Clinical Trials /

GMCI, Nivolumab, and Radiation Therapy in Treating Patients With Newly Diagnosed High-Grade Gliomas

NCT03576612

Description:

The purpose of this phase I trial is to test the safety of combining GMCI, an immunostimulator, plus nivolumab, an immune checkpoint inhibitor (ICI), with standard of care radiation therapy, and temozolomide in treating patients with newly diagnosed high-grade gliomas. Gene Mediated Cytotoxic Immunotherapy (GMCI) involves the use of aglatimagene besadenovec (AdV-tk) injection into the tumor site and oral valacyclovir to kill tumor cells and stimulate the immune system. Nivolumab is an immune checkpoint inhibitor that may also stimulate the immune system by blocking the PD-1 immune suppressive pathway. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors and temozolomide is a chemotherapy drug that kills tumor cells. Giving GMCI, nivolumab, radiation therapy, and temozolomide may work better in treating patients with high-grade gliomas

Related Conditions:
  • Malignant Glioma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: GMCI, Nivolumab, and Radiation Therapy in Treating Patients With Newly Diagnosed High-Grade Gliomas
  • Official Title: Phase I Study of Neoadjuvant GMCI Plus Immune Checkpoint Inhibitor Combined With Standard of Care for Newly Diagnosed High-Grade Gliomas

Clinical Trial IDs

  • ORG STUDY ID: ABTC-1603
  • SECONDARY ID: IRB00172749
  • SECONDARY ID: UM1CA137443
  • NCT ID: NCT03576612

Conditions

  • Glioma, Malignant

Interventions

DrugSynonymsArms
AdV-tkAglatimagene BesadenovecCohort 1: MGMT Unmethylated Patients
Valacyclovir124832-26-4, L-Valine ester with 9-((2-hydroxyethoxy)methyl)guanine, ZelitrexCohort 1: MGMT Unmethylated Patients
TemozolomideTMZCohort 1: MGMT Unmethylated Patients
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoCohort 1: MGMT Unmethylated Patients

Purpose

The purpose of this phase I trial is to test the safety of combining GMCI, an immunostimulator, plus nivolumab, an immune checkpoint inhibitor (ICI), with standard of care radiation therapy, and temozolomide in treating patients with newly diagnosed high-grade gliomas. Gene Mediated Cytotoxic Immunotherapy (GMCI) involves the use of aglatimagene besadenovec (AdV-tk) injection into the tumor site and oral valacyclovir to kill tumor cells and stimulate the immune system. Nivolumab is an immune checkpoint inhibitor that may also stimulate the immune system by blocking the PD-1 immune suppressive pathway. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors and temozolomide is a chemotherapy drug that kills tumor cells. Giving GMCI, nivolumab, radiation therapy, and temozolomide may work better in treating patients with high-grade gliomas

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the safety/maximum tolerated dose (MTD) of the combination of aglatimagene
      besadenovec (AdV-tk) given intra-cranially at the time of initial tumor resection followed by
      valacyclovir (GMCI), nivolumab, and standard of care (radiation therapy [RT]+temozolomide
      [TMZ]) in patients with high-grade gliomas (HGG).

      PRIMARY OBJECTIVES:

      I. To assess the safety/maximum tolerated dose (MTD) of the combination of aglatimagene
      besadenovec (AdV-tk) given intra-cranially at the time of initial tumor resection followed by
      valacyclovir (GMCI), nivolumab, and standard of care (radiation therapy [RT]+temozolomide
      [TMZ]) in patients with high-grade gliomas (HGG).

      SECONDARY OBJECTIVES:

      I. To evaluate safety and toxicity of this combined treatment regimen. II. To estimate
      overall survival. III. To estimate progression free survival. IV. Immune biomarkers,
      including serum extracellular vesicles (EVs).

      OUTLINE:

      Patients undergo tumor resection and receive AdV-tk injection into the wall of the resection
      cavity. Patients then receive valacyclovir orally three times per day for 14 days. Beginning
      on approximately day 8, patients undergo radiation therapy five days per week for 6 weeks.
      Temozolomide will be initiated on approximately day 15 after valacyclovir is completed and
      will continue until MGMT methylation status is known. If unmethylated, temozolomide will be
      discontinued: these patients will constitute Cohort 1. In Cohort 2 - patients with methylated
      MGMT - temozolomide will continue. If methylation status is unable to be determined, those
      patients will also continue receiving temozolomide (Cohort 2). Both cohorts will receive
      nivolumab intravenously every two weeks for up to 52 weeks in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 2 months for 2 years, and
      then every 6 months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1: MGMT Unmethylated PatientsExperimentalAfter confirmation of high grade glioma, AdV-tk injection into wall of resection cavity. Valacyclovir starting 1-3 days post-surgery for 14 days. Radiation begins approximately day 8 and continues for 6 weeks. Temozolomide started after complete valacyclovir and stop when MGMT unmethylated result obtained. Nivolumab every 2 weeks x 26 doses up to 52 weeks. MRI every 8 weeks until progression.
  • AdV-tk
  • Valacyclovir
  • Temozolomide
  • Nivolumab
Cohort 2: MGMT Methylated & undetermined PatientsExperimentalAfter confirmation of high grade glioma, AdV-tk injection into wall of resection cavity. Valacyclovir starting 1-3 days post-surgery for 14 days. Radiation begins approximately day 8. Temozolomide started after complete valacyclovir and continue during radiation then 5 week break and then begin adjuvant temozolomide dosing. Nivolumab every 2 weeks x 26 doses up to 52 weeks. MRI every 8 weeks until progression.
  • AdV-tk
  • Valacyclovir
  • Temozolomide
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have operable brain tumor presumed to be high grade glioma (HGG) based
             on clinical and radiologic evaluation, where a gross total surgical resection of the
             contrast-enhancing area is intended; pathologic confirmation of HGG must be made at
             the time of surgery prior to AdV-tk injection, if not previously determined

          -  Patients must have a Karnofsky performance status >= 70% (i.e. the patient must be
             able to care for himself/herself with occasional help from others)

          -  Absolute neutrophil count >= 1,500/uL

          -  Platelets >= 100,000/uL

          -  Hemoglobin >= 9 g/dL

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN), (except for
             patients with known Gilbert's syndrome who must have normal direct bilirubin)

          -  Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase
             (SGOT)/alanine aminotransaminase (ALT) serum glutamate pyruvate transaminase (SGPT) =<
             3.0 x institutional ULN

          -  Creatinine =< institutional ULN

          -  Calculated creatinine clearance >= 40 ml/min (use a modified Cockcroft-Gault equation)

          -  Activated partial thromboplastin time/partial thromboplastin time (APTT/PTT) =< 1.5 x
             institutional ULN

          -  Patients must be able to provide written informed consent

          -  Patients must have magnetic resonance imaging (MRI) within 14 days of starting
             treatment; patients must be able to tolerate MRI

          -  Women of childbearing potential must agree to have a negative serum pregnancy test
             within 24 hours prior to treatment start; women of childbearing potential must agree
             to use adequate contraception (hormonal or barrier method of birth control;
             abstinence) prior to study entry, for the duration of study treatment, and through at
             least 5 months after the last dose of study drug; should a woman become pregnant or
             suspect she is pregnant while participating in this study, she should inform her
             treating physician immediately; sexually active men of reproductive potential who are
             partners of women with reproductive potential must also agree to use adequate
             contraception prior to the study, for the duration of study participation, and through
             at least 7 months after the last dose of study drug; adequate methods of effective
             birth control include sexual abstinence (men, women); vasectomy; or a condom with
             spermicide (men) in combination with barrier methods, hormonal birth control or
             intrauterine device (IUD) (women)

          -  Patients must have no concurrent malignancy except curatively treated basal or
             squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or
             bladder; patients with prior malignancies must be disease-free for >= two years;
             patients with low-risk prostate cancer on active surveillance are eligible

          -  Patients must be able to swallow oral medications

          -  Patients must not have received prior radiation therapy, chemotherapy, immunotherapy
             or therapy with biologic agent (including immunotoxins, immunoconjugates, antisense,
             peptide receptor antagonists, interferons, interleukins, tumor infiltrating lymphocyte
             [TIL], lymphokine-activated killer [LAK] or gene therapy), or hormonal therapy for
             their brain tumor; glucocorticoid therapy is allowed

        Exclusion Criteria:

          -  Patients receiving any other investigational agents are ineligible

          -  Patients with a history of hypersensitivity or allergic reactions attributed to
             compounds of similar chemical or biologic composition to valacyclovir, acyclovir, or
             temozolomide are ineligible; the valacyclovir and temozolomide package inserts can be
             referenced for more information

          -  Patients with a history of severe hypersensitivity reaction to any monoclonal antibody
             are ineligible

          -  Patients who require therapy with systemic immunosuppressive drugs except
             corticosteroids are ineligible

          -  Patients with a history of active autoimmune disease requiring treatment in the past 2
             years are ineligible

          -  Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
             or active infection, symptomatic congestive heart failure, unstable angina pectoris,
             cardiac arrhythmia, active liver disease or active hepatitis, or psychiatric
             illness/social situations that would limit compliance with study requirements, are
             ineligible

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
             the mother is treated with these agents through 1 week after receiving the last dose
             of study drugs

          -  Patients who are known to be human immunodeficiency virus (HIV) positive are
             ineligible
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 will be used for scoring toxicity and adverse events. The severity and frequency of toxicity will be tabulated by the tested dose or doses using descriptive statistics. The proportions of subjects who experienced grade 3 or above toxicities will be estimated, along with 95% confidence intervals by each type of toxicity.

Secondary Outcome Measures

Measure:Overall survival (death)
Time Frame:From initial diagnosis to the date of death/or censored at the time of last known alive, assessed for up to 2 years
Safety Issue:
Description:To estimate overall survival - endpoint is death. Median time of survival along with 95% confidence interval will be estimated using the Kaplan-Meier method.
Measure:Progression-free survival (progression)
Time Frame:From initial diagnosis to the date progression is defined, assessed for up to 2 years
Safety Issue:
Description:To estimate progression-free survival - endpoint is progression. Median time of progression-free survival along with 95% confidence interval will be estimated using Kaplan-Meier method.
Measure:Immune profiling - Tumor Tissue
Time Frame:Up to 2 years
Safety Issue:
Description:Tumor profiling by immunohistochemistry and Nanostring at baseline and when samples available after treatment.
Measure:Tumor mutation - Tumor Tissue
Time Frame:Up to 2 years
Safety Issue:
Description:Mutational profiling by sequence or transcriptome analysis from tumor tissue
Measure:Peripheral blood mononuclear cells (PBMCs) in serum samples
Time Frame:Up to 2 years
Safety Issue:
Description:Standard descriptive statistics will be used to summarize proportion of PBMCs.
Measure:Immune characterization as determined by Cytokines
Time Frame:Up to 2 years
Safety Issue:
Description:Immune characterization of surface and content proteins is determined by presence of cytokines in serum.
Measure:Immune characterization as determined by Extracellular vesicles (EVs) proteins
Time Frame:Up to 2 years
Safety Issue:
Description:Immune characterization of surface and content proteins based on presence of extracellular vesicles in serum samples.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Trial Keywords

  • glioblastoma, newly diagnosed, GMCI, Checkpoint inhibitor

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