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Pembrolizumab and Standard Therapy in Treating Patients With Glioblastoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03197506
Recruitment Status : Recruiting
First Posted : June 23, 2017
Last Update Posted : December 11, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Tracking Information
First Submitted Date  ICMJE June 21, 2017
First Posted Date  ICMJE June 23, 2017
Last Update Posted Date December 11, 2019
Actual Study Start Date  ICMJE September 15, 2017
Estimated Primary Completion Date July 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 21, 2017)
  • Incidence of dose limiting toxicities [ Time Frame: Up to 5 years ]
    Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The number and severity of all adverse events will be tabulated and summarized in this patient population.
  • Overall survival [ Time Frame: Beginning of study therapy to death, assessed at 18 months ]
    Will be defined as the number of patients who are alive up to 18 months after beginning study therapy divided by the total evaluable patients.
  • Progression-free survival [ Time Frame: Up to 5 years ]
    Will assess the progression-free survival.
  • Time to progression [ Time Frame: Up to 5 years ]
    Will assess the time to progression.
  • Time to treatment failure [ Time Frame: Time from beginning study therapy to documentation of progression, unacceptable adverse event(s), or refusal to continue participation by the patient, assessed up to 5 years ]
    Will assess the time to treatment failure.
  • Time until any treatment related adverse event [ Time Frame: Up to 5 years ]
    Will assess the time until any treatment related adverse event.
  • Time until hematologic nadirs [ Time Frame: Up to 5 years ]
    Will assess the time until hematologic nadirs (white blood cell count, absolute neutrophil count, platelets).
  • Time until treatment related grade 3+ adverse event [ Time Frame: Up to 5 years ]
    Will assess the time until treatment related grade 3+ adverse event.
  • Incidence of dose limiting toxicities [ Time Frame: Up to 5 years ]
    Grade 3+ adverse events will also be described and summarized. This summary will provide an indication of the level of tolerance for this treatment combination. Non-hematologic adverse events will be evaluated via the ordinal CTCAE grading. Measures of thrombocytopenia, neutropenia, and leukopenia will be assessed using continuous variables as the outc
  • Incidence of dose limiting toxicities [ Time Frame: Up to 5 years ]
    Non-hematologic adverse events will be evaluated via the ordinal CTCAE grading. Measures of thrombocytopenia, neutropenia, and leukopenia will be assessed using continuous variables as the outcome
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03197506 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures
 (submitted: June 21, 2017)
Biomarkers [ Time Frame: Baseline up to 5 years ]
Will be explored descriptively to detect patterns and substantial changes. In addition, differences between post-baseline and baseline apoptotic scores will be analyzed using a paired-sample t-test or the nonparametric equivalent.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Pembrolizumab and Standard Therapy in Treating Patients With Glioblastoma
Official Title  ICMJE Phase II Study of Pembrolizumab (MK-3475) in Combination With Standard Therapy for Newly Diagnosed Glioblastoma
Brief Summary This phase II trial studies the side effects and how well pembrolizumab works in combination with standard therapy in treating patients with glioblastoma. Drugs used in the chemotherapy, such as pembrolizumab and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy beams to kill tumor cells and shrink tumors. Giving pembrolizumab and standard therapy comprising of temozolomide and radiation therapy may kill tumor cells.
Detailed Description

PRIMARY OBJECTIVES:

I. To assess the 18 month overall survival rate of pembrolizumab in combination with standard therapy (surgery, external beam radiation therapy and temozolomide [TMZ] chemotherapy) in patients with newly diagnosed glioblastoma multiforme (GBM).

SECONDARY OBJECTIVES:

I. To assess adverse events (AE) and toxicity profile of pembrolizumab in combination with standard therapy in patients with newly diagnosed GBM.

II. To assess time to progression in patients treated with pembrolizumab in combination with standard therapy in patients with newly diagnosed GBM.

III. To assess progression-free survival in patients treated with pembrolizumab in combination with standard therapy in patients with newly diagnosed GBM.

IV. To assess time to treatment failure in patients treated with pembrolizumab in combination with standard therapy in patients with newly diagnosed GBM.

TERTIARY OBJECTIVES:

I. To assess the tumor PD-1/PD-L1 expression and inflammatory microenvironment profile by comparing PD-1/PD-L1 expression and T lymphocyte/monocytic infiltrates before and after administration of pembrolizumab treatment.

II. To assess the peripheral immunophenotype profile and GBM-associated antigen-specific T cell responses before and after receiving pembrolizumab treatment in combination with standard therapy.

OUTLINE:

NEOADJUVANT (COURSE 1): Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1.

SURGERY (COURSE 2): Patients undergo standard of care surgery within days 4-7.

CONCURRENT (COURSE 3): Starting 21-35 days after surgery, patients receive pembrolizumab IV over 30 minutes on days 1, 22, and 43 and temozolomide orally (PO) daily on days 8-54. Patients also undergo external beam radiation therapy every 5 days per week on days 8-54.

ADJUVANT (COURSE 4-8): Within 3-5 weeks after completing radiation therapy, patients receive pembrolizumab IV over 30 minutes on days 1, 22, and 43 and temozolomide PO daily on days 1-5 every 28 days. Treatment repeats every 63 days for up to 5 courses in the absence of disease progression or unexpected toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3-4 months thereafter.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Glioblastoma
  • Gliosarcoma
  • Supratentorial Glioblastoma
Intervention  ICMJE
  • Radiation: External Beam Radiation Therapy
    Undergo external beam radiation therapy
    Other Names:
    • Definitive Radiation Therapy
    • EBRT
    • External Beam Radiotherapy
    • External Beam RT
    • external radiation
    • External Radiation Therapy
    • external-beam radiation
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Biological: Pembrolizumab
    Given IV
    Other Names:
    • Keytruda
    • Lambrolizumab
    • MK-3475
    • SCH 900475
  • Radiation: Radiation Therapy
    Undergo radiation therapy
    Other Names:
    • Cancer Radiotherapy
    • Irradiate
    • Irradiated
    • Irradiation
    • RADIATION
    • Radiotherapeutics
    • Radiotherapy
    • RT
    • Therapy, Radiation
  • Drug: Temozolomide
    Given PO
    Other Names:
    • CCRG-81045
    • Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-
    • M & B 39831
    • M and B 39831
    • Methazolastone
    • RP-46161
    • SCH 52365
    • Temcad
    • Temodal
    • Temodar
    • Temomedac
  • Procedure: Therapeutic Conventional Surgery
    Undergo surgery
Study Arms  ICMJE Experimental: Treatment (pembrolizumab, standard therapy)

NEOADJUVANT (COURSE 1): Patients receive pembrolizumab IV over 30 minutes on day 1.

SURGERY (COURSE 2): Patients undergo standard of care surgery within days 4-7.

CONCURRENT (COURSE 3): Starting 21-35 days after surgery, patients receive pembrolizumab IV over 30 minutes on days 1, 22, and 43 and temozolomide PO daily on days 8-54. Patients also undergo external beam radiation therapy every 5 days per week on days 8-54.

ADJUVANT (COURSE 4-8): Within 3-5 weeks after completing radiation therapy, patients receive pembrolizumab IV over 30 minutes on days 1, 22, and 43 and temozolomide PO daily on days 1-5 every 28 days. Treatment repeats every 63 days for up to 5 courses in the absence of disease progression or unexpected toxicity.

Interventions:
  • Radiation: External Beam Radiation Therapy
  • Other: Laboratory Biomarker Analysis
  • Biological: Pembrolizumab
  • Radiation: Radiation Therapy
  • Drug: Temozolomide
  • Procedure: Therapeutic Conventional Surgery
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 21, 2017)
90
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 31, 2022
Estimated Primary Completion Date July 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histological confirmation of supratentorial glioblastoma (also known as astrocytoma grade IV, gliosarcoma) amenable to surgical resection =< 28 days prior to registration
  • Have an enhancing mass on magnetic resonance imaging (MRI) amenable to > 90% resection of contrast-enhancing tumor (as determined by the neurosurgeon pre-operatively) and histological diagnosis of glioblastoma from a prior stereotactic biopsy
  • Willing to undergo craniotomy and resection of their glioblastoma
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
  • Absolute neutrophil count (ANC) >= 1500/mm^3
  • Platelet count >= 100,000/mm^3
  • Hemoglobin >= 9.0 g/dL without transfusion or erythropoietin (EPO) dependency (=< 7 days prior to assessment)
  • Prothrombin time (PT) =< 1.5 x upper limit of normal (ULN) unless patient is receiving anticoagulant therapy and PT or partial prothrombin time (PTT) is within therapeutic range of intended use of coagulants
  • Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless patient is receiving anticoagulant therapy and PT or PTT is within therapeutic range of intended use of coagulants
  • Albumin >= 2.5 mg/dL
  • Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for patients with total bilirubin levels > 1.5 x ULN
  • Aspartate transaminase (AST) AND alanine transaminase (ALT) =< 2.5 x ULN
  • Creatinine =< 1.0 x ULN OR measured or calculated creatinine clearance (per institutional standard) must be >= 60 ml/min
  • Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only (POCBP)

    • NOTE: Serum or urine pregnancy test allowed; if urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • POCBP must be willing to use adequate contraception starting with first dose through 120 days after last dose
  • Provide written informed consent
  • Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)

    • Note: During the active monitoring phase of a study (i.e., active treatment and observation), participants must be willing to return to the consenting institution for follow-up
  • Willing to provide tissue and blood samples for correlative research purposes

Exclusion Criteria:

  • Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:

    • Pregnant women
    • Nursing women
    • Men or women of childbearing potential who are unwilling to employ adequate contraception
  • Signs or symptoms of life-threatening raised intracranial pressure: as defined by the treating neurosurgeon, including severe headache, nausea, decreasing level of consciousness, precluding 4-7 day delay in scheduling neurosurgery
  • Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
  • Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
  • Other active malignancy =< 5 years prior to registration

    • EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix
    • NOTE: If there is a history or prior malignancy, the patient must not be receiving other specific treatment for their cancer
  • History of myocardial infarction =< 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
  • 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 (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • 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)
  • Known history of active TB (Bacillus tuberculosis)
  • Received a live vaccine =< 30 days prior to registration
  • History of (non-infectious) pneumonitis that required steroids or current pneumonitis
  • Hypersensitivity to pembrolizumab or any of its excipients
  • Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03197506
Other Study ID Numbers  ICMJE MC1572
NCI-2017-01106 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MC1572 ( Other Identifier: Mayo Clinic )
P30CA015083 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Mayo Clinic
Study Sponsor  ICMJE Mayo Clinic
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Ian Parney Mayo Clinic
PRS Account Mayo Clinic
Verification Date December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP