FIREFLY-1: A Study to Evaluate DAY101 in Pediatric and Young Adult Patients With Relapsed or Progressive Low-Grade Glioma

• Sponsor: Day One Biopharmaceuticals, Inc. (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT04775485
• Collaborator: Pacific Pediatric Neuro-Oncology Consortium (Other)
• Enrollment: 140
• Locations: 36
• Arms: 3
• Anticipated Duration (Months): 35.4
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

FIREFLY-1 is a 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 BRAF alteration.

Condition or Disease	Intervention/Treatment	Phase
Low-grade Glioma; Advanced Solid Tumor	Drug: DAY101	Phase 2

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 Design

• Study Type: Interventional
• Anticipated Enrollment: 140 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 BRAF-Altered, Recurrent or Progressive Low-Grade Glioma and Advanced Solid Tumors
• Actual Study Start Date: Mar 17, 2021
• Anticipated Primary Completion Date: Mar 30, 2023
• Anticipated Study Completion Date: Feb 28, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm #1 Pediatric patients with low-grade glioma treated with DAY101 (Registrational Arm)	Drug: DAY101; DAY101 is an oral pan-RAF inhibitor provided as an immediate-release tablet (100 mg) or powder for reconstitution (25 mg/mL).
Experimental: Arm #2 Expanded access arm of pediatric patients with low-grade glioma treated with DAY101	Drug: DAY101; DAY101 is an oral pan-RAF inhibitor provided as an immediate-release tablet (100 mg) or powder for reconstitution (25 mg/mL).
Experimental: Arm #3 Pediatric patients with advanced solid tumors treated with DAY101	Drug: DAY101; DAY101 is an oral pan-RAF inhibitor provided as an immediate-release tablet (100 mg) or powder for reconstitution (25 mg/mL).

Outcome Measures

Primary Outcome Measures

1. Arm 1: Overall response rate (ORR) by independent radiology review committee (IRC) based on RANO criteria [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

2. Arm 2: Assess the safety and tolerability of DAY101 [Up to 48 months]

   Type, frequency, and severity of treatment-emergent adverse events and laboratory

3. Arm 3: Overall response rate (ORR) by independent radiology review committee (IRC) based on RECIST v1.1 criteria [Up to 48 months]

   Measured by the proportion of patients with best overall confirmed response of CR or PR by RECIST v1.1 criteria

Secondary Outcome Measures

1. Relationship between pharmacokinetics (PK) and drug effects [Up to 48 months]

   Pharmacokinetic profile of DAY101 (e.g., area under the concentration-time curve [AUC], Cmin, etc.)

2. Effect on electrocardiogram (ECG) and QT interval corrected for heart rate by Fridericia's formula (QTcF) prolongation [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

3. ORR by Investigator [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

4. Evaluate the concordance of prior local laboratory BRAF molecular profiling with a central BRAF alteration assay being evaluated by the Sponsor [Up to 48 months]

   Molecular analysis of cells obtained from archival tissue

5. Arm 1: Evaluate visual acuity (VA) outcomes compared with baseline [Up to 48 months]

   Measured by Teller Acuity Cards® II

6. Arms 1 & 2: ORR by IRC and Investigator using RAPNO criteria [Up to 48 months]

   Measured by the proportion of patients with best overall confirmed response of CR or PR by RAPNO-LGG criteria

7. Arms 1 & 2: Progression free survival (PFS) using RANO and RAPNO criteria by 1) an IRC and 2) the treating Investigator (RANO only) [Up to 48 months]

   Measured by the time following initiation of DAY101 to progression or death in patients treated with DAY101

8. 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) [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

9. Arms 1 & 2: Time to response following initiation of DAY101 [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)

10. Arms 1 & 2: Clinical benefit rate based on the proportion of patients with best overall response using RANO or RAPNO criteria [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)

11. Arms 1 & 3: Assess the safety and tolerability of DAY101 [Up to 48 months]

    Type, frequency, and severity of treatment-emergent adverse events and laboratory abnormalities

12. 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 [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

13. Arm 3: Time to response following initiation of DAY101 [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

14. Arm 3: Clinical benefit rate based on the proportion of patients with best overall response using RECIST v1.1 criteria [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

Other Outcome Measures

1. 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 [Up to 48 months]

   Measured by changes from baseline in quality-of-life and health utilities measures using the PedsQL-Core and PROMIS assessment

2. Evaluate the concordance of prior local laboratory BRAF molecular profiling with a central BRAF alteration assay [Up to 48 months]

   Molecular analysis of cells obtained from archival tissue

3. Arm 1: Compare the response and time to progression following initiation of DAY101 to that of the prior line of systemic therapy [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

4. Arms 1 & 2: Characterize changes in total tumor volume following treatment with DAY101 by magnetic resonance imaging (MRI) volumetric image analysis [Up to 48 months]

   Measured by determining tumor volume and volume changes based on MRI scan data

5. Arms 1 & 2: Characterize changes in apparent diffusion coefficients following treatment with DAY101 using diffusion-weighted imaging analysis [Up to 48 months]

   Measured by diffusion-weighted imaging based on MRI scan data

6. Arms 1 & 2: Describe the improvement in motor function compared with baseline [Up to 48 months]

   Measured by changes in the Vineland 3 Adaptive Behavior Scales

7. Arms 1 & 2: Determine the durability of response following discontinuation of DAY101 for patients with a radiographic response to DAY101 [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)

8. 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 [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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months to 25 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Benioff Children's Hospital	San Francisco	California	United States	94143
2	Children's National Medical Center	Washington	District of Columbia	United States	20010
3	Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
4	Johns Hopkins Hospital	Baltimore	Maryland	United States	21231
5	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
6	CS Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
7	St. Louis Children's Hospital	Saint Louis	Missouri	United States	63110
8	NYU Langone Health	New York	New York	United States	10016
9	Duke Cancer Center	Durham	North Carolina	United States	27710
10	Doernbecher Children's Hospital Oregon & Health Science University	Portland	Oregon	United States	97239
11	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
12	Texas Children's Hospital	Houston	Texas	United States	77030
13	University of Utah	Salt Lake City	Utah	United States	84113
14	Seattle Children's Hospital	Seattle	Washington	United States	98105
15	Queensland Children's Hospital	Brisbane		Australia	4101
16	Royal Children's Hospital	Parkville		Australia	3052
17	Perth Children's Hospital	Perth		Australia	WA 6009
18	Sydney Children's Hospital	Randwick		Australia	NSW 2031
19	The Children's Hospital at Westmead	Westmead		Australia	2145
20	Centre Hospitalier Universitaire Ste-Justine	Montreal	Quebec	Canada	H3T 1C5
21	Montreal Children's Hospital	Montreal	Quebec	Canada	H4A 3J1
22	Centre Mère-Enfant Soleil du CHU	Québec	Quebec	Canada	G1V 4G2
23	Centre Hospitalier Universitaire Ste-Justine	Montréal		Canada	QC H3T 1C5
24	Rigshospitalet	Copenhagen		Denmark
25	Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Otto-Heubner-Centrum für Kinder	Berlin		Germany	13353
26	Hopp-Kindertumorzentrum Heidelberg (KiTZ), KiTZ Clinical Trial Unit (ZIPO)	Heidelberg		Germany	69120
27	Rambam Health Care Campus	Haifa		Israel	3109601
28	Schneider Children's Medical Center of Israel	Petah Tikva		Israel	4920235
29	The Chaim Sheba Medical Center	Ramat Gan		Israel	5265601
30	Seoul National University Hospital	Seoul		Korea, Republic of	3080
31	Severance Hospital - Yonsei University	Seoul		Korea, Republic of	3722
32	Princess Maxima Center for Pediatric Oncology	Utrecht		Netherlands	3584 CS
33	KK Women's and Children's Hospital	Singapore		Singapore	229899
34	Universitäts-Kinderspital Zürich - Eleonorenstiftung	Zürich		Switzerland	8032
35	UCL Great Ormond Street Institute of Child Health	London		United Kingdom	WC1N 1EH
36	Newcastle University	Newcastle Upon Tyne		United Kingdom	NE1 7RU

Sponsors and Collaborators

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

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Day One Biopharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT04775485
• Other Study ID Numbers: DAY101-001/PNOC026
• First Posted: Mar 1, 2021
• Last Update Posted: Jun 1, 2022
• Last Verified: May 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Glioma

Study Results

No Results Posted as of Jun 1, 2022