Assessments
intraspinal disease, primary malignancy, optic pathway glioma, IE, disability
ADVERSE EVENT, DISEASE, DISEASE, EVENT
Disease assessments in arm 1 were conducted by MRI of the brain and spine and were performed at screening up to 28 d before first dose, at the end of cycle 3 and then at the end of every three cycles thereafter. Spinal scans were only required to be repeated after screening in patients with known or clinically suspected intraspinal disease. Patients who had an optic pathway glioma (OPG) or underlying visual function deficit related to the primary malignancy had a visual acuity examination every time they had a radiographic disease assessment.A central imaging laboratory was used. Imaging Endpoints (IE) is a research and imaging core laboratory providing blinded independent central review of response assessments with dual reader plus adjudication paradigm using neuro-radiologists trained in all three response assessment criteria as readers for the following assessments: RANO-HGG criteria, RAPNO-LGG criteria and RANO-LGG criteria. All activities at IE meet or exceed GCP standards, and IE underwent a GCP audit by the sponsor. A prospectively designed imaging charter was developed for the FIREFLY-1 study before the initiation of the study. This outlined the processes for initial imaging review, data transfers and data review, and queries were followed throughout the study. IE functions as the centralized imaging core laboratory responsible for the collection, quality control, archiving and blinded independent central review (BICR) of imaging for the FIREFLY-1 trial. IE is responsible for management of the image analysis system, reporting methods, implementation of the analysis criteria and reader management, including qualification, training and oversight.Reader performance was assessed by evaluating reader variability at defined and prespecified milestones during ongoing imaging interpretation. Variability metrics included inter-reader and intra-reader variability to monitor for consistency of reads. If the reader acceptance rate fell outside the caution or alert limits, IE determined the appropriate unbiased action(s).For this report, safety was assessed in the arm 1 and 2 safety analysis set, which comprised all enrolled patients who received at least one dose of trial treatment. The assessment period for AEs was from the first dose of tovorafenib until 30 d after the last dose. For the current trial, an AE was defined as treatment emergent if it occurred at any time after the first dose of trial drug until 30 d after the last dose of trial drug. A TRAE was any treatment-emergent event that the investigator assessed had at least a reasonable possibility of having a causal relationship with the trial drug based on temporal association with initiation of treatment and assessment of other potential etiologies. An AE was considered serious if it met one of the following criteria: required or prolonged hospitalization, was life-threatening, caused disability or was considered a medically important event by the investigator (regardless of symptoms or Common Terminology Criteria for Adverse Events (CTCAE) grade).Routine laboratory tests were performed locally and included pregnancy tests for female patients of childbearing potential (at screening and on day 1 of every cycle); assessments of hematology parameters and serum chemistries (at screening, days 1 and 15 of cycle 1, day 1 of cycle 2 and every cycle thereafter); and thyroid function (at screening, on day 1 of cycles 1–3 and every other cycle thereafter). Scheduled cardiac function assessments included independently centrally reviewed 12-lead resting ECGs (performed in triplicate at baseline, on days 1 and 15 of cycle 1, on day 1 of cycles 2 and 4 and on day 1 of every third cycle thereafter) and ECGs or MUGA scans (conducted throughout by the same technique, on day 1 of cycles 2 and 4 and on day 1 of every third cycle thereafter). CPK level was assessed at screening, on day 1 of cycles 2 and 4 and on day 1 of every fourth cycle thereafter.In patients 2 years of age or older, health-related quality of life was assessed using the PedsQL-Core, PedsQL-Cancer and PROMIS assessments for the patient or their parent/caregiver every third cycle. The PROMIS questionnaire was administered only to English-speaking patients enrolled in the United States, Australia and the United Kingdom.