Glioma
Conditions
Interventions
Investigational Product, Dosage, and Mode of Administration:
AG-881 40 mg QD will be taken orally by the subject on Days 1 to 28 in 28-day
cycles. Dosing is continuous
there are no planned intercycle rest periods.
Reference Therapy, Dosage, and Mode of Administration:
AG-881-matched placebo 40 mg QD will be taken orally by the subject on Days 1
to 28 in 28-day cyc
there are no planned intercycle
rest periods.
Approximately 340 subjects are planned to be randomized 1:1 to receive AG-881
or AG-881-matched placebo.
Sponsors
Institut de Recherches Internationales Servier I.R.I.S
Eligibility
Age
12 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Be at least 12 years of age and weigh at least 40 kg. 3. Have Grade 2 oligodendroglioma or astrocytoma per WHO 2016 criteria. 4. Have had at least 1 prior surgery for glioma (biopsy, sub-total resection, gross-total resection), with the most recent surgery having occurred at least 1 year (-1 month) and not more than 5 years (+3 months) before the date of randomization, and no other prior anticancer therapy, including chemotherapy and radiotherapy and not be in need of immediate chemotherapy or radiotherapy in the opinion of the Investigator. 5. Have confirmed IDH1 (IDH1 R132H/C/G/S/L mutation variants tested) or IDH2 (IDH2 R172K/M/W/S/G mutation variants tested) gene mutation status disease by central laboratory testing during the Prescreening period and available 1p19q status by local testing (eg, fluorescence in situ hybridization [FISH], comparative genomic hybridization [CGH] array, sequencing) using an accredited laboratory. 6. Have MRI-evaluable, measurable, non-enhancing disease, as confirmed by the BIRC, assessed at Screening on 2D T2-weighted or 2D T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI with =1 cm × >=1 cm (bidimensional). Centrally confirmed, minimal, non-nodular, and non-measurable enhancement that has not changed between the 2 most recent scans (including screening scan) will be permitted. 7. Have a KPS (Appendix 11.7) score (for subjects >=16 years of age) or LPPS (Appendix 11.6) score (for subjects =80%. 8. Have expected survival of >=12 months. 9. Have adequate bone marrow function 10. Have adequate hepatic function 11. Have adequate renal function 12. Have recovered from any clinically relevant toxicities associated with any prior surgery for the treatment of glioma unless stabilized under medical management. For the complete and extended list, see protocol section 4.2 Inclusion Criteria
Exclusion criteria
Exclusion criteria: 1. Have had any prior anticancer therapy other than surgery (biopsy, sub-total resection, gross-total resection) for treatment of glioma including systemic chemotherapy, radiotherapy, vaccines, small-molecules, IDH inhibitors, investigational agents, laser ablation etc. 2. Have features assessed as high-risk by the Investigator, including brainstem involvement either as primary location or by tumor extension, clinically relevant functional or neurocognitive deficits due to the tumor in the opinion of the Investigator (deficits resulting from surgery are allowed), or uncontrolled seizures (defined as persistent seizures interfering with activities of daily life AND failed 3 lines of antiepileptic drug regimens including at least 1 combination regimen). 3. Concurrent active malignancy except for a) curatively resected nonmelanoma skin cancer or b) curatively treated carcinoma in situ. Subjects with previously treated malignancies are eligible provided they have been disease-free for 3 years at Screening. 4. Are pregnant or breastfeeding. 5. Have an active infection that requires systemic anti-infective therapy or with an unexplained fever >38.5°C within 7 days of C1D1. 6. Have a known hypersensitivity to any of the components of AG-881. 7. Have significant active cardiac disease within 6 months before the start of study treatment, including New York Heart Association Class III or IV congestive heart failure (Appendix 11.2), myocardial infarction, unstable angina, and/or stroke. 8. Have LVEF =450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (eg, heart failure, hypokalemia, family history of long QT interval syndrome). Subjects with bundle branch block and prolonged QTcF are permitted with approval of the Medical Monitor. 10. Are taking therapeutic doses of steroids for signs/symptoms of glioma. Subjects taking physiologic doses (defined as equivalent of <=10 mg prednisone daily) for medical conditions not related to glioma will be permitted. 11. Exclusion Criterion 11 removed in Protocol Amendment 1 (v2.0). 12. Are taking any medications that are CYP3A or CYP2C9 substrates with a narrow therapeutic index as listed in Appendix 11.4. (Subjects should be transferred to other medications before receiving the first dose of study drug.) 13. Have known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, known positive human immunodeficiency virus antibody results, or AIDS-related illness. Subjects with a sustained viral response to HCV treatment or immunity to prior HBV infection will be permitted. Subjects with chronic HBV that is adequately suppressed by institutional practice will be permitted. 14. Have known active inflammatory gastrointestinal disease, chronic diarrhea, previous gastric resection or lap band dysphagia, short-gut syndrome, gastroparesis, or other condition that limits the ingestion or gastrointestinal absorption of drugs administered orally. Gastroesophageal reflux disease under medical treatment is allowed (assuming no drug interaction potential). 15. Have any other ac
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The primary endpoint is PFS, defined as the time from date of randomization to date of the first occurrence of radiographic PD by modified RANO-LGG assessed by the BIRC or death from any cause, whichever occurs earlier. Progression-free survival for subjects without centrally confirmed radiographic PD by RANO-LGG by the BIRC or death will be censored at the date of the last disease assessment. Censoring reasons also include start of a subsequent anticancer therapy, withdrawal of consent from overall study participation, and loss to follow-up. The primary efficacy analysis will compare the PFS time between the 2 treatment arms using a 1-sided stratified log-rank test. The test will be stratified by 1p19q status and baseline tumor size. A Cox proportional hazards (PH) model stratified by randomization stratification factors will be used to estimate the hazard ratio of PFS, along with its 95% CI. Assuming a median PFS of 18 months for the placebo arm and a median PFS of 30 months for the vorasidenib arm, a total of 164 PFS events are required to provide at least 90% power to detect a hazard ratio of 0.6 at a 1-sided alpha of 0.025 level of significance using a log-rank test stratified by the randomization stratification factors, and a 3-look group sequential design with a Gamma family (-24) a-spending function to determine the efficacy boundaries and a Gamma family (-5) β-spending function to determine the nonbinding futility boundaries. Assuming a recruitment period of approximately 42 months, and a 10% dropout rate in PFS at 12 months, approximately 340 subjects will need to be randomized to the 2 treatment arms in a 1:1 ratio. There are 3 planned analyses for PFS: an interim analysis for futility, an interim analysis for superiority, and a final analysis. A small alpha will be allocated to the PFS futility analysis based on the selected a-spending function. The interim analyses for PFS will be performed based on FAS and will take plac | — |
Secondary
| Measure | Time frame |
|---|---|
| Key secondary endpoint: The key secondary endpoint is TTNI, defined as the time from randomization to the initiation of the first subsequent anticancer therapy (including vorasidenib, for subjects randomized to placebo who subsequently cross over) or death due to any cause. The secondary efficacy analysis will compare the TTNI between the 2 treatment arms using a 1-sided stratified log-rank test. The test will be stratified by 1p19q status and baseline tumor size. A Cox PH model stratified by randomization stratification factors will be used to estimate the hazard ratio of TTNI, along with its 95% CI. The sample size of 340 subjects will also allow an assessment for TTNI assuming a 10% dropout rate for TTNI at 12 months. With an assumed median TTNI of 21 months for the placebo arm, a total of 152 TTNI events are required to provide approximately 80% power to detect a hazard ratio of 0.636 at a 1-sided alpha of 0.025 level of significance using a log-rank test stratified by the randomization stratification factors, and a 2-look group sequential design with a Gamma family (-22) a-spending function to determine the efficacy boundaries. To control the overall type I error rate at the 1-sided 2.5% level, the fixed sequence testing procedure will be used to adjust for multiple statistical testing of the primary endpoint and key secondary efficacy endpoint TTNI. These endpoints will be tested in the following order: • PFS per BIRC • TTNI. Other secondary endpoints: Other secondary efficacy endpoints are TGR, objective response, CR+PR, time to response, time to CR+PR, duration of response, duration of CR+PR, OS, FACT-Br scores, and PFS by investigator. Safety: Safety will be evaluated by the incidence, severity, and type of adverse events, and by evaluation of vital signs, KPS/LPPS, clinical laboratory results, electrocardiograms, and LVEF data (as clinically indicated). All data will be provided in by-subject listings. All safety data will be | — |
Countries
Netherlands
Outcome results
None listed