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

Overview

FIREFLY-1 is an ongoing, 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 RAF alteration.

Description

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).

Eligibility

Inclusion Criteria:

• Age 6 months to 25 years with:
  1. Arms 1 & 2: a relapsed or progressive LGG with documented known activating BRAF alteration
  2. 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