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Pain

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Neurodegenerative Diseases

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Schwannoma

Schwannomatosis

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Antibodies, Monoclonal

Erenumab

Immunoglobulins

Immunoglobulin G

Immunoglobulins, Intravenous

Siltuximab

Calcitonin

Salmon calcitonin

Calcitonin Gene-Related Peptide

Katacalcin

Immunologic Factors

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).

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).

A chimeric immunoglobulin G mAb, via intravenous infusion.

Human monoclonal antibody, single-dose prefilled SureClick® autoinjector, via subcutaneous injection.

Erenumab-Aooe

Dextrose 5% in water, via intravenous infusion.

Siltuximab Matching Placebo

0.9% saline, 1 mL single-dose prefilled syringe, via subcutaneous injection.

Erenumab-Aooe Matching Placebo

Scott Plotkin, MD, PhD

Lei Xu, PhD

Lauren Hibyan, RN

Marie Aste, RN

Scott Plotkin, MD

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

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).

(1) Double-Blind period for Siltuximab or Placebo Arm; and (2) Single-Blind period for Erenumab-Aooe or Placebo Arm

Screening Trial for Pain Relief in Schwannomatosis (STARFISH)

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: \[contact information for Sponsor Investigator or designee\]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

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

Graded according to NCI CTCAE v5.0. All participants will be evaluable for toxicity from the time of first treatment.

United States Department of Defense

Recordati Rare Diseases

Massachusetts General Hospital

Principal Investigator

Spots Global Cancer Trial Database for siltuximab matching placebo