Clinical trial NCT01811992: Combined Cytotoxic and Immune-Stimulatory Therapy for Glioma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malignant Glioma
Glioblastoma Multiforme
Lead sponsor: University of Michigan Rogel Cancer Center
Sponsor class: OTHER
Collaborators: name: Phase One Foundation
First posted: 2013-03-15
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
measure: Maximum Tolerated Dose (MTD)
timeFrame: 21 days post administration of study vectors
Secondary outcomes:
measure: Number of Patients Alive at 12 and 24 Months
timeFrame: 24 Months
Other outcomes:
Locations:
city: Ann Arbor
country: United States
facility: University of Michigan Health System Department of Neurosurgery
state: Michigan
Study officials:
affiliation: University of Michigan
name: Pedro Lowenstein, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Umemura Y, Orringer D, Junck L, Varela ML, West MEJ, Faisal SM, Comba A, Heth J, Sagher O, Leung D, Mammoser A, Hervey-Jumper S, Zamler D, Yadav VN, Dunn P, Al-Holou W, Hollon T, Kim MM, Wahl DR, Camelo-Piragua S, Lieberman AP, Venneti S, McKeever P, Lawrence T, Kurokawa R, Sagher K, Altshuler D, Zhao L, Muraszko K, Castro MG, Lowenstein PR. Combined cytotoxic and immune-stimulatory gene therapy for primary adult high-grade glioma: a phase 1, first-in-human trial. Lancet Oncol. 2023 Sep;24(9):1042-1052. doi: 10.1016/S1470-2045(23)00347-9.
citation: Lowenstein PR, Castro MG. Evolutionary basis of a new gene- and immune-therapeutic approach for the treatment of malignant brain tumors: from mice to clinical trials for glioma patients. Clin Immunol. 2018 Apr;189:43-51. doi: 10.1016/j.clim.2017.07.006. Epub 2017 Jul 15.