DAY101 vs. Standard of Care Chemotherapy in Pediatric Participants With Low-Grade Glioma Requiring First-Line Systemic Therapy (LOGGIC/FIREFLY-2)
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.
Study details:
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).
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
- 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.
Eligibility
Age eligible for study : NA
Healthy volunteers accepted : No
Gender eligible for study: ALL
Things to know
Study dates
Study start:
Primary completion:
Study completion finish:
Study type
TREATMENT
Phase
- PHASE3
Study ID
NCT05566795
Intervention or treatment
DRUG: Tovorafenib
DRUG: Chemotherapeutic Agent
Conditions
- Low-grade Glioma
- Rapidly Accelerated Fibrosarcoma (RAF) Altered Glioma
- Pediatric Low-grade Glioma
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Research sites nearby
Closest Location:
Children's Health Queensland Hospital and Health Service
Select from list below to view details:
Children's Health Queensland Hospital and Health Service
South Brisbane, Queensland, Australia
Perth Children's Hospital
Nedlands, Australia
Women's and Children's Health Network
North Adelaide, Australia
The Royal Children's Hospital - Children's Cancer Centre
Parkville, Australia
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Who is running the clinical trial?
Day One Biopharmaceuticals, Inc.
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: Tovorafenib
| Drug: Tovorafenib |
ACTIVE_COMPARATOR: Investigator's choice of Standard of care therapy
| Drug: Chemotherapeutic Agent |
What is the study measuring?
Primary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| Objective response rate (ORR) of tovorafenib monotherapy versus SoC chemotherapy | 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). | Up to 60 months |
Secondary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| Progression-free survival (PFS) of tovorafenib monotherapy versus SoC chemotherapy | PFS assessed per RAPNO criteria by IRC, and defined as time from randomization to PD or death from any cause, whichever comes first. | Up to 60 months |
| Event-free survival (EFS) of tovorafenib monotherapy versus SoC chemotherapy | 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. | Up to 60 months |
| Overall survival (OS) of tovorafenib monotherapy versus SoC chemotherapy | Overall survival is defined as time from randomization up to death from any cause. | Up to 60 months |
| Number of participants with any treatment-emergent adverse events, and Serious adverse events | Type, frequency, and severity of adverse events of tovorafenib monotherapy versus SoC chemotherapy will be assessed. | Up to 60 months |
| . Number of participants with clinically significant vital signs and laboratory abnormalities findings | Type, frequency, and severity of vital signs and laboratory abnormalities of tovorafenib monotherapy versus SoC chemotherapy will be assessed. | Up to 60 months |
| Change from baseline in Adaptive Behavior Composite Score (ABS) of tovorafenib monotherapy versus SoC chemotherapy | Adaptive behavior Composite Score will be evaluated using domain scores collected from the comprehensive Vineland III Adaptive Behavior Scale (VABS). | Baseline, Year 1, 2 and 5 |
| Change from baseline in the Motor Skills Domain Score of tovorafenib monotherapy versus SoC chemotherapy | The motor skills (gross and fine) will be assessed using the Motor Skills Score domain of the VABS in pediatric participants. | Baseline, Year 1, 2 and 5 |
| Change from baseline in the Daily Living Domain Score of tovorafenib monotherapy versus SoC chemotherapy | The daily living (personal, domestic and community) will be assessed using Daily Living Domain Score of VABS. | Baseline, Year 1, 2 and 5 |
| Change from baseline in the Communication Domain Score of tovorafenib monotherapy versus SoC chemotherapy | The communication skills (receptive, expressive and written) will be assessed using Communication Domain Score of VABS. | Baseline, Year 1, 2 and 5 |
| Change from baseline in the Socialization Domain Score of tovorafenib monotherapy versus SoC chemotherapy | The socialization skills (Interpersonal relationships, play and leisure time and coping skills) will be assessed using Socialization Domain Score of VABS. | Baseline, Year 1, 2 and 5 |
| Change in age-adjusted visual acuity (VA) of tovorafenib monotherapy versus SoC chemotherapy in optic pathway glioma (OPG) participants aged < 3 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. | Baseline and up to 5 years |
| Change in best corrected visual acuity of tovorafenib monotherapy versus SoC chemotherapy in OPG participants aged ≥ 3 years | Visual acuity assessments to be performed by an ophthalmologist or another qualified site clinical personnel. | Baseline and up to 5 years |
| Visual progression-free survival (v-PFS) of tovorafenib monotherapy versus SoC chemotherapy | Visual progression-free survival is defined as the time from start of treatment to visual event for OPG participants aged ≥ 3 years. | Up to 60 months |
| ORR of tovorafenib monotherapy versus SoC chemotherapy | 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. | Up to 60 months |
| Clinical benefit rate (CBR) of tovorafenib monotherapy versus SoC chemotherapy | 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. | Up to 60 months |
| Time to response (TTR) of tovorafenib monotherapy versus SoC chemotherapy | 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. | Up to 60 months |
| PFS of tovorafenib monotherapy versus SoC chemotherapy | 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. | Up to 60 months |
| EFS of tovorafenib monotherapy versus SoC chemotherapy | 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. | Up to 60 months |
| Duration of response (DOR) of tovorafenib monotherapy versus SoC chemotherapy | 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. | Up to 60 months |
| Change from Baseline in health-related quality of life (HRQoL) total score of tovorafenib monotherapy versus SoC chemotherapy | The Patient-Reported Outcomes Measurement Information System (PROMIS®) Pediatric/Parent Proxy Profile 49 v2.0 will be used to assess mental and social HRQoL. | Baseline, Year 1, 2 and 5 |
References
Clinical Trials Gov: DAY101 vs. Standard of Care Chemotherapy in Pediatric Participants With Low-Grade Glioma Requiring First-Line Systemic Therapy (LOGGIC/FIREFLY-2)Other trials to consider
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