Erenumab + Siltuximab for Schwannomatosis Pain

Overseen By Scott Plotkin, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must not be taking: Investigational agents

Disqualifiers: Chemotherapy, Nervous system tumors, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 24 weeks

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of two experimental treatments: erenumab-aooe (Aimovig, a migraine prevention drug) and siltuximab (Sylvant, an anti-inflammatory drug), for individuals with moderate-to-severe pain from schwannomatosis, a nerve-tumor disorder. The trial aims to assess how well these treatments reduce pain and their mechanisms in the body. Participants will receive either the study drug or a placebo, followed by the actual treatment for all. Those living with schwannomatosis and experiencing persistent, intense pain unresponsive to other treatments might be suitable candidates for this trial. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in pain management.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that erenumab-aooe has been tested in various situations and received FDA approval for treating migraine headaches. Previous studies found it generally safe and well-tolerated over long periods, with some participants experiencing minor side effects. In three-month trials comparing it to a placebo and in one-year studies where participants knew they were receiving the drug, erenumab-aooe maintained a good safety record.

Siltuximab is already approved for conditions other than schwannomatosis and has demonstrated a reliable safety record in long-term studies. Some patients might experience reactions during infusion or allergic responses, but these are uncommon. Trials have treated over 945 patients, with only a few reporting serious issues.

Both treatments have been used safely for other conditions, suggesting they could be well-tolerated for schwannomatosis pain, though individual experiences may vary. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for schwannomatosis pain because they offer new approaches compared to traditional pain management methods, which often include painkillers or anti-inflammatory drugs. Erenumab-aooe is unique because it targets the calcitonin gene-related peptide (CGRP) pathway, a novel mechanism that plays a crucial role in pain transmission, potentially providing relief with fewer side effects. On the other hand, Siltuximab is an antibody that targets interleukin-6, a protein linked to inflammation and pain, offering a different approach to managing the symptoms. These treatments are promising because they address the underlying biological pathways of pain, rather than just masking the symptoms.

What evidence suggests that this trial's treatments could be effective for schwannomatosis pain?

This trial will compare Erenumab-Aooe and Siltuximab for their effectiveness in reducing pain associated with schwannomatosis. Research has shown that Erenumab-Aooe, which participants in this trial may receive, can block pain signals in the body, potentially reducing pain for people with schwannomatosis. In previous studies, patients experienced a noticeable decrease in pain after using Erenumab-Aooe. Meanwhile, Siltuximab, another treatment option in this trial, works by blocking IL-6, a protein that can lead to inflammation and pain in schwannomatosis. This might help reduce tumor growth and inflammation, potentially easing pain. Both treatments show promise, but more research is needed to confirm their effectiveness in relieving pain in schwannomatosis. ^{1 2 6 7 8}

Who Is on the Research Team?

Scott Plotkin, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Erenumab-Aooe
• Siltuximab

Trial Overview 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.

How Is the Trial Designed?

Group I: Sub-study B: Erenumab-Aooe Experimental Treatment 2 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: Siltuximab Experimental Treatment 2 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

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

RECORDATI GROUP

Industry Sponsor

Trials

13

Recruited

4,500+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Recordati Rare Diseases

Industry Sponsor

Trials

14

Recruited

540+

Published Research Related to This Trial

A 62-year-old woman with anti-MAG polyneuropathy and no MYD88 mutation showed significant improvement after 12 months of treatment with venetoclax and rituximab, regaining the ability to walk independently and performing daily tasks.

This case suggests that venetoclax combined with rituximab may be an effective treatment option for patients with anti-MAG neuropathy who do not have the MYD88 mutation, providing a new avenue for therapy in this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The BCL2 Inhibitor Venetoclax Plus Rituximab Is Active in MYD88 Wild-Type Polyneuropathy With Anti-MAG Antibodies. Briani, C., Visentin, A., Castellani, F., et al.[2023]

A 62-year-old woman with anti-MAG polyneuropathy and no MYD88 mutation showed significant improvement after 12 months of treatment with venetoclax and rituximab, regaining the ability to walk independently and performing daily tasks.

This case suggests that venetoclax combined with rituximab may be an effective treatment option for patients with anti-MAG neuropathy who do not have the MYD88 mutation, providing a new avenue for therapy in this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The BCL2 Inhibitor Venetoclax Plus Rituximab Is Active in MYD88 Wild-Type Polyneuropathy With Anti-MAG Antibodies. Briani, C., Visentin, A., Castellani, F., et al.[2023]

In a study of nine patients with schwannomatosis followed for a median of 9.9 years, the clinical outcomes showed that while some patients developed new or residual schwannomas, the overall prognosis was distinct from neurofibromatosis type 2 (NF2).

Histopathological examination revealed that schwannomas in these patients often exhibited features similar to NF2, but no germline mutations of the NF2 gene were found, indicating that schwannomatosis has a different genetic mechanism compared to NF2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple schwannomas: schwannomatosis or neurofibromatosis type 2? Seppälä, MT., Sainio, MA., Haltia, MJ., et al.[2015]

A patient-derived cell line from a schwannomatosis patient was successfully created, demonstrating the feasibility of using precision medicine approaches to develop tailored treatments for rare disorders.

The study identified WP1066, a STAT3 inhibitor, as a promising compound that reduced cell viability and induced cell death in schwannoma cells, suggesting potential for targeted therapy in managing tumor growth in schwannomatosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

WP1066 induces cell death in a schwannomatosis patient-derived schwannoma cell line. Allaf, A., Victoria, B., Rosario, R., et al.[2022]

This phase 2 clinical trial is the first to investigate the safety and efficacy of tanezumab, a monoclonal antibody that inhibits nerve growth factor, for treating chronic pain in patients with Schwannomatosis (SWN), involving 46 participants over a 10-month period.

The study aims to assess the analgesic effects of tanezumab while participants continue their existing pain therapies, and it seeks to establish a framework for future clinical trials in SWN and similar rare diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design of a randomized, placebo-controlled, phase 2 study evaluating the safety and efficacy of tanezumab for treatment of schwannomatosis-related pain. Da, JLW., Merker, VL., Jordan, JT., et al.[2023]

A 71-year-old man with Waldenström macroglobulinemia experienced significant neurological improvement after receiving 6 cycles of bendamustine monotherapy, indicating its efficacy in treating both the cancer and associated neuropathy.

Bendamustine treatment led to normalization of serum IgM levels and substantial reduction of MRI lesions, suggesting it effectively targets the underlying mechanisms of anti-MAG/SGPG neuropathy and Bing-Neel syndrome related to Waldenström macroglobulinemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beneficial Effect of Bendamustine in a Patient with Anti-MAG/SGPG Neuropathy and Bing-Neel Syndrome Associated with Waldenström Macroglobulinemia: A Case Report. Ueki, S., Nakamura, M., Sasaki, R., et al.[2020]

A 53-year-old woman with relapsed lymphoplasmacytic lymphoma developed Bing-Neel syndrome, characterized by neurological symptoms and spinal cord MRI abnormalities, after treatment with R-CHOP.

Treatment with tirabrutinib led to significant improvements in muscle strength and MRI findings within 2 months, suggesting it may be an effective therapy for Bing-Neel syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment with tirabrutinib for relapsed lymphoplasmacytic lymphoma complicated by Bing-Neel syndrome. Saburi, M., Saburi, Y., Kawano, K., et al.[2022]

A 20-year-old male developed sensorimotor axonal polyneuropathy after starting treatment with guselkumab, an IL-23 inhibitor for plaque psoriasis, indicating a potential adverse effect of the medication.

Symptoms improved within 5 months after discontinuing guselkumab, suggesting a possible link between the drug and the neuropathy, although the evidence is not definitive.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axonal sensorimotor polyneuropathy after starting guselkumab. Hamadah, I., Chisti, MA.[2022]

A systematic review identified 38 individuals with sporadic schwannomatosis from 15 studies, highlighting that the average age of affected patients is 48 years, with a predominance of peripheral nerve tumors (33 patients) and spinal tumors (17 patients).

The study found that most tumors were unilateral (83.3%) and often segmental (73.7%), which are important characteristics for diagnosing and classifying this condition in relation to neurofibromatosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sporadic Schwannomatosis: A Systematic Review Following the 2005 Consensus Statement. Chick, G., Victor, J., Poujade, T., et al.[2019]

Research identified that in patients with Schwannomatosis, chronic pain is driven by macrophage influx into dorsal root ganglia, stimulated by HMGB1 secreted from schwannomas, rather than just tumor size or mechanical compression.

Blocking IL-6 significantly reduces pain in these patients, and combining IL-6 and EGFR blockade shows promise in controlling both pain and tumor growth, leading to the initiation of a phase II clinical trial for pain relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Co-Targeting IL-6 and EGFR signaling for the treatment of schwannomatosis and associated pain. Yin, Z., Wu, L., Zhang, Y., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT05684692

Screening Trial for Pain Relief in Schwannomatosis ... Erenumab-aooe acts by blocking pain signals in the body. By blocking pain signals, erenumabaooe may reduce pain associated with schwannomatosis. Upon meeting ...

2. withpower.com withpower.com/trial/phase-2-neurilemmoma-2-2023-7c638

Erenumab + Siltuximab for 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 ...

3. clinicaltrial.be clinicaltrial.be/en/details/188515?per_page=20&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

Screening Trial for Pain Relief in Schwannomatosis (STARFISH) Erenumab-Aooe was identified as a potential treatment for schwannomatosis pain. Erenumab-aooe acts by blocking pain signals in the body. By blocking pain ...

4. cancer.gov cancer.gov/clinicaltrials/NCI-2023-06932

Screening Trial for Pain Relief in Schwannomatosis ... By reducing tumor growth and inflammation, siltuximab may reduce pain associated with schwannomatosis. Erenumab-aooe acts by blocking pain signals in the body.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9635079/

Two-year effectiveness of erenumab in resistant chronic ... Patients had failed a mean of 8.4 preventive treatments at baseline. At month 6, 76 patients (48%) were 30% responders to erenumab, 50 patients ...

6. trialx.com trialx.com/clinical-trials/listings/276195/screening-trial-for-pain-relief-in-schwannomatosis-starfish/

Screening Trial for Pain Relief in Schwannomatosis ... Erenumab-Aooe was identified as a potential treatment for schwannomatosis pain. ... safety or interfere with the evaluation of erenumab-aooe.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6779015/

Long-term safety and tolerability of erenumab: Three-plus year ... Previously published three-month placebo-controlled and one-year open-label clinical trial data have provided information on the efficacy and safety of erenumab ...

8. apps.dtic.mil apps.dtic.mil/sti/trecms/pdf/AD1212458.pdf

Screening Trial for Pain Relief in Schwannomatosis (STARFISH) To determine the safety and tolerability of erenumab-aooe in SWN patients with moderate-to-severe pain. Aim 3: To identify circulating and imaging ...