Inclusion Criteria:
Cohort A Only:
- - Patients with histologically confirmed diagnosis of pediatric high- or low-grade
glioma harboring a KIAA1549-BRAF fusion: Low-grade glioma that is recurrent or
progressive OR High-grade glioma that is newly diagnosed or recurrent OR.
- - Patients with NF1-associated gliomas or NF1-altered glioma: Low-grade glioma that is
recurrent or progressive OR High-grade glioma that is newly diagnosed or recurrent
OR Transforming glioma that is newly diagnosed or recurrent.
Cohort B Only:
- - Patients with histologically confirmed diagnosis of pediatric low-grade glioma
harboring a BRAFV600 mutation that is recurrent or progressive OR.
- - Patients with histologically confirmed diagnosis of non-brainstem pediatric
high-grade glioma harboring BRAFV600 mutation that is newly diagnosed, recurrent, or
progressive.
All Cohorts:
- - Patients must be ≥1 and ≤26 years of age at the time of enrollment.
- - Patients must have a performance status of Karnofsky >50% for patients >16 years old
and Lansky >50% for patients <16 years old.
- - Patients must have adequate organ and bone marrow function.
- - The effects of dabrafenib, trametinib, and nivolumab on the developing human fetus
are unknown.
For this reason, patients of childbearing potential (POCBP) and
patients with sperm-producing reproductive capacity (PWSPRC) must agree to use
adequate contraception (hormonal or barrier method of birth control; abstinence)
from time of informed consent for the duration of study participation and for 30
days following completion of therapy. POCBP must have a negative pregnancy test.
- - Patients with neurological deficits that are stable for a minimum of 1 week prior to
enrollment are eligible.
Note: A baseline detailed neurological exam should clearly document the neurological
status of the patient at the time of enrollment on the study.
- - Patients who are receiving dexamethasone must be on a stable or decreasing dose for
at least 1 week prior to enrollment.
Total dexamethasone dose at time of enrollment
must be less than or equal to 2 mg/day total or 0.5 mg/kg/day, whichever is smaller.
LGG Only.
- - Patients must have received a prior BRAF inhibitor (first or second generation), MEK
inhibitor, or a combination.
The response to this therapy must be known and
information provided at study enrollment.
- - Patients must have recovered from acute treatment-related toxicities (defined as
HGG Only.
- - Patients must have received prior radiotherapy >12 weeks prior to enrollment.
- - Patients must have recovered from acute treatment-related toxicities (defined as
- - NF1 patients with transforming gliomas and high-grade gliomas are eligible
regardless of prior systemic therapy.
- - Patients who have received prior radiation therapy must have experienced progression
post-radiation OR have measurable disease defined as residual tumor >1cm in at least
one dimension.
Exclusion Criteria:
- - Patients with disseminated disease.
- - Patients who have had prior radiation therapy <12 weeks prior to registration.
- - Patients 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).
- - Patients who receiving any other investigational agents.
Note: There will be a
21-day washout period for all chemotherapeutic agents, a washout period of two
half-lives for any targeted agents (e.g., MAPK inhibitors), and/or a washout period
of 4 weeks for any antibody therapies (e.g., bevacizumab).
- - Patients who have a history of allergic reactions attributed to compounds of similar
chemical or biological composition to dabrafenib, trametinib, or nivolumab.
- - Patients who have received MAPK inhibitor and checkpoint blockade combination
therapy.
Note: Patients may have received MAPK inhibitor monotherapy or checkpoint blockade
monotherapy.
- - Patients who previously discontinued BRAF inhibitor (type 1 inhibitor or dimer
inhibitor, such as, DAY101), MEK inhibitor, or the combination because of grade 3 or
higher toxicity or clinically significant grade 2 toxicity requiring discontinuation
of therapy are not eligible.
- - Patients with the following:
- Known autoimmune disorders.
- - Patients with Crohn's disease, ulcerative colitis, or other inflammatory bowel
disease.
- - Patients with active pancreatitis or history of pancreatitis within the last 3
months.
- - Patients with active interstitial lung disease (ILD)/pneumonitis or a history of
ILD/pneumonitis requiring treatment with systemic steroids.
- - Patients who have a known active Human Immunodeficiency Virus (HIV), Hepatitis B, or
Hepatitis C infection are ineligible.
Patient must have documented evidence of
negative tests for the presence of HIV, Hepatitis B surface antigen, and Hepatitis C
(anti-HCV antibody OR Hep C RNA-qualitative).
- - Patients who have received a major surgical procedure ≤ 28 days of beginning study
treatment, or minor surgical procedures (including VP shunt placement or
stereotactic biopsy of the tumor) ≤ 7 days are not eligible.
- - Patients who are taking herbal preparations.
These medications include but are not
limited to St. John's wort, kava, ephedra (ma hung), gingko biloba,
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Cannabis products
of any type are not allowed throughout the study. Patients should stop using these
herbal medications or cannabis products 7 days prior to enrollment.
- - Patients who are pregnant.
Patients of childbearing potential must have a negative
serum or urine pregnancy test. (If the urine test is positive or cannot be confirmed
as negative, a serum pregnancy test will be required.)
- - Patients who are lactating (unless they have agreed to not breastfeed).
Breastfeeding patients are excluded from this study due to risks of fetal and
teratogenic adverse events as seen in animal/human studies.
- - Patients with any clinically significant unrelated systemic illness (serious
infections or significant cardiac, pulmonary, hepatic, or other organ dysfunction),
that in the opinion of the investigator would compromise the patient's ability to
tolerate protocol therapy, put them at additional risk for toxicity or would
interfere with the study procedures or results.
- - Patients with a prior or concurrent malignancy whose natural history or treatment
has the potential to interfere with the safety or efficacy assessment of the
investigational regimen for this trial.
- - Patients with bulky tumor on imaging are ineligible.
Bulky tumor is defined as:
- - Tumor with any evidence of clinically significant uncal herniation or midline
shift.
- - Tumor with diameter of >5cm in one dimension on T2/FLAIR except for those
patients with newly diagnosed HGG treated following irradiation without signs
of tumor progression.
For the latter group, a maximum diameter of contrast
enhancing solid or necrotic tumor and of T2/FLAIR abnormality will be 5 cm and
8 cm, respectively.
- - Tumor that in the opinion of the site investigator, shows significant mass
effect.
- - Metastatic disease: Patients with ≤ 5 separate foci of metastatic disease not
causing mass effect on adjacent parenchyma and each measuring less than 0.5 cm
in maximum diameter will be eligible for this arm of the study.
Patients with
leptomeningeal disease are eligible.
- - Multi-focal disease (patients with multi-focal parenchymal disease will be
eligible if the sum of the product of the maximum perpendicular diameters of
all measurable non-contiguous lesions is less than 16 cm2 based on the T2/FLAIR
abnormality).
