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

Completed · Phase 2

Conditions studied: Glioblastoma

In brief

The purpose of this study is to test how safe and effective treatment with the combination of Avelumab and radiation is for IDH mutant gliomas that have transformed to glioblastoma after chemotherapy.

Key facts

Study ID

NCT02968940

Run by

NYU Langone Health

People needed

6

Starts

2017-03-17

Expected to finish

2019-08-29

Last updated by the study team

2022-06-29

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• 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 fractionation, including hypofractionated regimens, stereotactic radiosurgery, etc.
• Patients can have had any number of prior therapies, including but not limited to molecularly targeted therapies and anti-angiogenic therapies, however they must have had prior chemotherapy with either temozolomide or lomustine as per Eligibility Criteria 6.

You may not qualify if…

• Investigational drug use within 28 days of the first dose of Avelumab.
• Planned participation in another study of an investigational agent or investigational device or use of a therapeutic device intended for therapy of glioma.
• Prior therapy with an agent that blocks the PD-1/PD-L1 pathway.
• Primary brainstem or spinal cord tumor.
• Diffuse leptomeningeal disease at recurrence
• Recurrent infratentorial tumor
• Prior re-irradiation or stereotactic radiosurgery for recurrent disease at the same tumor location intended for HFRT in this study.
• Maximal tumor diameter >4 cm
• Patients with evidence of significant intracranial mass effect that requires >4 mg of dexamethasone or bioequivalent per day for 5 consecutive days for management of symptoms at any time within 14 days of registration.
• Subjects on a standard high-dose steroid taper after craniotomy may receive a higher dose of corticosteroids within 14 days of registration, however must be at a dose ≤4 mg of dexamethasone or bioequivalent per day within 5 days prior to registration.
• Administration of steroids through a route known to result in a minimal systemic exposure [i.e., intranasal, intraocular, inhaled, topical, or local injection (e.g., intra-articular injection) corticosteroids (<5% of body surface area)] are permitted.
• Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are at doses ≤ 10 mg prednisone or bioequivalent per day.
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) are allowed.
• Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. The following are not exclusions:
• a. Patients with diabetes type I, vitiligo, hypo- or hyperthyroid diseases, or psoriasis not requiring systemic immunosuppressive treatment are eligible.
• Prior organ transplantation, including allogeneic stem cell transplantation.
• Known history of, or any evidence of active, non-infectious pneumonitis within the last 5 years.
• Known prior, severe hypersensitivity (NCI-CTCAE v4.03 Grade 3 or 4) to investigational product or any component in its formulations including known severe hypersensitivity reactions to monoclonal antibodies, any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma).
• Active infection requiring systemic therapy.
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome.
• Positive test for Hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus (HCV antibody) at screening indicating acute or chronic infection.
• Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
• Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
• Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 4.03; however, alopecia and sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment, are acceptable.
• Patients with another active cancer [excluding basal cell carcinoma, cervical carcinoma in situ or melanoma in situ]. Prior history of other cancer is allowed, as long as there was no active disease within the prior 2 years.

Where it is running

• University of California, Los Angeles (UCLA) — Los Angeles, California, United States
• UCSF Medical Center — San Francisco, California, United States
• Massachusetts General Hospital — Boston, Massachusetts, United States
• Laura & Isaac Perlmutter Cancer Center & NYU Langone Medical Center — New York, New York, United States

Full record on ClinicalTrials.gov

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