphamide, vincristine, and prednisolone) resulted in complete remission, but LPL/WM relapsed in 2015. After six courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone), the M-peak disappeared, but the patient presented with muscle weakness and sensory disturbance in the lower extremities. No lesions were apparent in the brain parenchyma, but T2-weighted magnetic resonance imaging (MRI) showed a signal-hyperintense area with contrast enhancement in the spinal cord at the C2-4 and Th2-3 levels, and cerebrospinal fluid (CSF) examination showed only a few mononuclear cells. In 2020, the patient started to require walking assistance, and MRI findings worsened. Neurologically, lower limb muscle strength was reduced (manual muscle test score 3), and sensations of touch and pain were about 30% of normal. Vibratory sensation was absent at the knees and medial malleoli, accompanied by dysuria due to neurogenic bladder. CSF cell count was 15/μl (all mononuclear cells). Bing-Neel syndrome (BNS) was diagnosed and tirabrutinib was started. Within 2 months of treatment, lower extremity muscle strength had normalized and MRI findings had improved. Tirabrutinib may offer a promising therapeutic option for BNS.
Adverse events of rituximab in neuromyelitis optica spectrum disorder: a systematic review and meta-analysis. [2022]The adverse events (AEs) of rituximab (RTX) for neuromyelitis optica spectrum disorder (NMOSD) are incompletely understood.
Adverse Drug Reactions with Drugs Used in Multiple Sclerosis: An Analysis from the Italian Pharmacovigilance Database. [2022]Given the importance of inflammation at the onset of multiple sclerosis (MS), therapy is mainly based on the use of anti-inflammatory drugs including disease modifying therapies (DMTs). Considering the recent approval of some DMTs, pharmacovigilance becomes a fundamental tool for the acquisition of new safety data. The aim of the study was to analyze adverse drug reactions (ADRs) related to the use of drugs approved for MS. All national publicly-available aggregated ADR reports recorded from 2002 to 2020 into the Reports of Adverse Reactions of Medicines (RAM) system and all complete Sicilian data reported into the Italian spontaneous reporting system (SRS) database having as suspected drugs interferon β-1a (IFN β-1a), interferon β-1b (IFN β-1b), peginterferon β-1a (PEG-IFN β-1a), glatiramer acetate (GA), natalizumab (NTZ), fingolimod (FNG), teriflunomide (TRF), dimethyl fumarate (DMF), alemtuzumab (Alem), ocrelizumab (OCZ), or cladribine (Cladr), were collected. Descriptive analyses of national, publicly-available aggregated data and full-access regional data were performed to assess demographic characteristics and drug-related variables followed by a more in-depth analysis of all Sicilian ADRs with a case-by-case assessment and a disproportionality analysis of unexpected ADRs. A total of 13,880 national reports have been collected from 2002 to 2020: they were mainly not serious ADRs (67.9% vs. 26.1%) and related to females (71.7% vs. 26.3%) in the age group 18-65 years (76.5%). The most reported ADRs were general and administration site conditions (n = 6,565; 47.3%), followed by nervous (n = 3,090; 22.3%), skin (n = 2,763; 19.9%) and blood disorders (n = 2,180; 15.7%). Some unexpected Sicilian ADRs were shown, including dyslipidemia for FNG (n = 10; ROR 28.5, CI 14.3-59.6), NTZ (n = 5; 10.3, 4.1-25.8), and IFN β-1a (n = 4; 8.7, 3.1-24.1), abortion and alopecia for NTZ (n = 9; 208.1, 73.4-590.1; n = 3; 4.9, 1.5-15.7), and vitamin D deficiency for GA (n = 3; 121.2, 30.9-475.3). Moreover, breast cancer with DMF (n = 4, 62.8, 20.5-191.9) and hypothyroidism with Cladr (n = 3; 89.2, 25.9-307.5) were also unexpected. The reporting of drugs-related ADRs in MS were mostly reported in the literature, but some unknown ADRs were also found. However, further studies are necessary to increase the awareness about the safety profiles of new drugs on the market.
Challenges and Opportunities of Real-World Data: Statistical Analysis Plan for the Optimise:MS Multicenter Prospective Cohort Pharmacovigilance Study. [2022]Optimise:MS is an observational pharmacovigilance study aimed at characterizing the safety profile of disease-modifying therapies (DMTs) for multiple sclerosis (MS) in a real world population. The study will categorize and quantify the occurrence of serious adverse events (SAEs) in a cohort of MS patients recruited from clinical sites around the UK. The study was motivated particularly by a need to establish the safety profile of newer DMTs, but will also gather data on outcomes among treatment-eligible but untreated patients and those receiving established DMTs (interferons and glatiramer acetate). It will also explore the impact of treatment switching.
The BCL2 Inhibitor Venetoclax Plus Rituximab Is Active in MYD88 Wild-Type Polyneuropathy With Anti-MAG Antibodies. [2023]Label="OBJECTIVES">Ibrutinib is active in anti-myelin-associated glycoprotein (MAG) polyneuropathy with MYD88L265P mutation; however, its efficacy is likely to be low in MYD88 wild-type patients. Venetoclax, an oral inhibitor of BCL2, in combination with rituximab is highly active in ibrutinib-resistant hematologic malignancies. We report on the first patient with anti-MAG polyneuropathy and MYD88 wild-type who responded to venetoclax-rituximab.
WP1066 induces cell death in a schwannomatosis patient-derived schwannoma cell line. [2022]Schwannomatosis is a rare genetic disorder that predisposes individuals to development of multiple schwannomas mainly in spinal and peripheral nerves and to debilitating chronic pain often unrelated to any schwannoma. Pathogenic variants of two genes, SMARCB1 and LZTR1, are causal in familial cases. However, many schwannomatosis patients lack mutations in these genes. Surgery is the standard treatment for schwannomas but leaves patients with increasing neurological deficits. Pain management is a daily struggle controlled by the use of multiple analgesic and anti-inflammatory drugs. There is a need for both nonsurgical treatment to manage tumor growth and nonaddictive, nonsedative pain control. Because standard clinical trials are exceedingly difficult for patients with rare disorders, precision medicine approaches offer the possibility of bespoke therapeutic regimens to control tumor growth. As a proof of principle, we obtained a bio-specimen of paraspinal schwannoma from a schwannomatosis patient with a germline point mutation in the SMARCB1/INI gene. We created an hTERT immortalized cell line and tested the ability of targeted small molecules with efficacy in neurofibromatosis type 2-related schwannomas to reduce cell viability and induce cell death. We identified WP1066, a STAT3 inhibitor, currently in phase 2 clinical trials for pediatric and adult brain tumors as a lead compound. It reduced cell viability and STAT-3 phosphorylation and induced expression of markers for both necroptosis and caspase-dependent cell death. The results demonstrate feasibility in creating patient-derived cell lines for use in precision medicine studies.
The BCL2 Inhibitor Venetoclax Plus Rituximab Is Active in MYD88 Wild-Type Polyneuropathy With Anti-MAG Antibodies. [2023]Label="OBJECTIVES">Ibrutinib is active in anti-myelin-associated glycoprotein (MAG) polyneuropathy with MYD88L265P mutation; however, its efficacy is likely to be low in MYD88 wild-type patients. Venetoclax, an oral inhibitor of BCL2, in combination with rituximab is highly active in ibrutinib-resistant hematologic malignancies. We report on the first patient with anti-MAG polyneuropathy and MYD88 wild-type who responded to venetoclax-rituximab.
Design of a randomized, placebo-controlled, phase 2 study evaluating the safety and efficacy of tanezumab for treatment of schwannomatosis-related pain. [2023]Schwannomatosis (SWN) is a rare tumor suppressor syndrome that predisposes affected individuals to develop multiple schwannomas and, less often, meningiomas. The most common symptom is chronic, severe pain. No medications are broadly effective in treating SWN-associated pain. The clinical trial described in this manuscript is a phase 2, randomized, double-blind, placebo-controlled study investigating the safety and efficacy of tanezumab - a humanized monoclonal antibody that inhibits nerve growth factor - for treatment of SWN-related pain. As the first therapeutic trial for SWN-related pain, it also aims to evaluate trial endpoints, understand recruitment patterns, and improve clinical trial design in this rare disease.
Co-Targeting IL-6 and EGFR signaling for the treatment of schwannomatosis and associated pain. [2023]Patients with Schwannomatosis (SWN) overwhelmingly present with intractable, debilitating chronic pain. There are no effective therapies to treat SWN. The drivers of pain response and tumor progression in SWN are not clear. The pain is not proportionally linked to tumor size and is not always relieved by tumor resection, suggesting that mechanisms other than mechanical nerve compression exist to cause pain. SWN research is limited by the lack of clinically-relevant models. Here, we established novel patient-derived xenograft (PDX) models, dorsal root ganglia (DRG) imaging model, and combined with single-cell resolution intravital imaging and RNASeq, we discovered: i) schwannomas on the peripheral nerve cause macrophage influx into the DRG, via secreting HMGB1 to directly stimulate DRG neurons to express CCL2, the key macrophage chemokine, ii) once recruited, macrophages cause pain response via overproduction of IL-6, iii) IL-6 blockade in a therapeutic setting significantly reduces pain but has modest efficacy on tumor growth, iv) EGF signaling is a potential driver of schwannoma growth and escape mechanism from anti-IL6 treatment, and v) combined IL-6 and EGFR blockade simultaneously controlled pain and tumor growth in SWN models. Our findings prompted the initiation of phase II clinical trial ( NCT05684692 ) for pain relief in patients with SWN.
Multiple Cranial Neuropathies Similar to Orbital Apex Syndrome Associated with Pembrolizumab: A Case Report. [2023]Neurotoxicity is one of the more serious immune-related adverse events (irAEs) linked to immune checkpoint inhibitors and calls for prompt diagnosis and treatment. We describe a case of posttreatment anti-programmed death-1 immune checkpoint inhibitor pembrolizumab-induced oculomotor, optic, and trigeminal neuropathy in an 84-year-old female patient with recurrent pulmonary adenocarcinoma. After she received 13 cycles of pembrolizumab, she experienced hyponatremia, anorexia, and right ptosis. There were signs of the suspected irAEs of pembrolizumab, including trigeminal neuropathy, optic neuropathy, and oculomotor neuropathy. Steroid pulse therapy had good results for her neurological findings. We reported this case despite reports of pembrolizumab-induced mononeuropathy of the oculomotor and optic nerves because multiple cranial neuropathies like orbital apex syndrome are thought to be uncommon.