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

Trial Status: Active

This phase I trial studies the side effects and best dose of aglatimagene besadenovec and valacyclovir (gene mediated cytotoxic immunotherapy [GMCI]), nivolumab, radiation therapy, and temozolomide in treating patients with newly diagnosed high-grade gliomas. Aglatimagene besadenovec and valacyclovir may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving GMCI, nivolumab, radiation therapy, and temozolomide may work better in treating patients with high-grade gliomas.

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. Remote consenting is acceptable per institutional requirements, and must be approved by each clinical site’s reviewing Institutional Review Board (IRB)
  • 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 because the agents used in this study have potential for teratogenic or abortifacients effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is treated with these agents through 5 months after receiving the last dose of study drugs
  • Patients who are known to be human immunodeficiency virus (HIV) positive are ineligible; these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 410-955-8804

Massachusetts

Boston
Brigham and Women's Hospital
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 617-724-5200
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-442-3324

Michigan

Detroit
Henry Ford Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 313-916-3721

North Carolina

Winston-Salem
Wake Forest University Health Sciences
Status: ACTIVE
Contact: Site Public Contact
Phone: 336-713-6771

Pennsylvania

Philadelphia
University of Pennsylvania / Abramson Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-474-9892
Pittsburgh
University of Pittsburgh Cancer Institute (UPCI)
Status: ACTIVE
Contact: Site Public Contact
Phone: 412-647-8073

PRIMARY OBJECTIVE:

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:

Patient undergo tumor resection and receive aglatimagene besadenovec intratumorally (IT). Patients then receive valacyclovir orally (PO) three times per day (TID) on days 1-14. Beginning on day 8, patients undergo radiation therapy five days per week for 6 weeks. Beginning on day 15, patients also receive temozolomide PO until methylation status is known. Patients also receive nivolumab IV over approximately 60 minutes once every 2 weeks for up to 52 weeks in the absence of disease progression or unacceptable toxicity. Patients who have tumors determined to be MGMT unmethylated continue receiving radiation therapy and nivolumab. Patients who have tumors determined to be MGMT methylated continue receiving temozolomide during radiation therapy and nivolumab.

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

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Adult Brain Tumor Consortium

Principal Investigator
Patrick Yung Chih Wen

  • Primary ID ABTC-1603
  • Secondary IDs NCI-2017-01315
  • Clinicaltrials.gov ID NCT03576612