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DAY101 Vs. Standard of Care Chemotherapy in Pediatric Patients with Low-Grade Glioma Requiring First-Line Systemic Therapy (LOGGIC/FIREFLY-2)

PHASE3RECRUITING

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 patients with pediatric low-grade glioma (LGG) harboring an activating rapidly accelerated fibrosarcoma (RAF) alteration requiring front-line systemic therapy.

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Study details:

Approximately 400 treatment-naïve low-grade glioma patients 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. Patients will continue tovorafenib until any of the following occurs: disease progression based on Response Assessment in Neuro-Oncology (RANO-LGG) criteria, unacceptable toxicity, withdrawal of consent to treatment, or end of study.

Arm 2 (Investigator's Choice of SoC Chemotherapy): patients will receive one of 3 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, or vinblastine (VBL) regimen. The choice of SoC chemotherapy regimen will be selected prior to patient randomization. Treatment will continue until completion of therapy or until any of the following occurs: disease progression based on RANO-LGG criteria, unacceptable toxicity, withdrawal of consent to treatment, or end of study.

Patients who discontinue treatment due to disease progression will have (1) radiographic evidence of progressive disease based on RANO-LGG, as determined by the Investigator and confirmed by the IRC, or (2) clinical progression based on RANO-LGG criteria determined by the Investigator. Investigators are encouraged to discuss cases of clinical progression and early radiographic progression without clinical symptom with the Sponsor Medical Monitor prior to treatment discontinuation or initiation of a different form of treatment for the malignancy. Patients may continue therapy beyond progressive disease.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

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

Patient 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

Patient's tumor has additional pathogenic molecular alterations, including but not limited to a) IDH 1/2 mutation, b) Histone H3 mutation, and c) NF-1 loss of function alteration.

Known or suspected diagnosis of neurofibromatosis Type 1 or 2 (NF-1/NF-2)

Prior or ongoing nonsurgical anticancer therapy for this indication (eg, chemotherapy, oral/intravenous targeted therapy) including radiation

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Eligibility

Age eligible for study : 0 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2023-02-27

Primary completion: 2026-02-01

Study completion finish: 2030-03-01

Study type

TREATMENT

Phase

PHASE3

Trial ID

NCT05566795

Intervention or treatment

DRUG: Tovorafenib

DRUG: Chemotherapeutic Agent

Conditions

• Low-grade Glioma

Condition: Low-grade Glioma
DRUG: Tovorafenib and other drugs
South Brisbane, Queensland, Australia and more
Sponsor: Day One Biopharmaceuticals, Inc.

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Find a site

Closest Location:

Children's Health Queensland Hospital and Health Service

Research sites nearby

Select from list below to view details:

Children's Health Queensland Hospital and Health Service
South Brisbane, Queensland, Australia
Perth Children's Hospital
Nedlands, Not Specified, Australia
Women's and Children's Health Network
North Adelaide, Not Specified, Australia
The Royal Children's Hospital - Children's Cancer Centre
Parkville, Not Specified, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Arm #1 Tovorafenib	DRUG: Tovorafenib Oral type II RAF kinase inhibitor
ACTIVE_COMPARATOR: Arm #2 Investigator's choice of one of the following current standard of care for pediatric patients with low-grade gliomas: 1. Children's Oncology Group - Vincristine/Carboplatin (COG-V/C) 2. International Society for Paediatric Oncology - Low-Grade Glioma Vincristine/Carboplatin (SIOPe-LGG-V/C) 3. Vinblastine (VBL)	DRUG: Chemotherapeutic Agent Intravenous solution for injection

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Compare the objective response rate (ORR) assessed per RANO-LGG criteria by Independent Review Committee (IRC) of tovorafenib monotherapy versus standard of care (SoC) chemotherapy	ORR, per RANO-LGG criteria, defined as the proportion of patients with overall confirmed response of complete response (CR) or partial response (PR)	Up to 60 months

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Compare the progression-free survival (PFS) assessed by IRC of tovorafenib monotherapy versus SoC chemotherapy per RANO-LGG criteria	PFS per RANO-LGG criteria, deﬁned as time from randomization to PD or death from any cause	Up to 60 months
Compare the duration of response (DOR) assessed by IRC of tovorafenib monotherapy versus SoC chemotherapy per RANO-LGG criteria	DOR per RANO-LGG criteria, deﬁned as time from confirmed response to PD or death from any cause for patients with confirmed response	Up to 60 months
Compare the overall survival (OS) of tovorafenib monotherapy versus SoC chemotherapy	OS, defined as time from randomization up to death from any cause	Up to 60 months
Compare the safety and tolerability of tovorafenib monotherapy versus SoC chemotherapy	Type, frequency, and severity of treatment-emergent adverse events	Up to 60 months
Compare the safety and tolerability of tovorafenib monotherapy versus SoC chemotherapy	Measured by incidence of clinically significant laboratory abnormalities	Up to 60 months
Evaluate changes in neurological function and adaptive behavior between tovorafenib versus SoC	Change from baseline in the Vineland Adaptive Behavior Composite Scales \[age-adjusted standard scores range between 20 to 140, with a mean of 100 and standard deviation of 15, and lower scores indicate worse functional outcomes\]	Up to 60 months
Compare changes in visual function outcomes of tovorafenib monotherapy versus SoC chemotherapy in patients with optic pathway glioma (OPG)	Measured by Teller Acuity Cards® or alternative	Up to 60 months
Compare the ORR of tovorafenib monotherapy versus SoC chemotherapy as assessed by IRC per RANO-HGG and Response Assessment in Pediatric Neuro-Oncology (RAPNO-LGG) criteria	ORR, deﬁned as the proportion of patients with overall conﬁrmed response per RANO-HGG, RANO-LGG, or RAPNO-LGG criteria.	Up to 60 months
Compare the clinical beneﬁt rate (CBR) of tovorafenib monotherapy versus SoC chemotherapy as assessed by IRC per RANO-LGG, RANO-HGG and RAPNO-LGG criteria	CBR, deﬁned as the proportion of patients with radiological tumor stabilization or regression per RANO-LGG, RANO-HGG or RAPNO-LGG criteria, as applicable	Up to 60 months
Compare time to response (TTR) of tovorafenib monotherapy versus SoC chemotherapy as assessed by IRC per RANO-LGG, RANO-HGG and RAPNO-LGG criteria	Measured by the time to ﬁrst response following initiation of therapy in patients with best overall conﬁrmed response per RANO-LGG, RANO-HGG or RAPNO-LGG criteria, as applicable	Up to 60 months
Compare the PFS of tovorafenib monotherapy versus SoC chemotherapy as assessed by IRC per RAPNO-LGG and RANO-HGG criteria	PFS per RANO-HGG or RAPNO-LGG (as applicable), deﬁned as time from randomization to progressive disease (PD) or death from any cause	Up to 60 months
Compare the DOR of tovorafenib monotherapy versus SoC chemotherapy as assessed by IRC per RAPNO-LGG and RANO-HGG criteria	DOR, deﬁned as time from conﬁrmed response to PD or death from any cause for patients with confirmed response per RANO or RAPNO criteria, as applicable	Up to 60 months
Evaluate the health-related quality of life (HRQoL) in tovorafenib versus SoC chemotherapy using Patient-Reported Outcomes Measurement Information System (PROMIS) test battery	Measured by change from baseline in Total Score at 1, 2, 5 years	Up to 60 months

Frequently Asked Questions

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References

Clinical Trials Gov: DAY101 Vs. Standard of Care Chemotherapy in Pediatric Patients with Low-Grade Glioma Requiring First-Line Systemic Therapy (LOGGIC/FIREFLY-2)