Erenumab + Siltuximab for Schwannomatosis Pain

Recruiting in Palo Alto (17 mi)

Overseen by Scott Plotkin, MD

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. ^{1 2 3 4 5}

How 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. ^{6 7 8 9 10}

Research Team

Scott Plotkin, MD

Principal Investigator

Massachusetts General Hospital

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.

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

Treatment Details

Interventions

• Erenumab-Aooe (Monoclonal Antibodies)
• Siltuximab (Monoclonal Antibodies)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Dr. William Curry

Massachusetts General Hospital

Chief Medical Officer

MD from Harvard Medical School

Dr. Anne Klibanski

Massachusetts General Hospital

Chief Executive Officer since 2019

MD from Harvard Medical School

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Pete Hegseth

United States Department of Defense

Chief Executive Officer

Bachelor's degree in Political Science from Princeton University, JD from Harvard Law School

Lisa Hershman

United States Department of Defense

Chief Medical Officer since 2021

MD from Uniformed Services University of the Health Sciences

Recordati Rare Diseases

Industry Sponsor

Trials

14

Recruited

540+

Findings from Research

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]

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]

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]

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]

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 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 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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Co-Targeting IL-6 and EGFR signaling for the treatment of schwannomatosis and associated pain. [2023]

2. Germany pubmed.ncbi.nlm.nih.gov

Sporadic Schwannomatosis: A Systematic Review Following the 2005 Consensus Statement. [2019]

3. United States 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. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Multiple schwannomas: schwannomatosis or neurofibromatosis type 2? [2015]

5. United States pubmed.ncbi.nlm.nih.gov

WP1066 induces cell death in a schwannomatosis patient-derived schwannoma cell line. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Axonal sensorimotor polyneuropathy after starting guselkumab. [2022]

7. Switzerland 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. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

The BCL2 Inhibitor Venetoclax Plus Rituximab Is Active in MYD88 Wild-Type Polyneuropathy With Anti-MAG Antibodies. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

The BCL2 Inhibitor Venetoclax Plus Rituximab Is Active in MYD88 Wild-Type Polyneuropathy With Anti-MAG Antibodies. [2023]

10. Japan pubmed.ncbi.nlm.nih.gov

Successful treatment with tirabrutinib for relapsed lymphoplasmacytic lymphoma complicated by Bing-Neel syndrome. [2022]