Avelumab With Hypofractionated Radiation Therapy in Adults With Isocitrate Dehydrogenase (IDH) Mutant Glioblastoma

Inclusion Criteria

• Male or female subjects aged ≥18 years.
• Documentation of IDH1 or IDH2 mutation in any tumor specimen.
• Pathologic evidence (either diagnostic pathology slides or pathology report) of a diagnosis of WHO grade II or III glioma prior to treatment with temozolomide or PCV chemotherapy.
• Histopathological evidence of glioblastoma (WHO grade IV) on a progressive tumor specimen after treatment with temozolomide or PCV chemotherapy. The diagnosis of glioblastoma must be confirmed on central review by a study-designated neuropathologist at NYULMC at screening.

Exceptions to this eligibility include the following:

a. Any progressive glioma with IDH1 or IDH2 mutation, regardless of WHO grade, histopathological diagnosis, or prior therapy, will be eligible if the progressive tumor specimen is found to have one of the genetic alterations below:

• ≥20 somatic mutations per Mb by whole-exome sequencing
• High mutation burden or microsatellite instability (MSI) identified by Foundation Medicine panel next-generation sequencing (FoundationOne®, FoundationOne CDx™). Foundation Medicine's threshold for high mutation burden (HMB) in their panel NGS assays is ≥20 somatic mutations per Mb. Foundation Medicine's panel NGS assay has been validated by whole-exome and whole-genome sequencing to correlate tightly with tumor mutation burden (R2 = 0.94).96
• Mutation in a mismatch repair gene or other genes known to be associated with hypermutator phenotypes or microsatellite instability, including but not limited to MSH2, MSH6, MLH1, POLE, PMS2, POLD as determined by validated methods.
• Microsatellite instability as identified by polymerase chain reaction (PCR) or other validated methods.

b. Progressive oligodendroglioma (with 1p/19q codeletion) that has hallmark histopathological features of glioblastoma (i.e. necrosis, pseudopalisading necrosis, or microvascular proliferation) is eligible as IDH1/2 mutant, 1p/19q codeleted oligodendrogliomas that have progressed after chemotherapy have been shown to develop hypermutation phenotype.

• Availability of a paraffin-embedded or frozen tumor-tissue block with a minimum of 1 cm2 of tumor surface area from a tissue specimen that demonstrates pathological transformation to glioblastoma (WHO grade IV) or a progressive specimen that harbors one of the genetic alterations specified in Inclusion Criteria 4a. a. If a tumor block cannot be submitted, then 20 unstained slides (preferably 10 slides from two different tumor blocks from the same surgery) from the tumor specimen must be submitted.
• Patients must have had treatment with temozolomide, lomustine (CCNU) or PCV [procarbazine, lomustine (CCNU), vincristine] chemotherapy prior to histopathologic transformation to glioblastoma or prior to identification of one of the genetic alterations specified in Inclusion

Criteria 4a. Notes or records from the treating oncologist are required for documentation of treatment history. Prior treatment with at least one of the following chemotherapy schedules is required to be eligible:

• At least one 6 week course of continuous daily temozolomide
• At least six 28-day cycles given in one of the following schedules:
• Daily for 5 days of a 28-day cycle
• Daily for 21 days of a 28-day cycle
• Daily for 14 days of a 28-day cycle
• Alternating 7 days on/7 days per 28-day cycle
• Continuous daily dosing of a 28-day cycle.
• Other schedules of temozolomide may be considered after discussion with the overall Principal Investigator.
• At least 3 cycles of PCV or lomustine (CCNU) chemotherapy. 7. Patients who received anti-tumor therapy after histopathologic transformation to glioblastoma must have shown unequivocal radiographic evidence of tumor progression by contrast-enhanced MRI scan (or CT scan if MRI is contraindicated).
• Patients must have had prior CNS radiotherapy for their glioma, including standard doses for lowgrade or high-grade glioma as well as non-standard dose and f