Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

Combined Cytotoxic and Immune-Stimulatory Therapy for Glioma

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2016 by University of Michigan
Phase One Foundation
Information provided by (Responsible Party):
University of Michigan Identifier:
First received: February 13, 2013
Last updated: October 20, 2016
Last verified: October 2016
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.

Condition Intervention Phase
Malignant Glioma
Glioblastoma Multiforme
Biological: Dose Escalation of Ad-hCMV-TK and Ad-hCMV-Flt3L
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Non-randomized, Open-label Dose-finding Trial of Combined Cytotoxic and Immune-Stimulatory Strategy for the Treatment of Resectable Primary Malignant Glioma

Resource links provided by NLM:

Further study details as provided by University of Michigan:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Number of Patients Alive at 12 and 24 Months [ Time Frame: 24 Months ] [ Designated as safety issue: No ]
    To assess in a preliminary fashion the potential benefit of AdhCMV- TK and Ad-hCMV-Flt3L treatment of primary malignant gliomas by assessing overall survival (OS) at 12 and 24 months.

Estimated Enrollment: 18
Study Start Date: December 2013
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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:

  • Cohort A= Ad-hCMV-TK: 1x1010 vp and Ad-hCMV-Flt3L: 1x109 vp
  • Cohort B= Ad-hCMV-TK: 1x1011 vp and Ad-hCMV-Flt3L: 1x109 vp
  • Cohort C= Ad-hCMV-TK: 1x1010 vp and Ad-hCMV-Flt3L: 1x1010 vp
  • Cohort D= Ad-hCMV-TK: 1x1011 vp and Ad-hCMV-Flt3L: 1x1010 vp
  • Cohort E= Ad-hCMV-TK: 1x1010 vp and Ad-hCMV-Flt3L: 1x1011 vp
  • Cohort F= Ad-hCMV-TK: 1x1011 vp and Ad-hCMV-Flt3L: 1x1011 vp

Subjects will be treated sequentially with a minimum of 21 days before treatment of new subjects within a cohort or before dose escalation. Once the Maximum Tolerated Dose (MTD) is determined, or after all subjects have been evaluated and found to tolerate the highest dose, the study will end.

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.

Detailed Description:
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.

Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01811992

Contact: Karen Frisch 734.232.4843

United States, Michigan
University of Michigan Health System Department of Neurosurgery Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Karen Frisch    734-232-4843   
Sponsors and Collaborators
University of Michigan
Phase One Foundation
Principal Investigator: Pedro Lowenstein, MD, PhD University of Michigan
  More Information

Responsible Party: University of Michigan Identifier: NCT01811992     History of Changes
Other Study ID Numbers: HUM00057130  UMCC 2015.024 
Study First Received: February 13, 2013
Last Updated: October 20, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Flt3 ligand protein
Antiviral Agents
Anti-Infective Agents
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs
Radiation-Protective Agents
Protective Agents processed this record on October 25, 2016