Erenumab + Siltuximab for Schwannomatosis Pain
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Massachusetts General Hospital
Must not be taking: Investigational agents
Disqualifiers: Chemotherapy, Nervous system tumors, others
No Placebo Group
Prior Safety Data
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.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, it mentions that participants must have an insufficient response to, intolerance of, or unwillingness to try certain pain medications, which suggests that some current medications might be continued if they are not effective. It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the drugs Erenumab-Aooe, Aimovig, Siltuximab, and Sylvant for treating Schwannomatosis pain?
Research suggests that blocking IL-6, a protein involved in inflammation, can significantly reduce pain in Schwannomatosis, and combining IL-6 blockade with other treatments may help control both pain and tumor growth. Siltuximab, one of the drugs in the trial, is known to block IL-6, which may contribute to its effectiveness in managing Schwannomatosis pain.
12345How is the drug Erenumab + Siltuximab unique for treating Schwannomatosis pain?
Erenumab + Siltuximab is unique because it combines two drugs that target different pathways: Erenumab blocks a protein involved in migraine pathways, while Siltuximab targets a protein involved in inflammation. This combination may offer a novel approach for managing pain in Schwannomatosis, a condition with no standard treatment.
678910Eligibility 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.
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants are randomized to receive either Siltuximab or Erenumab-Aooe, with a placebo-controlled period followed by an open-label period
24 weeks
Every 3 weeks for Siltuximab, every 4 weeks for Erenumab-Aooe
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Long-term Observation
Participants may remain under observation to understand the natural history of schwannomatosis-related pain and tumor growth pattern
Up to 10 years
Participant Groups
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
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.