Multiple Therapies for Glioblastoma

(GBM AGILE Trial)

Recruiting at62 trial locations

Overseen by Tim Cloughesy, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Recruiting

Sponsor: Global Coalition for Adaptive Research

Must not be taking: Carmustine, Lomustine, Bevacizumab, others

Disqualifiers: Leptomeningeal disease, QTc prolongation, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, it mentions that participants should not be receiving additional, concurrent, active therapy for glioblastoma outside of the trial.

What data supports the effectiveness of the drugs used in the Multiple Therapies for Glioblastoma trial?

Research shows that lomustine and temozolomide, when used together, have been effective in treating glioblastoma, a type of brain cancer. Lomustine is often used for recurrent glioblastoma, while temozolomide is a standard treatment for newly diagnosed cases, and both have shown promise in improving patient outcomes. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

Lomustine (CCNU) can cause lung issues like pulmonary fibrosis (scarring of lung tissue), which is rare but serious. Temozolomide (TMZ) and carmustine (BCNU) have been studied for safety in brain cancer treatments, with carmustine wafers being used for over a decade, indicating a known safety profile. ^{1 2 3 5 6}

What makes this glioblastoma treatment unique?

This treatment is unique because it combines multiple therapies, including lomustine, temozolomide, and radiation, which have shown promise in improving survival for glioblastoma patients. Lomustine, a nitrosourea, is often used when other treatments fail, and combining it with temozolomide and radiation may enhance its effectiveness. ^{1 4 7 8 9}

Research Team

Tim Cloughesy, MD

Principal Investigator

GCAR CMO and GBM AGILE Global PI

Eligibility Criteria

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.

Inclusion Criteria

I can provide tumor samples from my brain cancer surgery.

I am mostly independent and can care for myself.

I have a confirmed diagnosis of Grade IV brain cancer with specific genetic features.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive various experimental therapies, including radiation and chemotherapy, based on their assigned treatment arm. This includes dose finding and maintenance phases.

6-12 weeks

Rest Period

Participants undergo a rest period following radiation therapy before starting maintenance therapy.

2-6 weeks

Maintenance Therapy

Participants continue with maintenance therapy cycles, which may include temozolomide and other drugs depending on the treatment arm.

up to 6 cycles of 28 days each

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments of overall survival and progression-free survival.

up to 2 years

Treatment Details

Interventions

• Lomustine (Alkylating agents)
• Paxalisib (Other)
• Radiation (Radiation)
• Regorafenib (Other)
• Temozolomide (Alkylating agents)
• Troriluzole (Other)
• VAL-083 (Alkylating agents)
• VT1021 (Other)

Trial Overview 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.

Participant Groups

Group I: VT1021 Treatment Arm - Enhanced Safety Management (ESM) Experimental Treatment 1 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 Phase Experimental Treatment 1 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 Arm Experimental Treatment 1 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 Arm Experimental Treatment 1 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 Treatment 1 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 Phase Experimental Treatment 1 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 Arm Experimental Treatment 1 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 Arm Experimental Treatment 1 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 Arm Experimental Treatment 1 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 Treatment 1 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 Phase Experimental Treatment 1 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 Arm Experimental Treatment 1 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 Arm Active Control 3 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.

Lomustine is already approved in Canada for the following indications:

Approved in Canada as Gleostine for:

• Brain tumors
• Breast cancer
• Lung cancer
• Hodgkin's lymphoma
• Melanoma

Who Is Running the Clinical Trial?

Global Coalition for Adaptive Research

Lead Sponsor

Trials

7

Recruited

22,600+

Bayer

Industry Sponsor

Trials

2,291

Recruited

25,560,000+

Founded

1863

Headquarters

Leverkusen, Germany

Known For

Pharmaceutical Innovations

Top Products

Aspirin, Aleve, Yaz, Nexavar

Bill Anderson

Bayer

Chief Executive Officer since 2023

BSc in Chemical Engineering from the University of Texas, MSc in Chemical Engineering and Management from MIT

Michael Devoy

Bayer

Chief Medical Officer since 2014

MD, PhD

Kintara Therapeutics, Inc.

Industry Sponsor

Trials

5

Recruited

1,200+

Biohaven Pharmaceuticals, Inc.

Industry Sponsor

Trials

49

Recruited

30,100+

Vigeo Therapeutics, Inc.

Industry Sponsor

Trials

2

Recruited

1,100+

Polaris Group

Industry Sponsor

Trials

25

Recruited

3,400+

Headquarters

Cayman Islands

Known For

Anti-Cancer Therapies

Top Products

ADI-PEG 20

Kazia Therapeutics Limited

Industry Sponsor

Trials

12

Recruited

1,600+

Findings from Research

In a study of 31 patients with relapsed high-grade gliomas, combining radiation therapy with the chemotherapy drug lomustine (CCNU) resulted in a median overall survival of 13.7 months, indicating a potential benefit for patients after relapse.

The treatment was associated with moderate acute toxicity, with some patients experiencing mild to moderate side effects like leucopenia and nausea, but overall patient compliance was good, suggesting the regimen is manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reirradiation and lomustine in patients with relapsed high-grade gliomas. Arcicasa, M., Roncadin, M., Bidoli, E., et al.[2022]

In a study of 166 brain tumor patients treated with CCNU, there was no significant overall change in lung function, but a notable decrease in vital capacity was observed in patients with prior lung diseases and smokers.

The results suggest that lung function monitoring during CCNU treatment should be focused on patients with existing pulmonary risk factors, while all patients should be monitored for clinical symptoms of lung issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lung toxicity of lomustine in the treatment of progressive gliomas. Seliger, C., Nürnberg, C., Wick, W., et al.[2022]

In a study of 40 patients with inoperable glioblastoma multiforme, the combination of carmustine (BCNU) and temozolomide showed a promising objective response rate of 42.5%, indicating its potential effectiveness as a first-line chemotherapy before and after radiotherapy.

The treatment was generally well-tolerated, with manageable grade 3-4 toxicities such as thrombocytopenia and neutropenia, and no patients discontinued treatment due to side effects, suggesting a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in combination with BCNU before and after radiotherapy in patients with inoperable newly diagnosed glioblastoma multiforme. Barrié, M., Couprie, C., Dufour, H., et al.[2022]

Nitrosoureas, such as lomustine, carmustine, and fotemustine, are among the most effective treatments for high-grade gliomas and glioblastoma, highlighting their importance in cancer therapy.

Due to their toxicity and the introduction of temozolomide, nitrosoureas are now primarily used for recurrent cases of gliomas, indicating a shift in their clinical application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrosoureas in the Management of Malignant Gliomas. Brandes, AA., Bartolotti, M., Tosoni, A., et al.[2018]

In a study involving 97 patients with malignant gliomas, temozolomide (TMZ) demonstrated a significantly higher response rate (35.71%) compared to lomustine (CCNU) (9.09%), indicating its greater efficacy in treating these aggressive brain tumors.

TMZ was found to have an acceptable safety profile, with common side effects being mild nausea and vomiting, suggesting it could be a preferred chemotherapy option for patients with refractory malignant brain gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A multicenter randomized controlled study of temozolomide in 97 patients with malignant brain glioma]. Qian, ZZ., Wang, HQ., Liu, XM., et al.[2018]

A review of 29 studies involving BCNU wafers for treating malignant gliomas found that adverse event rates were generally low and comparable to those in initial registration studies, with common issues including seizures (19-33%) and healing abnormalities (14-16%).

The safety profile of BCNU wafers remains consistent across different treatment regimens, suggesting that with proper management, the risk of complications can be minimized, making it a viable option for patients with recurrent glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of carmustine wafers in malignant glioma: a review of controlled trials and a decade of clinical experience. Sabel, M., Giese, A.[2019]

In a study of 39 patients with newly diagnosed glioblastoma, the combination of radiotherapy and chemotherapy (lomustine and temozolomide) resulted in a median overall survival of 23.1 months, with 47.4% of patients surviving for 2 years and 18.5% for 4 years.

Patients receiving an intensified dose of chemotherapy showed significantly higher survival rates compared to those on standard doses, with some patients in the intensified group surviving over 56 months, although this came with a higher risk of severe hematotoxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide. Glas, M., Happold, C., Rieger, J., et al.[2022]

In a study of 31 adult patients with newly diagnosed glioblastoma, the combination of lomustine, temozolomide (TMZ), and involved-field radiotherapy showed promising efficacy, with a median overall survival time of 22.6 months and a 2-year survival rate of 44.7%.

The treatment had acceptable toxicity levels, with 16% of patients experiencing severe hematotoxicity, and the presence of MGMT gene-promoter methylation in tumors was linked to longer progression-free survival and overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of lomustine plus temozolomide chemotherapy in addition to radiotherapy in newly diagnosed glioblastoma: UKT-03. Herrlinger, U., Rieger, J., Koch, D., et al.[2018]

In a study of 16 patients with recurrent high-grade gliomas treated with CCNU (Lomustine), the median progression-free survival was 192 days and overall survival was 282 days, indicating modest efficacy of this salvage treatment.

However, 33.3% of patients experienced severe myelosuppression (grade 3-4), highlighting a significant safety concern that needs to be addressed in future treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case series of salvage CCNU in high-grade glioma who have previously received temozolomide from a tertiary care institute in Mumbai. Patil, VM., Abhinav, R., Tonse, R., et al.[2018]

References

1. United States pubmed.ncbi.nlm.nih.gov

Reirradiation and lomustine in patients with relapsed high-grade gliomas. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Lung toxicity of lomustine in the treatment of progressive gliomas. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Temozolomide in combination with BCNU before and after radiotherapy in patients with inoperable newly diagnosed glioblastoma multiforme. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Nitrosoureas in the Management of Malignant Gliomas. [2018]

5. China pubmed.ncbi.nlm.nih.gov

[A multicenter randomized controlled study of temozolomide in 97 patients with malignant brain glioma]. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Safety profile of carmustine wafers in malignant glioma: a review of controlled trials and a decade of clinical experience. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Long-term survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Phase II trial of lomustine plus temozolomide chemotherapy in addition to radiotherapy in newly diagnosed glioblastoma: UKT-03. [2018]

9. India pubmed.ncbi.nlm.nih.gov

A case series of salvage CCNU in high-grade glioma who have previously received temozolomide from a tertiary care institute in Mumbai. [2018]