Neoplasms

All Conditions

Rare Diseases

Oligodendroglioma

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Anaplastic Oligodendroglioma

Oligoastrocytoma

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

p.o.(by mouth), 150 mg/m2/d x days 1-7 and 15-21, given every 28 days \[i.e., 7 days on/7 days off\] using a standardized dosing range.

Administration: Temozolomide will be administered on an empty stomach (i.e., 1 hour before or 2 hours after any oral intake).

Herbert Newton, MD

Rationale:

Standard therapy for anaplastic oligodendrogliomas and mixed oligoastrocytomas includes radiation and chemotherapy. However, due to the potential long-term central nervous system toxicity from radiation, researchers speculate that it may be better to reserve radiation therapy for progressive disease. In addition, some patients with anaplastic oligodendroglioma and mixed oligoastrocytoma have unusually chemosensitive tumors. Previous research indicates that brain tumor patients with a deletion of the 1p chromosome have a higher response to the chemotherapy drug temozolomide.

Temozolomide has demonstrated clinical antitumor efficacy against malignant gliomas at both relapse and initial diagnosis. This drug appears to have less adverse effects compared to other drugs used against brain tumors. Therefore, temozolomide is often better tolerated in brain tumor patients compared to other brain tumor drugs. The current study builds on previous research to test the efficacy of chemotherapy alone in patients with anaplastic oligodendroglioma and mixed oligoastrocytoma.

Purpose:

This study will evaluate response rate, or how the disease size changes in patients, and survival without disease growth, in patients with anaplastic oligodendroglioma and mixed oligoastrocytoma treated with temozolomide. Quality of life will also be assessed in this patient population treated with the study regimen.

Treatment:

Study participants will be treated with the drug temozolomide. This drug will be administered in oral pills. Temozolomide will be taken for seven consecutive days followed by seven days without the drug. This treatment schedule of seven days on temozolomide followed by seven days off will continue throughout the study. Several tests and exams will be given to closely monitor patients. MRI scans will be performed every 8 weeks to measure disease response. Temozolomide as a study drug will be given to study participants for a total of 8 week four cycles. However, treatments will be discontinued due to disease growth or unacceptable adverse events.

Temozolomide in Patients With Newly Diagnosed Anaplastic Oligodendroglioma and Mixed Oligoastrocytoma

Phase II Trial of Continuous Dose Temozolomide in Patients With Newly Diagnosed Anaplastic Oligodendroglioma and Mixed Oligoastrocytoma

Ohio State University Comprehensive Cancer Center

Symptoms and General Pathology

Nervous System Diseases

Infections

Recurrence

Glioblastoma

Brain Neoplasms

Adenoviridae Infections

Gliosarcoma

Anaplastic Astrocytoma

Anti-Infective Agents

Interferons

Interferon-beta

Antiviral Agents

Immunologic Factors

Medical Director

In this study an investigational replication-defective, recombinant adenovirus expressing the interferon-beta gene (BG00001) will be directly injected into tumors, in patients with recurrent Grade III and Grade IV Gliomas, in order to deliver the hIFN-beta gene. The purpose of the study is to evaluate the safety and any harmful effects of injection of BG00001 into brain tumors. Also, this study will help determine whether the virus carrying the beta interferon gene will enter brain tumor cells and cause the cancer cells to die. This study will require one hospital admission for the actual procedure of drug administration. All other visits will be conducted on an out-patient basis

Dose Escalation Study to Determine the Safety of IFN-Beta Gene Transfer in the Treatment of Grade III & Grade IV Gliomas

A Multi-center, Open Label, Two Part, Dose Escalation Study to Determine the Tolerability of Interferon-Beta Gene Transfer (BG00001) in the Treatment of Recurrent or Progressive Grade III and Grade IV Gliomas

Biogen

Pharmaceutical Solutions

Antibodies

Antibodies, Monoclonal

Vaccines

Immunomodulating Agents

Poly ICLC

Immunoglobulins

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).

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.

IMA950

poly-ICLC

Varlilumab

Hideho Okada, MD, PhD

Nicholas Butowski, MD

This is a pilot, randomized, two arm neoadjuvant vaccine study in human leukocyte antigen-A2 positive (HLA-A2+) adults with World Health Organization (WHO) grade II glioma, for which surgical resection of the tumor is clinically indicated. Co-primary objectives are to determine: 1) the safety of the novel combination of subcutaneously administered IMA950 peptides and poly-ICLC (Hiltonol) and i.v. administered CDX-1127 (Varlilumab) in the neoadjuvant approach; and 2) whether addition of i.v. CDX-1127 (Varlilumab) increases the response rate and magnitude of CD4+ and CD8+ T-cell responses against the IMA950 peptides in post-vaccine peripheral blood mononuclear cell (PBMC) samples obtained from participating patients.

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 retinoblastoma tumor suppressor (RB) and Protein kinase B (AKT)-Mechanistic target of rapamycin (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.

A Study of Varlilumab and IMA950 Vaccine Plus Poly-ICLC in Patients With WHO Grade II Low-Grade Glioma (LGG)

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)

Number of tumor-infiltrating CD4+ and CD8+ T-cells (by flow-cytometry) in IMA950-reactive populations using multi-color flow cytometry will be calculated to determine IMA950-reactive T-cell infiltration in the tumor.

Frequency of CXCL10 expression (by RT-PCR) in IMA950-reactive populations using multi-color flow cytometry will be calculated.

Frequency of CXCL9/10 expression via reverse transcription polymerase chain reaction (RT-PCR) will be calculated.

The number of IMA950-reactive T-cell receptor (TCR) clonotypes via Flow-cytometry will be reported.

OS is defined as the median 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. Product limit (Kaplan-Meier) estimates of the OS functions will be calculated with 95% Greenwood confidence regions.

PFS is defined as the median 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. Product limit (Kaplan-Meier) estimates of the PFS functions will be calculated with 95% Greenwood confidence regions.

Calculate frequency of PBMC responses against IMA950 in association with OS and PFS

The frequency of PBMC responses in association with the frequency of IMA950 reactive T-cells in the tumor will be calculated.

Tumor objective response rates (ORR) according to Lower-grade gliomas (LGG) Response Assessment in Neuro-Oncology (RANO) if there is measurable tumor after surgery will be reported by response type.

The proportion of participants experiencing Regimen Limiting Toxicity (RLT) in each arm will be tabulated with 95% exact (Clopper-Pearson) confidence intervals.

Percentage of CD4+ cell responses will be compared against IMA950 peptides using the novel 2D multimer flowcytometric analysis.

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 will be compared against IMA950 peptides using the novel 2D multimer flowcytometric analysis.

Magnitude of CD8+ T-cell responses will be compared against IMA950 peptides using the novel 2D multimer flowcytometric analysis.

Celldex Therapeutics

Nicholas Butowski

Gastrointestinal Agents

Poly I-C

Carboxymethylcellulose Sodium

Laxatives

Cathartics

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).

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.

Subcutaneous vaccination with GBM6-AD lysate protein and poly-ICLC combination

GBM6-AD and poly-ICLC before and after surgery

GBM6-AD and poly-ICLC after surgery only

Jennie Taylor, MD

This is a pilot neoadjuvant vaccine study in adults with WHO grade II glioma, for which surgical resection of the tumor is clinically indicated. Co-primary objectives are to determine: 1) the safety and feasibility of the neoadjuvant approach; and 2) whether the regimen increases the level of type-1 chemokine CXCL10 and vaccine-specific (i.e., reactive to GBM6-AD) CD8+ T-cells in tumor-infiltrating leukocytes (TILs) in the surgically resected glioma.

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.

Neo-adjuvant Evaluation of Glioma Lysate Vaccines in WHO Grade II Glioma

Pilot Randomized Neo-adjuvant Evaluation of Poly-ICLC-Assisted Tumor Lysate Vaccines in Adult Patients With WHO Grade II Glioma

Delay of the scheduled surgery for longer than 2 weeks due to toxicity of the neoadjuvant treatment will also be considered RLT and reported for each arm will be tabulated with 95% exact (ClopperPearson) confidence intervals

Evaluate whether surgically resected tumors from Arm 1 (the neoadjuvant arm) patients demonstrate significantly higher levels of CD8+ T-cell infiltration and CXCL10 expression compared with those resected from Arm 2 (control) patients The mean CD8+ T-cells in TILs and CXCL10 expression will be compared between arms by means of a two-sample Student's t test. If the t test assumptions are not met and the data cannot be transformed in such a way that the assumptions are met, a Wilcoxon Rank Sum test will be used

To describe the response rate and magnitude of CD4+ and CD8+ T-cell responses against the GBM6-AD lysate in pre- and postvaccine PBMC using interferon (IFN)-γ-ELISPOT. Further, we will determine whether T-cell clonotypes changes in PBMC during the course of the vaccines. We will also determine whether T-cell clonotypes that increased in post-vaccine PBMC are found in tumor infiltrating lymphocytes (TILs).

To describe tumor tissue expression of glioma-associated antigens (GAAs) and antigen-presentation machinery (APM) molecules. We will evaluate whether there are changes in GAA and APM expression status over the course

OS is defined as the duration of time from start of treatment to death. All patients will be followed for a minimum of 2 years

objective response rate (ORR) will be tabulated by response according to low-grade gliomas (LGG) Response Assessment in Neuro-Oncology (RANO)

PFS is defined as the duration of time from start of treatment to time of progression. All patients will be followed for a minimum of 2 years.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Temozolomide in Patients With Newly Diagnosed Anaplastic Oligodendroglioma and Mixed Oligoastrocytoma	NCT00362570	Oligoastrocytom... Anaplastic Olig...	Temozolomide	18 Years -	Ohio State University Comprehensive Cancer Center
Dose Escalation Study to Determine the Safety of IFN-Beta Gene Transfer in the Treatment of Grade III & Grade IV Gliomas	NCT00031083	Glioblastoma Mu... Anaplastic Astr... Oligoastrocytom... Gliosarcoma	Interferon-beta	18 Years -	Biogen
A Study of Varlilumab and IMA950 Vaccine Plus Poly-ICLC in Patients With WHO Grade II Low-Grade Glioma (LGG)	NCT02924038	Glioma Malignant Gliom... Astrocytoma, Gr... Oligodendroglio... Glioma, Astrocy... Oligoastrocytom...	IMA950 poly-ICLC Varlilumab	18 Years -	University of California, San Francisco
A Study of Varlilumab and IMA950 Vaccine Plus Poly-ICLC in Patients With WHO Grade II Low-Grade Glioma (LGG)	NCT02924038	Glioma Malignant Gliom... Astrocytoma, Gr... Oligodendroglio... Glioma, Astrocy... Oligoastrocytom...	IMA950 poly-ICLC Varlilumab	18 Years -	University of California, San Francisco
A Study of Varlilumab and IMA950 Vaccine Plus Poly-ICLC in Patients With WHO Grade II Low-Grade Glioma (LGG)	NCT02924038	Glioma Malignant Gliom... Astrocytoma, Gr... Oligodendroglio... Glioma, Astrocy... Oligoastrocytom...	IMA950 poly-ICLC Varlilumab	18 Years -	University of California, San Francisco
Temozolomide in Patients With Newly Diagnosed Anaplastic Oligodendroglioma and Mixed Oligoastrocytoma	NCT00362570	Oligoastrocytom... Anaplastic Olig...	Temozolomide	18 Years -	Ohio State University Comprehensive Cancer Center
Neo-adjuvant Evaluation of Glioma Lysate Vaccines in WHO Grade II Glioma	NCT02549833	Oligodendroglio... Astrocytoma, Gr... Glioma, Astrocy... Glioma Malignant Gliom... Oligoastrocytom...	GBM6-AD and pol... GBM6-AD and pol...	18 Years -	University of California, San Francisco

Spots Global Cancer Trial Database for oligoastrocytoma, mixed