Qualitative, Qualitative, and Functional Studies Over the First Year in Measuring Immune System Response During the First Year of Therapy in Patients With Brain Tumors

Determining the Competence of the Immune System Over the First Year of Therapy in Patients With Glioma: A Battery of Quantitative, Qualitative and Functional Measures of Immune Readiness

This research trial studies qualitative, qualitative, and functional studies over the first year in measuring immune system response in patients with brain tumors. Measuring the number of immune cells, whether these immune cells work correctly, and response to 2 vaccines at several times during the first year of treatment may help find out how active the immune system responds to fight infection and cancer.

Study Overview

• Status: Completed
• Conditions: Glioma; Astrocytoma; Oligodendroglioma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Biological: Hepatitis A Vaccine; Biological: Tetanus Toxoid Vaccine; Biological: Trivalent Influenza Vaccine

Detailed Description

PRIMARY OBJECTIVES:

I. To describe the quantity of immune cells underlying the antitumor immune response including dendritic cells, naive and activated T- and B-cells, regulatory T-cells, and natural killer cells.

II. To determine the proliferative ability of lymphocytes via T-cell activation.

SECONDARY OBJECTIVES:

I. To describe the immunologic response to the hepatitis A vaccine (or hepatitis B vaccine in those who are hepatitis A exposed) in comparison to expected/known normal responses either prior to (i.e. pre-treatment) or following chemoradiation (i.e. post-treatment).

II. To describe the immunologic response to tetanus toxoid vaccination compared to expected/known normal responses either prior to (i.e. pre-treatment) or following chemoradiation (i.e. post-treatment).

TERTIARY OBJECTIVES:

I. To describe the immunologic response to the yearly influenza vaccination over the course of the first year of therapy for glioma (timing of administration will be when clinically indicated over this year of therapy).

II. To describe the frequency of viral infection in glioma patients hospitalized during the respiratory viral season within year 1 of therapy.

III. To describe the overall survival of glioma patients enrolled in this study and describe the overall survival in these patients by changes in immunologic function.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients receive standard of care hepatitis A or B vaccine, tetanus toxoid vaccine, and trivalent influenza vaccine and then undergo standard of care treatment external beam radiation therapy and receive standard of care temozolomide. Patients also undergo collection of blood Samples monthly for the first 8 months and then bimonthly for up to 12 months for analysis via flow cytometry, carboxyfluorescein diacetate succinimidyl ester (CFSE) assay, live cell/dead cell distinction assay, and determination of naïve and memory immune response.

GROUP II: Patients undergo standard of care treatment and collection of blood samples as in Group I. Patients then receive hepatitis A and tetanus toxoid vaccinations at month 9.

• Study Type: Observational
• Enrollment (Actual): 55

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Comprehensive Cancer Center of Wake Forest University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Adults with primary central nervous system astrocytoma or oligodendroglioma

Description

Inclusion Criteria:

• Clinically or histologically diagnosed primary central nervous system astrocytoma or oligodendroglioma of World Health Organization grade II, III or IV
• Anticipated to undergo treatment with concurrent chemoradiation with conformal external beam radiotherapy in combination with low-dose temozolomide (75 mg/m^2) followed by adjuvant temozolomide (150-200 mg/m^2)
• Able to provide informed consent
• Karnofsky performance status >= 50%
• Willing and able to receive the tetanus toxoid and hepatitis vaccination (though prior vaccination with either vaccine is not a contraindication to eligibility)

Exclusion Criteria:

• Concurrent enrollment on an experimental study involving an agent whose primary mechanism of action is the immune system (i.e. immune checkpoint inhibition, oncologic vaccine, or other immune-directed therapies); Note: patients enrolled on an experimental study or receiving another concurrent treatment in addition to standard chemoradiation whose primary mechanism of action is NOT the immune system will be eligible for enrollment

• Patients unable to receive tetanus toxoid vaccination

  • Guillain-Barré syndrome =< 6 weeks after previous dose of a tetanus toxoid-containing vaccine; unstable neurologic condition (e.g., cerebrovascular events and acute encephalopathic conditions) which does not include the patient's primary brain tumor; history of an Arthus reaction following a previous dose of a tetanus toxoid-containing and/or diphtheria toxoid-containing vaccine
• Patients unable to receive hepatitis vaccination

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Basic Science Group II (vaccination at 9 months); Patients undergo standard of care treatment and collection of blood samples as in Group I. Patients then receive hepatitis A and tetanus toxoid vaccinations at month 9.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Hepatitis A Vaccine; Other Names: Havrix; Hepatitis A Vaccine, Inactivated; Vaqta; Biological: Tetanus Toxoid Vaccine; Other Names: TT; Tetanus Toxoid; Biological: Trivalent Influenza Vaccine; Other Names: Flushield; Fluzone; TIV; Fluarix; Agriflu; Flu prevention; Flu prophylaxis; Flu shot; Flu vaccination; Flublok; FluLaval; Fluvirin; Influenza Vaccine; Influenza Virus Vaccine, Trivalent, Types A and B
Basic Science Groups I (vaccination pre-treatment); Patients receive standard of care hepatitis A or B vaccine, tetanus toxoid vaccine, and trivalent influenza vaccine and then undergo standard of care treatment external beam radiation therapy and receive standard of care temozolomide. Patients also undergo collection of blood Samples monthly for the first 8 months and then bimonthly for up to 12 months for analysis via flow cytometry, (CFSE) assay, live cell/dead cell distinction assay, and determination of naïve and memory immune response.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Hepatitis A Vaccine; Other Names: Havrix; Hepatitis A Vaccine, Inactivated; Vaqta; Biological: Tetanus Toxoid Vaccine; Other Names: TT; Tetanus Toxoid; Biological: Trivalent Influenza Vaccine; Other Names: Flushield; Fluzone; TIV; Fluarix; Agriflu; Flu prevention; Flu prophylaxis; Flu shot; Flu vaccination; Flublok; FluLaval; Fluvirin; Influenza Vaccine; Influenza Virus Vaccine, Trivalent, Types A and B

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proliferative ability of lymphocytes by carboxyfluorescein diacetate succinimidyl ester assay	Mean values of the quantitative measures and proliferative ability will be calculated for each four time points and compared to determine the trajectory over time as described. In addition, the repeated measures for quantitative measures will be displayed graphically with individual trajectories. The linear mixed model will be performed to identify predictors (e.g., sex) that are associated with the quantitative measures. Furthermore, the generalized estimating equations model with the logit link and binomial distribution will be used to identify predictors for qualitative measures (e.g., prol	Up to 1 year
The quantity of cells determined by flow cytometry	Mean values of the quantitative measures and proliferative ability will be calculated for each four time points and compared to determine the trajectory over time as described. In addition, the repeated measures for quantitative measures will be displayed graphically with individual trajectories. The linear mixed model will be performed to identify predictors (e.g., sex) that are associated with the quantitative measures. Furthermore, the generalized estimating equations model with the logit link and binomial distribution will be used to identify predictors for qualitative measures (e.g., prol	Up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response of the tetanus toxoid vaccine-specific IgG antibody	Baseline and day 28 geometric mean titers (GMTs) will be calculated for hepatitis A or B and tetanus. GMTs for patients undergoing vaccination pre- and post-treatment will be performed. The difference in 28 day GMT between pretreatment and posttreatment will be compared using the paired t test. Analysis of covariance will be used to identify predictors that are associated with the change of 28 day difference in GMT. Seroconversion or a 4-fold rise in GMT from baseline to day 28 will be determined for pre and post treatment patient cohorts. Seroconversion proportion will be compared against kno	At 28 days following tetanus toxoid vaccination
Vaccine-specific total antibody response after hepatitis A vaccination. In hepatitis A exposed patients, hepatitis B will be used.	Baseline and day 28 geometric mean titers (GMTs) will be calculated for each vaccine (i.e. hepatitis A or B and tetanus). GMTs for patients undergoing vaccination pre- and post-treatment will be performed. The difference in 28-day GMT between pre-treatment and post-treatment will be compared using the paired-t test. Analysis of covariance will be used to identify predictors that are associated with the change of 28-day difference in GMT. Seroconversion or a 4-fold rise in GMT from baseline to day-28 will be determined for pre- and post-treatment patient cohorts. Seroconversion proportion will	At 28 days post hepatitis A vaccination

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of viral infection	The distribution will be plotted using a histogram. Assessment of influenza vaccine immunogenicity will be performed. GMTs will be calculated at baseline and day 28. Seroconversion (i.e. 4-fold rise in GMT from baseline to day 28) will be determined. Proportions will be binned according to the timing of influenza vaccination: (1) pre-treatment, (2) during radiation, (3) during adjuvant chemotherapy, and (4) post-treatment. Seroconversion proportion within each time point will be compared against known normal using a one proportion test.	Up to 1 year
Overall survival (OS)	The Kaplan Meier method will be used to estimate OS probability and median time of survival along with 95% confidence interval. Proportional hazards models will be used to assess for associations between mortality and baseline quantitative immunologic values, baseline qualitative immunologic function, and baseline and post-treatment seroconversion to each vaccine (treated as a time dependent variable). All p-values will be reported as two-sided.	Date of surgery to death from any cause, assessed up to 14 months
Titer of the influenza vaccine-specific IgG antibody	Baseline and day 28 geometric mean titers (GMTs) will be calculated for hepatitis A or B and tetanus. GMTs for patients undergoing vaccination pre- and post-treatment will be performed. The difference in 28 day GMT between pretreatment and posttreatment will be compared using the paired t test. Analysis of covariance will be used to identify predictors that are associated with the change of 28 day difference in GMT. Seroconversion or a 4-fold rise in GMT from baseline to day 28 will be determined for pre and post treatment patient cohorts. Seroconversion proportion will be compared against kno	At 28 days following vaccination with the trivalent inactivated influenza vaccine

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Roy Strowd, Wake Forest University Health Sciences

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2016
• Primary Completion (Actual): January 1, 2020
• Study Completion (Actual): September 9, 2021

Study Registration Dates

• First Submitted: April 19, 2016
• First Submitted That Met QC Criteria: April 20, 2016
• First Posted (Estimate): April 21, 2016

Study Record Updates

• Last Update Posted (Actual): October 29, 2021
• Last Update Submitted That Met QC Criteria: October 28, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma; Astrocytoma; Oligodendroglioma; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: IRB00037250; P30CA012197 (U.S. NIH Grant/Contract); NCI-2016-00472 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); CCCWFU 01316 (Other Identifier: Comprehensive Cancer Center of Wake Forest University)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No