Rare Pediatric Disease Designation Granted to DAY101 for Low-Grade Glioma

DAY101, an investigational, oral, brain-penetrant, and highly selective type II pan-RAF kinase inhibitor for the treatment of rare, pediatric low-grade glioma (pLGG), was granted a rare pediatric disease designation by the FDA, according to a press release by Day One Biopharmaceuticals.¹

DAY101 is meant to target a key MAPK signaling enzyme. Previous research has found that DAY101 has high brain distribution and exposure. It inhibits both monomeric and dimeric RAF kinase, potentially broadening its clinical benefit to other RAF-altered tumors.¹

The agent has been studied in over 250 patients and has a tolerable safety profile and encouraging anti-tumor activity. Preliminary results of 1 such trial, PNOC014 (NCT03429803) found that of the 8 patients with RAFfusions evaluated, 2 patients achieved a complete response per the Responses Assessment for Neuro-Oncology, 3 had partial responses, 2 achieved stable disease and 1 patient experienced progressive disease. The median time to response was 10.5 weeks. Common adverse events (AEs) were skin rash and hair color changes.²

The phase 1 PNOC014 trial has an estimated enrollment of 53 patients and is planned to be completed in December 2024. The study is made up of 2 arms. In arm 1, patients received 1.5 m2 or less of the study drug. In arm 2, they received more than 1.5 m2 of the study drug. The primary end point of the trial is dose-limiting toxicities. Secondary end points include best overall response, the number of patients with AEs, and the number of patients with serious AEs.

The results of PNOC014 lead to the initiation of FIREFLY-1 (NCT04775485), a phase 2 trial with an estimated enrollment of 60 participants. The primary end point of the study is overall response rate. Secondary end points include safety and tolerability, the relationship between pharmacokinetics and drug effects, progression-free survival, duration of response, time to response, and clinical benefit rate. 

The study will have a single arm split into 2 cohorts. In cohort 1, patients will receive 20 mg of DAY101 and in cohort 2, patients will receive 100 mg.

In order to participate, patients must be between 6 months and 25 years of age, have a confirmed diagnosis of LGG and a molecular diagnosis of activating BRAF alteration, must have received at least one line of systemic therapy and have evidence of radiographic progression, and have at least 1 measurable lesion. Patients with previously known activating molecular alterations, symptoms of clinical progression in the absence of radiographic progression and known or suspected diagnosis of neurofibromatosis type 1 are not eligible to participate.

“Historical approaches to treating pLGG such as surgery, radiation, and chemotherapy are associated with significant acute and life-long adverse effects, and new options are urgently needed,” said Davy Chiodin, PharmD, chief development officer of Day One, in a press release. “DAY101 has the potential to become the first approved treatment option specifically for these patients. Receiving Rare Pediatric Disease Designation from the FDA underscores the critical value of our focus on pediatric indications at Day One and represents another significant milestone for the DAY101 program as we continue to enroll patients with pLGG in our pivotal phase 2 FIREFLY-1 study.”

FIREFLY-1 is currently recruiting in the District of Columbia, Michigan, Missouri, North Carolina, Texas, and Canada.

_REFERENCE:

_{1.Day One receives FDA rare pediatric disease designation for DAY101 for the treatment of pediatric low-grade glioma. News release. Day One Biopharmaceuticals. July 27, 2021. Accessed July 27, 2021. https://bit.ly/3749R0K.}

_{2.Day One announces preliminary phase 1 results for DAY101 in pediatric low-grade glioma, receipt of breakthrough therapy designation (BTD) and new phase 2 study. News release. Day One Pharmaceuticals. July 27, 2021. Accessed July 27, 2021. https://bit.ly/3BMQVli.}