A Study of Varlilumab and IMA950 Vaccine Plus Poly-ICLC in Patients With WHO Grade II Low-Grade Glioma (LGG)
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|ClinicalTrials.gov Identifier: NCT02924038|
Recruitment Status : Active, not recruiting
First Posted : October 5, 2016
Last Update Posted : July 18, 2022
|Condition or disease||Intervention/treatment||Phase|
|Glioma Malignant Glioma Astrocytoma, Grade II Oligodendroglioma Glioma, Astrocytic Oligoastrocytoma, Mixed||Biological: IMA950 Biological: poly-ICLC Biological: Varlilumab||Phase 1|
Low-grade gliomas (LGG), the most common of which are pilocytic astrocytomas, diffuse astrocytomas, and oligodendrogliomas 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 1,800 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 age. Diffuse astrocytomas and oligodendrogliomas 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 and oligodendrogliomas are more infiltrative and less amenable to complete resection. From a molecular genetics standpoint, the most common alterations in LGG are IDH1 mutations 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 isocitrate dehydrogenase (IDH) mutations.
WHO grade II LGGs are at 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 improved 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, while IDH mutations were the only type of mutations that persisted in the initial and recurrent tumors. 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 :||14 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Pilot Randomized Neo-adjuvant Evaluation of Agonist Anti-CD27 Monoclonal Antibody Varlilumab on Immunologic Activities of IMA950 Vaccine Plus Poly-ICLC in Patients With WHO Grade II Low-Grade Glioma (LGG)|
|Actual Study Start Date :||April 3, 2017|
|Estimated Primary Completion Date :||December 31, 2022|
|Estimated Study Completion Date :||December 31, 2022|
Experimental: IMA950/poly-ICLC subcutaneous (subQ) + Varlilumab IV
IMA950 4.96mg and poly-ICLC 1.4mg administered as one formulation subcutaneously followed immediately by a Varlilumab 3mg/kg infusion (intravenously) -23±2 days (about 3 weeks) before the date of scheduled standard-of-care surgery to remove the WHO grade II glioma. Patients will continue receiving IMA950/poly-ICLC subcutaneous injections every week leading up to surgery (Days -16±2, -9±2 and 24-48 hours prior to scheduled surgery) and every 3 weeks after surgery (Weeks A1, A4, A7, A10, A13, A16, A19, A22; defining Week A1 as the first post-surgery vaccine). After surgery, patients will continue receiving a Varlilumab infusion every 6 weeks immediately following the IMA950/poly-ICLC injection (Weeks A1, A7, A13, and A19).
Other Name: IMA950 peptides
Other Name: Hiltonol
Other Name: CDX-1127
Experimental: IMA950/poly-ICLC subQ only
IMA950 4.96mg and poly-ICLC 1.4mg administered as one formulation subcutaneously 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) and every three weeks after surgery (Weeks A1, A4, A7, A10, A13, A16, A19, A22; defining Week A1 as the first post-surgery vaccine). Patients will not receive Varlilumab.
Other Name: IMA950 peptides
Other Name: Hiltonol
- Number of Treatment-related Adverse Events (AE) [ Time Frame: up to 2 years ]Incidence and severity of treatment-related adverse events, using standard criteria as well as close clinical follow-up as would be performed normally in this group of participants following vaccinations. All reported or observed toxicities and adverse events at all clinic visits will be graded, documented and reported according to a standard toxicity table, the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
- Response rate of CD4+ T-cell responses in pre- and post-vaccine PBMC [ Time Frame: up to 2 years ]Percentage of CD4+ cell responses will be compared against IMA950 peptides using the novel 2D multimer flowcytometric analysis.
- Response rate of CD8+ T-cell responses in pre- and post-vaccine PBMC [ Time Frame: up to 2 years ]Percentage of CD8+ T-cell responses will be compared against IMA950 peptides in pre- using the novel 2D multimer flowcytometric analysis.
- Magnitude of CD4+ T-cell responses responses in pre- and post-vaccine PBMC [ Time Frame: up to 2 years ]Magnitude of CD4+ T-cell responses will be compared against IMA950 peptides using the novel 2D multimer flowcytometric analysis.
- Magnitude of CD8+ T-cell responses responses in pre- and post-vaccine PBMC [ Time Frame: up to 2 years ]Magnitude of CD8+ T-cell responses will be compared against IMA950 peptides using the novel 2D multimer flowcytometric analysis.
- IMA950-reactive T-cell infiltration in tumor [ Time Frame: up to 2 years ]Number of tumor-infiltrating CD4+ and CD8+ T-cells (by flow-cytometry) in IMA950-reactive populations using multi-color flow cytometry will be calculated
- Frequency of IMA950-reactive CXCL9/10 expression in tumor [ Time Frame: up to 2 years ]Frequency of CXCL10 expression (by RT-PCR) in IMA950-reactive populations using multi-color flow cytometry will be calculated
- Frequency of CXCL9/10 expression [ Time Frame: up to 2 years ]Frequency of CXCL9/10 expression via reverse transcription polymerase chain reaction (RT-PCR)
- Number of IMA950-reactive T-cell receptor (TCR) clonotypes [ Time Frame: up to 2 years ]Flow-cytometry
- Overall survival (OS) [ Time Frame: minimum of 2 years ]OS is defined as the time from start of treatment to time of death. Patients who have not yet died will be censored at the time of their last follow-up. All patients will be followed for a minimum of 2 years.
- Progression-free survival (PFS) [ Time Frame: minimum of 2 years ]PFS is defined as the duration of time from start of treatment to time of progression or death. Patients who have not yet progressed or died will be censored at the time of their last follow-up. All patients will be followed for a minimum of 2 years
- Association of PBMC responses with overall survival [ Time Frame: up to 2 years ]Calculate frequency of PBMC responses against IMA950 in association with OS and PFS
- Association of PBMC responses with reactive T-cells in the tumor [ Time Frame: up to 2 years ]Calculate the frequency of PBMC responses in association with frequency of IMA950 reactive T-cells in the tumor
- Objective response rate (ORR) [ Time Frame: up to 2 years ]Tabulate tumor objective response rate (ORR) according to Lower-grade gliomas (LGG) Response Assessment in Neuro-Oncology (RANO) if there is measurable tumor after surgery.
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): NCT02924038
|United States, California|
|University of California|
|San Francisco, California, United States, 94143|
|Principal Investigator:||Hideho Okada, MD, PhD||University of California, San Francisco|
|Principal Investigator:||Nicholas Butowski, MD||University of California, San Francisco|