DAY101 vs. Standard of Care Chemotherapy in Pediatric Participants With Low-Grade Glioma Requiring First-Line Systemic Therapy (LOGGIC/FIREFLY-2)

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. Treatment will continue until completion of therapy or until any of the following occurs: disease progression, unacceptable toxicity, withdrawal of consent to treatment, or end of study.

Participants who discontinue treatment due to disease progression will have (1) radiographic evidence of disease progression, as determined by the Investigator, or (2) clinical progression, as determined by the Investigator. Investigators are encouraged to discuss cases of clinical progression and early radiographic progression without clinical symptoms with the Sponsor Medical Monitor prior to treatment discontinuation or initiation of a different form of treatment for the malignancy. Participants may continue therapy beyond progressive disease (PD).

Primary Outcome Measures

1. Objective response rate (ORR) of tovorafenib monotherapy versus SoC chemotherapy
   ORR assessed per Response Assessment in Pediatric Neuro Oncology (RAPNO) criteria by Independent Review Committee (IRC), and defined as the proportion of participants with overall confirmed response of complete response (CR), partial response (PR), or minor response (MR).

Secondary Outcome Measures

1. Progression-free survival (PFS) of tovorafenib monotherapy versus SoC chemotherapy
   PFS assessed per RAPNO criteria by IRC, and defined as time from randomization to PD or death from any cause, whichever comes first.
2. Event-free survival (EFS) of tovorafenib monotherapy versus SoC chemotherapy
   EFS assessed per RAPNO criteria by IRC, defined as time from randomization to PD, death from any cause, or initiation of any new anticancer therapy, whichever comes first.
3. Overall survival (OS) of tovorafenib monotherapy versus SoC chemotherapy
   Overall survival is defined as time from randomization up to death from any cause.
4. Number of participants with any treatment-emergent adverse events, and Serious adverse events
   Type, frequency, and severity of adverse events of tovorafenib monotherapy versus SoC chemotherapy will be assessed.
5. . Number of participants with clinically significant vital signs and laboratory abnormalities findings
   Type, frequency, and severity of vital signs and laboratory abnormalities of tovorafenib monotherapy versus SoC chemotherapy will be assessed.
6. Change from baseline in Adaptive Behavior Composite Score (ABS) of tovorafenib monotherapy versus SoC chemotherapy
   Adaptive behavior Composite Score will be evaluated using domain scores collected from the comprehensive Vineland III Adaptive Behavior Scale (VABS).
7. Change from baseline in the Motor Skills Domain Score of tovorafenib monotherapy versus SoC chemotherapy
   The motor skills (gross and fine) will be assessed using the Motor Skills Score domain of the VABS in pediatric participants.
8. Change from baseline in the Daily Living Domain Score of tovorafenib monotherapy versus SoC chemotherapy
   The daily living (personal, domestic and community) will be assessed using Daily Living Domain Score of VABS.
9. Change from baseline in the Communication Domain Score of tovorafenib monotherapy versus SoC chemotherapy
   The communication skills (receptive, expressive and written) will be assessed using Communication Domain Score of VABS.
10. Change from baseline in the Socialization Domain Score of tovorafenib monotherapy versus SoC chemotherapy
    The socialization skills (Interpersonal relationships, play and leisure time and coping skills) will be assessed using Socialization Domain Score of VABS.
11. Change in age-adjusted visual acuity (VA) of tovorafenib monotherapy versus SoC chemotherapy in optic pathway glioma (OPG) participants aged < 3 years
    Visual acuity testing using current age-appropriate testing methodology will be performed for all participants at Screening. For participants with OPG or an underlying visual deficit related to the primary malignancy, visual acuity testing will be performed every time participants have a radiographic response assessment. Assessments will be performed in each eye separately at a recommended testing distance of 3 meters.
12. Change in best corrected visual acuity of tovorafenib monotherapy versus SoC chemotherapy in OPG participants aged ≥ 3 years
    Visual acuity assessments to be performed by an ophthalmologist or another qualified site clinical personnel.
13. Visual progression-free survival (v-PFS) of tovorafenib monotherapy versus SoC chemotherapy
    Visual progression-free survival is defined as the time from start of treatment to visual event for OPG participants aged &ge; 3 years.
14. ORR of tovorafenib monotherapy versus SoC chemotherapy
    ORR, defined as the proportion of participants with overall confirmed response per Response Assessment in Neuro-Oncology for High-Grade Glioma (RANO-HGG) criteria (CR or PR) and RANO-LGG criteria (CR, PR, or MR), as applicable.
15. Clinical benefit rate (CBR) of tovorafenib monotherapy versus SoC chemotherapy
    CBR, defined as the proportion of participants with radiological tumor stabilization or regression per RANO-LGG (CR, PR, MR, or SD lasting 12 months or more), RANO-HGG (CR, PR, or SD lasting 12 months or more) or RAPNO criteria (CR, PR, MR or SD lasting 12 months or more), as applicable.
16. Time to response (TTR) of tovorafenib monotherapy versus SoC chemotherapy
    TTR, measured by the time following randomization to first imaging of tumor response that was subsequently confirmed per RANO-HGG criteria (CR or PR), RANO-LGG criteria (CR, or PR, or MR), or RAPNO criteria (CR, PR, or MR), as applicable.
17. PFS of tovorafenib monotherapy versus SoC chemotherapy
    PFS per RANO-HGG or RANO-LGG criteria (as applicable), defined as time from randomization to PD or death from any cause, whichever occurs first.
18. EFS of tovorafenib monotherapy versus SoC chemotherapy
    EFS per RANO-HGG or RANO-LGG criteria (as applicable), defined as time from randomization to PD, death from any cause, or initiation of any new anticancer therapy, whichever comes first.
19. Duration of response (DOR) of tovorafenib monotherapy versus SoC chemotherapy
    DOR, defined as time from first imaging of tumor response per RANO-LGG, RANO-HGG or RAPNO criteria, as applicable, that was subsequently confirmed to radiographic PD or death from any cause, whichever comes first.
20. Change from Baseline in health-related quality of life (HRQoL) total score of tovorafenib monotherapy versus SoC chemotherapy
    The Patient-Reported Outcomes Measurement Information System (PROMIS&reg;) Pediatric/Parent Proxy Profile 49 v2.0 will be used to assess mental and social HRQoL.