Low-grade Glioma, Advanced Solid Tumor
Conditions
Keywords
Low-grade Glioma, Advanced Solid Tumor, FIREFLY-1, DAY101, Tovorafenib
Brief summary
This is a Phase 2, multi center, open-label study to evaluate the safety and efficacy of Type II RAF (tovorafenib) in pediatric participants with low-grade glioma or advanced solid tumors. Qualifying genomic alterations will be identified through molecular assays as routinely performed at Clinical Laboratory Improvement Amendments (CLIA) of 1988 or other similarly certified laboratories prior to enrollment into any of the arms. The study will consist of a screening period, a treatment period, a long-term extension phase, end of treatment (EOT) visit(s), a safety follow-up visit, and long-term follow-up assessments.
Interventions
DRUGTovorafenib
Tovorafenib is an oral Type II RAF kinase inhibitor available in 100 mg immediate-release tablet or 25 mg/milliliter (mL) powder for reconstitution.
Sponsors
Pacific Pediatric Neuro-Oncology Consortium
Day One Biopharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 25 Years
Healthy volunteers
No
Inclusion criteria
* Low Grade Glioma & Low-Grade Glioma Extension: a relapsed or progressive LGG with documented known activating BRAF alteration. * Advanced Solid Tumor: locally advanced or metastatic solid tumor with documented known or expected to be activating RAF fusion. * Participants must have histopathologic verification of malignancy at either original diagnosis or relapse. * Must have received at least one line of prior systemic therapy and have documented evidence of radiographic progression. * Must have at least 1 measurable lesion as defined by RANO (Arms 1 & 2) or RECIST v1.1 (Arm 3) criteria
Exclusion criteria
* Participant's tumor has additional previously-known activating molecular alterations. * Participant has symptoms of without radiographically recurrent or radiographically progressive disease. * Known or suspected diagnosis of neurofibromatosis type 1 (NF-1) via genetic testing or current diagnostic criteria. Other inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Arm 1: Overall response rate | Up to 48 months | ORR is defined as percentage of participants with best overall confirmed response of complete response (CR) or partial response (PR) by the Response Assessment in Neuro-Oncology - high-grade glioma (RANO-HGG) criteria. |
| Arm 2: Number of participants reporting adverse events | Up to 48 months | An adverse event (AE) is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. |
| Arm 2: Number of participants with clinically significant changes in clinical chemistry parameters | Up to 48 months | — |
| Arm 2: Number of participants with clinically significant changes in hematology parameters | Up to 48 months | — |
| Arm 3: Overall response rate | Up to 48 months | Determined by the treating investigator and measured by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or RANO-HGG criteria, as appropriate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Arm 1: Change from Baseline QT interval corrected for heart rate by Fridericia's formula (ΔQTcF) | Baseline to 48 months | — |
| Arm 1: Change from Baseline PR interval (ΔPR) | Baseline to 48 months | — |
| Arm 1: Change from Baseline QRS interval (ΔQRS) | Baseline to 48 months | — |
| Arm 1: Change from baseline heart rate (ΔHR) | Baseline to 48 months | — |
| Arm 1: Change in electrocardiogram (ECG) waveform morphology | Baseline to 48 months | — |
| Arm 1 and Arm 2: Overall response rate | Up to 48 months | ORR is defined as percentage of participants with best overall confirmed response of CR or PR by the RANO-HGG criteria. |
| Arm 1, Arm 2 and Arm 3: Overall response rate in Pediatric participants | Up to 48 months | ORR is defined as percentage of participants with best overall confirmed response of CR or PR or minor response (MR) by Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria.CR or PR by RECIST v1.1 criteria. |
| Arm 1 and 3: Number of participants reporting adverse events | Up to 48 months | An adverse event (AE) is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. |
| Arm 1, Arm 2 and Arm 3: Duration of response (DOR) | Up to 48 months | DOR as defined by the length of response in participants with best overall confirmed response of CR or PR or MR and measured by RANO-HGG, RAPNO, and/or RECIST v1.1 criteria, as applicable. |
| Arm 1, Arm 2 and Arm 3: Time to response (TTR) | Up to 48 months | TTR as defined as the time to first response following initiation of tovorafenib in participants with best overall confirmed response of CR or PR measured by RECIST v1.1 or RANO-HGG criteria, as applicable. |
| Arm 1, Arm 2 and Arm 3: Clinical benefit rate (CBR) | Up to 48 months | CBR as defined as participants with BOR of CR, PR or stable disease (SD) measured by RECIST v1.1 or RANO-HGG, as applicable, and lasting 12 months or more following initiation of tovorafenib. |
| Arm 1 and Arm 2: Duration of overall survival | Up to 48 months | Overall survival as defined by the time following initiation of tovorafenib to death of any cause in participants treated with tovorafenib. |
| Arm 1: Change from baseline in best corrected visual acuity (BCVA) outcomes | Baseline to 48 months | — |
| Arm 1: Changes in molecular analysis of cells obtained from archival tissue | At Screening | — |
| Arm 1, Arm 2 and Arm 3: duration of progression-free survival (PFS) | Up to 48 months | PFS as defined by the time following initiation of tovorafenib to progression or death in participants treated with tovorafenib measured by RECIST v1.1, RAPNO, or RANO-HGG criteria as determined by the treating investigator and an IRC. |
| Arm 1 and 3: Number of participants with clinically significant changes in clinical chemistry parameters | Up to 48 months | — |
| Arm 1 and 3: Number of participants with clinically significant changes in hematology parameters | Up to 48 months | — |
| Arm 1: Area under the concentration-time curve (AUC) of Tovorafenib | Cycle 1: Day 1 and Day 15; Cycles 2, 4, 7, 10 and 13: Day 1 | — |
| Arm 1: Minimum drug concentration (Cmin) | Cycle 1: Day 1 and Day 15; Cycles 2, 4, 7, 10 and 13: Day 1 | — |
Countries
Australia, Canada, Denmark, Germany, Israel, Netherlands, Singapore, South Korea, Switzerland, United Kingdom, United States
Contacts
Primary ContactDay One Biopharmaceuticals, Inc.
Outcome results
None listed