A Phase 2, Open-Label, Multicenter Study to Evaluate the Safety and Efficacy of the Oral Pan-RAF Inhibitor DAY101 in Pediatric Patients with RAF-Altered, Recurrent or Progressive Low-Grade Glioma and Advanced Solid Tumors

1. Patients must be age 6 months to 25 years, inclusive, with:
a) Arm 1 (Low-Grade Glioma): A relapsed or progressive low-grade glioma with a
documented known activating BRAF alteration, as identified through molecular
assays as routinely performed at CLIA or other similarly certified laboratories
b) Arm 2 (Low-Grade Glioma Extension): A relapsed or progressive low-grade
glioma with a documented known or expected to be activating BRAF mutation or
RAF fusion, as identified through molecular assays as routinely performed at
CLIA-certified or other similarly certified laboratories
c) Arm 3 (Advanced Solid Tumor): Locally advanced or metastatic solid tumor with
a documented known or expected to be activating RAF fusion, as identified
through molecular assays as routinely performed at CLIA-certified or other
similarly certified laboratories, that has relapsed or progressed or was
nonresponsive to available therapies and for which no standard or available
systemic curative therapy exists
2. Patients must have histopathologic verification of malignancy at either
original diagnosis
or relapse.
3. Patients must have received at least one line of prior systemic therapy and
have
documented evidence of radiographic progression.
4. Patients must have evaluable and/or measurable disease (imaging must be
performed
within 28 days of the initiation of treatment) as specified below:
a) Arm 1 (Low-Grade Glioma): Must have at least one measurable lesion as defined
by RANO criteria (T1-weighted lesion that can be reproducibly measured in at
least 2 dimensions of at least 10 mm, visible on 2 or more axial slices that
are preferably, at most, 5 mm apart with 0-mm skip)
b) Arm 2 (Low-Grade Glioma Extension): Must have evaluable (either
unidimensionally measurable lesions, masses with margins not clearly defined,
or lesions with maximal perpendicular diameters less than 10 mm) and/or
measurable disease as defined by RANO criteria
c) Arm 3 (Advanced Solid Tumor): Must have at least one measurable lesion as
defined by RECIST v1.1 (>= 10 mm by CT/MRI scan [slice thickness <= 5 mm],
>= 20 mm by chest X-ray, or >= 10 mm with calipers by clinical exam, or
pathologic lymph nodes with a short axis of >= 15 mm by CT scan/MRI)
5. Radiation therapy to the measurable lesion(s) must be completed at least six
months prior
to administration of DAY101. Patients who have documented radiographic
progression less than six months from radiotherapy in one or more measurable
lesions are eligible.
6. Patients must have Karnofsky (those 16 years and older) or Lansky (those
younger than
16 years) performance score of at least 50. Patients who are unable to walk
because of paralysis, but who are able to sit in a wheelchair, will be
considered ambulatory for the purpose of assessing the performance score.
7. Patients must have fully recovered from the acute toxic effects of all prior
anticancer
chemotherapy and have undergone the following washout periods, as applicable:
a) Myelosuppressive chemotherapy: At least 21 days must have elapsed after the
last
dose of myelosuppressive chemotherapy (42 days if prior nitrosourea).
b) Radiation therapy (XRT): At least 14 days must have elapsed after the last
dose
fraction of XRT.
c) Stem cell transplant or adoptive cell therapy: At least 100 days must have
elapsed
after cell infusion.
d) Investigational agent or any other anticancer therapy not defined above: At
least
four weeks prior to planned start of DAY101, or five half-lives, whichever is
shorter.
8. Chronic toxicities from prior anticancer therapy must be stable and at Common
Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade <= 2.
a) Ongoing retinopathy must be <= Grade 1.
9. Patients must have fully recovered from any prior surgery.
10. An archival tumor tissue sample must be available. If an archival tumor
tissue sample is
not available, a fresh biopsy should be performed at baseline. For patients
enrolling to Arm 2 (Low-Grade Glioma Extension) that do not have archival tumor
tissue, enrollment may be considered on a case-by-case basis following a
discussion between the investigator and the Day One Medical Monitor.
11. Patients must have adequate hematologic function, as defined by the
following:
a) Absolute neutrophil count >= 1000/mm3
b) Platelet count >= 75.0 ** 109/L (transfusions allowed per institutional
guidelines;
last transfusion > 2 weeks prior to C1D1)
c) Hemoglobin >= 10.0 g/dL (transfusions allowed per institutional guidelines;
last
transfusion > 4 weeks prior to C1D1)
d) Hematopoietic growth factors: At least 14 days after the last dose of a
long-acting
growth factor (e.g., Neulasta®) or seven days for short-acting growth factor
12. Patients must have adequate hepatic and renal function, defined by the
following:
a) Total bilirubin <= 1.5 ** upper limit of normal (ULN) for age (patients with
documented Gilbert*s Disease may be enrolled with Sponsor approval and total
bilirubin <= 2.0 ** ULN)
b) Serum glutamic-pyruvic transaminase (SGPT)/alanine aminotransferase (ALT)
<= 2.5 ** ULN
c) Serum glutamic-oxaloacetic transaminase (SGOT)/aspartate transaminase (AST)
<= 2.5 ** ULN
d) Serum creatinine within normal limits, or estimated glomerular filtration
rate
>= 60 mL/min/1.73 m2 based on local institutional practice for determination
13. Thyroid function tests must be consistent with stable thyroid function.
Patients on a stable
dose of thyroid replacement therapy for a minimum of three weeks before
starting DAY101 are eligible.
14. Patients must have left ventricular ejection fraction (LVEF) of >= 50% as
measured by
echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan, or fractional
shortening (FS) >= 25% (Tissot et al., 2018) as measured by ECHO, within 28 days
before the first dose of DAY101. If normal practice at the institution is to
provide the LVEF result as a range of values, then the upper value of the range
will be used to determine the result.
15. Patients receiving steroids for tumor-associated symptoms must be on a
stable dose (e.g.,
no initial/loading dose, no increase or decrease) for 14 days prior to C1D1.
16. Patients must be able to comply with treatment, laboratory monitoring, and
required
clinic visits for the duration of study participation.
17. Male and female patients with reproductive potential must be willing to use
a highly
effective birth control method for the duration of treatment and for 180 days
following the last dose of study drug. Highly effective birth control methods
are described in Appendix K.
18. Patients must have ability to swallow tablets or liquid or be willing to
comply with
administration of a nasal or gastric tube for gastric access.
19. Parent/guardian of child or adolescent patient must have the ability to
understand, agree
to, and sign the study ICF and applicable pediatric assent form before
initiation of any protocol-related procedures; patient must have the ability to
give assent, as applicable, at the time of parental/guardian consent.

Patient*s tumor has an additional previously known or expected to be activating
molecular alteration(s) (e.g., histone mutation, IDH1/2 mutations, FGFR
mutations or fusions, MYBL alterations, NF-1 somatic or germline mutations).
2. Patient has symptoms of clinical progression without radiographically
recurrent or
radiographically progressive disease.
Patient has known or suspected diagnosis of neurofibromatosis type 1 (NF-1)
via genetic
testing or current diagnostic criteria.
4. Patient has history of any major disease, other than the primary malignancy
under study,
that might interfere with safe protocol participation.
5. Patient has a history or current evidence of central serous retinopathy
(CSR), retinal vein
occlusion (RVO), or ophthalmopathy present at baseline that would be considered
a risk factor for CSR or RVO. Ophthalmological findings secondary to
long-standing optic pathway glioma (such as visual loss, optic nerve pallor, or
strabismus) will NOT be considered significant abnormalities for the purposes
of this study.
6. Patient has major surgery within 14 days (two weeks) prior to C1D1 (does not
include
central venous access, cyst fenestration or cyst drainage, or
ventriculoperitoneal shunt placement or revision).
7. Patient has clinically significant active cardiovascular disease, or history
of myocardial
infarction, or deep vein thrombosis/pulmonary embolism within six months prior
to C1D1, ongoing cardiomyopathy, or current prolonged QT interval corrected for
heart rate by Fridericia*s formula (QTcF) interval > 470 milliseconds based on
triplicate electrocardiogram (ECG) average.
8. Patient is currently enrolled in any other investigational treatment study.
Participation in
a concurrent observational or bio-sampling study is allowed.
9. Patient has active systemic bacterial, viral, or fungal infection.
10. Patient has nausea and vomiting >= National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE) v5.0 Grade 2, malabsorption
requiring supplementation, or significant bowel or stomach resection that would
preclude adequate absorption of DAY101.
11. Patient is neurologically unstable despite adequate treatment (e.g.,
uncontrolled seizures). 12. Patient is currently being treated with a strong
CYP2C8 inhibitor or inducer other than
those allowed per Section 5.3.2. Medications that are substrates of CYP2C8 are
allowed
but should be used with caution.
13. Patient is pregnant or lactating.
14. Patient has a history of any drug reaction with eosinophilia and systemic
symptoms
(DRESS) syndrome or Stevens Johnsons syndrome (SJS), or hypersensitivity to the
investigational medicinal product or to any drug with similar chemical
structure or to any other excipient present in the pharmaceutical form of the
investigational medicinal product.
15. There are other unspecified reasons that, in the opinion of the
investigator, make the
patient unsuitable for enrollment.