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

Advanced Solid Tumor Clinical Trial

— FIREFLY-1  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04775485
• Other study ID #: DAY101-001/PNOC026
• Status: Recruiting
• Phase: Phase 2
• Start date: April 22, 2021
• Est. completion date: June 10, 2024

Study information

• Verified date: December 2023
• Source: Day One Biopharmaceuticals, Inc.
• Contact: Day One Biopharmaceuticals
• Phone: 650-484-0899
• Email: firefly-1[@]dayonebio.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 140
• Est. completion date: June 10, 2024
• Est. primary completion date: December 22, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 25 Years

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

Related Conditions & MeSH terms

• Advanced Solid Tumor
• Glioma
• Low-grade Glioma

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).

Locations

Country	Name	City	State
Australia	Queensland Children's Hospital	Brisbane
Australia	Royal Children's Hospital	Parkville
Australia	Perth Children's Hospital	Perth
Australia	Sydney Children's Hospital	Randwick
Australia	The Children's Hospital at Westmead	Westmead
Canada	Centre Hospitalier Universitaire Ste-Justine	Montreal	Quebec
Canada	Montreal Children's Hospital	Montreal	Quebec
Canada	Centre Mère-Enfant Soleil du CHU	Québec	Quebec
Denmark	Rigshospitalet	Copenhagen
Germany	Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Otto-Heubner-Centrum für Kinder	Berlin
Germany	Hopp-Kindertumorzentrum Heidelberg (KiTZ), KiTZ Clinical Trial Unit (ZIPO)	Heidelberg
Israel	Rambam Health Care Campus	Haifa
Israel	Schneider Children's Medical Center of Israel	Petah Tikva
Israel	The Chaim Sheba Medical Center	Ramat Gan
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital - Yonsei University	Seoul
Netherlands	Princess Maxima Center for Pediatric Oncology	Utrecht
Singapore	KK Women's and Children's Hospital	Singapore
Switzerland	Universitäts-Kinderspital Zürich - Eleonorenstiftung	Zürich
United Kingdom	UCL Great Ormond Street Institute of Child Health	London
United Kingdom	Newcastle University	Newcastle Upon Tyne
United States	CS Mott Children's Hospital	Ann Arbor	Michigan
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Duke Cancer Center	Durham	North Carolina
United States	Texas Children's Hospital	Houston	Texas
United States	NYU Langone Health	New York	New York
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Doernbecher Children's Hospital Oregon & Health Science University	Portland	Oregon
United States	St. Louis Children's Hospital	Saint Louis	Missouri
United States	University of Utah	Salt Lake City	Utah
United States	UCSF Benioff Children's Hospital	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Day One Biopharmaceuticals, Inc.	Pacific Pediatric Neuro-Oncology Consortium

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Denmark,  Germany,  Israel,  Korea, Republic of,  Netherlands,  Singapore,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	Arm 1: Overall response rate (ORR) by independent radiology review committee (IRC) based on RANO criteria	ORR defined as the proportion of patients with best overall confirmed response of complete response (CR) or partial response (PR) by RANO criteria	Up to 48 months
Primary	Arm 2: Assess the safety and tolerability of DAY101	Type, frequency, and severity of treatment-emergent adverse events and laboratory	Up to 48 months
Primary	Arm 3: Overall response rate (ORR) by independent radiology review committee (IRC) based on RECIST v1.1 criteria	Measured by the proportion of patients with best overall confirmed response of CR or PR by RECIST v1.1 criteria	Up to 48 months
Secondary	Relationship between pharmacokinetics (PK) and drug effects	Pharmacokinetic profile of DAY101 (e.g., area under the concentration-time curve [AUC], Cmin, etc.)	Up to 48 months
Secondary	Effect on electrocardiogram (ECG) and QT interval corrected for heart rate by Fridericia's formula (QTcF) prolongation	Change from baseline QT interval corrected for HR by Fridericia's formula (?QTcF); change from baseline PR interval (?PR); change from baseline QRS interval (?QRS); change from baseline heart rate (?HR); ECG waveform morphology	Up to 48 months
Secondary	ORR by Investigator	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	Up to 48 months
Secondary	Evaluate the concordance of prior local laboratory BRAF molecular profiling with a central BRAF alteration assay being evaluated by the Sponsor	Molecular analysis of cells obtained from archival tissue	Up to 48 months
Secondary	Arm 1: Evaluate visual acuity (VA) outcomes compared with baseline	Measured by Teller Acuity Cards® II	Up to 48 months
Secondary	Arms 1 & 2: ORR by IRC and Investigator using RAPNO criteria	Measured by the proportion of patients with best overall confirmed response of CR or PR by RAPNO-LGG criteria	Up to 48 months
Secondary	Arms 1 & 2: Progression free survival (PFS) using RANO and RAPNO criteria by 1) an IRC and 2) the treating Investigator (RANO only)	Measured by the time following initiation of DAY101 to progression or death in patients treated with DAY101	Up to 48 months
Secondary	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)	Measured by the length of response in patients with best overall confirmed response of CR or PR by RANO and RAPNO criteria	Up to 48 months
Secondary	Arms 1 & 2: Time to response following initiation of DAY101	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)	Up to 48 months
Secondary	Arms 1 & 2: Clinical benefit rate based on the proportion of patients with best overall response using RANO or RAPNO criteria	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)	Up to 48 months
Secondary	Arms 1 & 3: Assess the safety and tolerability of DAY101	Type, frequency, and severity of treatment-emergent adverse events and laboratory abnormalities	Up to 48 months
Secondary	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	Measured by the length of response in patients with best overall confirmed response of CR or PR by RECIST v1.1 criteria	Up to 48 months
Secondary	Arm 3: Time to response following initiation of DAY101	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	Up to 48 months
Secondary	Arm 3: Clinical benefit rate based on the proportion of patients with best overall response using RECIST v1.1 criteria	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	Up to 48 months