Pembrolizumab (MK-3475) in Patients With Recurrent Malignant Glioma With a Hypermutator Phenotype

Open to people ages 18 years and up

• Histologically confirmed diagnosis of malignant glioma by enrolling institution:
• WHO grade IV tumors (GBM or its variants)
• WHO grade III anaplastic astrocytoma or oligodendroglial tumors or
• WHO grade II gliomas, if MRI shows contrast enhancement
• Tumor recurrence after previous treatment, which must have included at least radiation therapy and one cytotoxic chemotherapy. There is no limit on number of previous recurrences or lines of treatment.
• Previously obtained tumor sample exhibits a hypermutator phenotype. For the purposes of this trial, a hypermutator phenotype is defined as tumors harboring 30 mutations (non-synonymous somatic point or indel mutations) detected by the MSK-IMPACT or comparable next generation sequencing performed in a CLIA environment. Contingent to approval by the MSK Principal Investigator, patients with less than 30 mutations may be eligible if they display a mutation in a mismatch repair gene or other mutations in genes known to be associated with hypermutator phenotypes or microsatellite instability, including but not limited to MLH1, MSH2, MSH6, PMS2, POLE, POLD as determined by validated methods, or if microsatellite instability is present, as identified by polymerase chain reaction (PCR) or other validated methods.

*Note: The MSK-IMPACT (Integrated Mutation Profiling for Actionable Cancer Targets) assay is a next generation genomic profiling performed on formalin-fixed, paraffin-embedded (FFPE) tumor tissue in a CLIA-certified Molecular Diagnostic Service laboratory. IMPACT provides full exon coverage of 410 cancer related genes and can detect base substitutions, small indels, copy number alterations and selected gene re-rearrangements. In some cases, additional assays such as Sanger Sequencing or fluorescence in situ hybridization (FISH) may be required to confirm specific results detected on IMPACT. Patients at MSK will have this assay to determine eligibility. Use of other validated next-generation sequencing techniques for eligibility may be considered, provided they are performed in a CLIA-certified laboratory and are approved by the MSK Principal Investigator.

• Be willing and able to provide written informed consent/assent for the trial.
• Be ≥ 18 years of age on day of signing informed consent.
• An interval of ≥ 12 weeks from the end of prior radiation therapy is required unless there is either: i) histopathologic confirmation of recurrent tumor, or ii) new enhancement on MRI outside of the radiation treatment field
• An interval of ≥ 4 weeks after the last administration of any investigational agent or any other treatment prior to first dose of pembrolizumab
• Must have recovered (i.e., ≤ Grade 1 or at baseline) from adverse events of any previous treatment. Note: Surgical resection for recurrent tumor prior to enrollment is allowed.
• Karnofsky performance status of ≥ 70
• Demonstrate adequate organ function as per below. All screening labs should be performed within 14 days of treatment initiation.
• Absolute neutrophil count (ANC) ≥1,500 /mcL
• Platelets ≥100,000 / mcL
• Hemoglobin ≥9 g/dL or ≥ 5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment)
• Serum creatinine ≤1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥ 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
• Serum total bilirubin ≤ 1.5 X ULN OR direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
• AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN
• Albumin >2.5 mg/dL
• International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• Female subject of childbearing potential should have a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication (Reference Section 9.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.