Low-grade Glioma, Rapidly Accelerated Fibrosarcoma (RAF) Altered Glioma, Pediatric Low-grade Glioma
Conditions
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).
Interventions
DRUGTovorafenib
Oral Tablet Powder for Oral Suspension
Intravenous solution for injection
Sponsors
Day One Biopharmaceuticals, Inc.
SIOPe Brain Tumor Group LOGGIC Consortium
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 harboring a documented known activating RAF alteration, as identified through molecular assays performed at Clinical Laboratory Improvement Amendments (CLIA) or other similarly certified laboratories. * Histopathologic diagnosis of glioma or glioneuronal tumor. * At least one measurable T2/FLAIR lesion that can be reproducibly measured in at least 2 dimensions of at least 10 millimetres (mm), visible on 2 or more axial slices that are preferably, at most, 5 mm apart with 0-mm skip. * 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, (even if histologically low-grade) including but not limited to any of the following: 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) via genetic testing or current diagnostic clinical criteria. * 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 |
|---|---|---|
| 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. |
| Time to next treatment (TTNT) of tovorafenib monotherapy versus SoC chemotherapy | Up to 60 months | Time to next treatment is defined as time from randomization to initiation of any new anticancer treatment or death from any cause, whichever occurs 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. |
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
Outcome results
None listed