Pembrolizumab in Treating Patients with Recurrent Malignant Glioma with a Hypermutator Phenotype

Status: Active

Description

This phase II trial studies pembrolizumab in treating patients with malignant glioma (a cancer of the brain that begins in glial cells [cells that surround and support nerve cells]) that has come back. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Eligibility Criteria

Inclusion Criteria

  • Histologically confirmed diagnosis of malignant glioma by enrolling institution: * World Health Organization (WHO) grade IV tumors (glioblastoma [GBM] or its variants) * WHO grade III anaplastic astrocytoma or oligodendroglial tumors or * WHO grade II gliomas, if magnetic resonance imaging (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 Memorial Sloan Kettering (MSK)-Integrated Mutation Profiling for Actionable Cancer Targets (IMPACT) or comparable next generation sequencing performed in a Clinical Laboratory Improvement Act (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 MutL homolog (MLH)1, MutS protein homolog (MSH)2, MSH6, PMS2 postmeiotic segregation increased 2 (S. cerevisiae) (PMS)2, polymerase (deoxyribonucleic acid [DNA] directed), epsilon-1 (POLE), polymerase (DNA directed), delta 1, catalytic subunit (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
  • An interval of >= 12 weeks from the end of prior radiation therapy is required unless there is either: * Histopathologic confirmation of recurrent tumor, or * 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
  • Absolute neutrophil count (ANC) >= 1,500/mcL (within 14 days of treatment initiation)
  • Platelets >= 100,000/mcL (within 14 days of treatment initiation)
  • Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (within 14 days of treatment initiation)
  • Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (within 14 days of treatment initiation)
  • Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 14 days of treatment initiation)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate-pyruvate transaminase [SGPT]) =< 2.5 X ULN (within 14 days of treatment initiation)
  • Albumin > 2.5 mg/dL (within 14 days of treatment initiation)
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 14 days of treatment initiation)
  • 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 (within 14 days of treatment initiation)
  • Female subject of childbearing potential should have a negative urine or serum pregnancy; 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; 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-cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed death (PD)-1, anti-PD ligand (PD-L)1, 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., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [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

Locations & Contacts

California

Los Angeles
UCLA / Jonsson Comprehensive Cancer Center
Status: Active
Contact: Timothy Francis Cloughesy
Phone: 310-825-5321
San Francisco
UCSF Medical Center-Mount Zion
Status: Active
Contact: Jennifer Leigh Clarke
Phone: 415-353-2966

Florida

Miami
University of Miami Miller School of Medicine-Sylvester Cancer Center
Status: Active
Contact: Macarena Ines De La Fuente
Phone: 305-243-5302

Massachusetts

Boston
Brigham and Women's Hospital
Status: Active
Contact: Patrick Yung Chih Wen
Phone: 617-732-5771
Dana-Farber Cancer Institute
Status: Active
Contact: Patrick Yung Chih Wen
Phone: 877-442-3324

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: Active
Contact: Thomas J. Kaley
Phone: 212-639-5122
Middletown
Memorial Sloan Kettering Monmouth
Status: Active
Contact: Thomas J. Kaley
Phone: 212-639-5122
Montvale
Memorial Sloan Kettering Bergen
Status: Active
Contact: Thomas J. Kaley
Phone: 212-639-5122

New York

Commack
Memorial Sloan Kettering Commack
Status: Active
Contact: Thomas J. Kaley
Phone: 212-639-5122
New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Thomas J. Kaley
Phone: 212-639-5122
Uniondale
Memorial Sloan Kettering Nassau
Status: Active
Contact: Thomas J. Kaley
Phone: 212-639-5122
West Harrison
Memorial Sloan Kettering Westchester
Status: Active
Contact: Thomas J. Kaley
Phone: 212-639-5122

Texas

Houston
M D Anderson Cancer Center
Status: Active
Contact: John Frederick de Groot
Phone: 855-767-4757

Utah

Salt Lake City
Huntsman Cancer Institute / University of Utah
Status: Active
Contact: Howard Colman
Phone: 801-587-4024

Trial Objectives and Outline

PRIMARY OBJECTIVE:

I. To evaluate the efficacy of pembrolizumab in recurrent malignant glioma with a hypermutator phenotype.

SECONDARY OBJECTIVE:

I. To describe the safety profile of pembrolizumab when administered to this population.

EXPLORATORY OBJECTIVES:

I. To evaluate (progression-free survival) PFS and response rate in this population.

II. To examine the role of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) perfusion parameters in differentiating pseudoprogression from true disease progression, following treatment with pembrolizumab.

III. To explore tissue and blood-based potential biomarkers associated with response to pembrolizumab in this disease.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 9-12 weeks for at least 5 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Thomas J. Kaley

Trial IDs

Primary ID 15-227
Secondary IDs NCI-2016-00116
Clinicaltrials.gov ID NCT02658279