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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.

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.

Oral daily per predetermined dosage per protocol.

Brigatinib

Scott Plotkin, MD

Phioanh (Leia) Nghiemphu, MD

Christine Dinh, MD

Jaishri Blakeley, MD

Scott Plokin, MD

Dusica Babovic-Vuksanovic, MD

Kaleb Yohay, MD

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

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of investigational drugs to learn whether the drug(s) works in treating a specific disease. As a basket study, the trial will enroll patients with NF2-SWN with associated progressive tumors of vestibular schwannomas (VS), non-vestibular schwannomas (non-VS), meningiomas, and ependymomas

The MASTER STUDY is intended to enroll participants who will be allocated into different treatment arms (SUB-STUDIES) which will each have an additional consent and enrollment processes.

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.

* Participants who have tumors grow during a treatment sub-study will be permitted to enroll in a different experimental treatment sub-study if they are eligible.
* Participants who are not eligible for enrollment in a different treatment sub-study will be permitted to remain under observation on the Master Study to understand the growth pattern of these tumors (natural history)

  * Participants will be eligible to remain on this Master study for up to 10 years.
  * It is expected that about 80 people will take part in the Master Study
  * The study will randomize a maximum of 40 patients to each of the experimental arms. The overall size of the trial is not fixed by design because it include arm-dropping rules for futility and allow for the possibility of arm addition by amendment.

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 people with anaplastic lymphoma kinase (ALK)- positive metastatic non-small cell lung cancer (NSCLC) who have progressed or are intolerant to crizotinib. In preclinical models, brigatinib has shown evidence of activity against models of NF2-deficient tumors.
* Forty (40) people will take part in the Brigatinib Sub-study.
* The sub-study with brigatinib includes two stages.
* In Stage 1, 20 subjects with any allowable tumor type will be accrued to each arm. A minimum of 2 subjects per tumor type (vestibular schwannoma, non-vestibular schwannoma, meningioma, and ependymoma) must be accrued in Stage 1. Interim analysis will be performed after Stage 1 to determine the radiographic response rate (RR) for each tumor types. Subsequently, in stage 2, another 20 subjects will be accrued into the 2 baskets with the most promising early results. If the results are equally promising for more than 2 baskets, subjects will be allocated to the appropriate number of baskets.

SUB-STUDY B (neratinib) Collaborator: National Comprehensive Cancer Network (NCCN) through a grant provided by Puma Biotechnology Drug Sub-study B will test the activity of neratinib for treatment of NF2-related tumors.

* Neratinib is approved for the treatment of people with early stage HER2-overexpressed/amplified breast cancer following treatment with trastuzumab-based therapy. In preclinical models, neratinib has shown evidence of activity against models of NF2-deficient tumors.

  - It is expected that 20 people will take part in the Neratinib Sub-study. A minimum of 2 subjects per tumor type (vestibular schwannoma, non-vestibular schwannoma, meningioma, and ependymoma) must be accrued. Analysis will be performed to determine the radiographic response rate (RR) for each tumor types.
* A subset of 5 participants will be enrolled into the PET imaging biomarker study. These participants will have additional PET scans performed just prior to the first dose of neratinib and after starting the treatment (witin 24 to 72 hours).

The study is a platform-basket trial that includes a Master Protocol with embedded Drug Sub-studies. Currently, there are two drug sub-studies: sub-study A (brigatinib) and sub-study B (neratinib). The overall number of arms is not fixed by design because the investigators include arm-dropping rules for futility and allow for the possibility of arm addition by amendment.

Innovative Trial for Understanding the Impact of Targeted Therapies in NF2-Related Schwannomatosis (INTUITT-NF2)

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 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.

Radiographic response rates in target tumors according to tumor-associated criteria:

* VS, non-VS, and meningiomas: Dombi criteria (2013)
* Ependymomas: RECIST 1.12

Number of Participants with Treatment Emergent Adverse Events as Assessed CTCAE v5.0

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Innovative Trial for Understanding the Impact of Targeted Therapies in NF2-Related Schwannomatosis (INTUITT-NF2)	NCT04374305	Neurofibromatos... Vestibular Schw... Non-vestibular ... Meningioma Ependymoma	Brigatinib Neratinib	12 Years -	Massachusetts General Hospital
Innovative Trial for Understanding the Impact of Targeted Therapies in NF2-Related Schwannomatosis (INTUITT-NF2)	NCT04374305	Neurofibromatos... Vestibular Schw... Non-vestibular ... Meningioma Ependymoma	Brigatinib Neratinib	12 Years -	Massachusetts General Hospital

Spots Global Cancer Trial Database for neurofibromatosis type 2 (nf2)