INDIGO/AG881-C-004: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-Controlled Study of AG-881 in Subjects With Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation
Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation
Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation
Rue du Bugon 46
Prof. Denis Migliorini
Hôpitaux universitaires de Genève (HUG)
Rue Gabrielle Perret-Gentil 4
+41 22 37 22 914
Primary objective :
The primary objective of the study is to demonstrate the efficacy of AG-881 based on radiographic PFS per BIRC compared with placebo in subjects with residual or recurrent Grade 2 oligodendroglioma and astrocytoma with an IDH1 or IDH2 mutation who have undergone surgery as their only treatment.
Inclusion criteria :
- Be at least 12 years of age and weigh at least 40 kg.
- Be able to understand and willing to sign informed consent (for subjects ≥18 years of age) or assent (for subjects <18 years of age) and willing to comply with scheduled visits, treatment plans, procedures, and laboratory tests, including serial peripheral blood sampling and urine sampling, during the study. A legally authorized representative may consent on behalf of a subject who is otherwise unable to provide informed consent, if acceptable to and approved by the site and/or site’s institutional review board/independent ethics committee. A parent or legal guardian must sign informed consent for subjects <18 years of age.
- Have Grade 2 oligodendroglioma or astrocytoma per WHO 2016 criteria.
- 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 and not more than 5 years before the date of randomization, and no other prior anticancer therapy, including chemotherapy and radiotherapy.
- 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, comparative genomic hybridization array, sequencing) using an accredited laboratory.
- 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 MRI with ≤4 mm slice thickness and no interslice gap. Measurable non-enhancing disease is defined as a least 1 target lesion measuring ≥1 cm × ≥1 cm (bidimensional). Centrally confirmed, minimal, non-nodular, non-measurable enhancement that has not changed between the 2 most recent scans (including screening scan) will be permitted.
- Have a Karnofsky Performance Scale (KPS) score (for subjects ≥16 years of age) or Lansky Play Performance Scale (LPPS) score (for subjects <16 years of age) of ≥80%.
- Have expected survival of ≥12 months.
- Have adequate bone marrow function
- Have adequate hepatic function
- Have adequate renal function
- Have recovered from any clinically relevant toxicities associated with any prior surgery for the treatment of glioma unless stabilized under medical management.
- Female subjects of childbearing potential must have a negative serum pregnancy test before the start of therapy. Women of childbearing potential are defined as having had onset of their first menstrual period and who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion, or are not been naturally postmenopausal (ie, have not menstruated at all in the preceding 24 consecutive months). Women of childbearing potential as well as fertile men with partners who are women of childbearing potential must agree to abstain from sexual intercourse or to use 2 highly effective forms of contraception (including at least 1 barrier method) from the time of giving informed consent or assent, throughout the study, and for 90 days after the last dose of AG-881. Highly effective forms of contraception are defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, intrauterine hormone release systems, bilateral tubal ligation, condoms with spermicide, or male partner sterilization.
Exclusion criteria :
- Have had any prior anticancer therapy other than surgery (biopsy, sub-total resection, grosstotal resection) for treatment of glioma including systemic chemotherapy, radiotherapy, vaccines, small-molecules, IDH inhibitors, investigational agents, etc.
- Have high-risk features as assessed 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).
- 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.
- Are pregnant or breastfeeding.
- Have an active infection that requires systemic anti-infective therapy or with an unexplained fever >38.5°C within 7 days of C1D1.
- Have a known hypersensitivity to any of the components of AG-881.
- 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, myocardial infarction, unstable angina, and/or stroke.
- Have left ventricular ejection fraction (LVEF) <40% by echocardiogram (or by other methods according to institutional practice) obtained within 28 days before the start of study treatment.
- Have a heart-rate corrected QT interval using Fridericia’s formula (QTcF) ≥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.
- 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.
- Exclusion Criterion 11 removed in Protocol Amendment 1 (v2.0).
- Are taking any medications that are cytochrome P450 (CYP) 3A or CYP2C9 substrates with a narrow therapeutic index. (Subjects should be transferred to other medications before receiving the first dose of study drug.)
- 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.
- 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).
- Have any other acute or chronic medical or psychiatric condition, including recent (within 12 months of C1D1) or active suicidal ideation or behavior, or a laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study.