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Combined Cytotoxic and Immune-Stimulatory Therapy for Glioma

Study Purpose

Despite the marginal improvements in survival of patients suffering from malignant glioma treated with gene therapy vectors, the clinical trials conducted so far using viral vectors, in particular adenoviral vectors, have proven that the use of adenoviral vectors is a safe therapeutic approach, even in large, multicenter, phase 3 clinical trials. Treatment of malignant glioma using gene transfer modalities typically consists of surgical debulking of the tumor mass followed by the administration of the viral vectors into the brain tissue surrounding the tumor cavity. This study will combine direct tumor cell killing (TK) and immune-mediated stimulatory (Flt3L) gene transfer approaches delivered by first generation adenoviral vectors.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years - 75 Years
Gender All
More Inclusion & Exclusion Criteria

Inclusion Criteria:

  • - Newly diagnosed supratentorial brain lesion compatible with a high grade glioma by MR (magnetic resonance) with no prior treatment with either gene therapy, chemotherapy or radiation treatments that is amenable to attempted gross total resection (GTR).
Intraoperative histological frozen section at the time of tumor resection should be compatible with high-grade glioma. If intraoperative diagnosis is not high grade glioma, the patient will not be enrolled. "High grade glioma" can include:Glioblastoma multiforme (WHO grade IV); Anaplastic astrocytoma (WHO grade III); Anaplastic oligodendroglioma (WHO grade III); and Anaplastic ependymoma (WHO grade III).
  • - Karnofsky score ≥70 (Karnofsky scoring system used to quantify general well-being and activities of daily life; scores range from 0 to 100 where 100 represents perfect health and 0 represents death) - CBC (complete blood count)/differential obtained within 14 days prior, with adequate bone marrow function defined as follows: - Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3; - Platelets ≥ 100,000 cells/mm3; - Hemoglobin ≥ 10.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥10.0 g/dl is acceptable.
);
  • - Adequate renal function, as defined below: - BUN (blood urea nitrogen) ≤ 30 mg/dl within 14 days prior.
  • - Creatinine ≤ 1.7 mg/dl within 14 days prior.
  • - Adequate hepatic function, as defined below: - Bilirubin ≤ 2.0 mg/dl within 14 days prior.
  • - ALT (alanine aminotransferase)/AST (aspartate aminotransferase) ≤ 3x laboratory upper limit of normal within 14 days prior.
  • - 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 surgery.

Exclusion Criteria:

  • - Diffusely multifocal lesion that is not amenable to GTR (gross total resection) - Tumors infiltrating the cerebellum, bilateral corpus callosum ("butterfly glioma"), ventricular system, or brain stem.
  • - Infratentorial high grade glioma.
  • - Primary central nervous system (CNS) disease that would interfere with subject evaluation.
  • - 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 hematologic, renal or liver disease that is not explained by the patient's current medical condition or concomitant disease, (i.e. levels of absolute neutrophil count (ANC), hemoglobin, platelets, clotting time, serum creatinine, etc).
Final decision on inclusion will be made by physician, concerning suitability of patient for surgery.
  • - HIV, Hepatitis B, Hepatitis.
  • - Active systemic infection.
  • - Immunosuppressive disorders (chronic steroid therapy, acquired or congenital immune deficiency syndromes, autoimmune disease) - Serious medical conditions (CHF (congestive heart failure), angina, diabetes mellitus, Chronic obstructive pulmonary disease, abnormal bleeding diathesis) - Any contraindication for undergoing MRI (magnetic resonance imaging) - 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

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT01811992
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 1
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

University of Michigan Rogel Cancer Center
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Pedro Lowenstein, MD, PhD
Principal Investigator Affiliation University of Michigan
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Other
Overall Status Completed
Countries United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Malignant Glioma, Glioblastoma Multiforme
Study Website: View Trial Website
Additional Details

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.

Arms & Interventions

Arms

Experimental: Dose escalation of Ad-hCMV-TK and Ad-hCMV-Flt3L

This protocol is a dose escalation study of Ad-hCMV-TK and Ad-hCMV-Flt3L infused at the time of surgical resection followed by systemic oral administration of valacyclovir in addition to current standard of care with temozolomide and radiotherapy. Eligible subjects will be enrolled in six sequential dosing cohorts: - A= Ad-hCMV-TK: 1x10^10 vp and Ad-hCMV-Flt3L: 1x10^9 vp - B= Ad-hCMV-TK: 1x10^11 vp and Ad-hCMV-Flt3L: 1x10^9 vp - C= Ad-hCMV-TK: 1x10^10 vp and Ad-hCMV-Flt3L: 1x10^10 vp - D= Ad-hCMV-TK: 1x10^11 vp and Ad-hCMV-Flt3L: 1x10^10 vp - E= Ad-hCMV-TK: 1x10^10 vp and Ad-hCMV-Flt3L: 1x10^11 vp - F= Ad-hCMV-TK: 1x10^11 vp and Ad-hCMV-Flt3L: 1x10^11 vp Subjects will be treated sequentially with a minimum of 21 days before treatment of new subjects within a cohort or before dose escalation.

Interventions

Biological: - Dose Escalation of Ad-hCMV-TK and Ad-hCMV-Flt3L

Two adenoviral vectors will be used, each to deliver one of the therapeutic genes. Both vectors are human serotype 5, replication-defective, first generation adenoviral vectors deleted in E1a and E3 viral encoding regions. Each vector will constitutively express their respective therapeutic transgene (i.e. HSV1-TK or Flt3L) under the control of the human cytomegalovirus promoter (hCMV). Valacyclovir treatment will begin 1-3 days after vector administration at a dose of 2 grams given orally 3X per day for 14 days. A second course of valacyclovir will be given beginning Week 10. Radiation and chemotherapy will be administered as per standard of care.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Ann Arbor, Michigan

Status

Address

University of Michigan Health System Department of Neurosurgery

Ann Arbor, Michigan, 48109