A Phase I Study of Tovorafenib/DAY101 (formerly TAK-580, MLN2480) for Children with Low-Grade Gliomas and Other RAS/RAF/MEK/ERK Pathway Activated Tumors

This research study is studying a drug Tovorafenib/DAY101 (formerly TAK-580, MLN2480) as a
possible treatment a low-grade glioma that has not responded to other treatments.

The name of the study drug involved in this study is:

• Tovorafenib/DAY101 (formerly TAK-580, MLN2480)

Inclusion Criteria:

- Participants must meet the following criteria on screening examination to be eligible
to participate in the study:

- Phase I

- Pediatric patients with radiographically recurrent or radiographically
progressive non-hematologic malignancies (Central Nervous System (CNS) or
solid tumors) associated with activation of the RAS/RAF/MEK/ERK pathway will
be eligible with the exception of patients with NF1.

- Mutational status requires a pathology report, genomic sequencing, or
immunohistochemical report of a mutation or activation of the
RAS/RAF/MEK/ERK pathway.

- The remaining criteria include:

- Patients must be >1 year and <25 years old.

- Patients must have adequate performance status:

- Karnofsky ≥ 50 for patients ≥ 16 years of age (See Appendix A).

- Lansky ≥ 50 for patients < 16 years of age (See Appendix A).

- Patients who are unable to walk because of paralysis, but who are up in a
wheelchair, will be considered ambulatory for the purpose of assessing the
performance score (See Appendix A).

- A patient who has failed standard therapy. Note: standard of care for
resectable low grade glioma, as an example, is surgery. Therefore, patients
with low grade glioma that recurs after presumed gross total resection may
enroll without prior chemotherapy exposure.

- At least 1 measurable lesion that can be reproducibly measured in 2
dimensions

- Previous chemotherapy and hormone therapy (excluding physiologic
replacement) must be completed at least 4 weeks or 4 half-lives, whichever
is longer, prior to administration of DAY101.

- Previous immunotherapy/ monoclonal antibody use must be completed at least 4
weeks or 4 half lives, whichever is longer prior to administration of
DAY101.

- Previous MEK or BRAF inhibitors must be completed at least 7 days prior to
the administration of DAY101.

- Focal or cranial spinal irradiation to the target lesion (whether as
treatment or palliation) must be completed at least 6 months prior to
administration of DAY101 to address the possibility of pseudoprogression. If
pseudoprogression is definitively ruled out with tissue sampling (biopsy or
repeat surgery), the patient may enroll after completion of radiation
therapy at time of defined progression (and not wait 6 months) as long as
patient meets other eligibility requirements.

- All associated toxicities from previous therapies must be resolved to ≤
Grade 1 or considered baseline prior to administration of DAY101.

- Female patients who:

- Are postmenopausal for at least 1 year before the screening visit, OR

- Are surgically sterile, OR

- If they are of childbearing potential, agree to practice 1 effective
method of contraception and 1 additional effective (barrier) method, at
the same time, from the time of signing the informed consent through 90
days (or longer as mandated by local labeling [e.g., United States
Protection and Investigations (USPI), Summary of Product
Characteristics (SmPC), etc,]) after the last dose of study drug, OR

- Agree to practice true abstinence, when this is in line with the
preferred and usual lifestyle of the patient. (Periodic abstinence
[e.g., calendar, ovulation, symptothermal, postovulation methods],
withdrawal, spermicides only, and lactational amenorrhea are not
acceptable methods of contraception. Female and male condoms should not
be used together.)

- Male patients, even if surgically sterilized (i.e., status post-vasectomy),
who:

- Agree to practice highly effective barrier contraception during the
entire study treatment period and through 120 days after the last dose
of study drug, OR

- Agree to practice true abstinence, when this is in line with the
preferred and usual lifestyle of the patient. (Periodic abstinence
[e.g., calendar, ovulation, symptothermal, postovulation methods for
the female partner], withdrawal, spermicides only, and lactational
amenorrhea are not acceptable methods of contraception. Female and male
condoms should not be used together.)

- Agree not to donate sperm during the course of this study or within 120
days after receiving their last dose of study drug

- Patient must be able to swallow pills whole.

- Patient, parent, or legal guardian must be able to understand and be willing
to provide informed consent.

- Thyroid function tests must be consistent with stable thyroid function.
Patients on a stable dose of thyroid replacement therapy for a suggested
minimum of 3 weeks before Cycle 1, Day 1 are eligible.

- Left ventricular ejection fraction (LVEF) of 50% or greater, as measured by
echocardiogram (ECHO) or multiple gated acquisition (MUGA) scan, within 28
days before the first dose of DAY101

- Inclusion of Women, Minorities, and Other Underrepresented Populations: This
protocol is open to males and females of all races. See inclusion criteria
above regarding specific eligibility requirements for female and male
patients of child-bearing or child-fathering potential, respectively.

- Exclusion Criteria: Patients with any of the following characteristics will NOT be
eligible:

- Patients with clinical progression but without radiographically recurrent or
radiographically progressive disease.

- Patients with NF1

- History of any major disease that might interfere with safe protocol
participation, as determined by the investigator

- Patients with 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

--- Patients with history of Drug Rash with Eosinophilia and Systemic Symptoms
(DRESS) or Steven Johnson Syndrome in the setting of prior MEK or BRAF inhibitor
exposure

- Laboratory values:

- Absolute neutrophil count (ANC) ≤ 1000/μL

- Platelet count ≤ 75,000/μL (transfusion independent)

- Hemoglobin < 9 g/dL (hemoglobin may be supported by transfusion,
erythropoietin, or other approved hematopoietic growth factors)

- Serum bilirubin ≥ 1.5 × upper limit of normal (ULN) or ³ 2 ´ ULN if patient
is known to have Gilbert's Disease as the only underlying hepatic disorder

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥ 2.5 ×
ULN. AST and ALT ≥ 5 × ULN for patients with liver metastasis

- Serum creatinine ≥ 2.0 mg/dL

- Current enrollment in any other investigational treatment study

- Evidence of current uncontrolled cardiovascular conditions, including but not
limited to clinically significant cardiac arrhythmias, congestive heart failure,
angina, or myocardial infarction, within the past 6 months

- Active hepatitis or human immunodeficiency virus infection

- Active bacterial or viral infection

- Female patients who are pregnant or currently breastfeeding. Female patients of
childbearing potential must have a negative serum pregnancy test prior to
enrollment.

- Major surgery within 28 days of Day 1 (does not include central venous access or
shunts)

- Inability to comply with study requirements

- Refractory nausea and vomiting, malabsorption, or significant bowel or stomach
resection that would preclude adequate absorption of DAY101

- Treatment with any of the strong CYP2C inducers within 14 days before the first
dose of DAY101 (see Appendix H).

- Treatment with gemfibrozil (strong CYP2C8 inhibitor) within 14 days before the
first dose of DAY101.

- Other unspecified reasons that, in the opinion of the investigator, make the
patient unsuitable for enrollment.

- Important note: The eligibility criteria listed above are interpreted literally
and cannot be waived.