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

NCT03576612 | Completed Phase 1 DMC FDA Drug

• 3 other identifiers: ABTC-1603IRB00172749UM1CA137443
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 5

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

Conditions

Glioma, Malignant

Keywords

glioblastoma, newly diagnosed, GMCI, Checkpoint inhibitor

Outcome Measures

Primary Outcomes (1)

• Incidence of adverse events

  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.

  Up to 2 years

Secondary Outcomes (7)

• Overall survival (death)

  From initial diagnosis to the date of death/or censored at the time of last known alive, assessed for up to 2 years

• Progression-free survival (progression)

  From initial diagnosis to the date progression is defined, assessed for up to 2 years

• Immune profiling - Tumor Tissue

  Up to 2 years

• Tumor mutation - Tumor Tissue

  Up to 2 years

• Peripheral blood mononuclear cells (PBMCs) in serum samples

  Up to 2 years

Study Arms (2)

Cohort 1: MGMT Unmethylated Patients

EXPERIMENTAL

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; Drug: Valacyclovir; Radiation: Radiation; Drug: Temozolomide; Biological: Nivolumab; Other: Laboratory Biomarker Analysis

Cohort 2: MGMT Methylated & undetermined Patients

EXPERIMENTAL

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; Drug: Valacyclovir; Radiation: Radiation; Drug: Temozolomide; Biological: Nivolumab; Other: Laboratory Biomarker Analysis

Interventions

AdV-tk BIOLOGICAL

Given IT

Also known as: Aglatimagene Besadenovec

Cohort 1: MGMT Unmethylated Patients; Cohort 2: MGMT Methylated & undetermined Patients

Valacyclovir DRUG

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

Also known as: 124832-26-4, L-Valine ester with 9-((2-hydroxyethoxy)methyl)guanine, Zelitrex

Cohort 1: MGMT Unmethylated Patients; Cohort 2: MGMT Methylated & undetermined Patients

Radiation RADIATION

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

Also known as: Irradiate, irradiation, radiotherapy, RT

Cohort 1: MGMT Unmethylated Patients; Cohort 2: MGMT Methylated & undetermined Patients

Temozolomide DRUG

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)

Also known as: TMZ

Cohort 1: MGMT Unmethylated Patients; Cohort 2: MGMT Methylated & undetermined Patients

Nivolumab BIOLOGICAL

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

Also known as: BMS-936558, MDX-1106, NIVO, ONO-4538, Opdivo

Cohort 1: MGMT Unmethylated Patients; Cohort 2: MGMT Methylated & undetermined Patients

Laboratory Biomarker Analysis OTHER

correlative studies

Cohort 1: MGMT Unmethylated Patients; Cohort 2: MGMT Methylated & undetermined Patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Candel Therapeutics, Inc.: lead
• National Cancer Institute (NCI): collaborator
• Bristol-Myers Squibb: collaborator

Study Sites (5)

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

Wake Forest University Comprehensive Cancer Center

Winston-Salem, North Carolina, 27157, United States

Location

Abrams Cancer Center of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Hillman Cancer Center at University of Pittsburgh Cancer Institute

Pittsburgh, Pennsylvania, 15232, United States

Location

Related Publications (1)

• Wen PY, Manzanera A, Duault C, Gonzalez-Kozlova E, Lopez L, Grossman SA, Ye X, Fisher J, Lee I, Walbert T, Snyder J, Brem S, Desai A, Bagley SJ, Kakani C, Strowd R, Tatter S, Laxton A, Lesser G, Amankulor N, Lieberman F, Drappatz J, Mantica M, Triggs D, Haymaker C, Wistuba II, Al-Atrash G, Mendoza Perez J, Futreal A, Little LD, Islam MDH, Duose D, Jiang P, Reuben A, Lawler SE, Pichavant M, Gentles A, Bendall S, Kong A, Camacho C, Del Valle D, Kim-Schulze S, Gnjatic S, Sharon E, Nowicki MO, Peruzzi P, Lane D, Aguilar-Cordova E, Aguilar LK, Nichols G, Dwyer J, Tak PP, Maecker H, Barone F, Chiocca EA. A multi-institutional phase 1 clinical trial exploring upfront multimodal standard of care and combined immunotherapies for newly diagnosed glioblastoma. Neuro Oncol. 2025 Mar 22:noaf079. doi: 10.1093/neuonc/noaf079. Online ahead of print.

  PMID: 40120123 DERIVED

MeSH Terms

Conditions

Glioma; Glioblastoma

Interventions

Valacyclovir; Radiation; Radiotherapy; Temozolomide; Nivolumab

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Astrocytoma

Intervention Hierarchy (Ancestors)

Acyclovir; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Physical Phenomena; Therapeutics; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Patrick Wen, MD

  Dana Farber

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: May 24, 2018
• First Posted: July 3, 2018
• Study Start: February 27, 2018
• Primary Completion: June 30, 2023
• Study Completion: June 30, 2023
• Last Updated: February 14, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)