TAK-580 In Gliomas and Other Tumors

This is a Phase I/II clinical trial. A Phase I clinical trial tests the safety of an
investigational drug and also tries to define the appropriate dose of the investigational
drug to use for further studies. "Investigational" means that the drug is being studied.

The U.S. Food and Drug Administration (FDA) has not approved TAK-580 as a treatment for any
disease.

This is the first time that TAK-580 will be given to children. There is limited experience
with TAK-580 in humans.

The purpose of this study is to test the safety TAK-580 in children and adolescent
participants with brain tumors. The investigators want to find out what effects, good and/or
bad, it has on participants and the participant's brain tumor, and find the dose of TAK-580
that is tolerated by participants without too many side effects to use in Phase II of the
study.

Research in the laboratory has shown that TAK-580 may have activity against cancer cells.
TAK-580 belongs to a group of drugs called type II BRAF inhibitors. BRAF abnormalities are
found in cancer cells. There are no type II BRAF inhibitors approved by the FDA for humans at
the time of this study's start. TAK-580 functions by locking the mutant BRAF molecule and the
next molecule in the activation chain together so that the signal that tells the tumor cell
to divide is blocked.

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.

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

- Phase II

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

- Patients with measurable radiographically recurrent or radiographically
progressive disease that is measureable in at least two dimensions on
imaging after standard up-front therapy as defined in the following three
strata below will be eligible:

- Stratum 1: Patients with radiographically recurrent or radiographically
progressive low-grade gliomas with a BRAF KIAA1549 (or similar)
truncated fusion duplication not previously treated with a BRAF or MEK
inhibitor

- Stratum 2: Patients with Neurofibromatosis 1 (NF1) and radiographically
recurrent or radiographically progressive LGG (NF1 may be defined
clinically - see Appendix S - OR genetically) not previously treated
with a BRAF or MEK inhibitor

- Stratum 3: Patients with radiographically recurrent or radiographically
progressive tumors thought to involve the RAS/RAF/MEK/ERK pathway but
not included in Stratum 1 or 2. This includes any radiographically
recurrent or radiographically progressive LGG not included in Stratum 1
or 2 (i.e., any LGG without a BRAF truncated fusion in a patient
without NF1), any CNS tumor other than LGG in a patient with NF1, and
any other CNS or solid tumor (regardless of grade) with a documented
activating BRAF, NRAS, or KRAS mutation

- Tumor tissue for correlative studies is required for all patients except
those with NF1 and LGG (stratum 2) unless surgery was performed prior to
enrollment or any patient with optic pathway glioma (stratum 2 or 3), for
whom tumor tissue is optional

- Patients must have received at least one prior chemotherapy or radiation
regimen prior to radiographic progression.

- Patients for whom tumor biopsy and/or resection is clinically indicated and
who are eligible for and enrolled on the phase II component (any stratum)
will also be eligible for the optional target validation stratum.

- Tumor must be measurable in at least two dimensions on imaging.

- The remaining criteria apply for all phases:

- Patients must be >1 year and <18 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 with low grade glioma who has failed standard therapy.

- 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 TAK-580.

- Previous immunotherapy/ monoclonal antibody use must be completed at least 4
weeks or 4 half lives, whichever is longer prior to administration of
TAK-580. In addition, radiation therapy to the target lesion must be
completed at least 6 months prior to administration of TAK-580. All
associated toxicity from previous therapies must be resolved to ≤ Grade 1 or
considered baseline prior to administration of TAK-580.

- 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 TAK-580

- 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.

- 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

- 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 TAK-580

- Treatment with any of the strong CYP2C inducers within 14 days before the first
dose of TAK-580 (see Appendix H).

- Treatment with gemfibrozil (strong CYP2C8 inhibitor) within 14 days before the
first dose of TAK-580.

- 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.