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

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ClinicalTrials.gov Identifier: NCT03576612
Recruitment Status : Recruiting
First Posted : July 3, 2018
Last Update Posted : October 4, 2019
Sponsor:
Collaborators:
Advantagene, Inc.
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary:

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


Condition or disease Intervention/treatment Phase
Glioma, Malignant Biological: AdV-tk Drug: Valacyclovir Radiation: Radiation Drug: Temozolomide Biological: Nivolumab Other: Laboratory Biomarker Analysis Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description: Newly diagnosed HGG: surgically eligible patients AdV-tk into wall of resection cavity; 1-3 days post-surgery Valacyclovir d1-14; Day 8 RT for 6 wks; day 15 TMZ 75mg/m2 daily; Nivo 240mgIV every 2 weeks
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Neoadjuvant GMCI Plus Immune Checkpoint Inhibitor Combined With Standard of Care for Newly Diagnosed High-Grade Gliomas
Actual Study Start Date : February 27, 2018
Estimated Primary Completion Date : February 28, 2021
Estimated Study Completion Date : February 28, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort 1: MGMT Unmethylated Patients
After 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.
Biological: AdV-tk
Given IT
Other Name: Aglatimagene Besadenovec

Drug: Valacyclovir
Given PO days 1-14; 1-3 days post surgery
Other Names:
  • 124832-26-4
  • L-Valine ester with 9-((2-hydroxyethoxy)methyl)guanine
  • Zelitrex

Radiation: Radiation
Undergo RT, 60Gy in 30 daily fractions M-F for 6weeks
Other Names:
  • Irradiate
  • irradiation
  • radiotherapy
  • RT

Drug: Temozolomide
Given PO during RT 75mg/m2 daily during RT Post RT cycle 1: 150mg/m2 days 1-5 150mg/m2 cycle 2-6: days 1-5 (150-200mg/m2)
Other Name: TMZ

Biological: Nivolumab
day 15 post surgery 240mg IV q2wks x 26 doses , up to 52 weeks
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Other: Laboratory Biomarker Analysis
correlative studies

Experimental: Cohort 2: MGMT Methylated & undetermined Patients
After 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.
Biological: AdV-tk
Given IT
Other Name: Aglatimagene Besadenovec

Drug: Valacyclovir
Given PO days 1-14; 1-3 days post surgery
Other Names:
  • 124832-26-4
  • L-Valine ester with 9-((2-hydroxyethoxy)methyl)guanine
  • Zelitrex

Radiation: Radiation
Undergo RT, 60Gy in 30 daily fractions M-F for 6weeks
Other Names:
  • Irradiate
  • irradiation
  • radiotherapy
  • RT

Drug: Temozolomide
Given PO during RT 75mg/m2 daily during RT Post RT cycle 1: 150mg/m2 days 1-5 150mg/m2 cycle 2-6: days 1-5 (150-200mg/m2)
Other Name: TMZ

Biological: Nivolumab
day 15 post surgery 240mg IV q2wks x 26 doses , up to 52 weeks
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Other: Laboratory Biomarker Analysis
correlative studies




Primary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 2 years ]
    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 :
  1. 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 ]
    To estimate overall survival - endpoint is death. Median time of survival along with 95% confidence interval will be estimated using the Kaplan-Meier method.

  2. Progression-free survival (progression) [ Time Frame: From initial diagnosis to the date progression is defined, assessed for up to 2 years ]
    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.

  3. Immune profiling - Tumor Tissue [ Time Frame: Up to 2 years ]
    Tumor profiling by immunohistochemistry and Nanostring at baseline and when samples available after treatment.

  4. Tumor mutation - Tumor Tissue [ Time Frame: Up to 2 years ]
    Mutational profiling by sequence or transcriptome analysis from tumor tissue

  5. Peripheral blood mononuclear cells (PBMCs) in serum samples [ Time Frame: Up to 2 years ]
    Standard descriptive statistics will be used to summarize proportion of PBMCs.

  6. Immune characterization as determined by Cytokines [ Time Frame: Up to 2 years ]
    Immune characterization of surface and content proteins is determined by presence of cytokines in serum.

  7. Immune characterization as determined by Extracellular vesicles (EVs) proteins [ Time Frame: Up to 2 years ]
    Immune characterization of surface and content proteins based on presence of extracellular vesicles in serum samples.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03576612


Contacts
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Contact: ABTC Operations Office 410-955-3657 jfisher@jhmi.edu
Contact: ABTC Operations Office 410-614-4400 sdeside1@jhmi.edu

Locations
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United States, Alabama
University of Alabama at Birmingham Comprehensive Cancer Center Not yet recruiting
Birmingham, Alabama, United States, 35294
Contact: Clinical Trials Office - UAB Comprehensive Cancer Center    205-934-0309      
Principal Investigator: Louis B Nabors, MD         
United States, California
Jonsson Comprehensive Cancer Center at UCLA Not yet recruiting
Los Angeles, California, United States, 90095
Contact: Timothy Cloughesy, MD    310-825-5321    TCloughesy@mednet.ucla.edu   
Principal Investigator: Timothy Cloughesy, MD         
University of California San Francisco Medical Center Not yet recruiting
San Francisco, California, United States, 94143
Contact: Susan M. Chang, MD    415-353-2270    changs@neurosurg.ucsf.edu   
Principal Investigator: Susan Chang, MD         
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21231
Contact: Michaella Iacoboni, RN    410-955-4009    msheeh13@jhmi.edu   
Principal Investigator: Cheten Bettegowda, MD         
Sub-Investigator: Stuart Grossman, MD         
United States, Massachusetts
Massachusetts General Hospital Cancer Center Not yet recruiting
Boston, Massachusetts, United States, 02114
Contact: Clinical Trials Office - Massachusetts General Hospital Cancer    877-726-5130      
Contact: , MD         
Principal Investigator: Elizabeth Gerstner, MD         
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Gina Cach       Gina_Cach@DFCI.HARVARD.EDU   
Contact: Swati Madhok       Swati_Madhok@DFCI.Harvard.edu   
Principal Investigator: Patrick Wen, MD         
United States, Michigan
Henry Ford Hospital Recruiting
Detroit, Michigan, United States, 48202
Contact: Amy Williamson, RN       awillia12@hfhs.org   
Contact: Emily Krozek, MHSA       ekrozek1@hfhs.org   
Principal Investigator: Ian Lee, MD         
United States, New York
Memorial Sloan-Kettering Cancer Center Not yet recruiting
New York, New York, United States, 10021
Contact: Tom Kaley, MD    212-639-5122      
Principal Investigator: Tom Kaley, MD         
United States, North Carolina
Wake Forest University Comprehensive Cancer Center Recruiting
Winston-Salem, North Carolina, United States, 27157
Contact: Clinical Trials Office    336-713-6771      
Contact: Roy Strowd    336-716-2357      
Principal Investigator: Roy Strowd, MD         
United States, Ohio
Cleveland Clinic Taussig Cancer Center Not yet recruiting
Cleveland, Ohio, United States, 44195
Contact: Cancer Center-Cares    216-444-7923      
Principal Investigator: Manmeet Ahluwalia, MD         
Sub-Investigator: David Peereboom, MD         
United States, Pennsylvania
Abrams Cancer Center of the University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Timothy Prior    215-615-3673    NCRD-BTC@uphs.upenn.edu   
Principal Investigator: Steven Brem, MD         
Hillman Cancer Center at University of Pittsburgh Cancer Institute Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Clinical Trials Office - Hillman Cancer Center    412-647-8073      
Principal Investigator: Nduka Amankulor, MD         
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Advantagene, Inc.
National Cancer Institute (NCI)
Investigators
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Study Chair: Patrick Wen, MD Dana Farber

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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT03576612     History of Changes
Other Study ID Numbers: ABTC-1603
IRB00172749 ( Other Identifier: JHM IRB )
UM1CA137443 ( U.S. NIH Grant/Contract )
First Posted: July 3, 2018    Key Record Dates
Last Update Posted: October 4, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
glioblastoma, newly diagnosed, GMCI, Checkpoint inhibitor
Additional relevant MeSH terms:
Layout table for MeSH terms
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Valacyclovir
Acyclovir
Nivolumab
Temozolomide
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents