Recruiting PHASE2 Neurofibromatosis Type 2

New treatment option for Neurofibromatosis Type 2

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

ClinicalTrials.gov ID: NCT04374305

What this study is testing

What is Brigatinib?

Brigatinib is an investigational medicine, given as an once-daily pill taken by mouth, being studied as a potential treatment for neurofibromatosis type 2.

Also referred to as Alunbrig.

Plain-language explanation of the investigational treatment - it is being studied and is not an approved or proven therapy. The study team can confirm the details.

What it's testing: 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.

Phase 2: a mid-size study of how well it works
Time commitment: about 10 years

A plain-language read of the study's public ClinicalTrials.gov listing. The study team confirms the details.

Who can take part

Ages 12 and older

You may be able to join if

Eligibility Specific For MASTER PROTOCOL: \- Patients must have a pathogenic variant in the NF2 gene (either in the germline or in two NF2-related...
Bilateral vestibular schwannomas, OR
First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR two of the following: neurofibroma, meningioma, glioma, schwannoma...
Bilateral vestibular schwannomas, OR
First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR two of the following: neurofibroma, meningioma, glioma, schwannoma...

You likely can't join if

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...
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...
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...
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina...

See the full eligibility criteria

Who can join

Eligibility Specific For MASTER PROTOCOL: \- 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...
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...
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. people must have a target NF2-related tumor (VS, non-VS, meningioma, or ependymoma) with...
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...
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...
Must have established relationship with primary care physician and provide contact information

What rules you out

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...
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...
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...
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...
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...
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...
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...
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 Eligibility Criteria Specific...
Participants must be willing and able to provide written informed consent/assent for the neratinib arm of the INTUITT-NF2 trial.
Participant must be ≥ 12 years of age and have body weight ≥ 40 kg on Day 1 of treatment.
Patient must be able to swallow pills.
Recovery (ie, to Grade 1 or baseline) from all clinically significant AEs related to prior therapies (excluding alopecia, neuropathy, and nail changes).
Clinical laboratory values as specified below within 14 days before the first dose of study drug:
ALT/aspartate aminotransferase (AST) ≤ 2.5 × institutional upper limit of normal (ULN);
Total serum bilirubin ≤ 1.5 × institutional ULN (\<3.0 × institutional ULN for patients with Gilbert syndrome)
Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, using the modification of diet in renal disease (MDRD) equation
Serum lipase ≤1.5 × institutional ULN
Absolute neutrophil count ≥1.5 × 109/L
Platelet count ≥75 × 109/L
Hemoglobin ≥9 g/dL
Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
It is not known what effects neratinib has on human pregnancy or development of the embryo or fetus. Therefore, female patients participating in this study should avoid becoming pregnant, and male patients should avoid...
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...
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.
Female patients must have negative β-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12...
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 28 days 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 neratinib. Minor surgical procedures such as catheter placement or minimally invasive biopsies are allowed.
Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:
Myocardial infarction within 6 months before the first dose of neratinib.
Unstable angina within 6 months before first dose of neratinib.
Congestive heart failure within 6 months before first dose of neratinib.
History of clinically significant atrial arrhythmia (including clinically significant bradyarrhythmia), as determined by the treating physician.
Any history of clinically significant ventricular arrhythmia.
Had a cerebrovascular accident or transient ischemic attack within 6 months before first dose of neratinib.
QTc interval \>0.450 seconds (males) or \>0.470 (females), or known history of QTc prolongation or Torsade de Pointes (TdP)
Have a known history of HIV infection. Testing is not required in the absence of history.
Have malabsorption syndrome or other GI illness that could affect oral absorption of neratinib. Note: This includes any predisposing chronic condition resulting in baseline grade 2 or higher diarrhea
History of severe allergic reactions or intolerability attributed to compounds of similar chemical or biologic composition to neratinib.
Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of neratinib.
Concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs), including phenytoin, carbamazepine, oxcarbazepine, fosphenytoin, phenobarbital, pentobarbital, or primidone
Received systemic treatment with certain cytochrome P-450 inhibitors or inducers within 14 days before enrollment. Enrollment Criteria Specific to SUB-STUDY C (retifanlimab plus bevacizumab arm): Inclusion Criteria
Participants must be willing and able to provide written informed consent/assent for the retifanlimab-bevacizumab arm of the INTUITT-NF2 trial.
Participants must have a target NF2-related tumor (VS, non-VS, meningioma, or ependymoma) with documented radiographic progression within the preceding 36-months.
Age between 12 and 25 years on day 1 of treatment.
Life expectancy of greater than 1 year.
Participants must meet the following organ and marrow function as defined below:
Leukocytes ≥3000/mcL
Platelets ≥100,000/mcL
Total Bilirubin ≤ 1.5 institutional upper limit of normal (ULN), (\<3.0 × institutional ULN for patients with Gilbert Syndrome)
AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN
Urine Protein:Creatinine Ratio ≤ 1.9
Glomerular Filtration Rate (GFR) ≥30 mL/min/1.73 m2
Inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. Therefore, female patients participating in this study should avoid becoming...
Postmenopausal, defined as ≥12 consecutive months of amenorrhea in the absence of endocrine or anti-endocrine therapy, for a minimum of 1 year prior to 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...
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
History of allergic reactions or hypersensitivity attributed to compounds of similar chemical or biologic composition to retifanlimab or bevacizumab
Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period prior to registration.
Treatment with any investigational products or chemotherapy within 28 days or 5 half-lives (whichever is longer) before the first dose of study drug.
Treatment with bevacizumab or any PD-1/PD-L1 inhibitor within 180 days before the first dose of study drug.
Had major surgery within 30 days of the first dose of study drug. Minor surgical procedures such as catheter placement or minimally invasive biopsies are allowed.
Serious or non-healing wound, ulcer, or bone fracture.
History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to Day 1.
Imaging (CT or MRI) evidence of hemorrhage deemed significant by the treating physician (\> grade 1). people with significantly increased risk of CNS hemorrhage are not eligible.
Concurrent use of anti-coagulant drugs (not including prophylactic doses), history of coagulopathy, or evidence of bleeding diathesis or coagulopathy.
Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> Grade 1) with the exception of alopecia.
Evidence of interstitial lung disease, history of interstitial lung disease, or active, noninfectious pneumonitis.
Immune related toxicity during prior checkpoint inhibitor therapy for which permanent discontinuation of therapy was recommended (per product label or consensus guidelines) or any immune-related toxicity requiring...
Active autoimmune disease requiring systemic immunosuppression in excess of physiologic maintenance doses of corticosteroids (\> 10 mg/day of prednisone or equivalent).
Physiologic corticosteroid replacement therapy at doses ≤ 10 mg/day of prednisone or equivalent for adrenal or pituitary insufficiency and in the absence of active autoimmune disease is permitted.
Participants with asthma that requires intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections may participate.
Participants using topical, ocular, intra-articular, or intranasal corticosteroids (with minimal systemic absorption) may participate.
Brief courses of corticosteroids for prophylaxis (eg, contrast dye allergy) or study treatment-related standard premedications are permitted.
Active infections requiring systemic antibiotics or antifungal or antiviral treatment within 10 days before first dose of study treatment.
Has received a live vaccine within 28 days before the planned start of study treatment (with the exception of COVID-19 vaccines). Note: Examples of live vaccines include but are not limited to measles, mumps, rubella...
History of organ transplant, including allogeneic stem cell transplantation.
Clinically significant cardiovascular disease, such as:
Inadequately controlled HTN (defined as an average systolic blood pressure \>160 or an average diastolic blood pressure \> 100 for adult patients ≥ 21 years and as an average systolic BP \> 130 or an average diastolic...
History of CVA within 12 months of registration
Myocardial infarction or unstable angina within 12 months of registration
New York heart association grade II or greater congestive heart failure
Serious and inadequately controlled cardiac arrhythmia
Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection)
Clinically significant peripheral vascular disease

The study team makes the final eligibility decision.

Where it's taking place

Los Angeles, California, United States
Miami, Florida, United States
Indianopolis, Indiana, United States
Baltimore, Maryland, United States
Boston, Massachusetts, United States
New York, New York, United States

Questions & answers

Do participants get paid in this trial?

This listing doesn't specify compensation. Many trials still reimburse travel or offer a stipend, so it's worth asking the study team when you connect.

Is it free to join, and do I need insurance?

Searching and applying through BridgeMD is free. In clinical trials the study-related treatment and visits are generally provided at no cost to you. You usually don't need insurance to take part - confirm specifics with the study team.

How long does this study last?

The study runs about 10 years per participant, based on its public description. The team confirms the exact schedule and number of visits before you enroll.

Who can join this trial?

This study is enrolling all sexes, 12 years and older. The study team makes the final eligibility decision.

Where is this trial taking place?

Study sites include Los Angeles, California, United States; Miami, Florida, United States; Indianopolis, Indiana, United States; Baltimore, Maryland, United States; Boston, Massachusetts, United States; New York, New York, United States. Enter your location above to see the nearest site and check your eligibility.

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BridgeMD is an information and trial-matching tool - not medical advice, and not the study sponsor. Details come from ClinicalTrials.gov; the study team decides eligibility.