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

Study Overview
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Brief Summary
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This is a 2-arm, randomized, open-label, multicenter, global, Phase 3 trial to evaluate the efficacy, safety, and tolerability of DAY101 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.

Detailed Description
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Approximately 400 treatment-naïve low-grade glioma patients will be randomized 1:1 to either DAY101 (Arm 1) or an Investigator's choice of SoC chemotherapy (Arm 2). Arm 1 (DAY101): treatment cycles will repeat every 28 days in the absence of disease progression. Patients will continue DAY101 until any of the following occurs: radiographic progression based on Response Assessment in Neuro-Oncology (RANO) criteria as determined by the Investigator and confirmed by the Independent Review Committee (IRC), 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: radiographic progression based on RANO criteria as determined by the Investigator and confirmed by the IRC, unacceptable toxicity, withdrawal of consent to treatment, or end of study. During treatment phase, patients who demonstrate radiographic progression per RANO criteria as determined by the Investigator and confirmed by IRC in Arm 1 (DAY101) may be allowed to continue DAY101 if, in the opinion of the Investigator, the patient is deriving clinical benefit from continuing study treatment and approved by the Sponsor. Patients who demonstrate radiographic progression per RANO criteria as determined by the Investigator and confirmed by IRC during the treatment phase in Arm 2 (SoC chemotherapy) and discontinue treatment may be eligible to receive DAY101 at the same treatment and assessment schedule. In addition, Arm 2 patients who demonstrate radiographic progression after completion of chemotherapy [ie, during long-term follow-up (LTFU)] may be eligible to receive DAY101.

Official Title
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LOGGIC/FIREFLY-2: A Phase 3, Randomized, International Multicenter Trial of DAY101 Monotherapy Versus Standard of Care Chemotherapy in Patients With Pediatric Low-Grade Glioma Harboring an Activating RAF Alteration Requiring First-Line Systemic Therapy

Conditions
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Low-grade Glioma

Intervention / Treatment
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* Drug: DAY101
* Drug: Chemotherapeutic Agent


Participation Criteria
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Eligibility Criteria
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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: Schwannoma Subependymal giant cell astrocytoma (Tuberous Sclerosis) Diffuse intrinsic pontine glioma, even if histologically diagnosed as World Health Organization (WHO) Grade I-II Patient's tumor has additional activating molecular alterations 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

Ages Eligible for Study
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Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: DAY101 versus standard of care chemotherapy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm #1<br>DAY101 | Drug: DAY101<br>* Oral pan-RAF inhibitor<br>* Other names: tovorafenib;|
| Active Comparator: Arm #2<br>Investigator's choice of one of the following current standard of care for pediatric patients with low-grade gliomas: Children's Oncology Group - Vincristine/Carboplatin (COG-V/C) International Society for Paediatric Oncology - Low-Grade Glioma Vincristine/Carboplatin (SIOPe-LGG-V/C) Vinblastine (VBL) | Drug: Chemotherapeutic Agent<br>* Intravenous solution for injection<br>* Other names: VBL;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare the objective response rate (ORR) assessed per RANO criteria by independent review committee (IRC) of DAY101 monotherapy versus standard of care (SoC) chemotherapy | ORR, per RANO 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 Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare the progression-free survival (PFS) assessed by IRC of DAY101 monotherapy versus SoC chemotherapy per RANO criteria | PFS per RANO 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 DAY101 monotherapy versus SoC chemotherapy per RANO criteria | DOR per RANO 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 DAY101 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 DAY101 monotherapy versus SoC chemotherapy | Type, frequency, and severity of treatment-emergent adverse events | Up to 60 months | 
| Compare the safety and tolerability of DAY101 monotherapy versus SoC chemotherapy | Measured by incidence of clinically significant laboratory abnormalities | Up to 60 months | 
| Compare changes in neurological function between DAY101 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 DAY101 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 DAY101 monotherapy versus SoC chemotherapy as assessed by IRC per RANO criteria | ORR, deﬁned as the proportion of patients with overall conﬁrmed response per RANO | Up to 60 months | 
| Compare the ORR of DAY101 monotherapy versus SoC chemotherapy as assessed by IRC per Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria | ORR, deﬁned as the proportion of patients with overall confirmed response per RAPNO | Up to 60 months | 
| Compare the clinical beneﬁt rate (CBR) of DAY101 monotherapy versus SoC chemotherapy as assessed by IRC per RANO and RAPNO criteria | CBR, deﬁned as the proportion of patients with radiological tumor stabilization or regression per RANO or RAPNO criteria, as applicable | Up to 60 months | 
| Compare time to response (TTR) of DAY101 monotherapy versus SoC chemotherapy as assessed by IRC per RANO and RAPNO criteria | Measured by the time to ﬁrst response following initiation of therapy in patients with best overall conﬁrmed response per RANO or RAPNO criteria, as applicable | Up to 60 months | 
| Compare the PFS of DAY101 monotherapy versus SoC chemotherapy as assessed by IRC per RAPNO and RANO criteria | PFS per RANO or RAPNO (as applicable), deﬁned as time from randomization to progressive disease (PD) or death from any cause | Up to 60 months | 
| Compare the DOR of DAY101 monotherapy versus SoC chemotherapy as assessed by IRC per RAPNO and RANO 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 |