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

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 RAF-Altered, Recurrent or Progressive Low-Grade Glioma and Advanced Solid Tumors

This is a Phase 2, multi center, open-label study to evaluate the safety and efficacy of Type II RAF (tovorafenib) in pediatric participants with low-grade glioma or advanced solid tumors. 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 arms. The study will consist of a screening period, a treatment period, a long-term extension phase, end of treatment (EOT) visit(s), a safety follow-up visit, and long-term follow-up assessments.

Study Overview

• Status: Recruiting
• Conditions: Advanced Solid Tumor; Low-grade Glioma
• Intervention / Treatment: Drug: Tovorafenib

Detailed 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).

• Study Type: Interventional
• Enrollment (Estimated): 141
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Day One Biopharmaceuticals, Inc.; Phone Number: 650-484-0899; Email: firefly-1@dayonebio.com

Study Locations

• Australia
  • Brisbane, Australia, 4101
    • Recruiting
    • Queensland Children's Hospital
  • Parkville, Australia, 3052
    • Recruiting
    • Royal Children's Hospital
  • Perth, Australia, WA 6009
    • Recruiting
    • Perth Children's Hospital
  • Randwick, Australia, NSW 2031
    • Recruiting
    • Sydney Children's Hospital
  • Westmead, Australia, 2145
    • Recruiting
    • The Children's Hospital at Westmead
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • Recruiting
      • Montreal Children's Hospital
    • Montreal, Quebec, Canada, H3T 1C5
      • Recruiting
      • Centre hospitalier universitaire Ste-Justine
    • Québec, Quebec, Canada, G1V 4G2
      • Recruiting
      • Centre Mère-Enfant Soleil du CHU
• Denmark
  • Copenhagen, Denmark
    • Recruiting
    • Rigshospitalet
• Germany
  • Berlin, Germany, 13353
    • Recruiting
    • Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Otto-Heubner-Centrum für Kinder
  • Heidelberg, Germany, 69120
    • Recruiting
    • Hopp-Kindertumorzentrum Heidelberg (KiTZ), KiTZ Clinical Trial Unit (ZIPO)
• Israel
  • Haifa, Israel, 3109601
    • Recruiting
    • Rambam Health Care Campus
  • Petah Tikva, Israel, 4920235
    • Recruiting
    • Schneider Children's Medical Center of Israel
  • Ramat Gan, Israel, 5265601
    • Recruiting
    • The Chaim Sheba Medical Center
• Korea, Republic of
  • Seoul, Korea, Republic of, 3080
    • Recruiting
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 3722
    • Recruiting
    • Severance Hospital - Yonsei University
• Netherlands
  • Utrecht, Netherlands, 3584 CS
    • Recruiting
    • Princess Máxima Center for Pediatric Oncology
• Singapore
  • Singapore, Singapore, 229899
    • Recruiting
    • KK Women's and Children's Hospital
• Switzerland
  • Zürich, Switzerland, 8032
    • Recruiting
    • Universitäts-Kinderspital Zürich - Eleonorenstiftung
• United Kingdom
  • London, United Kingdom, WC1N 1EH
    • Recruiting
    • UCL Great Ormond Street Institute of Child Health
  • Newcastle Upon Tyne, United Kingdom, NE1 7RU
    • Recruiting
    • Newcastle University
• United States
  • California
    • San Francisco, California, United States, 94143
      • Recruiting
      • UCSF Benioff Children's Hospital
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Recruiting
      • Children's National Medical Center
      • Contact: braintumorresearch@childrensnational.org; Phone Number: 202-476-5000
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Lurie Children's Hospital of Chicago
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Terminated
      • Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • CS Mott Children's Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • St. Louis Children's Hospital
  • New York
    • New York, New York, United States, 10016
      • Recruiting
      • NYU Langone Health
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Recruiting
      • Duke Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Terminated
      • Doernbecher Children's Hospital Oregon & Health Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Children's Hospital of Philadelphia
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Texas Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Recruiting
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98105
      • Recruiting
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Low Grade Glioma & Low-Grade Glioma Extension: a relapsed or progressive LGG with documented known activating BRAF alteration.
• Advanced Solid Tumor: locally advanced or metastatic solid tumor with documented known or expected to be activating RAF fusion.
• Participants must have histopathologic verification of malignancy at either original diagnosis or relapse.
• Must have received at least one line of prior systemic therapy and have documented 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:

• Participant's tumor has additional previously-known activating molecular alterations.
• Participant has symptoms of without radiographically recurrent or radiographically progressive disease.
• Known or suspected diagnosis of neurofibromatosis type 1 (NF-1) via genetic testing or current diagnostic criteria.

Other inclusion/exclusion criteria as stipulated by protocol may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: Low-Grade Glioma; Participants with recurrent or progressive low-grade glioma will receive 420 milligrams/meters square (mg/m^2) of tovorafenib weekly according to dose rounding guidelines and according to their baseline body surface area (BSA).	Drug: Tovorafenib; Tovorafenib is an oral Type II RAF kinase inhibitor available in 100 mg immediate-release tablet or 25 mg/milliliter (mL) powder for reconstitution.; Other Names: DAY101
Experimental: Arm 2: Low-Grade Glioma Expanded Access; Participants with recurrent or progressive low-grade glioma will receive 420 mg/m^2 of tovorafenib weekly according to dose rounding guidelines and according to their baseline BSA.	Drug: Tovorafenib; Tovorafenib is an oral Type II RAF kinase inhibitor available in 100 mg immediate-release tablet or 25 mg/milliliter (mL) powder for reconstitution.; Other Names: DAY101
Experimental: Arm 3: Advanced Solid Tumor; Participants with advanced solid tumors will receive 420 mg/m^2) of tovorafenib weekly according to dose rounding guidelines and according to their baseline BSA.	Drug: Tovorafenib; Tovorafenib is an oral Type II RAF kinase inhibitor available in 100 mg immediate-release tablet or 25 mg/milliliter (mL) powder for reconstitution.; Other Names: DAY101

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arm 1: Overall response rate	ORR is defined as percentage of participants with best overall confirmed response of complete response (CR) or partial response (PR) by the Response Assessment in Neuro-Oncology - high-grade glioma (RANO-HGG) criteria.	Up to 48 months
Arm 2: Number of participants reporting adverse events	An adverse event (AE) is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.	Up to 48 months
Arm 2: Number of participants with clinically significant changes in clinical chemistry parameters		Up to 48 months
Arm 2: Number of participants with clinically significant changes in hematology parameters		Up to 48 months
Arm 3: Overall response rate	Determined by the treating investigator and measured by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or RANO-HGG criteria, as appropriate.	Up to 48 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arm 1 and 3: Number of participants reporting adverse events	An adverse event (AE) is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.	Up to 48 months
Arm 1 and 3: Number of participants with clinically significant changes in clinical chemistry parameters		Up to 48 months
Arm 1 and 3: Number of participants with clinically significant changes in hematology parameters		Up to 48 months
Arm 1: Area under the concentration-time curve (AUC) of Tovorafenib		Cycle 1: Day 1 and Day 15; Cycles 2, 4, 7, 10 and 13: Day 1
Arm 1: Minimum drug concentration (Cmin)		Cycle 1: Day 1 and Day 15; Cycles 2, 4, 7, 10 and 13: Day 1
Arm 1: Change from Baseline QT interval corrected for heart rate by Fridericia's formula (ΔQTcF)		Baseline to 48 months
Arm 1: Change from Baseline PR interval (ΔPR)		Baseline to 48 months
Arm 1: Change from Baseline QRS interval (ΔQRS)		Baseline to 48 months
Arm 1: Change from baseline heart rate (ΔHR)		Baseline to 48 months
Arm 1: Change in electrocardiogram (ECG) waveform morphology		Baseline to 48 months
Arm 1 and Arm 2: Overall response rate	ORR is defined as percentage of participants with best overall confirmed response of CR or PR by the RANO-HGG criteria.	Up to 48 months
Arm 1, Arm 2 and Arm 3: Overall response rate in Pediatric participants	ORR is defined as percentage of participants with best overall confirmed response of CR or PR or minor response (MR) by Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria.CR or PR by RECIST v1.1 criteria.	Up to 48 months
Arm 1, Arm 2 and Arm 3: duration of progression-free survival (PFS)	PFS as defined by the time following initiation of tovorafenib to progression or death in participants treated with tovorafenib measured by RECIST v1.1, RAPNO, or RANO-HGG criteria as determined by the treating investigator and an IRC.	Up to 48 months
Arm 1, Arm 2 and Arm 3: Duration of response (DOR)	DOR as defined by the length of response in participants with best overall confirmed response of CR or PR or MR and measured by RANO-HGG, RAPNO, and/or RECIST v1.1 criteria, as applicable.	Up to 48 months
Arm 1, Arm 2 and Arm 3: Time to response (TTR)	TTR as defined as the time to first response following initiation of tovorafenib in participants with best overall confirmed response of CR or PR measured by RECIST v1.1 or RANO-HGG criteria, as applicable.	Up to 48 months
Arm 1, Arm 2 and Arm 3: Clinical benefit rate (CBR)	CBR as defined as participants with BOR of CR, PR or stable disease (SD) measured by RECIST v1.1 or RANO-HGG, as applicable, and lasting 12 months or more following initiation of tovorafenib.	Up to 48 months
Arm 1 and Arm 2: Duration of overall survival	Overall survival as defined by the time following initiation of tovorafenib to death of any cause in participants treated with tovorafenib.	Up to 48 months
Arm 1: Change from baseline in best corrected visual acuity (BCVA) outcomes		Baseline to 48 months
Arm 1: Changes in molecular analysis of cells obtained from archival tissue		At Screening

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Up to 48 months
Evaluate the concordance of prior local laboratory BRAF molecular profiling with a central BRAF alteration assay	Molecular analysis of cells obtained from archival tissue	Up to 48 months
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	Up to 48 months
Arms 1 & 2: Characterize changes in total tumor volume following treatment with DAY101 by magnetic resonance imaging (MRI) volumetric image analysis	Measured by determining tumor volume and volume changes based on MRI scan data	Up to 48 months
Arms 1 & 2: Characterize changes in apparent diffusion coefficients following treatment with DAY101 using diffusion-weighted imaging analysis	Measured by diffusion-weighted imaging based on MRI scan data	Up to 48 months
Arms 1 & 2: Describe the improvement in motor function compared with baseline	Measured by changes in the Vineland 3 Adaptive Behavior Scales	Up to 48 months
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)	Up to 48 months
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	Up to 48 months

Collaborators and Investigators

• Sponsor: Day One Biopharmaceuticals, Inc.
• Collaborators: Pacific Pediatric Neuro-Oncology Consortium

Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2021
• Primary Completion (Estimated): May 31, 2027
• Study Completion (Estimated): May 31, 2027

Study Registration Dates

• First Submitted: February 3, 2021
• First Submitted That Met QC Criteria: February 25, 2021
• First Posted (Actual): March 1, 2021

Study Record Updates

• Last Update Posted (Actual): April 10, 2025
• Last Update Submitted That Met QC Criteria: March 27, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Advanced Solid Tumor; Low-grade Glioma; DAY101; FIREFLY-1; Tovorafenib
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma
• Other Study ID Numbers: DAY101-001/PNOC026

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No