Title
A Phase 3 Randomized Non-Inferiority Study of Carboplatin and Vincristine versus Selumetinib (NSC# 748727, IND# 77782) in Newly Diagnosed or Previously Untreated Low-Grade Glioma (LGG) not associated with BRAFV600E Mutations or Systemic Neurofibromatosis Type 1 (NF1)

Description
A Phase 3 Randomized Non-Inferiority Study of Carboplatin and Vincristine versus Selumetinib in Newly Diagnosed or Previously Untreated Low-Grade Glioma (LGG) not associated with BRAFV600E Mutations or Systemic Neurofibromatosis Type 1

Objective
This study looks at how well a drug called selumetinib works when given to children and young adults with Low Grade Glioma(LGG). Selumetinib is a drug that works by blocking a protein (a basic building block of the human body) that lets cancer cells grow without stopping. Early studies have shown that selumetinib was successful in treating patients with LGG that came back after a first attempt at treatment. However, the use of selumetinib in patients with previously-untreated LGG is considered experimental because selumetinib has not yet been FDA approved for this type of cancer

Treatment
Arm 1: Carboplatin and Vincristine which is standard therapy for people with Low Grade Glioma(LGG). For subjects getting Carboplatin and Vincristine the treatment on this study takes about 15 months.

Arm 2 is Selumetinib, which is an experimental therapy for people with Low Grade Glioma(LGG). For subjects getting Selumetinib, the treatment on this study takes about 27 months

Key Eligibility
Must have non-neurofibromatosis type 1 (non-NF1) low-grade glioma (LGG) without a BRAFV600E mutation as confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1 and that has not been treated with any modality besides surgery. Note: Patients may be newly-diagnosed OR previously diagnosed, and there is no required timeframe between biopsy/surgery and treatment initiation

Residual tumor after resection or progressive tumor after initial diagnosis (with or without surgery) who have not received treatment (chemotherapy and/or radiation)

Patients must have two-dimensional measurable tumor greater than or equal to 1 cm2

Histologies will include all tumors considered low-grade glioma or low-grade astrocytoma (WHO Grade I and II) by 5th edition WHO classification of CNS tumors with the exception of subependymal giant cell astrocytoma

Metastatic disease or multiple independent primary LGG

Adequate organ function(liver, renal, cardiac, bone marrow and central nervous system) as defined by the protocol

Must have a performance status corresponding to ECOG scores of 0, 1, or 2. Use Karnofsky for patients greater than 16 years of age and Lansky for patients less than or equal to 16 years of age

Must have the ability to swallow whole capsules

EXCLUSION

Must not have received any prior tumor-directed therapy including chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant. Prior surgical intervention is permitted

Patients with diffuse intrinsic pontine tumors as seen on MRI (greater than 2/3 of pons involvement on imaging) are not eligible even if biopsy reveals Grade I/II histology

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

Can not be pregnant or breast feeding

Male and Female of child bearing potential must agree to adequate birth control as defined by the protocol

Cardiac Conditions: Known genetic disorder that increases risk for coronary artery disease. Note: The presence of dyslipidemia in a family with a history of myocardial infarction is not in itself an exclusion unless there is a known genetic disorder documented, symptomatic heart failure, NYHA Class II-IV prior or current cardiomyopathy, severe valvular heart disease, history of atrial fibrillation

Ophthalmologic Conditions: Current or past history of central serous retinopathy, current or past history of retinal vein occlusion or retinal detachment, patients with uncontrolled glaucoma as defined by the protocol

Supplementation with vitamin E greater than 100% of the daily recommended dose. Any multivitamin containing vitamin E must be stopped prior to study enrollment even if less than 100% of the daily recommended dosing for vitamin E

Patients with uncontrolled infection are not eligible

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

Applicable Disease Sites
Brain/Central Nervous System

Participating Institutions
Gundersen Health System; UW Health University Hospital