Eligible patients will receive TAK-580 once weekly by mouth. One course is 28 days. Subsequent courses will immediately follow, with no break in the administration of the drug.

The RAS/RAF/MEK/ERK pathway is implicated in a number of adult cancers and NF1-associated tumors. Similarly, the majority of pediatric LGGs possess abnormal signaling through the RAS/RAF/MEK/ERK pathway as do a variety of other CNS tumor types including high grade glioma, pleomorphic xanthoastrocytoma and ganglioma. Complete resection is often not feasible and currently available therapies have limited efficacy, leading to an increased morbidity for these patients. More effective therapies using novel mechanisms of action are needed.

PRIMARY OBJECTIVE

To determine the maximal tolerated dose (MTD) or proposed recommended phase II dose (RP2D) of TAK-580 administered on a continuous, once weekly dosing schedule, in children and adolescents (>1 year and <18 years) with radiographically recurrent or radiographically progressive tumors after standard therapy.

SECONDARY OBJECTIVE

To characterize the safety and tolerability of TAK-580 in children and adolescents (>1 year and <18 years) with advanced solid tumors; (b) To assess pharmacokinetic profile of TAK-580 and its metabolites when administered to children and adolescents (>1 year and <18 years) with radiographically recurrent or radiographically progressive tumors; (c) To assess any preliminary antitumor activity of TAK-580 in children and adolescents (>1 year and <18 years) with advanced solid tumors.

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 (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 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 ≥ to 16 years of age.
    • Lansky ≥ 50 for patients < 16 years of age.
• 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.
• 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., USPI, 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 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 CSR (central serous retinopathy), RVO (rential vein occlusion), 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.
• 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.

Funding is provided by A Kids Brain Tumor Foundation (aka The PLGA Foundation), Team Jack Foundation, and Takeda.