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Radiation Therapy With Temozolomide and Pembrolizumab in Treating Patients With Newly Diagnosed Glioblastoma

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Jeffrey Raizer, Northwestern University
ClinicalTrials.gov Identifier:
NCT02530502
First received: August 19, 2015
Last updated: October 31, 2016
Last verified: October 2016
  Purpose
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). Phase II trial will evaluate if MK-3475 used in combination with temozolomide and radiation followed by radiation and temozolomide to see if this is better than using radiation and temozolomide alone. 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.

Condition Intervention Phase
Adult Glioblastoma
Other: Laboratory Biomarker Analysis
Biological: Pembrolizumab
Radiation: Radiation Therapy
Drug: Temozolomide
Phase 1
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Trial of Radiation Therapy Plus Temozolomide With MK-3475 in Patients With Newly Diagnosed Glioblastoma (GBM)

Resource links provided by NLM:


Further study details as provided by Northwestern University:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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)


Other Outcome Measures:
  • 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


Estimated Enrollment: 50
Study Start Date: October 2015
Estimated Primary Completion Date: March 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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

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. (Phase I) II. To determine the progression-free survival (PFS) in newly diagnosed glioblastoma multiforme (GBM) patients treated with RT + TMZ + MK-3475 followed by MK-3475 + TMZ x 6 cycles (1 cycle is 9 weeks), MK-3475 can continue for an additional 12 months. (Phase II)

SECONDARY OBJECTIVES:

I. To determine PFS-6 (percentage of patients alive and progression-free at 6 months post registration); response rate; overall survival (OS); OS-6, 12 and 24 (percentage of patients alive at 6, 12 and 24 months respectively); safety of MK-3475 in GBM. (Phase II)

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

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.

  Eligibility

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

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02530502

Locations
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
Sponsors and Collaborators
Northwestern University
Merck Sharp & Dohme Corp.
National Cancer Institute (NCI)
Investigators
Principal Investigator: Jeffrey Raizer, MD Northwestern University
  More Information

Responsible Party: Jeffrey Raizer, Principal Investigator, Northwestern University
ClinicalTrials.gov Identifier: NCT02530502     History of Changes
Other Study ID Numbers: NU 15C01
NCI-2015-00736 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
STU00200883
NU 15C01 ( Other Identifier: Northwestern University )
P30CA060553 ( US NIH Grant/Contract Award Number )
Study First Received: August 19, 2015
Last Updated: October 31, 2016

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Dacarbazine
Pembrolizumab
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents

ClinicalTrials.gov processed this record on April 27, 2017