Neoplasms

All Conditions

Rare Diseases

Glioma

Astrocytoma

Oligodendroglioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Jaap Jaspers, MD

Alejandra Mendez Romero, MD PhD

Alejandra Mendez Romero, MD, PhD

Frank Lagerwaard, MD, PhD

Marco van Vulpen, Prof. MD

Ida Coremans, MD, PhD

Ruud Wiggenraad, MD, PhD

Rationale: Standard postoperative treatment of isocitrate dehydrogenase 1/2 mutated grade 2 and 3 glioma (IDHmG) consists of radiotherapy and chemotherapy. The improving prognosis of these patients leads towards more emphasis on the long-term effects of treatment. Specifically radiotherapy has been implicated in the development of delayed neurocognitive deterioration. The impact of modern radiotherapy techniques (such as intensity modulated radiotherapy, volumetric modulated radiotherapy and proton beam therapy) and chemotherapy on general toxicity, late neurocognitive outcomes and imaging changes is currently unclear.

Objectives:

* To report treatment outcomes and radiation-induced toxicity from a prospective, multicentre observational cohort of IDHmG patients treated with radiotherapy and chemotherapy,
* To integrate radiotherapeutic dose distributions, imaging changes and neuropsychological outcome in IDHmG.
* To evaluate the Dutch selection criteria for proton therapy applied to IDHmG based on the outcomes collected in this observational study.
* To assess the impact of proton and photon therapy on health-related quality of life (HRQoL) and health-related economics (HR-E) in IDHmG patients.
* To collect genetic material for future translational research into the interaction between germline DNA, prognosis and radiation-induced toxicity.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: This project is a multicentre, observational cohort of patients undergoing radiotherapy and chemotherapy for IDHmG. The protocol closely follows the local guidelines for clinical follow-up. Specific to the study are extra questionnaires and specific imaging acquired during scheduled MRI's. Routine neuropsychological investigation is standard of care in Erasmus Medical Center (Erasmus MC), but not in all participating centers. We feel the additional burden of participation in this study to be low.

Radiotherapy in IDH Mutated Glioma: Evaluation of Late Outcomes

If feasible, pre- and 4 months post-treatment a scan protocol will be used that, besides the standard clinical imaging, will focus on (micro-)structural and microvascular characteristics that could predict neurocognitive outcome and treatment efficacy. This feasibility is site-specific.

The Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 displays Grade 1 to 5, ranging from 'mild' to 'death'. The case report form will include a predefined set of CTCAE items of expected radiotherapy related toxicities. In addition, other CTCAE toxicities grade ≥ 2 that are likely, possibly or definitely related to the radiotherapy should be recorded in the case report form (CRF), when they occur. All items will include a causality assessment: likely or definitely attributable to radiotherapy, unrelated or unlikely attributable to radiotherapy, or not assessable.

Neurocognitive functioning will be assessed with a standard and well established short neuropsychological test battery, developed for use in clinical trials. The following tests are included: Hopkins Verbal Learning Test (HVLT), Trail Making Test part A and B (TMT A/B), Controlled Oral Word Association (COWA), Medical Outcomes Study Cognitive Functioning Scale (MOS), Diagnostic Instrument for Mild Aphasia (DIMA)

NIFS is defined as time from first irradiation to date of initiation of further treatment after radio- and/or chemotherapy or death (any cause), whichever occurs first.

PFS is defined as the time from first irradiation to progressive disease, according to (any of) the Response Asessment in Neuro Oncology (RANO) criteria for progressive disease in low grade glioma.

OS is defined as time from first irradiation to date of death from any cause.

HRQoL will be assessed with the EORTC quality of life questionnaire (QLQ-C30) supplemented by the neuro-oncological module (QLQ-BN20) and the Euro Quality of Life questionnaire (EQ5D-5L)

For the Health Related Economics (HR-E) analyses, the EQ5D - 5L questionnaire will be used in conjunction with the Productivity Costs Questionnaire (iPCQ) and the Medical Consumption Questionnaire (iMCQ). These questionaires are optional.

HollandPTC

Amsterdam University Medical Center

Leiden University Medical Center

Delft University of Technology

Medical Center Haaglanden

Erasmus Medical Center

MD, PhD

Oligoastrocytoma

All Drugs and Chemicals

Pharmaceutical Solutions

Anti-Infective Agents

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Vaccines

Immunomodulating Agents

Poly ICLC

Immunoglobulins

Interferons

Immunologic Factors

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

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

Patients newly diagnosed with Grade II and III astrocytoma.

Patients will begin study treatment with temozolomide and TTFields within 2 weeks of the baseline evaluation, and no later than 6 weeks from last dose of concomitant temozolomide or radiation therapy (the latter of the two). A minimum of 6 and a maximum of 12 cycles of adjuvant temozolomide will be given, depending on tolerability and toxicity.

TTFields with adjuvant temozolomide

David Tran, MD, PhD

This is a phase 2, multi-institutional, historically-controlled, study of 100 patients with newly diagnosed Grade II and III astrocytoma comparing the combination of TTFields with adjuvant temozolomide versus temozolomide alone in historical controls after the completion of definitive chemoradiotherapy. Study treatment may continue past first tumor recurrence. The primary endpoint will be overall survival.

Patients with newly diagnosed high-risk Grade II or III astrocytoma must undergo maximal safe resection (biopsy alone may be eligible) and chemoradiotherapy: concomitant 75mg/m2 daily temozolomide with 80% prescribed dose completed and RT with minimal RT dose of 40 Gy delivered.

Within three weeks prior to beginning adjuvant temozolomide, all patients will undergo a Baseline contrast-enhanced MRI of the brain. Within two weeks prior to beginning adjuvant temozolomide, all patients will undergo baseline assessments. Patients will begin study treatment with temozolomide and TTFields within 2 weeks of the baseline evaluation, and no later than 6 weeks from last dose of concomitant temozolomide or radiation therapy (the latter of the two). A minimum of 6 and a maximum of 12 cycles of adjuvant temozolomide will be given. Patients will be seen and examined before each cycle of temozolomide. After a maximum of 12 cycles of adjuvant temozolomide, patients will be seen every 8 weeks. Brain MRI and QoL assessments will be performed every 8 weeks following the baseline MRI for the first 2 years then every 3 months thereafter until second progression (when TTFields treatment will be terminated).

FORWARD Optune and Adjuvant TMZ in Grade II/III Astrocytoma

A Phase 2, Historically Controlled Study Testing the Efficacy of TTFields (Optune®) With Adjuvant Temozolomide in High Risk WHO Grade II and III Astrocytomas (FORWARD)

Frequency of overall survival in study participants. 2 years of active treatment, lifelong survival follow-up.

NovoCure Ltd.

University of Florida

The control arm was a historical control.

Patients newly diagnosed with Grade II and III astrocytoma.

TTFields with adjuvant temozolomide: Patients will begin study treatment with temozolomide and TTFields within 2 weeks of the baseline evaluation, and no later than 6 weeks from last dose of concomitant temozolomide or radiation therapy (the latter of the two). A minimum of 6 and a maximum of 12 cycles of adjuvant temozolomide will be given, depending on tolerability and toxicity.

Astrocytoma Patients

Control Arm

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

No subjects were enrolled in the control arm.

This multicenter center study was terminated early by mutual decision between the Study Chair/IDE Sponsor and Novocure; therefore, statistical analysis of the 1 participant in the intervention arm was not done.

Overall Survival

Overall Study

Symptoms and General Pathology

Nervous System Diseases

Recurrence

Glioblastoma

Brain Neoplasms

Diffuse Intrinsic Pontine Glioma

Ependymoma

Brain Stem Neoplasms

Gliosarcoma

Infratentorial Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Anaplastic Astrocytoma

Anaplastic Ependymoma

Imetelstat

Motesanib diphosphate

Enzyme Inhibitors

Protein Kinase Inhibitors

Molecular Biology Phase: Patients will receive one infusion of imetelstat prior to surgery. Surgery will take place 12-24 hours after the infusion of imetelstat. Patients will continue to receive therapy on the same schedule as the Phase II patients starting 14-21 days after surgery.

Phase II: Patients receive imetelstat sodium IV over 2 hours on days 1 and 8. Treatment repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

imetelstat sodium

Maryam Fouladi

This molecular biology and phase II trial studies how well imetelstat sodium works in treating younger patients with recurrent or refractory brain tumors. Imetelstat sodium may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

\* Molecular Biology:

I. To test the ability of imetelstat (GRN163L) to inhibit telomerase activity by Telomere Repeat Amplification Protocol (TRAP) in tumor and peripheral blood mononuclear cells (PBMNCs) of children with recurrent or refractory HGG or ependymoma.

II. To characterize the pharmacokinetics of imetelstat in plasma, cerebrospinal fluid (CSF), and tumor tissue of children with recurrent or refractory HGG or ependymoma.

\* Phase II:

I. To estimate the sustained objective response rates (complete response (CR) plus partial response (PR), sustained for at least 6 weeks) to imetelstat administered intravenously on Days 1 and 8 of a 21-day course at the recommended Phase II pediatric dose, 285mg/m2, in children with recurrent or refractory HGG, ependymoma or DIPG. Independent estimates of the objective response rates will be made for each of the three strata, two of which are histologically defined.

SECONDARY OBJECTIVES:

\* Phase II only:

I. To assess evidence of telomerase expression by detection of hTERT mRNA and TERC RNA levels by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and telomerase activity by TRAP in archival tumor tissue (for HGG, and ependymoma strata) and to explore association of telomerase positivity with objective response and progression-free survival (PFS).

II. To estimate the stratum-specific PFS distributions of children with recurrent or refractory HGG, ependymoma or DIPG treated with imetelstat.

\* Molecular Biology and Phase II:

I. To characterize the plasma and CSF pharmacokinetics of imetelstat in children with recurrent or refractory HGG, ependymoma or DIPG.

II. To assess evidence of telomerase expression by detection of hTERT mRNA and TERC RNA levels by qRT-PCR, telomerase activity by TRAP, and telomere length by telomere terminal restriction fragment (TRF) analysis in PBMNCs prior to treatment with imetelstat and to assess evidence of telomerase inhibition by TRAP and telomere shortening by TRF analysis serially on treatment with imetelstat.

III. To compare incidence of Alternative Lengthening of Telomeres (ALT) mechanism in pediatric HGG, or ependymoma as determined by four different assays 1) ATRX/DAXX nuclear localization by immunofluorescence (IF) assay; 2) telomere-specific signal by fluorescence in situ hybridization (FISH); 3) telomeric terminal restriction fragment (TRF) analysis by Southern blot; and 4) by C circle assay and to assess correlation of these methods for ALT detection.

IV. To assess whether ALT status is associated with objective response rates for children with recurrent or refractory HGG, or ependymoma treated with imetelstat.

V. To describe MRI characteristics and diffusion changes of recurrent or refractory HGG, ependymoma and DIPG tumors prior to and after treatment with imetelstat to assess for an early diffusion indicator of response.

VI. To measure telomere length of tumors in children with recurrent or refractory HGG, or ependymoma and to assess association of tumor length with tumor response to imetelstat treatment.

VII. To assess hTERT promoter mutations and methylation, H3F3A, ATRX, and DAXX mutations, and examine the effects of these modifications in children with recurrent brain tumors using targeted gene, exome, RNA sequencing and methylation arrays of targeted genomic regions.

OUTLINE:

Molecular Biology Phase: Patients will receive one infusion of imetelstat prior to surgery. Surgery will take place 12-24 hours after the infusion of imetelstat. Patients will continue to receive therapy on the same schedule as the Phase II patients starting 14-21 days after surgery.

Phase II: Patients receive imetelstat sodium IV over 2 hours on days 1 and 8. Treatment repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors

A Molecular Biology and Phase II Study of Imetelstat (GRN163L) in Children With Recurrent High-Grade Glioma, Ependymoma and Diffuse Intrinsic Pontine Glioma

Other PBTC investigators can develop a concept proposal and submit it to the PBTC Scientific Committee for a decision to share data and to what extent to share it.

This outcome measure is for the Molecular biology study only. The assessment was done to identify cases with at least 50% reduction in telomerase activity.

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=50% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR sustained for at least 6 weeks.

For each stratum separately exact confidence interval estimates will be provided for the true, unknown rates of objective response. Estimated by cumulative incidence functions.

This outcome measure is applicable only for the Molecular biology study arm. Telomerase inhibition was assessed in PBMCs and summarised as 'yes-inhibited' vs. 'no inhibition'

Kaplan-Meier estimates of distributions of survival and PFS for all eligible subjects who received at least one dose of imetelstat will be provided separately.

This secondary objective is for Stratum-B and C only, which enroll HGG and ependymoma patients. We will describe the evidence of telomerase expression by detection of hTERT mRNA and TERC RNA levels by qRT-PCR and telomerase activity by TRAP in archival tumor tissue; Association of telomerase positivity with objective response and PFS will not be able to be conducted as the study was terminated early and there was no objective response.

This outcome measure was for both Molecular biology and Phase II studies. We will not be able to present the results of this objective as the study was terminated early.

National Cancer Institute (NCI)

Pediatric Brain Tumor Consortium

The AEs we report were experienced while the participants were on study.

Molecular Study arm for Recurrent or Refractory Medulloblastoma/PNET Patients

Molecular Study-A

Molecular Study arm for Recurrent or refractory high-grade glioma patients

Molecular Study-B

This is the Phase-II stratum for Recurrent or Refractory Medulloblastoma/PNET Patients

Stratum-A

This is the Phase-II stratum for Recurrent or refractory high-grade glioma patients

Stratum-B

This is the Phase-II stratum for Recurrent or refractory ependymoma patients

Stratum-C

This is the Phase-II stratum for Recurrent or refractory diffuse intrinsic pontine gliomas (DIPG) patients

Stratum-D

This is the Molecular Biology arm for Medulloblastoma/PNET Patients

Molecular Biology Stratum-A

This is the Molecular Biology arm for High-Grade Glioma Patients

Molecular Biology Stratum-B

Age, Continuous

Dr. Mehmet Kocak

Molecular Biology Phase: Patients will receive one infusion of imetelstat prior to surgery. Surgery will take place 12-24 hours after the infusion of imetelstat. Patients will continue to receive therapy on the same schedule as the Phase II patients starting 14-21 days after surgery.

Phase II: Patients receive imetelstat sodium IV over 2 hours on days 1 and 8. Treatment repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

imetelstat sodium: Given IV

Molecular Biology Study

This outcome measure is only for the molecular biology study. Telomerase inhibition was assessed and the inhibition level was compared with the baseline level to identify increased inhibition.

Numver of Patients With Telomerase-positive Archival Tumors Who Demonstrate at Least 50% Reduction

This is the Phase-II stratum for Recurrent or refractory diffuse intrinsic pontine glioma patients

This is the Phase-II study cohort, excluding the molecular study patients.

Phase II: Stratum-specific Objective Response (CR+PR) Rate

Samples from six patients were consequently considered evaluable and were analyzed.

Number of Participants With Telomerase Inhibition

Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

Stratum-specific Progression-free Survival (PFS) (Phase II)

TRAP

TERT

TERC

This objective is for HGG and ependymoma patients only.

This objective is for STRATUM-C patients only, having only 4 patients with TRAP, TERT and TERC levels measured. Due to small sample and having no objective response, association studies of these markers with Objective Reponse and PFS were not possible. Therefore, we only report the the percentage of cases with at least weak TRAP activity.

Number of Patients With Telomerase Expression Data by Detection of hTERT mRNA and TERC RNA Levels by qRT-PCR and Telomerase Activity by TRAP in Archival Tumor Tissue and to Explore Association of Telomerase Positivity With Objective Response and PFS

Treatment (Imetelstat Sodium)

This study has been terminated early and the study team decided not to pursue this aim as the results would be inconclusive due to small sample size. Neither the neuroimaging, nor the biology data are available for these patients.

Quantitative MRI Parameters of Tumors Prior to and After Treatment With Imetelstat (Molecular Biology and Phase II Studies)

This is the Molecular Biology arm for Ependymoma Patients

Molecular Biology Stratum-C

Gastrointestinal Agents

Poly I-C

Carboxymethylcellulose Sodium

Laxatives

Cathartics

Antiviral Agents

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).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Radiotherapy in IDH Mutated Glioma: Evaluation of Late Outcomes	NCT04304300	Astrocytoma, Gr... Astrocytoma, Gr... Oligodendroglio... Oligodendroglio...		18 Years -	Erasmus Medical Center
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
FORWARD Optune and Adjuvant TMZ in Grade II/III Astrocytoma	NCT03906448	Astrocytoma, Gr... Astrocytoma, Gr...	TTFields with a...	18 Years - 99 Years	University of Florida
Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors	NCT01836549	Anaplastic Astr... Anaplastic Epen... Astrocytoma, Gr... Ependymoma Giant Cell Glio... Glioblastoma Gliosarcoma Oligodendroglio... Brainstem Tumor...	imetelstat sodi...	12 Months - 21 Years	Pediatric Brain Tumor Consortium
Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors	NCT01836549	Anaplastic Astr... Anaplastic Epen... Astrocytoma, Gr... Ependymoma Giant Cell Glio... Glioblastoma Gliosarcoma Oligodendroglio... Brainstem Tumor...	imetelstat sodi...	12 Months - 21 Years	Pediatric Brain Tumor Consortium
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 astrocytoma, grade ii