Innovative Trial for Understanding the Impact of Targeted Therapies in Neurofibromatosis Type 2, The INTUITT-NF2 Trial
- MASTER STUDY: 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
- MASTER STUDY: Participants 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: * >= 20% increase in volume of enhancing tumor * >= 2 mm increase in greatest linear dimension of enhancing tumor
- MASTER STUDY: Participants must have measurable disease, defined as: * VS, non-VS, or meningioma target lesions that can be accurately measured as >= 1 ml by volumetric magnetic resonance imaging (MRI) scan or in at least one dimension as >=10 mm with conventional MRI scan * Ependymoma target lesions measurable linearly
- MASTER STUDY: 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)
- MASTER STUDY: Life expectancy of greater than 1 year
- MASTER STUDY: For participants 16 or older: Karnofsky performance status >= 70 or Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1; for participants age 12 to < 16: Lansky scale >= 70
- MASTER STUDY: Ability to understand and the willingness to sign written informed consent and assent documents
- MASTER STUDY: Must have established relationship with primary care physician and provide contact information
- BRIGATINIB ARM: Participants must meet all eligibility criteria outlined in the Master Study and complete initial registration
- BRIGATINIB ARM: 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 >= 40 kg on Day 1 of treatment
- BRIGATINIB ARM: Patient must be able to swallow pills
- BRIGATINIB ARM: Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 2.5 x institutional upper limit of normal (ULN) (within 28 days before the first dose of study drug)
- BRIGATINIB ARM: Total serum bilirubin =< 1.5 x institutional ULN (< 3.0 x institutional ULN for patients with Gilbert syndrome) (within 28 days before the first dose of study drug)
- BRIGATINIB ARM: Estimated glomerular filtration rate (eGFR) >= 30 mL/min/1.73 m^2, using the modification of diet in renal disease (MDRD) equation (within 28 days before the first dose of study drug)
- BRIGATINIB ARM: Serum lipase =< 1.5 x institutional ULN (within 28 days before the first dose of study drug)
- BRIGATINIB ARM: Absolute neutrophil count >= 1.5 x 10^9/L (within 28 days before the first dose of study drug)
- BRIGATINIB ARM: Platelet count >= 75 x 10^9/L (within 28 days before the first dose of study drug)
- BRIGATINIB ARM: Hemoglobin >= 9 g/dL (within 28 days before the first dose of study drug)
- BRIGATINIB ARM: It is not known what effects brigatinib 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 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 childbearing 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
- MASTER STUDY: 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)
- MASTER STUDY: Participants who have received radiation to the target tumor within the last 3 years prior to Master study registration
- MASTER STUDY: Participants who are receiving any other investigational agents
- MASTER STUDY: 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
- 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, and/or (b) malignancy was breast or cervical cancer in situ, superficial bladder cancer or basal cell or squamous cell carcinoma of the skin, and malignancy has been treated. Patients who meet the above listed criteria and are only on preventative treatment will be deemed eligible
- MASTER STUDY: 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
- MASTER STUDY: 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
- BRIGATINIB ARM: 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)
- BRIGATINIB ARM: Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
- BRIGATINIB ARM: Treatment with any investigational products within 1 month or 5 half-lives (whichever is longer) before the first dose of study drug
- BRIGATINIB ARM: 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
- BRIGATINIB ARM: Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: * Myocardial infarction within 6 months before the first dose of brigatinib * Unstable angina within 6 months before first dose of brigatinib * Congestive heart failure within 6 months before first dose of brigatinib * 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 brigatinib
- BRIGATINIB ARM: Have uncontrolled hypertension (defined as an average systolic blood pressure > 160 or an average diastolic blood pressure > 100 for adults; for children: please refer below for age-appropriate values indicating >= Grade 2) despite adequate treatment with medications. Patients with hypertension should be under treatment on study entry to control blood pressure * Diastolic blood pressure levels for BOYS aged 12-17 years (Grade 1: ULN diastolic blood pressure [DBP] mmHg; Grade 2: DBP =< 10 mmHg above ULN; Grade 3: DBP > 10 or =< 25 mmHg above ULN; Grade 4: DBP > 25 mmHg above ULN). NOTE: ULN =< 95th percentile for age and 50% height percentile ** Age 12, Grade 1: 80 ** Age 12, Grade 2: 81-90 ** Age 12, Grade 3: 91-105 ** Age 12, Grade 4: 106 ** Age 13, Grade 1: 80 ** Age 13, Grade 2: 81-90 ** Age 13, Grade 3: 91-105 ** Age 13, Grade 4: 106 ** Age 14, Grade 1: 81 ** Age 14, Grade 2: 82-91 ** Age 14, Grade 3: 92-106 ** Age 14, Grade 4: 107 ** Age 15, Grade 1: 82 ** Age 15, Grade 2: 83-92 ** Age 15, Grade 3: 93-107 ** Age 15, Grade 4: 108 ** Age 16, Grade 1: 83 ** Age 16, Grade 2: 84-93 ** Age 16, Grade 3: 94-108 ** Age 16, Grade 4: 109 ** Age 17, Grade 1: 86 ** Age 17, Grade 2: 85-94 ** Age 17, Grade 3: 95-111 ** Age 17, Grade 4: 112 * Diastolic blood pressure levels for GIRLS aged 12-17 years (Grade 1: ULN DBP mmHg; Grade 2: DBP =< 10 mmHg above ULN; Grade 3: DBP > 10 or =< 25 mmHg above ULN; Grade 4: DBP > 25 mmHg above ULN) ** Age 12, Grade 1: 79 ** Age 12, Grade 2: 80-89 ** Age 12, Grade 3: 90-104 ** Age 12, Grade 4: 105 ** Age 13, Grade 1: 80 ** Age 13, Grade 2: 81-90 ** Age 13, Grade 3: 91-105 ** Age 13, Grade 4: 106 ** Age 14, Grade 1: 81 ** Age 14, Grade 2: 82-91 ** Age 14, Grade 3: 92-106 ** Age 14, Grade 4: 107 ** Age 15, Grade 1: 82 ** Age 15, Grade 2: 83-92 ** Age 15, Grade 3: 93-107 ** Age 15, Grade 4: 108 ** Age 16, Grade 1: 83 ** Age 16, Grade 2: 84-93 ** Age 16, Grade 3: 94-108 ** Age 16, Grade 4: 109 ** Age 17, Grade 1: 83 ** Age 17, Grade 2: 84-93 ** Age 17, Grade 3: 94-108 ** Age 17, Grade 4: 109
- BRIGATINIB ARM: Have a history or the presence at baseline of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis
- BRIGATINIB ARM: Have an ongoing or active infection, including, but not limited to, the requirement for intravenous antibiotics. Note: superficial infections that are treated with topical medications or other infections that, in the opinion of the site principal investigator (PI), are uncomplicated are not considered exclusion criteria.
- BRIGATINIB ARM: Have a known history of human immunodeficiency virus (HIV) infection. Testing is not required in the absence of history
- BRIGATINIB ARM: Have malabsorption syndrome or other gastrointestinal (GI) illness that could affect oral absorption of brigatinib
- BRIGATINIB ARM: Have a known or suspected hypersensitivity to brigatinib or its excipients
- BRIGATINIB ARM: Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of brigatinib
- BRIGATINIB ARM: Received systemic treatment with strong cytochrome P-450 (CYP)3a inhibitors, strong CYP3a inducers, or moderate cyp3a inducers within 14 days before enrollment
I. Determine the biological activity of systemic therapies in neurofibromatosis type 2 (NF2)-related tumors.
I. Assess safety and tolerability.
I. Assess hearing response rate (vestibular schwannomas [VS] only).
II. Assess tumor progression.
III. Assess quality of life.
IV. Assess relationship between biomarkers and clinical response.
V. Assess pharmacokinetics (PK).
MASTER STUDY: Patients are first enrolled into the master study and then randomized to a treatment sub-study if eligible. Patients with disease progression on a treatment sub-study may be permitted to enroll in another treatment sub-study if eligible. Patients who are not eligible for enrollment in a different treatment sub-study are permitted to remain under observation on the master study for up to 10 years.
BRIGATINIB SUB-STUDY: Patients receive brigatinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of sub-study treatment, patients are followed up for 4 weeks and then every 6-12 months for up to 10 years.
Trial Phase Phase II
Trial Type Treatment
Dana-Farber Harvard Cancer Center
Scott Randall Plotkin
- Primary ID 19-828
- Secondary IDs NCI-2020-04572
- Clinicaltrials.gov ID NCT04374305