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
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.
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
