A Study to Evaluate DAY101 in Pediatric and Young Adult Patients With Relapsed or Progressive Low-Grade Glioma and Advance Solid Tumors (FIREFLY-1)

A Study to Evaluate DAY101 in Pediatric and Young Adult Patients With Relapsed or Progressive Low-Grade Glioma and Advance Solid Tumors

FIREFLY-1: A Phase 2, Open-Label, Multicenter Study to Evaluate the Safety and Efficacy of the Oral Pan-RAF Inhibitor DAY101 in Pediatric Patients With BRAF-Altered, Recurrent or Progressive Low-Grade Glioma and Advanced Solid Tumors

FIREFLY-1 is a Phase 2, multi center, open-label study to evaluate the safety and efficacy of oral pan-RAF inhibitor DAY101 in pediatric, adolescent, and young adult patients with recurrent or progressive low-grade glioma or an advanced solid tumor harboring a known BRAF alteration.

The study will consist of the following treatment arms: Arm 1 (Low-Grade Glioma): Patients aged 6 months to 25 years, inclusive, with recurrent or progressive low-grade glioma harboring a known activating BRAF alteration, including BRAF V600 mutations and KIAA1549:BRAF fusions. Arm 2 (Low-Grade Glioma Expanded Access): Patients aged 6 months to 25 years, inclusive, with recurrent or progressive low-grade glioma harboring a known or expected to be activating RAF alteration (e.g., BRAF or CRAF/RAF1 fusion or BRAF V600 mutations). Opening of Arm 2 to enrollment will be based on the recommendation of the Data Safety Monitoring Board (DSMB). Arm 3 (Advanced Solid Tumor): Patients aged 6 months to 25 years, inclusive, with advanced solid tumors harboring a known or expected to be activating RAF fusion (e.g., BRAF or CRAF/RAF1 fusion). Qualifying genomic alterations will be identified through molecular assays as routinely performed at Clinical Laboratory Improvement Amendments (CLIA) of 1988 or other similarly certified laboratories prior to enrollment into any of the aforementioned arms. Patients will be treated with DAY101, an oral pan-RAF inhibitor, for a planned period of 26 cycles will be treated with DAY101 for a planned period of 26 cycles (approximately 24 months). DAY101 will be administered at the recommended Phase 2 dose (RP2D) of 420 mg/m2 (not to exceed 600 mg) orally once weekly (QW) for each 28-day treatment cycle. Treatment cycles will repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients will undergo radiographic evaluation of their disease at the end of every third cycle. Patients will continue on DAY101 until radiographic evidence of disease progression by RANO (Arms 1 & 2) or RECIST v1.1 criteria (Arm 3) as determined by treating investigator, unacceptable toxicity, patient withdrawal of consent, or death. Patients who have radiographic evidence of disease progression may be allowed to continue DAY101 if, in the opinion of the investigator and approval by the Sponsor, the patient is deriving clinical benefit from continuing study treatment. Disease assessments for patients being treated beyond progression should continue as per regular schedule. DAY101 is an oral pan-RAF inhibitor administered as an oral tablet at 420 mg/m2 (not to exceed 600 mg).

DAY101 is an oral pan-RAF inhibitor provided as an immediate-release tablet (100 mg) or powder for reconstitution (25 mg/mL).

Arm 1: Overall response rate (ORR) by independent radiology review committee (IRC) based on RANO criteria

ORR defined as the proportion of patients with best overall confirmed response of complete response (CR) or partial response (PR) by RANO criteria

Arm 3: Overall response rate (ORR) by independent radiology review committee (IRC) based on RECIST v1.1 criteria

Measured by the proportion of patients with best overall confirmed response of CR or PR by RECIST v1.1 criteria

Effect on electrocardiogram (ECG) and QT interval corrected for heart rate by Fridericia's formula (QTcF) prolongation

Change from baseline QT interval corrected for HR by Fridericia's formula (ΔQTcF); change from baseline PR interval (ΔPR); change from baseline QRS interval (ΔQRS); change from baseline heart rate (ΔHR); ECG waveform morphology

Measured by the proportion of patients with best overall confirmed response of CR or PR by RANO (Arms 1 & 2) or RECIST (Arm 3) criteria

Evaluate the concordance of prior local laboratory BRAF molecular profiling with a central BRAF alteration assay being evaluated by the Sponsor

Measured by the proportion of patients with best overall confirmed response of CR or PR by RAPNO-LGG criteria

Arms 1 & 2: Progression free survival (PFS) using RANO and RAPNO criteria by 1) an IRC and 2) the treating Investigator (RANO only)

Measured by the time following initiation of DAY101 to progression or death in patients treated with DAY101

Arms 1 & 2: Duration of response (DOR) with best overall response of CR or PR using RANO and RAPNO criteria by 1) an IRC and 2) the treating Investigator (RANO only)

Measured by the length of response in patients with best overall confirmed response of CR or PR by RANO and RAPNO criteria

Measured by the time to first response following initiation of DAY101 in patients with best overall confirmed response of CR or PR by RANO and RAPNO criteria by 1) an IRC and 2) the treating Investigator (RANO only)

Arms 1 & 2: Clinical benefit rate based on the proportion of patients with best overall response using RANO or RAPNO criteria

Measured on the proportion of patients with best overall response of CR, PR, or SD lasting 12 months or more following initiation of DAY101 by 1) an IRC and 2) the treating Investigator (RANO only)

Arm 3: Duration of response (DOR) with best overall response of CR or PR using RECIST v1.1 criteria by 1) an IRC and 2) the treating Investigator

Measured by the length of response in patients with best overall confirmed response of CR or PR by RECIST v1.1 criteria

Measured by the time to first response following initiation of DAY101 in patients with best overall confirmed response of CR or PR by RECIST v1.1 criteria by 1) an IRC and 2) the treating Investigator

Arm 3: Clinical benefit rate based on the proportion of patients with best overall response using RECIST v1.1 criteria

Measured on the proportion of patients with best overall response of CR, PR, or SD lasting 12 months or more following initiation of DAY101 by 1) an IRC and 2) the treating Investigator

Evaluate changes from baseline in quality-of-life and health utilities measures using the Pediatrics Quality of Life™-Core Module (PedsQL-Core) and Patient-Reported Outcomes Measurement Information System (PROMIS®) assessment

Measured by changes from baseline in quality-of-life and health utilities measures using the PedsQL-Core and PROMIS assessment

Evaluate the concordance of prior local laboratory BRAF molecular profiling with a central BRAF alteration assay

Arm 1: Compare the response and time to progression following initiation of DAY101 to that of the prior line of systemic therapy

Measured by the proportion of patients with best overall confirmed response of CR or PR and time to response by RANO criteria based on the prior line of therapy

Arms 1 & 2: Characterize changes in total tumor volume following treatment with DAY101 by magnetic resonance imaging (MRI) volumetric image analysis

Arms 1 & 2: Characterize changes in apparent diffusion coefficients following treatment with DAY101 using diffusion-weighted imaging analysis

Arms 1 & 2: Determine the durability of response following discontinuation of DAY101 for patients with a radiographic response to DAY101

Measured by the proportion of patients with best overall confirmed response of CR or PR who enter a drug holiday period and time to progression based on RANO and RAPNO criteria as determined by 1) an IRC and 2) the treating Investigator (RANO only)

Arm 3: Determine the durability of response following discontinuation of DAY101 for patients with a radiographic response to DAY101 (CR or PR as based on RECIST v1.1 criteria) as determined by 1) an IRC and 2) the treating Investigator

Measured by the proportion of patients with best overall confirmed response of CR or PR who enter a drug holiday period and time to progression as determined by RECIST v1.1 or clinical criteria

Inclusion Criteria: Age 6 months to 25 years with: Arms 1 & 2: a relapsed or progressive LGG with documented known activating BRAF alteration Arm 3: locally advanced or metastatic solid tumor with documented known or expected to be activating RAF fusion Confirmation of histopathologic diagnosis of LGG and molecular diagnosis of activating BRAF alteration Must have received at least one line of systemic therapy and have evidence of radiographic progression Must have at least 1 measurable lesion as defined by RANO (Arms 1 & 2) or RECIST v1.1 (Arm 3) criteria Exclusion Criteria: Patient's tumor has additional previously-known activating molecular alterations Patient has symptoms of clinical progression in the absence of radiographic progression Known or suspected diagnosis of neurofibromatosis type 1 (NF-1) Other inclusion/exclusion criteria as stipulated by protocol may apply