This phase III trial compares the effect of vorasidenib to placebo in combination with usual treatment, temozolomide, in treating patients with newly diagnosed grade 3 astrocytoma after radiation. Temozolomide is in a class of medications called alkylating agents. It works by damaging the cell's deoxyribonucleic acid and may kill tumor cells and slow down or stop tumor growth. Vorasidenib citrate blocks the proteins made by the mutated IDH1 and IDH2 genes, which may help keep tumor cells from growing. It is a type of enzyme inhibitor and a type of targeted therapy. Adding vorasidenib to the usual treatment, temozolomide, may be more effective than temozolomide alone in treating patients with newly diagnosed grade 3 astrocytoma after radiation therapy.
STEP 0: Histologic diagnosis of astrocytoma, IDH-mutant (central nervous system [CNS] WHO grade 3)
STEP 0: Available diagnostic slides (hematoxylin and eosin staining method [H&E] and immunohistochemical stains for central review)
STEP 0: Tissue available for central biomarker testing (CDKN2A/B and1p/19q co-deletion [all patients], and IDH1/IDH2 [if needed])
STEP 1: Centrally-confirmed diagnosis of astrocytoma, IDH-mutant (CNS WHO grade 3)
None
Parallel
Intensity-Modulated Radiation Therapy
RadiationUndergo IMRT/VMAT
Volume Modulated Arc Therapy
RadiationUndergo IMRT/VMAT
Pencil Beam Scanning
RadiationUndergo PBS
Intensity-Modulated Proton Therapy
Procedure/SurgeryUndergo IMPT
Temozolomide
DrugGiven PO
Vorasidenib
DrugGiven PO
Placebo Administration
DrugGiven PO
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Questionnaire Administration
Other interventionAncillary Studies
Progression free survival (PFS) by blinded independent central review (BICR)
This is defined as the time from randomization to the time of documented disease progression, as determined by BICR using the Response Assessment in Neuro-Oncology (RANO) 2.0 criteria or death due to any cause. PFS distributions will be evaluated for each arm and will be graphically and quantitatively compared using Kaplan-Meier methods. These methods will be used to estimate the median PFS as well as 2-, 3-, and 5-year estimates for PFS by treatment arm along with corresponding 95% confidence intervals. Cox proportional hazards models will also be used to assess influential factors on PFS both in the univariate and the multivariable settings.
Progression free survival (PFS) by local review
This is defined as the time from randomization to the time of documented disease progression, as determined by local (institutional/investigator) review using the Response Assessment in Neuro-Oncology (RANO) 2.0 criteria or death due to any cause. PFS distributions will be evaluated for each arm and will be graphically and quantitatively compared using Kaplan-Meier methods. These methods will be used to estimate the median PFS as well as 2-, 3-, and 5-year estimates for PFS by treatment arm along with corresponding 95% confidence intervals. Cox proportional hazards models will also be used to assess influential factors on PFS both in the univariate and the multivariable settings.
Incidence of adverse events (AEs)
AEs will be evaluated by treatment regimen. Will be summarized per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 and where toxicities will be defined as AEs that are deemed to be at least possibly treatment-related. The maximum grade for each type of treatment-related AE will be recorded for each patient, and the frequency of each will be summarized by treatment arm. Frequency tables and graphical evaluations of AEs and treatment-related AEs will be summarized and evaluated to assess if there are any patterns or differences in the rates or types of AEs.
Overall survival (OS)
This is defined as the time from randomization to the date of death due to any cause. Distributions will be evaluated for each arm using the Kaplan Meier method to calculate 2-, 3-, and 5-year rates along with corresponding 95% confidence intervals. Distributions will be compared between arms using the log rank test.
Objective response rate (ORR) by blinded independent central review (BICR)
Will be summarized by treatment arm. This is defined as the proportion of patients with measurable tumor at baseline who achieve a minor, partial, or complete response to therapy divided by the total number of patients with measurable tumor at baseline who were randomized and treated on that arm. Response will be determined by BICR using the Response Assessment in Neuro-Oncology (RANO) 2.0 criteria. Assuming the number of patients who respond to therapy on each arm is binomially distributed, these proportions along with corresponding 95% confidence intervals will be estimated.
Health related quality of life
Will be assessed using the Functional Assessment of Cancer Therapy-Brain (FACT-BR). The total score ranges from 0 to 200, with higher score indicating better quality of life.
Symptom burden
Will be assessed using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT). It consists of 23 symptoms rated on an 11-point scale (0 to 10) to indicate the presence and severity of the symptom, with 0 being "not present" and 10 being "as bad as you can imagine.
Correlation of tumor genotype with PFS
Testing of banked biospecimens to determine tumor genotypes will not be conducted until a protocol amendment or separate correlative science proposal is approved. Details of planned statistical analyses will be included in the amendment or proposal.
Effect of the addition of vorasidenib to adjuvant temozolomide on seizure control
Results from the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) question for severity of seizures will be compared between arms.
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Alliance for Clinical Trials in Oncology
Lead sponsor
National Cancer Institute (NCI)
Collaborator
