Targeted Therapy for Neurofibromatosis

(INTUITT-NF2 Trial)

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatments for individuals with NF2-related schwannomatosis, a condition that causes tumors in the nervous system. It examines two drugs, brigatinib and neratinib (also known as Nerlynx), to evaluate their effectiveness against these tumors. Individuals with NF2 who have progressive, non-surgically removable tumors might be suitable candidates. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group.

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.

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

Research has shown that brigatinib is generally safe for people with NF2-related schwannomatosis (NF2-SWN). Previous studies found that brigatinib is well-tolerated, meaning patients did not stop treatment due to side effects. It has also effectively reduced the size of various tumors linked to this condition.

For neratinib, safety data from past studies in breast cancer patients indicate it is well-tolerated at doses up to 240 mg per day, which is the highest dose planned in the current trial. However, since these findings are from a different condition, discussing any concerns with a healthcare provider is advisable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about brigatinib and neratinib for treating neurofibromatosis because they offer fresh approaches compared to current options. Unlike standard treatments that primarily focus on managing symptoms, brigatinib and neratinib are targeted therapies. Brigatinib inhibits specific proteins involved in tumor growth, potentially slowing down or stopping the progression of tumors. Neratinib, on the other hand, blocks certain enzymes involved in cell growth, offering a novel method to control tumor development. These unique mechanisms of action could provide more effective and precise treatment options for those with neurofibromatosis.

What evidence suggests that this trial's treatments could be effective for NF2-SWN?

Research has shown that brigatinib, studied in Sub-study A (now closed to enrollment), has promising results in shrinking tumors related to NF2-related schwannomatosis. Specifically, studies found significant reductions in tumor size, particularly in meningiomas, after 12 months of treatment.

Sub-study B of this trial evaluates neratinib, which targets specific DNA changes that can cause tumors to grow. Although less information exists about neratinib for NF2-related tumors, it has proven effective in treating similar conditions by focusing on these genetic changes. This makes neratinib a potentially valuable option for those with tumors linked to these specific mutations. ^{1 2 5 6 7}

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 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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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, 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12012430/

Short‑term efficacy assessment of brigatinib for the treatment ... Their results showed that with brigatinib, significant radiological responses were achieved in multiple types of tumors. Of the target tumors, 10% (95% CI, 3–24 ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40264824/

Short‑term efficacy assessment of brigatinib for the ... A total of 12 patients were enrolled. After 12 months of oral brigatinib therapy, the meningioma volume significantly decreased (P<0.05) at both ...

3. nejm.org nejm.org/doi/abs/10.1056/NEJMoa2400985

Brigatinib in NF2-Related Schwannomatosis with ... Brigatinib treatment resulted in radiographic responses in multiple tumor types and clinical benefit in a heavily pretreated cohort of patients with NF2-SWN.

4. 2minutemedicine.com 2minutemedicine.com/brigatinib-decreases-the-size-of-nf2-related-progressive-tumors/

Brigatinib decreases the size of NF2-related progressive ... In summary, treating progressive tumors in patients with NF2-SWN with brigatinib was an effective and safe way to shrink multiple tumor types.

5. ctf.org ctf.org/news/discovery-to-impact-brigatinib-chapter-published/

How Collaboration Unlocked Brigatinib for NF2-Related ... To test Brigatinib's effectiveness for NF2-SWN patients, a pioneering platform trial model was used – a groundbreaking approach that allows ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04374305

Study Details | NCT04374305 | Innovative Trial for ... SUB-STUDY A (brigatinib) Drug Sub-study A will test the activity of brigatinib for treatment of NF2-related tumors. Brigatinib is approved for the treatment of ...

7. academic.oup.com academic.oup.com/neuro-oncology/article/26/11/1949/7817932

Expanding therapeutic options for people with NF2-related ... Brigatinib was well tolerated by NF2-SWN patients, and none stopped treatment due to toxicity. The INTUITT-NF2 study opens new opportunities for ...