Research & Development
First Patient Dosed in FIREFLY-1 Pivotal Phase 2 Clinical Trial of DAY101 in Pediatric Progressive Low-Grade Glioma
12 May 2021 - - The first patient has been dosed in FIREFLY-1, a Phase 2 clinical trial evaluating the safety and efficacy of DAY101 in pediatric, adolescent and young adult patients with recurrent or progressive low-grade glioma harboring a known BRAF alteration, US-based biopharmaceutical company Day One Biopharmaceuticals said.

Pediatric low-grade glioma is the most common form of childhood brain cancer and has no approved targeted therapeutics.

The trial is being conducted in collaboration with the Pacific Pediatric Neuro-Oncology Consortium and is designed to support the regulatory approval of DAY101.

DAY101 is an oral, brain-penetrant, highly-selective type II pan-RAF kinase inhibitor designed to target a key enzyme in the MAPK signaling pathway. Dysregulation of the MAPK pathway has been shown to occur in many cancers.

In pLGG, BRAF wild-type fusions are the most common cancer-causing genomic alterations.

DAY101 has been granted Breakthrough Therapy designation by the US Food and Drug Administration for the treatment of patients with pLGG harboring an activating RAF alteration who require systematic therapy and who have either progressed following prior treatment or who have no satisfactory alternative treatment options.

FIREFLY-1 is a pivotal Phase 2, multicenter, open-label study designed to evaluate the safety and efficacy of DAY101 in patients aged six months to 25 years with relapsed or progressive low-grade glioma harboring a known activating BRAF alteration.

The study aims to enroll approximately 60 patients, who will receive oral DAY101 at a dose of 420 mg/m2 once weekly.

The primary endpoint will be overall response rate, defined as the proportion of patients with best overall confirmed response rate based upon Response Assessment for Neuro-Oncology criteria.

Secondary and exploratory endpoints include the overall response rate based on Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria and volumetric analyses, event free survival, safety, functional outcomes, and quality of life measures.

Additional information about FIREFLY-1 may be found at ClinicalTrials.gov, using Identifier NCT04775485.

Pediatric low-grade glioma is the most common brain tumor diagnosed in children, accounting for 30% - 50% of all central nervous system tumors.

BRAF wild-type fusions are the most common cancer-causing genomic mutations in pediatric low-grade gliomas. These genomic alterations are also found in several adult solid tumors.

Currently approved BRAF inhibitors are only active in tumors harboring BRAF V600 mutations, exhibit limited activity in brain tumors, and cannot be used in patients harboring BRAF fusions.

Pediatric low-grade glioma can impact a child's health in many ways depending on tumor size and location, including vision loss and motor dysfunction.

There are no approved therapies for pLGG and current treatment approaches are associated with significant acute and life-long adverse effects.

While most children with pLGG survive their cancer, children who do not achieve a cure following surgery face years of increasingly aggressive therapies that can have lasting effects on learning, cognition, and quality of life.

Due to the indolent nature of pLGG, patients receive multiple years of systemic therapy.

DAY101 is an oral, brain-penetrant, highly-selective type II pan-RAF kinase inhibitor designed to target a key enzyme in the MAPK signaling pathway.

Studies have shown DAY101 has high brain distribution and exposure in comparison to other MAPK pathway inhibitors, thus potentially benefiting patients with primary brain tumors or brain metastases of solid tumors.

DAY101 is a type II RAF inhibitor that selectively inhibits both monomeric and dimeric RAF kinase, which broadens its potential clinical application to treat an array of RAF-altered tumors.

DAY101 has been studied in over 250 patients, and as a monotherapy demonstrated good tolerability and encouraging anti-tumor activity in pediatric and adult populations with specific MAPK pathway-alterations.

In November 2020, Day One announced preliminary results from PNOC014, an ongoing Phase 1 Pacific Pediatric Neuro-Oncology Consortium network study with DAY101 sponsored by the Dana-Farber Cancer Institute, in patients under 18 years of age with relapsed low-grade glioma.

Preliminary results demonstrated that of the eight patients in the study with RAF fusions, two patients achieved a complete response by Response Assessment for Neuro-Oncology, three had a partial response, two achieved prolonged stable disease, and one experienced progressive disease. DAY101 also demonstrated a tolerable safety profile.

DAY101 has been granted Breakthrough Therapy designation by the US Food and Drug Administration for the treatment of patients with pLGG harboring an activating RAF alteration who require systemic therapy and who have either progressed following prior treatment or who have no satisfactory alternative treatment options.

In addition, DAY101 has received Orphan Drug designation from the FDA for the treatment of malignant glioma.

Day One is conducting a pivotal Phase 2 trial (FIREFLY-1) of DAY101 in pediatric, adolescent and young adult patients with pLGG.

Day One also plans to study DAY101 alone or in combination with other agents that target key signaling nodes in the MAPK pathway, such as the company's MEK inhibitor pimasertib, in patient populations where various RAS and RAF alterations are believed to play an important role in driving disease.

The Pacific Pediatric Neuro-Oncology Consortium is an international consortium with study sites within the United States, Canada, Israel, Europe, and Australia dedicated to bringing new therapies to children and young adults with brain tumors.

Day One Biopharmaceuticals is a clinical-stage biopharmaceutical company dedicated to developing and commercializing targeted therapies for patients of all ages with genetically defined cancers.
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