DAY101 vs. Standard of Care Chemotherapy in Pediatric Participants With Low-Grade Glioma Requiring First-Line Systemic Therapy (LOGGIC/FIREFLY-2)

Conditions

Low-grade Glioma, Rapidly Accelerated Fibrosarcoma (RAF) Altered Glioma, Pediatric Low-grade Glioma

Keywords

Rapidly accelerated fibrosarcoma, RAF alteration glioma, Glioneural tumor, Ojemda

Brief summary

This is a 2-arm, randomized, open-label, multicenter, global, Phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy versus standard of care (SoC) chemotherapy in participants with pediatric low-grade glioma (LGG) harboring an activating rapidly accelerated fibrosarcoma (RAF) alteration requiring first-line systemic therapy.

Detailed description

Approximately 400 treatment-naïve LGG participants will be randomized 1:1 to either tovorafenib (Arm 1) or an Investigator's choice of SoC chemotherapy (Arm 2). Arm 1 (tovorafenib): Treatment cycles will repeat every 28 days in the absence of disease progression. Participants will continue tovorafenib until any of the following occurs: disease progression, unacceptable toxicity, withdrawal of consent to treatment, or end of study. Arm 2 (Investigator's Choice of SoC Chemotherapy): Participants will receive one of 4 SoC chemotherapy options selected by the treating Investigator: Children's Oncology Group - Vincristine/Carboplatin (COG-V/C) regimen, International Society for Paediatric Oncology - Low-Grade Glioma Vincristine/Carboplatin (SIOPe-LGG-V/C) regimen, vinblastine (VBL) regimen, or monthly carboplatin. The choice of SoC chemotherapy regimen will be selected prior to participant randomization. Treatment will continue until completion of therapy or until any of the following occurs: disease progression, unacceptable toxicity, withdrawal of consent to treatment, or end of study. Participants who discontinue treatment due to disease progression will have (1) radiographic evidence of disease progression, as determined by the Investigator, or (2) clinical progression, as determined by the Investigator. Investigators are encouraged to discuss cases of clinical progression and early radiographic progression without clinical symptoms with the Sponsor Medical Monitor prior to treatment discontinuation or initiation of a different form of treatment for the malignancy. Participants may continue therapy beyond progressive disease (PD).

Cornelis M. van Tilburg, Lindsay Kilburn, Sébastien Perreault, René Schmidt, Amedeo A. Azizi et al. (26 authors)

BMC Cancer2024-01-3048 citations

10.1186/s12885-024-11820-x

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial.

Kilburn LB, Khuong-Quang DA, Hansford JR, Landi D, van der Lugt J, Leary SES, Driever PH, Bailey S, Perreault S, McCowage G, Waanders AJ, Ziegler DS, Witt O, Baxter PA, Kang HJ, Hassall TE, Han JW, Hargrave D, Franson AT, Yalon Oren M, Toledano H, Larouche V, Kline C, Abdelbaki MS, Jabado N, Gottardo NG, Gerber NU, Whipple NS, Segal D, Chi SN, Oren L, Tan EEK, Mueller S, Cornelio I, McLeod L, Zhao X, Walter A, Da Costa D, Manley P, Blackman SC, Packer RJ, Nysom K.

2023-11-17102 citations

10.1038/s41591-023-02668-y

Clinical activity of pan-RAF inhibitor tovorafenib in the registrational pediatric low-grade glioma arm of the phase 2 FIREFLY-1 (PNOC026) study.

Lindsay Kilburn, Dong‐Anh Khuong‐Quang, Karsten Nysom, Daniel Landi, David S. Ziegler et al. (20 authors)

Journal of Clinical Oncology2023-06-0113 citations

10.1200/jco.2023.41.16_suppl.10004

LOGGIC/FIREFLY-2: A phase 3, randomized trial of tovorafenib vs. chemotherapy in pediatric and young adult patients with newly diagnosed low-grade glioma harboring an activating <i>RAF</i> alteration.

Cornelis M. van Tilburg, Lindsay Kilburn, Erin Crotty, Amy Smith, Sébastien Perreault et al. (20 authors)

Journal of Clinical Oncology2023-06-014 citations

10.1200/jco.2023.41.16_suppl.tps10067

Phase 1 study of the pan-RAF inhibitor tovorafenib in patients with advanced solid tumors followed by dose expansion in patients with metastatic melanoma.

Rasco DW, Medina T, Corrie P, Pavlick AC, Middleton MR, Lorigan P, Hebert C, Plummer R, Larkin J, Agarwala SS, Daud AI, Qiu J, Bozon V, Kneissl M, Barry E, Olszanski AJ.

2023-05-2327 citations

10.1007/s00280-023-04544-5

Interventions

DRUGTovorafenib

Oral Tablet Powder for Oral Suspension

DRUGChemotherapeutic Agent

Intravenous solution for injection

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

Tovorafenib versus standard of care chemotherapy

Eligibility

Sex/Gender

ALL

Age

No minimum to 25 Years

Healthy volunteers

No

Inclusion criteria

* Less than 25 years of age with LGG with known activating RAF alteration. * Histopathologic diagnosis of glioma or glioneuronal tumor. * At least one measurable lesion as defined by RANO criteria. * Meet indication for first-line systemic therapy.

Exclusion criteria

* Participant has any of the following tumor-histological findings: 1. Schwannoma 2. Subependymal giant cell astrocytoma (Tuberous Sclerosis) 3. Diffuse intrinsic pontine glioma, even if histologically diagnosed as World Health Organization (WHO) Grade I-II * Participant's tumor has additional pathogenic molecular alterations, including but not limited to a) isocitrate dehydrogenase (IDH) 1/2 mutation, b) Histone H3 mutation, and c) neurofibromatosis Type 1 (NF-1) loss of function alteration. * Known or suspected diagnosis of NF-1/ neurofibromatosis Type 2 (NF-2). * Prior or ongoing nonsurgical anticancer therapy for this indication (eg, chemotherapy, oral/IV targeted therapy) including radiation.

Design outcomes

Primary

Measure	Time frame	Description
Objective response rate (ORR) of tovorafenib monotherapy versus SoC chemotherapy	Up to 60 months	ORR assessed per Response Assessment in Pediatric Neuro Oncology (RAPNO) criteria by Independent Review Committee (IRC), and defined as the proportion of participants with overall confirmed response of complete response (CR), partial response (PR), or minor response (MR).

Secondary

Measure	Time frame	Description
Visual progression-free survival (v-PFS) of tovorafenib monotherapy versus SoC chemotherapy	Up to 60 months	Visual progression-free survival is defined as the time from start of treatment to visual event for OPG participants aged ≥ 3 years.
Progression-free survival (PFS) of tovorafenib monotherapy versus SoC chemotherapy	Up to 60 months	PFS assessed per RAPNO criteria by IRC, and deﬁned as time from randomization to PD or death from any cause, whichever comes first.
Event-free survival (EFS) of tovorafenib monotherapy versus SoC chemotherapy	Up to 60 months	EFS assessed per RAPNO criteria by IRC, deﬁned as time from randomization to PD, death from any cause, or initiation of any new anticancer therapy, whichever comes first.
Overall survival (OS) of tovorafenib monotherapy versus SoC chemotherapy	Up to 60 months	Overall survival is defined as time from randomization up to death from any cause.
Number of participants with any treatment-emergent adverse events, and Serious adverse events	Up to 60 months	Type, frequency, and severity of adverse events of tovorafenib monotherapy versus SoC chemotherapy will be assessed.
. Number of participants with clinically significant vital signs and laboratory abnormalities findings	Up to 60 months	Type, frequency, and severity of vital signs and laboratory abnormalities of tovorafenib monotherapy versus SoC chemotherapy will be assessed.
Change from baseline in Adaptive Behavior Composite Score (ABS) of tovorafenib monotherapy versus SoC chemotherapy	Baseline, Year 1, 2 and 5	Adaptive behavior Composite Score will be evaluated using domain scores collected from the comprehensive Vineland III Adaptive Behavior Scale (VABS).
Change from baseline in the Motor Skills Domain Score of tovorafenib monotherapy versus SoC chemotherapy	Baseline, Year 1, 2 and 5	The motor skills (gross and fine) will be assessed using the Motor Skills Score domain of the VABS in pediatric participants.
Change from baseline in the Daily Living Domain Score of tovorafenib monotherapy versus SoC chemotherapy	Baseline, Year 1, 2 and 5	The daily living (personal, domestic and community) will be assessed using Daily Living Domain Score of VABS.
Change from baseline in the Communication Domain Score of tovorafenib monotherapy versus SoC chemotherapy	Baseline, Year 1, 2 and 5	The communication skills (receptive, expressive and written) will be assessed using Communication Domain Score of VABS.
Change from baseline in the Socialization Domain Score of tovorafenib monotherapy versus SoC chemotherapy	Baseline, Year 1, 2 and 5	The socialization skills (Interpersonal relationships, play and leisure time and coping skills) will be assessed using Socialization Domain Score of VABS.
Change in age-adjusted visual acuity (VA) of tovorafenib monotherapy versus SoC chemotherapy in optic pathway glioma (OPG) participants aged < 3 years	Baseline and up to 5 years	Visual acuity testing using current age-appropriate testing methodology will be performed for all participants at Screening. For participants with OPG or an underlying visual deficit related to the primary malignancy, visual acuity testing will be performed every time participants have a radiographic response assessment. Assessments will be performed in each eye separately at a recommended testing distance of 3 meters.
ORR of tovorafenib monotherapy versus SoC chemotherapy	Up to 60 months	ORR, defined as the proportion of participants with overall confirmed response per Response Assessment in Neuro-Oncology for High-Grade Glioma (RANO-HGG) criteria (CR or PR) and RANO-LGG criteria (CR, PR, or MR), as applicable.
Clinical beneﬁt rate (CBR) of tovorafenib monotherapy versus SoC chemotherapy	Up to 60 months	CBR, deﬁned as the proportion of participants with radiological tumor stabilization or regression per RANO-LGG (CR, PR, MR, or SD lasting 12 months or more), RANO-HGG (CR, PR, or SD lasting 12 months or more) or RAPNO criteria (CR, PR, MR or SD lasting 12 months or more), as applicable.
Time to response (TTR) of tovorafenib monotherapy versus SoC chemotherapy	Up to 60 months	TTR, measured by the time following randomization to ﬁrst imaging of tumor response that was subsequently conﬁrmed per RANO-HGG criteria (CR or PR), RANO-LGG criteria (CR, or PR, or MR), or RAPNO criteria (CR, PR, or MR), as applicable.
PFS of tovorafenib monotherapy versus SoC chemotherapy	Up to 60 months	PFS per RANO-HGG or RANO-LGG criteria (as applicable), deﬁned as time from randomization to PD or death from any cause, whichever occurs first.
EFS of tovorafenib monotherapy versus SoC chemotherapy	Up to 60 months	EFS per RANO-HGG or RANO-LGG criteria (as applicable), defined as time from randomization to PD, death from any cause, or initiation of any new anticancer therapy, whichever comes first.
Duration of response (DOR) of tovorafenib monotherapy versus SoC chemotherapy	Up to 60 months	DOR, deﬁned as time from first imaging of tumor response per RANO-LGG, RANO-HGG or RAPNO criteria, as applicable, that was subsequently confirmed to radiographic PD or death from any cause, whichever comes first.
Change in best corrected visual acuity of tovorafenib monotherapy versus SoC chemotherapy in OPG participants aged ≥ 3 years	Baseline and up to 5 years	Visual acuity assessments to be performed by an ophthalmologist or another qualified site clinical personnel.
Change from Baseline in health-related quality of life (HRQoL) total score of tovorafenib monotherapy versus SoC chemotherapy	Baseline, Year 1, 2 and 5	The Patient-Reported Outcomes Measurement Information System (PROMIS®) Pediatric/Parent Proxy Profile 49 v2.0 will be used to assess mental and social HRQoL.

Countries

Australia, Austria, Belgium, Brazil, Canada, Czechia, Denmark, Egypt, Finland, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Jordan, Netherlands, New Zealand, Norway, Qatar, Singapore, Slovenia, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States

Contacts

CONTACTDay One Clinical Trials Information

clinicaltrials@dayonebio.com650-484-0899

Outcome results

None listed