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

• ClinicalTrials.gov Identifier: NCT04775485
• Recruitment Status: Recruiting
• First Posted: March 1, 2021
• Last Update Posted: December 27, 2023
• Sponsor: Day One Biopharmaceuticals, Inc.
• Collaborator: Pacific Pediatric Neuro-Oncology Consortium
• Information provided by (Responsible Party): Day One Biopharmaceuticals, Inc.

Tracking Information

• First Submitted Date: February 3, 2021
• First Posted Date: March 1, 2021
• Last Update Posted Date: December 27, 2023
• Actual Study Start Date: April 22, 2021
• Actual Primary Completion Date: December 22, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 18, 2022)

• Arm 1: Overall response rate (ORR) by independent radiology review committee (IRC) based on RANO criteria [ Time Frame: Up to 48 months ]
  ORR defined as the proportion of patients with best overall confirmed response of complete response (CR) or partial response (PR) by RANO criteria
• Arm 2: Assess the safety and tolerability of DAY101 [ Time Frame: Up to 48 months ]
  Type, frequency, and severity of treatment-emergent adverse events and laboratory
• Arm 3: Overall response rate (ORR) by independent radiology review committee (IRC) based on RECIST v1.1 criteria [ Time Frame: Up to 48 months ]
  Measured by the proportion of patients with best overall confirmed response of CR or PR by RECIST v1.1 criteria

• Original Primary Outcome Measures (submitted: February 25, 2021): Overall response rate (ORR) by independent radiology review committee (IRC) based on RANO criteria [ Time Frame: Up to 48 months ]

Current Secondary Outcome Measures (submitted: May 18, 2022)

• Relationship between pharmacokinetics (PK) and drug effects [ Time Frame: Up to 48 months ]
  Pharmacokinetic profile of DAY101 (e.g., area under the concentration-time curve [AUC], Cmin, etc.)
• Effect on electrocardiogram (ECG) and QT interval corrected for heart rate by Fridericia's formula (QTcF) prolongation [ Time Frame: Up to 48 months ]
  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
• ORR by Investigator [ Time Frame: Up to 48 months ]
  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 [ Time Frame: Up to 48 months ]
  Molecular analysis of cells obtained from archival tissue
• Arm 1: Evaluate visual acuity (VA) outcomes compared with baseline [ Time Frame: Up to 48 months ]
  Measured by Teller Acuity Cards® II
• Arms 1 & 2: ORR by IRC and Investigator using RAPNO criteria [ Time Frame: Up to 48 months ]
  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) [ Time Frame: Up to 48 months ]
  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) [ Time Frame: Up to 48 months ]
  Measured by the length of response in patients with best overall confirmed response of CR or PR by RANO and RAPNO criteria
• Arms 1 & 2: Time to response following initiation of DAY101 [ Time Frame: Up to 48 months ]
  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 [ Time Frame: Up to 48 months ]
  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)
• Arms 1 & 3: Assess the safety and tolerability of DAY101 [ Time Frame: Up to 48 months ]
  Type, frequency, and severity of treatment-emergent adverse events and laboratory abnormalities
• 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 [ Time Frame: Up to 48 months ]
  Measured by the length of response in patients with best overall confirmed response of CR or PR by RECIST v1.1 criteria
• Arm 3: Time to response following initiation of DAY101 [ Time Frame: Up to 48 months ]
  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 [ Time Frame: Up to 48 months ]
  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

Original Secondary Outcome Measures (submitted: February 25, 2021)

• Assess the safety and tolerability of DAY101 [ Time Frame: Up to 48 months ]
  Type, frequency, and severity of treatment-emergent adverse events and laboratory abnormalities
• Relationship between pharmacokinetics (PK) and drug effects [ Time Frame: Up to 48 months ]
  Pharmacokinetic profile of DAY101 (e.g., area under the concentration-time curve [AUC], Cmin, etc.)
• Effect on electrocardiogram (ECG) and QT interval corrected for heart rate by Fridericia's formula (QTcF) prolongation [ Time Frame: Up to 48 months ]
  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
• ORR by Investigator using RANO criteria [ Time Frame: Up to 48 months ]
  Measured by the proportion of patients with best overall confirmed response of CR or PR by RANO criteria
• ORR by IRC and Investigator using RAPNO criteria [ Time Frame: Up to 48 months ]
  Measured by the proportion of patients with best overall confirmed response of CR or PR by RAPNO-LGG criteria
• Progression free survival (PFS) by IRC and Investigator using RANO and RAPNO criteria [ Time Frame: Up to 48 months ]
  Measured by the time following initiation of DAY101 to progression or death in patients treated with DAY101
• Duration of response (DOR) with best overall response of CR or PR using RANO and RAPNO criteria [ Time Frame: Up to 48 months ]
  Measured by the length of response in patients with best overall confirmed response of CR or PR by RANO criteria
• Time to response following initiation of DAY101 [ Time Frame: Up to 48 months ]
  Measured by the time to first response following initiation of DAY101 in patients with best overall confirmed response of CR or PR by RANO criteria
• Clinical benefit rate based on the proportion of patients with best overall response [ Time Frame: Up to 48 months ]
  Measured on the proportion of patients with best overall response of CR, PR, or SD lasting 12 months or more following initiation of DAY101
• Evaluate visual acuity (VA) outcomes compared with baseline [ Time Frame: Up to 48 months ]
  Measured by Teller Acuity Cards® II
• Evaluate the concordance of prior local laboratory BRAF molecular profiling with a central BRAF alteration assay being evaluated by the Sponsor [ Time Frame: Up to 48 months ]
  Molecular analysis of cells obtained from archival tissue

Current Other Pre-specified Outcome Measures (submitted: May 18, 2022)

• 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 [ Time Frame: Up to 48 months ]
  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 [ Time Frame: Up to 48 months ]
  Molecular analysis of cells obtained from archival tissue
• Arm 1: Compare the response and time to progression following initiation of DAY101 to that of the prior line of systemic therapy [ Time Frame: Up to 48 months ]
  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 [ Time Frame: Up to 48 months ]
  Measured by determining tumor volume and volume changes based on MRI scan data
• Arms 1 & 2: Characterize changes in apparent diffusion coefficients following treatment with DAY101 using diffusion-weighted imaging analysis [ Time Frame: Up to 48 months ]
  Measured by diffusion-weighted imaging based on MRI scan data
• Arms 1 & 2: Describe the improvement in motor function compared with baseline [ Time Frame: Up to 48 months ]
  Measured by changes in the Vineland 3 Adaptive Behavior Scales
• Arms 1 & 2: Determine the durability of response following discontinuation of DAY101 for patients with a radiographic response to DAY101 [ Time Frame: Up to 48 months ]
  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 [ Time Frame: Up to 48 months ]
  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

Original Other Pre-specified Outcome Measures (submitted: February 25, 2021)

• Compare the response and time to progression following initiation of DAY101 to that of the prior line of systemic therapy [ Time Frame: Up to 48 months ]
  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
• Characterize changes in total tumor volume following treatment with DAY101 by magnetic resonance imaging (MRI) volumetric image analysis [ Time Frame: Up to 48 months ]
  Measured by determining tumor volume and volume changes based on MRI scan data
• Characterize changes in apparent diffusion coefficients following treatment with DAY101 using diffusion-weighted imaging analysis [ Time Frame: Up to 48 months ]
  Measured by diffusion-weighted imaging based on MRI scan data
• 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 [ Time Frame: Up to 48 months ]
  Measured by changes from baseline in quality-of-life and health utilities measures using the PedsQL-Core and PROMIS assessment
• Describe the improvement in motor function compared with baseline [ Time Frame: Up to 48 months ]
  Measured by changes in the Vineland 3 Adaptive Behavior Scales
• Determine the durability of response following discontinuation of DAY101 for patients with a radiographic response to DAY101 (CR or PR as based on RANO and RAPNO criteria) as determined by 1) an IRC and 2) the treating Investigator [ Time Frame: Up to 48 months ]
  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 RANO or clinical criteria

Descriptive Information

• Brief Title: A Study to Evaluate DAY101 in Pediatric and Young Adult Patients With Relapsed or Progressive Low-Grade Glioma and Advance Solid Tumors
• Official Title: 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
• Brief Summary: 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.

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
• Study Phase: Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description:

Single intervention across 3 arms - - no comparator

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Low-grade Glioma
• Advanced Solid Tumor

Intervention

Drug: DAY101

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

Study Arms

• Experimental: Arm #1
  Pediatric patients with low-grade glioma treated with DAY101 (Registrational Arm)
  Intervention: Drug: DAY101
• Experimental: Arm #2
  Expanded access arm of pediatric patients with low-grade glioma treated with DAY101
  Intervention: Drug: DAY101
• Experimental: Arm #3
  Pediatric patients with advanced solid tumors treated with DAY101
  Intervention: Drug: DAY101

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 18, 2022): 140
• Original Estimated Enrollment (submitted: February 25, 2021): 60
• Estimated Study Completion Date: June 10, 2024
• Actual Primary Completion Date: December 22, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Months to 25 Years (Child, Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Day One Biopharmaceuticals; 650-484-0899; firefly-1@dayonebio.com

• Listed Location Countries: Australia, Canada, Denmark, Germany, Israel, Korea, Republic of, Netherlands, Singapore, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT04775485
• Other Study ID Numbers: DAY101-001/PNOC026
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Day One Biopharmaceuticals, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Day One Biopharmaceuticals, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Pacific Pediatric Neuro-Oncology Consortium
• Investigators: Not Provided
• PRS Account: Day One Biopharmaceuticals, Inc.
• Verification Date: December 2023