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

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ClinicalTrials.gov Identifier: NCT02658279
Recruitment Status : Recruiting
First Posted : January 18, 2016
Last Update Posted : September 25, 2017
Information provided by (Responsible Party):

Study Description
Brief Summary:
The purpose of this study is to test if the study drug called pembrolizumab could control the growth or shrink the cancer but it could also cause side effects. Researchers hope to learn if the study drug will shrink the cancer by half, or prevent it from growing for at least 6 months. Pembrolizumab is an antibody that targets the immune system and activates it to stop cancer growth and/or kill cancer cells.

Condition or disease Intervention/treatment
Glioma Recurrent Malignant Glioma Drug: Pembrolizumab

Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 44 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Proof-of-Concept, Pilot Study of Pembrolizumab (MK-3475) in Patients With Recurrent Malignant Glioma With a Hypermutator Phenotype
Actual Study Start Date : January 22, 2016
Estimated Primary Completion Date : January 2018
Estimated Study Completion Date : January 2018

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: Pembrolizumab (MK-3475)
Pembrolizumab (MK-3475) will be administered intravenously at a fixed dose of 200mg every 3 weeks until disease progression. Patients will be followed with DCE perfusion MRI done at baseline and every 9 weeks (+/- 7 days). Patients will be allowed to stay on treatment if increase in tumor size is believed to be due to pseudoprogression. Patients who undergo surgery for tumor management will have tissue collected for collateral studies. All collected tissue will be stored in the Pathology Core Tissue bank at MSK.
Drug: Pembrolizumab
Other Name: (MK-3475)

Outcome Measures

Primary Outcome Measures :
  1. response rate [ Time Frame: 1 year ]
    patients with stable disease will be considered responders if disease is stable for 27 weeks or more. The regimen will be considered worthy of further study if responses as defined above are observed in at least 3 of the 12 subjects. All subjects will undergo DCE-MRI of the head at the time points specified in Study Flow Chart . Local radiologic assessment of tumor measurements will be used during the study for clinical management and investigator-assessed disease progression. Additional MRIs may be obtained at the discretion of the investigators, as clinically indicated. Radiologic response (complete response or partial response) will be assessed by comparing on-treatment MRI scans with the pretreatment baseline MRI scans. Radiologic progression will be determined by using the smallest tumor measurement of either the pretreatment baseline or after initiation of study medication. The RANO criteria will be used for determining disease status.

Eligibility Criteria

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • Subjects requiring escalating or chronic supraphysiologic doses of corticosteroids (> 10 mg/d of prednisone equivalent) for control of disease at the time of registration
  • Previous or current treatment with an anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
  • Hypersensitivity to pembrolizumab or any of its excipients.
  • Has a diagnosis of immunodeficiency, including Human Immunodeficiency Virus (HIV) or acquired immunodeficiency syndrome (AIDS)
  • Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  • Has a known history of active TB (Bacillus Tuberculosis)
  • 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.
  • 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.

  • Has known history of, or any evidence of active, non-infectious pneumonitis.
  • Has an active infection requiring systemic therapy.
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  • Unable to undergo MRI of the brain (i.e. pacemaker or any other contraindication for MRIs).
  • 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.
  • Has previously received treatment with bevacizumab
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02658279

Contact: Thomas Kaley, MD 212-639-5122

United States, California
University of California, Los Angeles Not yet recruiting
Los Angeles, California, United States, 90095
Contact: Timothy Cloughesy, MD    310-825-5321      
University of California San Francisco Not yet recruiting
San Francisco, California, United States, 94143
Contact: Jennifer Clarke, MD, MPH    415-353-2966      
United States, Florida
University of Miami Not yet recruiting
Miami, Florida, United States
Contact: Macarena De La Fuente, MD    305-243-5302      
United States, Massachusetts
Massachusetts General Hospital Not yet recruiting
Boston, Massachusetts, United States, 02114
Contact: Isabel C Arrillaga-Romany, MD, PhD    617-724-8770      
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Contact: Patrick Wen, MD         
Principal Investigator: Patrick Wen, MD         
United States, New Jersey
Memoral Sloan Kettering Cancer Center Recruiting
Basking Ridge, New Jersey, United States
Contact: Thomas Kaley, MD    212-639-5122      
Memorial Sloan Kettering Monmouth Recruiting
Middletown, New Jersey, United States, 07748
Contact: Thomas Kaley, MD    212-639-5122      
United States, New York
Memorial Sloan Kettering Cancer Center at Commack Recruiting
Commack, New York, United States, 11725
Contact: Thomas Kaley, MD    212-639-5122      
Memorial Sloan Kettering Westchester Recruiting
Harrison, New York, United States, 10604
Contact: Thomas Kaley, MD    212-639-5122      
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Thomas Kaley, MD    212-639-5122      
Principal Investigator: Thomas Kaley, MD         
United States, Texas
Md Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: John de Groot, MD    855-767-4757      
United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Howard Colman, MD    801-587-4024      
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
Merck Sharp & Dohme Corp.
M.D. Anderson Cancer Center
Dana-Farber Cancer Institute
University of California, San Francisco
Huntsman Cancer Institute/ University of Utah
University of California, Los Angeles
Principal Investigator: Thomas Kaley, MD Memorial Sloan Kettering Cancer Center
More Information

Additional Information:
Responsible Party: Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT02658279     History of Changes
Other Study ID Numbers: 15-227
First Posted: January 18, 2016    Key Record Dates
Last Update Posted: September 25, 2017
Last Verified: September 2017

Keywords provided by Memorial Sloan Kettering Cancer Center:
Pembrolizumab (MK-3475)
Hypermutator Phenotype

Additional relevant MeSH terms:
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Antineoplastic Agents