humam stem cell derived neurons

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

 

Summary

The purpose of this study is to test the safety and efficacy of the immunotherapy drug pembrolizumab in treating recurrent gliomas (grades II-IV) with what is called “hypermutation” present. The objective is to learn whether pembrolizumab will shrink the cancer by half, or prevent it from growing for at least 6 months in tumors with hypermutation.

Pembrolizumab is an antibody-based immunotherapy, administered intravenously, that targets the immune system and activates it to stop cancer growth and/or kill cancer cells. More specifically, pembrolizumab works by binding and inhibiting PD-1, a protein that normally protects the body from attacking itself. Normally, PD-1 works by detecting a molecular signal (called PDL-1) made by various cells across the body. Some cancer cells take advantage of this protection mechanism making the protective signal themselves. Blocking PD-1 with pembrolizumab allows the immune system to activate its T-cells and recognize these tumors as cells to be attacked.

 

Inclusion Criteria
  1. Histologically confirmed diagnosis of malignant glioma by enrolling institution:
    1. WHO grade IV tumors (GBM or its variants)
    2. WHO grade III anaplastic astrocytoma or oligodendroglial tumors or
    3. WHO grade II gliomas, if MRI shows contrast enhancement
  2. 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 treatment3.
  3. 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.
  4. Be ≥ 18 years of age on day of signing informed consent.
  5. 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
  6. An interval of ≥ 4 weeks after the last administration of any investigational agent or any other treatment prior to first dose of pembrolizumab
  7. 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.
  8. Karnofsky performance status of ≥ 70
  9. Demonstrate adequate organ function as per below. All screening labs should be performed within 14 days of treatment initiation.
    1. Absolute neutrophil count (ANC) ≥1,500 /mcL
    2. Platelets ≥100,000 / mcL
    3. Hemoglobin ≥9 g/dL or ≥ 5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment)
    4. 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
    5. Serum total bilirubin ≤ 1.5 X ULN OR direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
    6. AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN
    7. Albumin >2.5 mg/dL
    8. 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
    9. 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
  10. 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.

For a full description of criteria, please visit clinicaltrials.gov.

Exclusion Criteria
  1. Subjects requiring escalating or chronic supraphysiologic doses of corticosteroids (> 10 mg/d of prednisone equivalent) for control of disease at the time of registration
  2. Previous or current treatment with an anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
  3. Hypersensitivity to pembrolizumab or any of its excipients.
  4. Has a diagnosis of immunodeficiency, including Human Immunodeficiency Virus (HIV) or acquired immunodeficiency syndrome (AIDS)
  5. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  6. Has a known history of active TB (Bacillus Tuberculosis)
  7. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
  8. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e.with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  9. Has known history of, or any evidence of active, non-infectious pneumonitis.
  10. Has an active infection requiring systemic therapy.
  11. Unable to undergo MRI of the brain (i.e. pacemaker or any other contraindication for MRIs).
  12. Has received a live vaccine within 30 days of planned start of study therapy. 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.
  13. Has previously received treatment with bevacizumab

For a full description of criteria, please visit clinicaltrials.gov.

Investigator(s)

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