Inclusion Criteria:

• Patients must be ≥ 2 years and ≤ 25 years of age at the time of enrollment on Step 0.
• All patients > 21 years of age at the time of enrollment must have had initial diagnosis of low-grade glioma by 21 years of age. 
• Patient is suspected of having progressive or recurrent low-grade glioma (LGG).
• Patient does not have a known diagnosis of neurofibromatosis type 1 (NF1) or tuberous sclerosis complex (TSC).
• Patient and/or their parents or legal guardians have signed informed consent for eligibility screening on APEC14B1 Part A.

Exclusion Criteria:

• Prior therapy with vinblastine and/or a MEK inhibitor is permitted, with the following exceptions:
  • Patients must not have had progressive disease while on therapy with vinblastine or a MEK inhibitor;
  • Patients must not have discontinued vinblastine or selumetinib due to toxicity.
• Patients with a concurrent malignancy or history of treatment (other than surgery) for another tumor within the last year.
• Patients with diffuse intrinsic pontine tumors as seen on MRI (> 2/3 of pons involvement on imaging) are not eligible even if biopsy reveals Grade I/II histology.
• Patients may not be receiving any other investigational agents.
• Patients must not have known hypersensitivity to selumetinib, vinblastine, or similar compounds.
• CYP3A4 Agents: Patients must not have received fluconazole or drugs that are strong inducers or inhibitors of CYP3A4 within 7 days prior to study enrollment.
• Patients with any serious medical or psychiatric illness/condition, including substance use disorders or ophthalmological conditions, likely in the judgment of the investigator to interfere or limit compliance with study requirements/treatment.
• Patients who, in the opinion of the investigator, are not able to comply with the study procedures.
• Surgery within 2 weeks prior to enrollment, with the exception of a surgical biopsy, placement of a vascular access device or CSF diverting procedure such as endoscopic third ventriculostomy (ETV) and ventriculoperitoneal (VP) shunt.
  • Note: Patients must have healed from any prior surgery.
• Patients who have an uncontrolled infection.
• Female patients who are pregnant are not eligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
• Lactating females who plan to breastfeed their infants.
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for 12 weeks after stopping study therapy.
  • Note: Women of child-bearing potential and males with sexual partners who are pregnant or who could become pregnant (i.e., women of child-bearing potential) should use effective methods of contraception for the duration of the study and for 12 weeks after stopping study therapy to avoid pregnancy and/or potential adverse effects on the developing embryo.