Clinical trial NCT02772094: Dendritic Cell-Based Tumor Vaccine Adjuvant Immunotherapy of Human Glioblastoma Multiforme (WHO Grade IV Gliomas)
Official title: Autologous Dendritic Cell-Based Adjuvant Immunotherapy of Malignant Gliomas (WHO Grade IV Glioblastoma Multiforme) - Phase II Clinical Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Glioblastoma Multiforme
Glioblastoma
Keywords: glioblastoma multiforme
glioblastoma
newly diagnosed glioblastoma
immunotherapy
dendritic cells
grade IV astrocytoma
oncology
neurology
glioma
brain tumor
ADCTA-G
Lead sponsor: China Medical University Hospital
Sponsor class: OTHER
Collaborators: name: Den-Mei Brain Tumor Education Foundation, Taichung, Taiwan
name: Ministry of Health and Welfare, Taiwan
First posted: 2016-05-13
Enrollment: 50
Sex: ALL
Minimum age (years): 13
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Purposes:

The purpose of this phase-II clinical trial is to determine whether or not ADCTA-G, a biologic "vaccine" preparation of patient's own dendritic cell (DC) for glioblastoma multiforme (GBM) treatment, is safe and effective in extending the GBM patient's life. The current conventional multi-modal regimen that may include surgery for tumor resection or biopsy, temozolomide (TMZ) combined chemo-radiotherapy (CCRT) and TMZ adjuvant chemotherapy almost always leaves residual GBM cells to cause fatal recurrence, leading to medium survival period of 8 -15 months and over-all survival rates of about 30% in 2 years and \<3% in 5 years after diagnosis/surgery. Thus, in neurosurgical oncology practice, GBM patients in the first 2-year period during and after receiving multi-modal therapy are watched closely for possible GBM tumor recurrence and mortal disease relapse and immediately given palliative treatments and health care, until death. In this phase-II trial, GBM patient participants who receive ADCTA-G "vaccine" adjuvant immunotherapy (added to the conventional multi-modal regimen) will be similarly watched closely by treatments and health care visits at least biweekly from the date of surgery/diagnosis to 24 months, and if alive followed by weekly phone calls and scheduled health care visits at least once every 3 months, up to 72 months after surgery. In the trial protocol, ADCT-G in 10 doses is administered after surgery, over a period of 6 or 8 months, as an adjuvant immunotherapy of the conventional multimodal regimen. Individual ADCTA-G "vaccine" lot of every participant GBM patient is manufactured from patient's own monocyte-derived dendritic cells and the patient's own tumor cell antigens, both of which are prepared by a distinct method of procedures performed within air particle-free barrier good laboratory practice (GLP) facility. Previous phase I/II clinical trial of ADCTA-G "vaccine" immunotherapy administered as an adjuvant to the conventional multimodal regimen, has obtained promising safety and efficacy results for GBM patients in a clinical center. This phase-II clinical trial in China Medical University Hospital-Taichung will employ essentially the same clinical protocols and the same distinct "vaccine" manufacturing method of standard operational procedures (SOP), that is, the conventional multimodal regimen plus adjuvant immunotherapy using personal ADCTA-G "vaccine" lot for every GBM patient participants.

Detailed description: Rationale and Background :

Glioblastoma multiforme (GBM) and other WHO grade IV malignant gliomas of the brain are among the most lethal of human cancers. Despite current intensive multimodal regimen including the use of temozolomide (TMZ) for combined chemo-radiotherapy (CCRT) and for subsequent adjuvant chemotherapy, the medium survival period of GBM patients is still 8-16 months after diagnosis and surgery, with prognosis varied according to demographic features such as age, radiotherapy types and chemotherapy measures.These fatal brain cancers in general contain cancer cells with mutation in certain genes. Also, the mutated GBM cancer cells are usually heterogenous; and different GBM patients may have individual sets of heterogenous glioma cancer cells in which the mutant genes would generate altered antigens that can be recognized by the patient's adaptive immune system to mount immuno-targeting responses to reject or kill the GBM tumor cells. However, GBM is still fatal because it is highly immunosuppressive, i.e. able to anergize the immune effector cells in the body. Although surgical resection of rapidly expanding tumor bulk will prevent further physical damages to the brain and curtail the immunosuppression, the already anergized effector T lymphocytes still require functional restoration. On the other hand, post-surgical TMZ CCRT and adjuvant chemotherapy may weaken the residual tumor cells, but TMZ will also impair if not kill the active T lymphocytes in general, including anti-GBM lymphocytes. It is therefore important to exploit the adaptive immunity system for effective therapy of GBM. To apply the adaptive immunotherapy, it is best to use each patient's surgical tumor specimen to prepare the own individual "tumor regression antigens" for loading onto the patient's own dendritic cells (the "professional" antigen processing and presenting cells of the immune system). Dendritic cells loaded with tumor-specific antigens, upon maturation and inoculation ("vaccination"), would migrate/home to the T cell area of lymph nodes and stimulate proliferation of tumor-specific cytotoxic T lymphocyte that would move out of lymph node to find the brain tumor lesion to attack and eradicate the residual GBM tumor cells, resulting in prevention of GBM recurrence.

With fore-mentioned working hypotheses, the investigators carried out translational research from 1997 to 2002. A special method has been developed for production of an immunotherapeutic, which is named "autologous dendritic cell/autologous tumor cell antigens of GBM" (ADCTA-G). For clinical trial purpose, the investigators have established standard operational procedures (SOP) of the method with the use of clinical Good Manufacturing Practice (cGMP)-grade cytokines and pharmaceutical reagents. Individual ADCTA-G lots of all participant GBM patients are manufactured in high efficiency particle arresting (HEPA) air-filtered, germ-free bio-safety barrier clinical Good Laboratory Practice (cGLP) facilities. The phase I/II clinical trial was officially approved by Taiwan Department of Health and performed in a clinical center to demonstrate that ADCTA-G adjuvant immunotherapy was safe and apparently could prolong the survival for GBM patients.

Eligibility criteria: Inclusion Criteria:

1. Histopathologically proved WHO grade-4 malignant glioma
2. Age: 13 years (physically mature) to 70 years
3. Karnofsky performance score before surgery: ≧70 \[Karnofsky 1951\] .
4. Adequate liver functions, including serum alanine aminotransferase (ALT or SGPT), serum aspartate aminotransferase (AST or SGOT), and alkaline phosphatase at ≤3.0 times upper limits of normal levels (ULN), total bilirubin ≤1.5mg/dl), total serum bilirubin \<3 mg/dl
5. Adequate renal function (BUN ≤25 mg/ml; creatinine≤1.8 mg/dl，creatinine clearance \>50 ml/min prior to starting therapy
6. Hemoblobin≧8 g/dl，platelet ≧100,000/μl，WBC\>2,000/μl; absolute neutrophil count \>1,000/μl
7. Prothrombin time and partial thromboplastin time≦1.5x the normal upper limit

Exclusion Criteria:

1. Pregnant or breast feeding
2. With radioactive implant
3. Acute infection, fever
4. Active collagen diseases
5. Acute cardiovascular diseases
6. Acute viral hepatitis
7. Syphilis
8. Human immunodeficiency virus (HIV) infection
9. Carrier of other transmissible infection
10. Immune deficiency due to chronic disease

Primary outcomes:
measure: Overall survival with measures of medium survival period (in days) and annual survival rates (in %)
timeFrame: Post-recruitment surgery to death due to GBM or any other causes; close follow-up at leas by biweekly health care or emergency visits for 24 months, then weekly phone calls and scheduled visits at least every 3 months, up to 6 years after surgery
measure: Adverse effects, acute and chronic, assessed according to NCI CTCAE Version 3
timeFrame: Post-recruitment surgery to death, due to ADCTA-G, GBM disease or temozolomide chemotherapy; if alive, bi-weekly follow up for 24 months after surgery and then at least one visit in 3 months, up to 72 months
Secondary outcomes:
measure: Disease progression-free period
timeFrame: From recruitment surgery to death, or if alive, biweekly for 24 months, and then weekly phone calls and at least once in 3 months, up to 72 months
Other outcomes:
Locations:
city: Taichung
country: Taiwan
facility: China Medical University Hospital
Study officials:
affiliation: China Medical University Hospital, Taichung Taiwan
name: Wen-Kuang Yang, M.D. PhD.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chang CN, Huang YC, Yang DM, Kikuta K, Wei KJ, Kubota T, Yang WK. A phase I/II clinical trial investigating the adverse and therapeutic effects of a postoperative autologous dendritic cell tumor vaccine in patients with malignant glioma. J Clin Neurosci. 2011 Aug;18(8):1048-54. doi: 10.1016/j.jocn.2010.11.034. Epub 2011 Jun 28.