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Radiation Therapy With Temozolomide and Pembrolizumab in Treating Patients With Newly Diagnosed 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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02530502
Recruitment Status : Active, not recruiting
First Posted : August 21, 2015
Last Update Posted : February 7, 2019
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Karan Dixit, Northwestern University

Tracking Information
First Submitted Date  ICMJE August 19, 2015
First Posted Date  ICMJE August 21, 2015
Last Update Posted Date February 7, 2019
Actual Study Start Date  ICMJE September 30, 2015
Actual Primary Completion Date May 10, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 5, 2019)
The dose-limiting toxicity of Radiation Therapy With Temozolomide and Pembrolizumab will be evaluated [ Time Frame: 9 weeks ]
Any dose-limiting toxicity (DLT) experienced during the first cycle (9 weeks) of study treatment, will be determined. The Maximum Tolerated Dose (MTD) will constitute the RP2D
Original Primary Outcome Measures  ICMJE
 (submitted: August 20, 2015)
  • For phase I of the study, the dose-limiting toxicity of Radiation Therapy With Temozolomide and Pembrolizumab will be evaluated [ Time Frame: 9 weeks ]
    Any dose-limiting toxicity (DLT) experienced during the first cycle (9 weeks) of study treatment, will be determined. The Maximum Tolerated Dose (MTD) will constitute the RP2D
  • For phase II of the study, PFS (Progression Free Survival) of Radiation Therapy With Temozolomide and Pembrolizumab will be measured [ Time Frame: 54 weeks ]
    PFS will be defined from the time of registration to the time of confirmed progression. In cases where this might be unclear, patients may continue on trial and if progression is confirmed later, then the original date where first changes occurred will be used.
Change History Complete list of historical versions of study NCT02530502 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 5, 2019)
Toxicity of Pembrolizumab [ Time Frame: Up to 30 days after the last dose of study drug ]
Adverse events will be described descriptively by giving frequencies of each event by type, severity, frequency, timing and attribution graded according to CTCAE version 4.0.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 20, 2015)
  • Toxicity of Pembrolizumab (Phase II) [ Time Frame: Up to 30 days after the last dose of study drug ]
    Adverse events will be described descriptively by giving frequencies of each event by type, severity, frequency, timing and attribution graded according to CTCAE version 4.0.
  • Overall survival (OS) (Phase II) [ Time Frame: From the time of registration to death, assessed up to 2 years ]
    Patients will be followed from registration until up to 2 years from end of treatment to determine OS
  • OS-12 (Overall survival at 12 months) [ Time Frame: 12 months ]
    OS-12 defined as the percentage of patients alive at 12 months (Phase II)
  • OS-24 (Overall survival at 24 months) [ Time Frame: 24 months ]
    OS-24 defined as the percentage of patients alive at 24 months (Phase II)
  • OS-6 (Overall survival at 6 months) [ Time Frame: 6 months ]
    OS-6 defined as the percentage of patients alive at 6 months (Phase II)
  • Response rate (Phase II) [ Time Frame: Up to 54 weeks ]
    Response will be defined as the detection of SD (Stable Disease), Partial Response (PR), Progressive Disease (PD), or CR (Complete Response) as indicated by MRI scans
  • PFS6 (Progression Free Survival at 6 months) of Radiation Therapy With Temozolomide and Pembrolizumab will be measured [ Time Frame: 6 months ]
    PFS6 defined as the percentage of patients alive and progression-free at 6 months post registration (Phase II)
Current Other Pre-specified Outcome Measures
 (submitted: February 5, 2019)
  • Methylguanine-DNA methyltransferase (MGMT) status [ Time Frame: Baseline ]
    Correlate MGMT status with outcome based on tumor tissue that will be analyzed
  • PDL1 expression in tumor [ Time Frame: Baseline ]
    Tumor tissue will be analyzed to assess for PDL-1 levels
  • Peripheral T-cell activation [ Time Frame: Up to 108 weeks (12 courses post-RT) ]
    Tumor tissue will be analyzed to collect peripheral markers of T-Cell activation
  • T-cell infiltrate in tumor [ Time Frame: Baseline ]
    Tumor tissue will be analyzed to assess for T-cell infiltration
  • Tryptophan metabolites [ Time Frame: Baseline ]
    Tumor tissue will be analyzed to collect peripheral markers of tryptophan metabolites
Original Other Pre-specified Outcome Measures
 (submitted: August 20, 2015)
  • Methylguanine-DNA methyltransferase (MGMT) status (Phase I/II) [ Time Frame: Baseline ]
    Correlate MGMT status with outcome based on tumor tissue that will be analyzed
  • PDL1 expression in tumor (Phase I/II) [ Time Frame: Baseline ]
    Tumor tissue will be analyzed to assess for PDL-1 levels
  • Peripheral T-cell activation (Phase I/II) [ Time Frame: Up to 108 weeks (12 courses post-RT) ]
    Tumor tissue will be analyzed to collect peripheral markers of T-Cell activation
  • T-cell infiltrate in tumor (Phase I/II) [ Time Frame: Baseline ]
    Tumor tissue will be analyzed to assess for T-cell infiltration
  • Tryptophan metabolites (Phase I/II) [ Time Frame: Baseline ]
    Tumor tissue will be analyzed to collect peripheral markers of tryptophan metabolites
 
Descriptive Information
Brief Title  ICMJE Radiation Therapy With Temozolomide and Pembrolizumab in Treating Patients With Newly Diagnosed Glioblastoma
Official Title  ICMJE Phase I Trial of Radiation Therapy Plus Temozolomide With MK-3475 in Patients With Newly Diagnosed Glioblastoma (GBM)
Brief Summary The purpose of phase I trial is to determine the safest, most effective dose of MK-3475 (pembrolizumab), when used with radiotherapy and temozolomide for treating newly diagnosed patients with glioblastoma (GBM). Temozolomide binds to the deoxyribonucleic acid (DNA), changes it, and triggers the death of tumor cells. MK-3475 is an investigational drug, it is not currently approved by the Federal Drug Administration (FDA) for use in treating GBM but it is approved for treating melanoma. MK-3475 works by targets the local tumor immune-protection in solid tumors. It is hoped the addition of MK-3475 to the usual treatment for GBM will improve the current treatment.
Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of radiation therapy (RT) + temozolomide (TMZ) + MK-3475 (pembrolizumab) followed by MK-3475 + TMZ x 6 cycles (1 cycle is 9 weeks), MK-3475 can continue for an additional 12 months.

SECONDARY OBJECTIVES:

Safety of MK-3475 in GBM.

TERTIARY OBJECTIVES:

I. To determine if there is a correlation of programmed cell death 1 (PD1) or programmed cell death 1 ligand 1 (PDL1) expression and T-cell infiltrate in pathology from first and, if applicable, second surgical specimens with outcome.

II. Assess changes in peripheral T-cell activation and tryptophan metabolites. III. Correlate o-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) status with outcome.

OUTLINE: This is a phase I, dose-escalation study of pembrolizumab, followed by a phase II study.

RT PORTION: Patients undergo focal RT over 42 days, and receive concurrent temozolomide orally (PO) once daily (QD) on days 1-42 and pembrolizumab IV over 30 minutes on days 1, 22, and 43.

POST-RT: After completion of RT, patients receive temozolomide PO QD on days 1-5 and 29-34 of course 1 and days 1-5 and 29-33 of subsequent courses, and pembrolizumab IV over 30 minutes on days 1, 22, and 43. Treatment repeats every 9 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients deriving benefit may continue to receive pembrolizumab for an additional 12 months.

After completion of study treatment, patients are followed up every 2-4 months.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Adult Glioblastoma
Intervention  ICMJE
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Biological: Pembrolizumab
    Given IV
    Other Names:
    • Keytruda
    • Lambrolizumab
    • MK-3475
    • SCH 900475
  • Radiation: Radiation Therapy
    Undergo focal RT
    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
    • Temodal
    • Temodar
Study Arms  ICMJE Experimental: Treatment (RT, temozolomide, pembrolizumab)

RT PORTION: Patients undergo focal RT over 42 days, and receive concurrent temozolomide PO QD on days 1-42 and pembrolizumab IV over 30 minutes on days 1, 22, and 43.

POST-RT: After completion of RT, patients receive temozolomide PO QD on days 1-5 and 29-34 of course 1 and days 1-5 and 29-33 of subsequent courses, and pembrolizumab IV over 30 minutes on days 1, 22, and 43. Treatment repeats every 9 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients deriving benefit may continue to receive pembrolizumab for an additional 12 months.

Interventions:
  • Other: Laboratory Biomarker Analysis
  • Biological: Pembrolizumab
  • Radiation: Radiation Therapy
  • Drug: Temozolomide
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 Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 5, 2019)
4
Original Estimated Enrollment  ICMJE
 (submitted: August 20, 2015)
50
Estimated Study Completion Date  ICMJE November 2020
Actual Primary Completion Date May 10, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically confirmed newly diagnosed glioblastoma; patients with an initial diagnosis of a lower-grade glioma are eligible if a subsequent biopsy was determined to be glioblastoma and they received no prior treatment
  • No prior treatment with radiation or chemotherapy for their GBM
  • No prior treatment with carmustine wafers
  • Patients who have undergone recent surgery:

    • Must be a minimum of 14 days from surgery
    • Craniotomy or intracranial biopsy site must be adequately healed and free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of registration
    • Magnetic resonance imaging (MRI) within 72 hours of surgery OR 4 weeks from surgery
  • Karnofsky performance status >= 70%
  • Stable or decreasing dose of corticosteroids within 5 days prior to treatment
  • Female subject of childbearing potential should have a negative urine or serum pregnancy within 7 days prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Patients need not have measurable or evaluable disease
  • Absolute neutrophil count (ANC) > 1.5 x 10^9/L
  • Platelet count > 100 x 10^9/L; or
  • Hemoglobin (Hb) > 9.0 g/dL within 7 days prior to enrollment; note: the use of transfusion or other intervention to achieve Hb >= 9 g/dL is acceptable
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (except in patients diagnosed with Gilbert's disease)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]), alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
  • Alkaline phosphatase (ALP) =< 2.5 x ULN
  • Serum creatinine < 1.5 x ULN
  • International normalized ratio (INR), prothrombin time (PT), or activated partial thromboplastin time (APTT) as follows: in the absence of therapeutic intent to anticoagulate the patient: INR < 1.5 or PT < 1.5 x ULN or aPTT < 1.5 x ULN; in the presence of therapeutic intent to anticoagulate the patient: INR or PT and aPTT within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose of anticoagulants for at least 2 weeks before registration
  • Females of child-bearing potential (FOCBP) and males must agree to use two adequate contraception methods (give examples, e.g. hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 120 days following completion of therapy; should a female patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

    • NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

      • Has not undergone a hysterectomy or bilateral oophorectomy
      • Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months)
  • Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study

Exclusion Criteria:

  • Any prior treatment for the patients GBM
  • Has a known diagnosis of immunodeficiency (human immunodeficiency virus [HIV] 1/2 antibodies) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment excluding steroids; attempts should be made to have patient on lowest possible dose of steroids
  • History of another malignancy in the previous 3 years, with a disease-free interval of < 3 years; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
  • Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections will not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study
  • Has evidence of or a history of interstitial lung disease, non-infectious pneumonitis or pneumonitis
  • Has an active infection requiring systemic antibiotics within 7 days of registration
  • 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; examples include

    • Hypertension (defined as 160/95) that is not controlled on medication
    • Ongoing or active infection requiring systemic treatment
    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • Cardiac arrhythmia
    • Psychiatric illness/social situations or substance abuse disorders that would limit compliance with study requirements
    • Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints
  • 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
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
  • 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 received a live vaccine within 30 days prior to the first dose of trial treatment
  • Patients receiving any other investigational agents within 30 days prior to the first dose of trial treatment
  • Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-3475 are not eligible; known hypersensitivity to any excipients of MK-3475
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02530502
Other Study ID Numbers  ICMJE NU 15C01
NCI-2015-00736 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
STU00200883
NU 15C01 ( Other Identifier: Northwestern University )
P30CA060553 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Karan Dixit, Northwestern University
Study Sponsor  ICMJE Northwestern University
Collaborators  ICMJE
  • Merck Sharp & Dohme Corp.
  • National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Karan Dixit, MD Northwestern University
PRS Account Northwestern University
Verification Date February 2019

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