Combined Cytotoxic and Immune-Stimulatory Therapy for Glioma
This study is currently recruiting participants.
(see Contacts and Locations)
Verified December 2013 by University of Michigan
Sponsor:
Pedro Lowenstein, MD PhD
Collaborator:
Phase One Foundation, Santa Monica, CA (USA)
Information provided by (Responsible Party):
Pedro Lowenstein, MD PhD, University of Michigan
ClinicalTrials.gov Identifier:
NCT01811992
First received: February 13, 2013
Last updated: December 5, 2013
Last verified: December 2013
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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.
| 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:
- Dose-Limiting Toxicity [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
- 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
Secondary Outcome Measures:
- Functional Status - Karnofsky Performance Status, Glasgow Coma Scale [ Time Frame: Pre-operative to three days post-operative ] [ Designated as safety issue: Yes ]
- Medical and Neurological Examinations - Hematology, Clinical Chemistry, Physical Exam, Neurological Assessment, Adenoviral antibodies [ Time Frame: 24 Month ] [ Designated as safety issue: Yes ]
- MRI [ Time Frame: Within 48 hours post-operative ] [ Designated as safety issue: No ]To determine the degree of tumor resection
- Survival from Date of Operation [ Time Frame: 24 Month ] [ Designated as safety issue: Yes ]
- Progression-free survival [ Time Frame: 24 Month ] [ Designated as safety issue: Yes ]
| 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:
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.
Eligibility| Ages Eligible for Study: | 18 Years to 75 Years (Adult, Senior) |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Newly diagnosed supratentorial brain lesion compatible with a high grade glioma (WHO III or 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).
- 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
- Hematologic, renal, and liver function as determined by hematology and clinical chemistry tests will be acceptable if within ±2x of "normal" reference range as defined by the local hospital clinical laboratory. Final decision on inclusion will be made by physician, concerning suitability of patient for surgery
- 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
- Tumors infiltrating the cerebellum, bilateral corpus callosum ("butterfly glioma"), ventricular system, or brain stem
- Infratentorial high grade glioma
- Anaplastic astrocytoma
- 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 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). Lab values, as determined by hematology and clinical chemistry tests, will be unacceptable if greater than ±2x of "normal" reference range as defined by the local hospital clinical laboratory. 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, 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
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 ClinicalTrials.gov identifier: NCT01811992
Please refer to this study by its ClinicalTrials.gov identifier: NCT01811992
Contacts
| Contact: Karen Frisch | 734.232.4843 | kfrisch@med.umich.edu |
Locations
| United States, Michigan | |
| University of Michigan Health System Department of Neurosurgery | Recruiting |
| Ann Arbor, Michigan, United States, 48109 | |
| Contact: Karen Frisch 734-232-4843 kfrisch@med.umich.edu | |
Sponsors and Collaborators
Pedro Lowenstein, MD PhD
Phase One Foundation, Santa Monica, CA (USA)
Investigators
| Principal Investigator: | Pedro Lowenstein, MD, PhD | University of Michigan |
More Information
| Responsible Party: | Pedro Lowenstein, MD PhD, Professor of Neurosurgery and Professor of Cell and Developmental Biology, University of Michigan |
| ClinicalTrials.gov Identifier: | NCT01811992 History of Changes |
| Other Study ID Numbers: | HUM00057130 |
| Study First Received: | February 13, 2013 |
| Last Updated: | December 5, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Glioblastoma Glioma Astrocytoma Neoplasms, Neuroepithelial Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Glandular and Epithelial Neoplasms, Nerve Tissue |
Valacyclovir Flt3 ligand protein Antiviral Agents Anti-Infective Agents Adjuvants, Immunologic Immunologic Factors Physiological Effects of Drugs Radiation-Protective Agents Protective Agents |
ClinicalTrials.gov processed this record on September 23, 2016