This is a Pilot, multicenter, open-label study of patients less than or equal to 25 years, with recurrent or progressive LGG harboring a CRAF or BRAF alteration, including BRAF V600 mutations and KIAA1549: BRAF fusions. Patients with BRAF or CRAF alterations will be identified through molecular assays as routinely performed at Clinical Laboratory Improvement Amendments (CLIA) of 1988 or other similarly certified laboratories.
The study will be conducted in two sequential phases:
Phase A: A Feasibility (combination dose finding) phase, followed by Phase B: An Efficacy phase. The maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) of the combination as determined in Phase A would be the dose used in Phase B. The patients on Phase A who were below the MTD/RP2D would be eligible for intra-patient dose escalation to MTD/RP2D subject to criteria outlined later
Age
Study Group
Diagnosis
All patients must have pathological confirmation of low-grade glioma with BRAF or CRAF alteration.
Patient's tumor has additional previously known activating molecular alterations, other than BRAF or CRAF.
Known or suspected diagnosis of neurofibromatosis Type 1 (NF-1) via genetic testing or current diagnostic clinical criteria.
History of any major disease, other than the diagnosis of LGG, that might interfere with safe protocol participation.
Patient with a history or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO), or ophthalmopathy present at baseline who would be considered a risk factor for CSR or RVO. Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor, or strabismus) will NOT be considered a significant abnormality for the purposes of this study.
Single group
Tovorafenib
DrugTovorafenib for oral dosing is provided as an immediate-release tablet in 100 mg strength. The 100 mg tablets are red to yellowish red oval tablets. All products are labeled tovorafenib. In addition, tovorafenib is provided as a powder for reconstitution (PfR) in bottles (430mg per bottle to deliver 300 mg dose). Upon reconstitution with water, the concentration is 25 mg/mL. Vinblastine is administered by intravenous route as IV push, sites to follow local administration guidelines, once weekly (central line, but peripheral line is also permitted)
Vinblastine
Drugvinblastine in combination with tovorafenib
MTD/RP2D
To determine the maximum tolerated dose (MTD/RP2D) of combination of vinblastine + tovorafenib for children with recurrent/progressive LGGs.
Safety and Tolerability
To assess safety and tolerability of combination of vinblastine and tovorafenib in pediatric patients with recurrent/progressive LGG through documentation of number of participants with treatment-related adverse events as assessed by CTCAE v5.0
Overall response rate
To determine overall response rate (ORR) of CR, PR and MR in patients with LGG treated with combination of vinblastine + tovorafenib by RANO-LGG criteria.
Pharmacokinetics (Cmax vinblastine and tovorafenib)
To characterize pharmacokinetics of tovorafenib and vinblastine in combination in the study population. The following PK parameters will be determined for each agent: Cmax, Tmax, AUC and reported using descriptive summary statistics
Pharmacokinetics (AUC of vinblastine and tovorafenib)
To characterize pharmacokinetics of tovorafenib and vinblastine in combination in the study population. The following PK parameters will be determined for each agent: Cmax, Tmax, AUC and reported using descriptive summary statistics
Progression free survival
Duration of response
DOR for patients with CR, PR or MR based on RANO-LGG criteria
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Daniel Morgenstern
Lead sponsor
The Hospital for Sick Children
Sponsor institution
The Hospital for Sick Children
Collaborator
