Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04374305
Recruitment Status : Recruiting
First Posted : May 5, 2020
Last Update Posted : April 27, 2021
Sponsor:
Collaborators:
Takeda
The Children's Tumor Foundation
Information provided by (Responsible Party):
Scott R. Plotkin, MD, PhD, Massachusetts General Hospital

Brief Summary:

This is a multi-arm phase II platform-basket screening study designed to test multiple experimental therapies simultaneously in patients with neurofibromatosis type 2 (NF2) 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 to receive new drugs throughout this study. Embedded within the Master Study are individual drug substudies.

- Investigational Drug Sub-study A: Brigatinib


Condition or disease Intervention/treatment Phase
Neurofibromatosis Type 2 Vestibular Schwannoma Non-vestibular Schwannoma Meningioma Ependymoma Drug: Brigatinib Phase 2

Detailed Description:

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.

The Master study is intended to enroll participants who will be placed into different treatment arms (sub-studies) which will each have an additional consent and enrollment processes.

-- 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.

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.

    - It is expected that 40 people will take part in the Brigatinib Sub-study.

  • The sub-study with brigatinib will include 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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: The study is a platform trial that includes a Master Protocol with embedded Drug Sub-studies. Initially, there is 1 drug substudy of brigatinib. 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.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Innovative Trial for Understanding the Impact of Targeted Therapies in NF2 (INTUITT-NF2)
Actual Study Start Date : June 20, 2020
Estimated Primary Completion Date : December 1, 2029
Estimated Study Completion Date : December 1, 2030


Arm Intervention/treatment
Experimental: Brigatinib Sub-Study
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.
Drug: Brigatinib
Oral daily per predetermined dosage per protocol.
Other Name: Alunbrig




Primary Outcome Measures :
  1. Radiographic response rate (for each drug substudy) [ Time Frame: 2 years ]

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

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


Secondary Outcome Measures :
  1. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability [ Time Frame: 2 years ]
    Number of Participants with Treatment Emergent Adverse Events as Assessed CTCAE v5.0



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Eligibility Specific For Master Protocol:

Inclusion Criteria:

- Patients must have a pathogenic variant in the NF2 gene (either in the germline or in two NF2-related tumors) OR a confirmed diagnosis of NF2 by fulfilling National Institute of Health (NIH) criteria or Manchester criteria:

The NIH criteria includes presence of:

  • Bilateral vestibular schwannomas, OR
  • First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity.

The Manchester criteria includes presence of:

  • Bilateral vestibular schwannomas, OR
  • First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, OR
  • Unilateral vestibular schwannoma AND any two of: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, OR
  • Multiple meningiomas (two or more) AND unilateral vestibular schwannoma OR any two of: schwannoma, glioma, neurofibroma, cataract.

Subjects must have a target NF2-related tumor (VS, non-VS, meningioma, or ependymoma) with documented radiographic progression within the preceding 36 months of Master Study registration defined as either:

  • at least 20% increase in volume of enhancing tumor
  • at least 2 mm increase in greatest linear dimension of enhancing tumor

Participants must have measurable disease, defined as:

  • VS, non-VS, or meningioma target lesions that can be accurately measured as at least 1 ml by volumetric MRI scan or in at least one dimension as ≥10 mm with conventional MRI scan. See protocol for the evaluation of measurable disease
  • Ependymoma target lesions measurable linearly.

Participant must have a target NF2-related tumor with the following qualities:

  • Not amenable to surgery due to patient refusal or due to high risk for surgical complications (e.g., damage to nerve function). Participant must be ≥ 12 years of age on Day 1 of treatment. Life expectancy of greater than 1 year Karnofsky performance status ≥ 70 or ECOG PS 0 or 1 (see Appendix A). Ability to understand and the willingness to sign written informed consent and assent documents.
  • Must have established relationship with primary care physician and provide contact information

Exclusion Criteria:

  • Participants who have had chemotherapy within a minimum of 4 weeks prior to Master Study registration (or a minimum of 5 half-lives and resolution to baseline of toxicities unless there are irreversible toxicities from prior drug that do not influence risk of next drug).
  • Participants who have received radiation to the target tumor within the last 3 years prior to Master study registration.
  • Participants who are receiving any other investigational agents.
  • Participants with target or non-target nervous system tumors that, in the opinion of the treating investigator, are likely to require active treatment (including surgery) within 6 months of registration to the Master Study.
  • History of a different malignancy, unless (a) have been disease-free for at least 2 years and are deemed by the treating investigator to be at low risk for recurrence of that malignancy.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant women are excluded from this study because the experimental agents may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these experimental agents, breastfeeding should be discontinued if the mother is treated.

Eligibility Criteria Specific to the Brigatinib Arm (substudy A):

Inclusion criteria

  • Participants must meet all eligibility criteria outlined in the Master Study
  • Participants must be willing and able to provide written informed consent/assent for the brigatinib arm of the INTUITT-NF2 trial.
  • Participant is ≥ 12 years of age and has body weight at least 40 kg on Day 1 of treatment.
  • Patient must be able to swallow pills.
  • Clinical laboratory values as specified below within 28 days before the first dose of study drug, as described in the protocol document:
  • Female patients participating in this study should avoid becoming pregnant, and male patients should avoid impregnating a female partner. Non-sterilized female patients of reproductive age group and male patients should use effective methods of contraception through defined periods during and after study treatment as specified below:

Female patients must meet 1 of the following:

  • Postmenopausal for at least 1 year before the screening visit, or
  • Surgically sterile, or
  • If they are of childbearing potential, agree to practice 2 effective methods of contraception from the time of signing of the informed consent form through 4 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse. Brigatinib may decrease effectiveness of hormonal contraceptives, therefore, women are recommended to use non-hormonal methods of contraception. Highly effective non-hormonal birth control for women of child bearing potential with male partners includes:

    • Sexual abstinence (no sexual intercourse)
    • Intrauterine device (IUD) or intrauterine system (IUS)
    • Bilateral tubal ligation (both tubes tied)
    • Vasectomized partner

Male patients, even if surgically sterilized (i.e., status post-vasectomy) must agree to 1 of the following:

- Practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or completely abstain from heterosexual intercourse.

Exclusion criteria:

  • Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug (if applicable)
  • Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
  • Treatment with any investigational products within 1 month or 5 half-lives (whichever is longer) before the first dose of study drug
  • Had major surgery within 30 days of the first dose of brigatinib. Minor surgical procedures such as catheter placement or minimally invasive biopsies are allowed.
  • Have significant, uncontrolled, or active cardiovascular disease (as outlined in the protocol):
  • Have uncontrolled hypertension (defined as an average systolic blood pressure >160 or an average diastolic blood pressure >100 for adults; for children: please refer to table in protocol

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04374305


Contacts
Layout table for location contacts
Contact: Scott Plotkin, MD 617-724-8770 splotkin@partners.org

Locations
Layout table for location information
United States, California
UCLA Medical Center Recruiting
Los Angeles, California, United States, 90095
Contact: Phioanh (Leia) Nghiemphu, MD       PNghiemphu@mednet.ucla.edu   
Principal Investigator: Phioanh (Leia) Nghiemphu, MD         
United States, Maryland
Johns Hopkins Hospital Recruiting
Baltimore, Maryland, United States, 21287
Contact: Jaishri Blakeley, MD       jblakel3@jhmi.edu   
Principal Investigator: Jaishri Blakeley, MD         
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Scott Plotkin, MD    617-724-8770    splotkin@partners.org   
Principal Investigator: Scott Plokin, MD         
United States, Minnesota
Mayo Clinic Hospital - Rochester Recruiting
Rochester, Minnesota, United States, 55905
Contact: Dusica Babovic-Vuksanovic, MD       dbabovic@mayo.edu   
Principal Investigator: Dusica Babovic-Vuksanovic, MD         
United States, New York
New York University Langone Medical Center Recruiting
New York, New York, United States, 10016
Contact: Kaleb Yohay, MD       Kaleb.Yohay@nyulangone.org   
Principal Investigator: Kaleb Yohay, MD         
Sponsors and Collaborators
Scott R. Plotkin, MD, PhD
Takeda
The Children's Tumor Foundation
Investigators
Layout table for investigator information
Principal Investigator: Scott Plotkin, MD Massachusetts General Hospital
Layout table for additonal information
Responsible Party: Scott R. Plotkin, MD, PhD, Sponsor Investigator, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT04374305    
Other Study ID Numbers: 19-828
First Posted: May 5, 2020    Key Record Dates
Last Update Posted: April 27, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Data can be shared no earlier than 1 year following the date of publication
Access Criteria: MGH - Contact the Partners Innovations team at http://www.partners.org/innovation

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Scott R. Plotkin, MD, PhD, Massachusetts General Hospital:
neurofibromatosis type 2 (NF2)
vestibular schwannomas (VS)
non-vestibular schwannomas (non-VS)
meningioma
ependymoma
Additional relevant MeSH terms:
Layout table for MeSH terms
Ependymoma
Meningioma
Neurofibromatoses
Neurofibromatosis 1
Neurofibroma
Neurilemmoma
Neuroma, Acoustic
Neurofibromatosis 2
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Vascular Tissue
Meningeal Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Nervous System Diseases
Nerve Sheath Neoplasms
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Peripheral Nervous System Diseases
Neuromuscular Diseases