What side effects are associated with this type of intervention?

Common treatments for Glioblastoma include surgery, radiation therapy, and chemotherapy, each with its own set of side effects. Surgery can lead to complications such as infection, bleeding, and neurological deficits. Radiation therapy often causes fatigue, hair loss, and cognitive decline. Chemotherapy, particularly with agents like temozolomide, can result in nausea, vomiting, bone marrow suppression, and increased risk of infections. Newer targeted therapies and immunotherapies, which are being evaluated in trials like GBM AGILE, may cause side effects such as skin rashes, diarrhea, liver toxicity, and immune-related adverse events. Patients should discuss these potential side effects with their healthcare provider to make informed treatment decisions.

What prior FDA approvals exist?

The FDA has approved several treatments for Glioblastoma, focusing on various mechanisms of action. Temozolomide, an oral alkylating agent, is commonly used in combination with radiotherapy. Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), is approved for recurrent Glioblastoma. Additionally, Tumor Treating Fields (TTF), a device that uses electric fields to disrupt cancer cell division, has been approved for newly diagnosed and recurrent Glioblastoma. These treatments reflect the diverse approaches being studied in trials evaluating multiple therapies for Glioblastoma.

What other types of research exist?

Promising novel alternatives for glioblastoma patients in 2024 include therapies being evaluated in the GBM AGILE trial and investigational IDH-targeted approaches such as Ivosidenib and Vorasidenib. These therapies focus on targeting specific genetic mutations, offering a more personalized treatment strategy.

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Alkylating agents

Multiple Therapies for Glioblastoma (GBM AGILE Trial)

Phase 2 & 3

Recruiting

Led By Tim Cloughesy, MD

Research Sponsored by Global Coalition for Adaptive Research

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry [IHC] or sequencing for IDH) at first or second recurrence after initial standard, control or experimental therapy that includes at a minimum radiation therapy (RT).

Age ≥ 18 years.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up from initiation of study treatment to date of disease progression, or until 12 months following last patient randomization (approximately 2 years), whichever comes first.

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing various treatments for patients with newly diagnosed or returning brain cancer. It adjusts treatments based on how well patients are doing to find the most effective options. The goal is to improve survival rates by matching the best treatments to specific patient types.

Who is the study for?

This trial is for adults with Grade IV Glioblastoma, confirmed by specific tests. Participants must have a certain level of physical function (Karnofsky performance status ≥ 60% or ≥ 70%). They should have had an MRI recently and available tumor tissue samples. It's not suitable for those who don't meet these criteria.

What is being tested?

The study is testing multiple drugs like Lomustine, VAL-083, and Temozolomide alongside Radiation and others in patients with new or recurrent Glioblastoma. It's a global trial that adapts as it learns from the results to find the best treatment options.

What are the potential side effects?

Potential side effects may include fatigue, nausea, hair loss due to chemotherapy and radiation, neurological changes from disease progression or treatments, liver issues from targeted therapies, and possible allergic reactions.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My brain tumor is a Grade IV GBM or gliosarcoma, confirmed by tests, and has recurred after initial treatment including radiation.

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I am 18 years old or older.

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I can provide a sample of my tumor from surgery or biopsy.

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I have recently been diagnosed with my condition.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ from date of randomization until the date of death from any cause, or until 12 months following last patient randomization (approximately 2 years), whichever comes first.

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~from date of randomization until the date of death from any cause, or until 12 months following last patient randomization (approximately 2 years), whichever comes first.

This trial's timeline: 3 weeks for screening, Varies for treatment, and from date of randomization until the date of death from any cause, or until 12 months following last patient randomization (approximately 2 years), whichever comes first. for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Overall Survival (OS)

Secondary study objectives

Duration of Response (CR + PR)

Progression-free survival (PFS)

Tumor Response

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

13Treatment groups

Experimental Treatment

Active Control

Group I: VT1021 Treatment Arm - Enhanced Safety Management (ESM)Experimental Treatment1 Intervention

Experimental: VT1021 Treatment Arm - Enhanced Safety Management (ESM) Newly diagnosed MGMT Methylated and Unmethylated GBM: Supplemental safety assessments including bi-weekly collection of adverse events, dose modification profile, hematology, serum chemistry and coagulation panels. PK and PD assessments are done for patients as a part of ESM. ESM will continue until the Data Safety Monitoring Board (DSMB) suspends collection of additional data. Recurrent GBM: ESM is not applicable for patients with Recurrent GBM in the VT1021 treatment arm.

Group II: VT1021 Treatment Arm - Dose Finding PhaseExperimental Treatment1 Intervention

Newly diagnosed MGMT Methylated and Unmethylated GBM: Rolling 6 design. Treatment as outlined in section "Experimental: VT1021 Treatment Arm" with the first 6 patients receiving VT1021 at 12 mg/kg twice weekly in combination with temozolomide and radiation therapy. If there are two dose limiting toxicities reported, the dose will be de-escalated to 9 mg/kg two times a week. 6 patients will then be receiving 9 mg/kg two times a week and observed for DLTs for 4 weeks. Recurrent GBM: Dose Finding Phase is not applicable for patients with Recurrent GBM in the VT1021 treatment arm.

Group III: VT1021 Treatment ArmExperimental Treatment1 Intervention

Newly diagnosed MGMT Methylated and Unmethylated GBM: XRT 60 Gy for 6 weeks. Temozolomide 75 mg/m2 orally daily and VT1021 (Dosage Form: Infusion for intravenous administration; Strength: 10 mg/mL; Dose: As confirmed through the dose finding phase) twice weekly during radiation therapy. Rest period: 2-6 weeks from last day of radiation. VT1021 dosing will continue during the rest period. Maintenance period: The first cycle of temozolomide will be at 150 mg/m2 for days 1-5 of a 28-day cycle. Second and subsequent cycles of maintenance therapy will be at 200 mg/m2 for days 1-5 of a 28-day cycle. Temozolomide will be administered for up to 6 cycles in the maintenance phase in combination with VT1021. After 6 cycles, VT1021 only. Recurrent GBM: VT1021 (Dosage Form: Infusion for intravenous administration; Strength: 10 mg/mL; Dose: 12mg/kg) twice weekly.

Group IV: VAL-083 Treatment ArmExperimental Treatment1 Intervention

Newly Diagnosed MGMT Methylated and Unmethylated GBM: XRT 60 Gy for 6 weeks. Temozolomide 75 mg/m2 orally daily during radiation therapy. Rest Period 4 weeks from the last day of radiation. Maintenance period: VAL-083 (Dosage Form: Infusion for intravenous administration; Strength: 30 mg/m2) on Day 1, 2 and 3 of 21-day cycle. Recurrent GBM: VAL-083 (Dosage Form: Infusion for intravenous administration; Strength: 30 mg/m2) on Day 1, 2 and 3 of 21-day cycle.

Group V: Troriluzole Treatment Arm - Enhanced Safety Management (ESM)Experimental Treatment1 Intervention

Newly diagnosed MGMT Methylated and Unmethylated GBM and Recurrent GBM: Supplemental safety assessments including bi-weekly collection of adverse events, dose modification profile, hematology, serum chemistry and coagulation panels. ESM will continue until the Data Safety Monitoring Board (DSMB) suspends collection of additional data.

Group VI: Troriluzole Treatment Arm - Dose Finding PhaseExperimental Treatment1 Intervention

Newly diagnosed MGMT Methylated and Unmethylated GBM: Rolling 6 design. The first 6 patients will receive troriluzole at 100 mg BID for the first two weeks followed by 200 mg BID for the next two weeks in combination with temozolomide and radiation therapy. If there are two dose limiting toxicities (DLTs) reported, the dose will be de-escalated to 100 mg in the morning and followed by 200 mg in the evening. 6 patients will receive this dose and observed for 4 weeks. If there are two DLTs reported, then this dose will be de-escalated to 100 mg BID. 6 patients will then be receiving this dose and observed for DLTs for 4 weeks. Recurrent GBM: Rolling 6 design. The first 6 patients receiving troriluzole 100 mg twice a day (BID) for the first two weeks followed by 200 mg BID for the next two weeks in combination with lomustine. The dose de-escalation is similar to that of newly diagnosed patients during the rolling 6 design.

Group VII: Troriluzole Treatment ArmExperimental Treatment1 Intervention

Newly diagnosed MGMT Methylated and Unmethylated GBM: XRT 60 Gy for 6 weeks. Temozolomide 75 mg/m2 orally daily and troriluzole (Dosage Form: Capsule for oral administration; Strength: 100 mg; Dose: As confirmed by dose finding phase) BID. Rest period: 2-6 weeks from last day of radiation. Troriluzole dosing will continue during the rest period. Maintenance period: The first cycle of temozolomide will be at 150 mg/m2 for days 1-5 of a 28-day cycle. Second and subsequent cycles of maintenance therapy will be at 200 mg/m2 for days 1-5 of a 28-day cycle. Temozolomide will be administered for up to 6 cycles in the maintenance phase in combination with troriluzole. After 6 cycles, troriluzole only. Recurrent GBM: Lomustine 100 mg/m2 orally on day 1 of a 42-day cycle in combination with troriluzole (Dosage Form: Capsule for oral administration; Strength: 100 mg; Dose: As confirmed by dose finding phase) BID. After 6 cycles, troriluzole only.

Group VIII: Regorafenib Treatment ArmExperimental Treatment1 Intervention

Newly Diagnosed MGMT Unmethylated GBM: XRT 60 Gy for 6 weeks. Temozolomide 75 mg/m2 orally daily during radiation therapy. Rest Period 4 weeks from the last day of radiation. Maintenance period: Regorafenib (Dosage Form: Tablet for oral administration; Strength: 40 mg) 160 mg orally (PO) every day (QD) for 3 weeks of every 4 week cycle (i.e., 3 weeks on, 1 week off). Recurrent GBM: Regorafenib (Dosage Form: Tablet for oral administration; Strength: 40 mg) 160 mg orally (PO) every day (QD) for 3 weeks of every 4 week cycle (i.e., 3 weeks on, 1 week off).

Group IX: Paxalisib Treatment ArmExperimental Treatment1 Intervention

Newly Diagnosed MGMT Unmethylated GBM: XRT 60 Gy for 6 weeks. Temozolomide 75 mg/m2 orally daily during radiation therapy. Rest Period 4 weeks from the last day of radiation. Maintenance period: Paxalisib (Dosage Form: Tablet for oral administration; Strength: 15 mg per tablet) 45 mg orally (PO) every day for 28 days for the first cycle. If tolerated, increase dose to 60 mg orally (PO) every day for 28 days for all subsequent cycles. Recurrent GBM: Paxalisib (Dosage Form: Tablet for oral administration; Strength: 15 mg per tablet) 45 mg orally (PO) every day for 21 days for the first cycle. If tolerated, increase dose to 60 mg orally (PO) every day for 21 days for all subsequent cycles.

Group X: ADI-PEG 20 Treatment Arm - Enhanced Safety Management (ESM)Experimental Treatment1 Intervention

Newly diagnosed MGMT Methylated and Unmethylated GBM: ESM is not applicable for newly diagnosed patients on the ADI-PEG 20 treatment arm. Recurrent GBM: Supplemental safety assessments including bi-weekly collection of adverse events, dose modification profile, hematology, serum chemistry and coagulation panels. ESM will continue until the Data Safety Monitoring Board (DSMB) suspends collection of additional data.

Group XI: ADI-PEG 20 Treatment Arm - Dose Finding PhaseExperimental Treatment1 Intervention

Newly diagnosed MGMT Methylated and Unmethylated GBM: Dose Finding Phase is not applicable for newly diagnosed patients on the ADI-PEG 20 treatment arm. Recurrent GBM: Rolling 6 design. The first 6 patients will receive ADI-PEG 20 at 36 mg/m2 once a week in combination with lomustine 100 mg/m2 orally on day 1 of a 42-day cycle. 6 patients will receive this dose and be observed for 4 weeks. If there are two dose limiting toxicities (DLTs) reported, the dose will be de-escalated to 18 mg/m2 once a week. 6 patients will receive this dose and be observed for 4 weeks.

Group XII: ADI-PEG 20 Treatment ArmExperimental Treatment1 Intervention

Newly diagnosed MGMT Methylated and Unmethylated GBM: XRT 60 Gy over 6 weeks. Temozolomide (75 mg/m2 orally daily and ADI-PEG 20 (Dosage Form: Solution for intramuscular injection; Strength: 11.5 ± 1.0 mg/ml; Dose: 36 mg/m2) once a week. Rest period: 2-6 weeks from last day of radiation. ADI-PEG 20 dosing will continue during rest period. Maintenance period: The first cycle of temozolomide will be at 150 mg/m2 for days 1-5 of a 28-day cycle. Subsequent cycles will be at 200 mg/m2 for days 1-5 of a 28-day cycle. Temozolomide will be administered for up to 6 cycles in the maintenance phase in combination with ADI-PEG 20. After 6 cycles, ADI-PEG 20 only for up to 104 weeks of total treatment. Recurrent GBM: Lomustine 100 mg/m2 orally on day 1 of a 42-day cycle in combination with ADI-PEG 20 (Dosage Form: Solution for IM injection; Strength: 11.5 ± 1.0 mg/ml; Dose: As confirmed by dose finding phase, once a week. After 6 cycles, ADI-PEG 20 only for up to 104 weeks of total treatment.

Group XIII: Control ArmActive Control3 Interventions

Newly Diagnosed GBM: Radiation therapy (XRT) 60 Gy for 6 weeks. Temozolomide 75 mg/m2 orally daily during radiation therapy. Rest Period 2-6 weeks from the last day of radiation, and the start of the first cycle of Maintenance Therapy 2-6 weeks after the last day of radiotherapy. The start of all subsequent maintenance therapy cycles (2-12) every 4 weeks + 7 days after the first daily dose of temozolomide of the preceding cycle. Total number of cycles should comply with institutional or country standards. During maintenance therapy, the first cycle of temozolomide will be at 150 mg/m2 for Days 1-5 of a 28-day cycle. Second and subsequent cycles of maintenance therapy will be at 200 mg/m2 for Days 1-5 of a 28-day cycle. Recurrent GBM: Lomustine started at 110 mg/m2/day on Day 1 of a 42-day cycle as per local standards. Treatment will continue for up to 6 total cycles.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Troriluzole

2016

Completed Phase 3

~1030

ADI-PEG 20

2013

Completed Phase 2

~190

Regorafenib

2014

Completed Phase 2

~1600

0 / 4Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Glioblastoma (GBM) include surgery, radiation therapy, and chemotherapy. Surgery aims to remove as much of the tumor as possible, reducing the tumor burden. Radiation therapy uses high-energy rays to kill cancer cells and shrink tumors by damaging their DNA, which is crucial for controlling local tumor growth. Chemotherapy, such as temozolomide, works by interfering with the DNA replication process in cancer cells, leading to cell death. These mechanisms are vital for GBM patients as they target the aggressive and infiltrative nature of GBM, aiming to prolong survival and improve quality of life. The trial evaluating multiple therapies seeks to optimize these mechanisms and explore new ones to enhance treatment efficacy.