Title
A Phase 3, Randomized, International Multicenter Trial of DAY101 Monotherapy Versus Standard of Care Chemotherapy in Patients with Pediatric Low-Grade Glioma Harboring an Activating RAF Alteration Requiring First-Line Systemic Therapy

Description
This is a 2-arm, randomized, open-label, multicenter, global, Phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy versus standard of care (SoC) chemotherapy in participants with pediatric low-grade glioma (LGG) harboring an activating rapidly accelerated fibrosarcoma (RAF) alteration requiring first-line systemic therapy.

Objective
Primary Objective:
- To compare the ORR assessed per RANO-LGG criteria by Independent Review Committee (IRC) of tovorafenib monotherapy versus SoC chemotherapy in patients with pediatric low-grade glioma harboring an activating RAF alteration requiring first-line systemic therapy.

Treatment Approximately 400 treatment-naïve LGG participants will be randomized 1:1 to either tovorafenib (Arm 1) or an Investigator's choice of SoC chemotherapy (Arm 2).

Arm 1 (tovorafenib): Treatment cycles will repeat every 28 days in the absence of disease progression. Participants will continue tovorafenib until any of the following occurs: disease progression, unacceptable toxicity, withdrawal of consent to treatment, or end of study.

Arm 2 (Investigator's Choice of SoC Chemotherapy): Participants will receive one of 4 SoC chemotherapy options selected by the treating Investigator: Children's Oncology Group - Vincristine/Carboplatin (COG-V/C) regimen, International Society for Paediatric Oncology - Low-Grade Glioma Vincristine/Carboplatin (SIOPe-LGG-V/C) regimen, vinblastine (VBL) regimen, or monthly carboplatin. The choice of SoC chemotherapy regimen will be selected prior to participant randomization.

Key Eligibility Inclusion Criteria:

Less than 25 years of age with LGG with known activating RAF alteration.

Histopathologic diagnosis of glioma or glioneuronal tumor.

At least one measurable lesion as defined by RANO criteria.

Meet indication for first-line systemic therapy.

Participant has any of the following tumor-histological findings:



Schwannoma

Subependymal giant cell astrocytoma (Tuberous Sclerosis)

Diffuse intrinsic pontine glioma, even if histologically diagnosed as World Health Organization (WHO) Grade I-II



Participant's tumor has additional pathogenic molecular alterations, including but not limited to a) isocitrate dehydrogenase (IDH) 1/2 mutation, b) Histone H3 mutation, and c) neurofibromatosis Type 1 (NF-1) loss of function alteration.

Known or suspected diagnosis of NF-1/ neurofibromatosis Type 2 (NF-2).

Prior or ongoing nonsurgical anticancer therapy for this indication (eg, chemotherapy, oral/IV targeted therapy) including radiation.

Applicable Disease Sites
Brain/Central Nervous System

Participating Institutions
UW Health University Hospital