Neo-adjuvant Evaluation of Glioma Lysate Vaccines in WHO Grade II Glioma
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02549833|
Recruitment Status : Recruiting
First Posted : September 15, 2015
Last Update Posted : May 4, 2018
|Condition or disease||Intervention/treatment||Phase|
|Oligodendroglioma Astrocytoma, Grade II Glioma, Astrocytic Glioma Malignant Glioma Oligoastrocytoma, Mixed||Biological: GBM6-AD and poly-ICLC before and after surgery Biological: GBM6-AD and poly-ICLC after surgery only||Phase 1|
Low-grade gliomas (LGG), the most common of which are pilocytic astrocytomas, diffuse astrocytomas, oligodendrogliomas, and mixed oligo-astrocytomas are a diverse family of central nervous system (CNS) neoplasms that occur in children and adults. Based on data from the American Cancer Society and Central Brain Tumor Registry of the United States (CBRTUS), approximately 1800 LGG were diagnosed in 2006, thus representing approximately 10% of newly diagnosed primary brain tumors in the United States. Pilocytic astrocytomas (WHO grade I) are the most common brain tumor in children 5 to 19 years of age3. Diffuse astrocytomas, oligodendrogliomas, and oligoastrocytomas are all considered WHO grade II low grade gliomas (LGG) and are more common in adults. Pilocytic astrocytomas are generally well circumscribed histologically and radiographically and amenable to cure with gross total resection. In contrast, the diffuse astrocytomas, oligodendrogliomas, and oligoastrocytomas are more infiltrative and less amenable to complete resection. From a molecular genetics standpoint, the most common alterations in LGG are IDH1 mutations6 and mutations in the tumor suppressor gene TP53, located on chromosome 17, the gene product of which is a multifunctional protein involved in the regulation of cell growth, cell death (apoptosis), and transcription. Additionally, several molecular factors are of favorable prognostic significance, particularly the presence of 1p/19q co-deletion and IDH1 mutations.
WHO grade II LGGs are at extremely high risk to undergo malignant transformation into more aggressive and lethal WHO grade III or IV high-grade glioma (HGG). Even with a combination of available therapeutic modalities (i.e., surgery, radiation therapy [RT], chemotherapy), the invasive growth and resistance to therapy exhibited by these tumors results in recurrence and death in most patients. Although postoperative RT in LGG significantly improves 5-year progression-free survival (PFS), it does not prolong overall survival (OS) compared with delayed RT given at the time of progression. Early results from a randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine (PCV) chemotherapy for supratentorial adult LGG (RTOG 9802) demonstrated improved PFS in patients receiving PCV plus RT compared RT alone. Nonetheless, PCV is considerably toxic and currently not widely used for management of glioma patients. Although chemotherapy with temozolomide (TMZ) is currently being investigated in LGG patients, it is unknown whether it confers improves OS in these patients. Further, our recent study has indicated that 6 of 10 LGG cases treated with TMZ progressed to HGG with markedly increased exome mutations and, more worrisome, driver mutations in the RB and AKT-mTOR pathways, with predominant C>T/G>A transitions at CpC and CpT dinucleotides, strongly suggesting a signature of TMZ-induced mutagenesis; this study also showed that in 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence. These data suggests the possibility that treatment of LGG patients with TMZ may enhance oncogenic mutations and genetic elusiveness of LGG, therefore calling for development of safer and effective therapeutic modalities such as vaccines.
Taken together, LGG are considered a premalignant condition for HGG, such that novel interventions to prevent malignant transformation need to be evaluated in patients with LGG. Immunotherapeutic modalities, such as vaccines, may offer a safe and effective option for these patients due to the slower growth rate of LGG (in contrast with HGG), which should allow sufficient time for multiple immunizations and hence high levels of anti-glioma immunity. Because patients with LGGs are generally not as immuno-compromised as patients with HGG, they may also exhibit greater immunological response to and benefit from the vaccines. Further, the generally mild toxicity of vaccines may improve quality of life compared with chemotherapy or RT.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||30 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Pilot Randomized Neo-adjuvant Evaluation of Poly-ICLC-Assisted Tumor Lysate Vaccines in Adult Patients With WHO Grade II Glioma|
|Study Start Date :||September 2016|
|Estimated Primary Completion Date :||September 2018|
|Estimated Study Completion Date :||September 2019|
Experimental: Vaccines before and after surgery
GBM6-AD lysate protein 1 mg and poly-ICLC 1.4 mg administered as one formulation every week leading up to standard-of-care surgery to remove the WHO grade II glioma (Days -23±2, -16±2, -9±2 and 24-48 hours prior to scheduled surgery), every 3 weeks after surgery (Weeks A1, A4, A7, A10, A13, A16; defining Week A1 as the first post-surgery vaccine), and two booster vaccines (Weeks A32 and A48).
Biological: GBM6-AD and poly-ICLC before and after surgery
Subcutaneous vaccination with GBM6-AD lysate protein and poly-ICLC combination
Active Comparator: Vaccines after surgery only
GBM6-AD lysate protein 1 mg and poly-ICLC 1.4 mg administered as one formulation every 3 weeks after standard-of-care surgery to remove the WHO grade II glioma only (Weeks A1, A4, A7, A10, A13, A16; defining Week A1 as the first post-surgery vaccine) and two booster vaccines (Weeks A32 and A48). Patients will not receive vaccines before surgery.
Biological: GBM6-AD and poly-ICLC after surgery only
Subcutaneous vaccination with GBM6-AD lysate protein and poly-ICLC combination
- Safety - incidence and severity of adverse events [ Time Frame: until disease progression, start of a new therapy, or for a maximum of 18 months from study registration (whichever occurs earlier) ]
- Measurement of vaccine-induced immune response in the resected tumor [ Time Frame: At time of surgery (as clinically indicated) ]
- Response rate and magnitude of CD4+ and CD8+ T-cell responses against the GM6-AD lysate in pre- and post-vaccine PBMC using IFN-γ-ELISPOT [ Time Frame: at Baseline, At time of surgery (as clinically indicated), Weeks 1, 10 and 16 post-surgery ]
- Tumor tissue expression of glioma-associated antigens (GAAs) and antigen-presentation machinery (APM) molecules [ Time Frame: At the time of clinically indicated surgical resection of the tumor ]
- Overall survival (OS) [ Time Frame: 2 years after enrollment ]
- To tabulate tumor objective response rate (ORR) [ Time Frame: 2 years after enrollment ]
- Progression-free survival (PFS) [ Time Frame: 2 years after enrollment ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02549833
|Contact: Tiffany D Jones, CCRPfirstname.lastname@example.org|
|Contact: Jane Rabbitt, BSN||415-353-2652||Jane.Rabbitt@ucsf.edu|
|United States, California|
|University of California||Recruiting|
|San Francisco, California, United States, 94143|
|Contact: Ute Vogrinec, RN 877-827-3222 email@example.com|
|Contact: Jane Rabbitt, BSN 415-353-2652 Jane.Rabbitt@ucsf.edu|
|Principal Investigator: Hideho Okada, MD, PhD|
|Principal Investigator: Jennie Taylor, MD|
|Principal Investigator:||Jennie Taylor, MD||University of California, San Francisco|
|Principal Investigator:||Hideho Okada, MD, PhD||University of California, San Francisco|