Neoplasms

All Conditions

Rare Diseases

Glioblastoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Amino Acids

Immune Checkpoint Inhibitors

Temozolomide

Nivolumab

Valacyclovir

Acyclovir

Antineoplastic Agents, Immunological

Antineoplastic Agents, Alkylating

Alkylating Agents

Antiviral Agents

Valine

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.

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.

AdV-tk

Given PO days 1-14; 1-3 days post surgery

Undergo RT, 60Gy in 30 daily fractions M-F for 6weeks

Radiation

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)

day 15 post surgery 240mg IV q2wks x 26 doses , up to 52 weeks

Laboratory Biomarker Analysis

Patrick Wen, MD

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

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.

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

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

Phase I Study of Neoadjuvant GMCI Plus Immune Checkpoint Inhibitor Combined With Standard of Care for Newly Diagnosed High-Grade Gliomas

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.

To estimate overall survival - endpoint is death. Median time of survival along with 95% confidence interval will be estimated using the Kaplan-Meier method.

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.

Tumor profiling by immunohistochemistry and Nanostring at baseline and when samples available after treatment.

Mutational profiling by sequence or transcriptome analysis from tumor tissue

Standard descriptive statistics will be used to summarize proportion of PBMCs.

Immune characterization of surface and content proteins is determined by presence of cytokines in serum.

Immune characterization of surface and content proteins based on presence of extracellular vesicles in serum samples.

Spots Global Cancer Trial Database for glioblastoma, newly diagnosed, gmci, checkpoint inhibitor