Targeted Therapy for Neurofibromatosis

(INTUITT-NF2 Trial)

Recruiting at 5 trial locations

Overseen By Scott Plotkin, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Scott R. Plotkin, MD, PhD

Must not be taking: Investigational agents, EIAEDs

Disqualifiers: Pregnancy, Cardiovascular disease, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 2 years

100 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a multi-arm phase II platform-basket screening study designed to test multiple experimental therapies simultaneously in patients with NF2-related schwannomatosis (NF2-SWN, formerly known as neurofibromatosis type 2) with associated progressive tumors of vestibular schwannomas (VS), non-vestibular schwannomas (non-VS), meningiomas, and ependymomas. This Master Study is being conducted as a "basket" study that may allow people with multiple tumor types associated with NF2-SWN to receive new drugs throughout this study. Embedded within the Master Study are individual drug substudies. * Investigational Drug Sub-study A: Brigatinib * Investigational Drug Sub-study B: Neratinib

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you have had chemotherapy within 4 weeks before the study or if you are using certain investigational drugs or enzyme-inducing antiepileptic drugs. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug Brigatinib for treating Neurofibromatosis?

Research shows that Brigatinib can shrink tumors in conditions related to Neurofibromatosis Type 2 by blocking certain proteins that help tumors grow. This suggests it might be effective for treating similar tumors in Neurofibromatosis. ^{1 2 3 4 5}

Is Brigatinib safe for humans?

Brigatinib, also known as ALUNBRIG®, is an FDA-approved drug that has been shown to inhibit tumor growth in certain types of tumors. While the study focused on its effectiveness, the fact that it is FDA-approved suggests it has undergone safety evaluations for human use. ^{1 3 6 7 8}

How is the drug Brigatinib unique for treating neurofibromatosis?

Brigatinib is unique because it targets multiple tyrosine kinases, which are proteins involved in cell growth, to shrink tumors in neurofibromatosis type 2, even though these tumors do not express the usual target, ALK. This approach is novel as there are no FDA-approved therapies for these tumors, making Brigatinib a promising option. ^{1 5 9 10 11}

Research Team

Scott Plotkin, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

This trial is for individuals with neurofibromatosis type 2 (NF2) and related progressive tumors like vestibular schwannomas, meningiomas, or ependymomas. Participants must be at least 12 years old, weigh over 40 kg, have a pathogenic NF2 gene variant or meet specific diagnostic criteria, and have measurable disease progression within the last three years. They should not need tumor treatment within six months of joining and must agree to use contraception.

Inclusion Criteria

I am following the required birth control measures.

Patient must be able to swallow pills

I am following the required contraceptive measures.

Exclusion Criteria

I have not had major surgery in the last 30 days.

I do not have any serious illnesses or social situations that would stop me from following the study's requirements.

Treatment with any investigational products within 1 month or 5 half-lives before the first dose of study drug

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to an experimental treatment sub-study, receiving either brigatinib or neratinib, with specific dosing regimens and stages for each sub-study.

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment, including radiographic response rates and adverse events.

2 years

Observation

Participants who are not eligible for further treatment sub-studies remain under observation to understand tumor growth patterns.

Up to 10 years

Treatment Details

Interventions

• Brigatinib
• Neratinib

Trial Overview The INTUITT-NF2 study is testing Neratinib and Brigatinib in separate substudies to see their effects on different types of tumors associated with NF2. It's a phase II trial where patients are given one of these drugs to measure their impact on tumor growth.

Participant Groups

Group I: Sub-study B (neratinib) Experimental Treatment 1 Intervention

The first three participants treated in this arm will receive neratinib 200 mg mg by mouth daily. If these participants tolerate the medication well, subsequent participants will receive neratinib 240 mg by mouth daily.

Group II: Sub-study A (brigatinib) - CLOSED TO ENROLLMENT Experimental Treatment 1 Intervention

Subjects treated in this arm will receive brigatinib 90 mg by mouth daily for 7 days and then increased to 180 mg by mouth daily if the drug is tolerated.

Who Is Running the Clinical Trial?

Scott R. Plotkin, MD, PhD

Lead Sponsor

Trials

1

Recruited

100+

Takeda

Industry Sponsor

Trials

1,255

Recruited

4,219,000+

Dr. Naoyoshi Hirota

Takeda

Chief Medical Officer since 2020

MD from University of Tokyo

Christophe Weber

Takeda

Chief Executive Officer since 2015

PhD in Molecular Biology from Université de Montpellier

The Children's Tumor Foundation

Collaborator

Trials

8

Recruited

20,300+

National Comprehensive Cancer Network

Collaborator

Trials

121

Recruited

7,400+

Findings from Research

Selumetinib, a MEK inhibitor, has shown a remarkable overall response rate of 68% in children with neurofibromatosis type 1 (NF1) and symptomatic inoperable plexiform neurofibromas (PNs), leading to its FDA approval in May 2020.

Other targeted therapies, including cabozantinib and mirdametinib, have also demonstrated efficacy in adults with NF1, indicating a growing range of treatment options for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: a comprehensive review. Solares, I., Viñal, D., Morales-Conejo, M., et al.[2021]

Selumetinib, a MEK inhibitor, has shown significant efficacy in treating plexiform neurofibromas in patients with neurofibromatosis type 1, with 68% of 50 symptomatic patients experiencing a partial response and a median tumor volume reduction of 27.9%.

The treatment demonstrated a favorable safety profile, with manageable adverse effects, and resulted in an 84% estimated progression-free survival at 3 years, marking it as the first FDA-approved therapy for inoperable plexiform neurofibromas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Review of Selumetinib in the Treatment of Neurofibromatosis Type 1-Related Plexiform Neurofibromas. Anderson, MK., Johnson, M., Thornburg, L., et al.[2022]

In a phase II trial involving 19 patients with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs), the MAPK/ERK kinase inhibitor mirdametinib showed a 42% partial response rate after 12 courses, indicating its efficacy in reducing tumor size.

Patients reported significant and durable decreases in pain, suggesting that mirdametinib not only affects tumor volume but also improves quality of life for those suffering from NF1-related PNs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NF106: A Neurofibromatosis Clinical Trials Consortium Phase II Trial of the MEK Inhibitor Mirdametinib (PD-0325901) in Adolescents and Adults With NF1-Related Plexiform Neurofibromas. Weiss, BD., Wolters, PL., Plotkin, SR., et al.[2022]

In a clinical trial, the MEK inhibitor selumetinib showed promising results, inducing partial responses in 70% of children with neurofibromatosis type 1 and inoperable plexiform neurofibromas.

The treatment demonstrated a high progression-free survival rate of 84% after 3 years, indicating its potential efficacy in managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selumetinib Shrinks Tumors in Neurofibromatosis. [2021]

A Phase I study involving 24 healthy male volunteers evaluated a new granule formulation of selumetinib, showing that its absorption is comparable to the existing capsule form, making it a potential alternative for younger patients or those who have difficulty swallowing capsules.

The study found that the granule formulation was well-tolerated with low incidence of mild adverse events, and participants rated its palatability positively, indicating they would be willing to take it again.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I, Open-label, Randomized, Crossover Study of the Relative Bioavailability of Capsule and Granule Formulations of Selumetinib. Cohen-Rabbie, S., Mattinson, A., So, K., et al.[2022]

Selumetinib, a MEK inhibitor, is the first FDA-approved targeted therapy for neurofibromatosis type 1 (NF1), showing efficacy in treating inoperable plexiform neurofibromas, which are common and problematic tumors in NF1 patients.

Research into NF1 has advanced with better understanding of genetic and signaling pathways, leading to promising developments in combination therapies and new animal models that could enhance treatment options for other NF1-related conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurofibromatosis in the Era of Precision Medicine: Development of MEK Inhibitors and Recent Successes with Selumetinib. Galvin, R., Watson, AL., Largaespada, DA., et al.[2022]

References

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

Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK. [2021]

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

Cotargeting Phosphoinositide 3-Kinase and Focal Adhesion Kinase Pathways Inhibits Proliferation of NF2 Schwannoma Cells. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Case Report: Precision Medicine Target Revealed by In Vitro Modeling of Relapsed, Refractory Acute Lymphoblastic Leukemia From a Child With Neurofibromatosis. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Prolonged disease control with MEK inhibitor in neurofibromatosis type I-associated glioblastoma. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: a comprehensive review. [2021]

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

A Review of Selumetinib in the Treatment of Neurofibromatosis Type 1-Related Plexiform Neurofibromas. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Neurofibromatosis Type 1: Pediatric Aspects and Review of Genotype-Phenotype Correlations. [2023]

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

NF106: A Neurofibromatosis Clinical Trials Consortium Phase II Trial of the MEK Inhibitor Mirdametinib (PD-0325901) in Adolescents and Adults With NF1-Related Plexiform Neurofibromas. [2022]

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

Selumetinib Shrinks Tumors in Neurofibromatosis. [2021]

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

A Phase I, Open-label, Randomized, Crossover Study of the Relative Bioavailability of Capsule and Granule Formulations of Selumetinib. [2022]

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

Neurofibromatosis in the Era of Precision Medicine: Development of MEK Inhibitors and Recent Successes with Selumetinib. [2022]