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A Non-randomized, Open-label Dose-finding Trial of Combined Cytotoxic and Immune-Stimulatory Strategy for the Treatment of Resectable Primary Malignant Glioma

Phase 1
18 Years
75 Years
Not Enrolling
Malignant Glioma, Glioblastoma Multiforme

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Trial Information

A Non-randomized, Open-label Dose-finding Trial of Combined Cytotoxic and Immune-Stimulatory Strategy for the Treatment of Resectable Primary Malignant Glioma

This is a Phase 1, multiple center open label, dose escalation safety study of Ad-hCMV-TK
and Ad-hCMV-Flt3L delivered to the peritumoral region after tumor resection. This study will
combine direct tumor cell killing (TK) and immune-mediated stimulatory (Flt3L) gene transfer
approaches delivered by first generation adenoviral vectors. Treatment with HSV1-TK is
expected to kill transduced brain cells, thus exposing tumor antigen. Treatment with Flt3L,
a cytokine known to cause proliferation of dendritic cells, should cause the migration of
dendritic cells to the peritumoral brain and remaining tumor. There, they will be exposed to
tumor antigens released from dying glioma cells through TK + valacyclovir-induced glioma
cell death, and thus mediate a specific anti-malignant glioma immune response against
remaining malignant glioma cells.

Inclusion Criteria:

- Newly diagnosed supratentorial brain lesion compatible with a high grade glioma
(glioblastoma multiforme WHO IV) by magnetic resonance imaging with no prior
treatment with either gene therapy, chemotherapy or radiation treatments that is
amenable to attempted gross total resection (GTR). Patients with anaplastic
astrocytoma or a grade III tumor are not eligible.

- Intraoperative histological frozen section at the time of tumor resection compatible
with high-grade glioma. If intraoperative diagnosis is not compatible with high grade
glioma, the patient will not be treated.

- Karnovsky score ≥70

- Normal hematologic, renal, and liver function as determined by hematology and
clinical chemistry tests

- Male and female; both genders must use contraception if of reproductive capacity

- Capable of informed consent

- 18-75 years of age

- For women of child bearing age, a negative pregnancy test performed within 14 days of

Exclusion Criteria:

- Diffusely multifocal lesion that is not amenable to GTR

- Tumors infiltrating the cerebellum, bilateral corpus callosum ("butterfly glioma"),
ventricular system, or brain stem

- Infratentorial high grade glioma

- History of primary central nervous system (CNS) disease that would interfere with
subject evaluation

- History of current diagnosis of other cancer except curative cervical cancer in situ,
basal or squamous cell carcinoma of the skin.

- Evidence of other significant disease including renal of liver disease [Absolute
neutrophil count (ANC) ≤ 1,500/mm3; hemoglobin < 10.0 g/dL (transfusion allowed),
platelets < 100,000/mm3 (transfusion independent); international normalized ratio or
activated partial thromboplastin time above upper limit of normal (ULN); aspartate
aminotransferase or alanine aminotransferase >2.5 x ULN or total bilirubin > 2.5
mg/dL; serum creatinine >1.5 mg/dL].

- HIV, Hepatitis B, Hepatitis

- Active systemic infection

- Immunosuppressive disorders (chronic steroid therapy, acquired or congenital immune
deficiency syndromes, autoimmune disease)

- Serious medical conditions (CHF, angina, diabetes mellitus, Chronic obstructive
pulmonary disease, abnormal prothrombin time/partial thromboplastin time)

- Any contraindication for undergoing MRI

- Pregnant or lactating females

- Unacceptable anesthesia risk

- Evidence of bleeding diathesis or use of anticoagulant medication or any medication
that may increase the risk of bleeding that cannot be stopped prior to surgery.

- Prior gene therapy

- Allergy to valacyclovir or unable to take oral tablets

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Dose-Limiting Toxicity

Outcome Description:

Grade 4 toxicity for constitutional symptoms as graded by the NCI Common Terminology Criteria for Adverse Events v4.03 (CTCAE) with the exception of fever >40°C for ≤24 hours. Grade 3 or greater CTCAE v4.03 neurologic toxicity relative to the changes from the pre-treatment neurological status and attributable to the study therapy regimen. Grade 3 or greater non hematologic toxicity as defined by CTCAE v.4.03, and attributable to the study therapy regimen. Grade 2 or greater autoimmune events as defined by CTCAE v.4.03

Outcome Time Frame:

24 months

Safety Issue:


Principal Investigator

Pedro Lowenstein, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Michigan


United States: Food and Drug Administration

Study ID:




Start Date:

March 2013

Completion Date:

March 2018

Related Keywords:

  • Malignant Glioma
  • Glioblastoma Multiforme
  • Glioblastoma
  • Glioma



University of Michigan Health System Department of Neurosurgery Ann Arbor, Michigan  48109