DAY101 In Gliomas and Other 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 (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