Adaptive Radiotherapy for Glioblastoma

(UNITED-3 Trial)

Overseen By Jay Detsky, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Sunnybrook Health Sciences Centre

Disqualifiers: Other malignancies, Leptomeningeal dissemination, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

70 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this study is to test whether an adaptive radiation therapy (RT), two-phase approach in participants with glioblastoma impacts local control compared to standard non-adaptive RT approach. The main questions of the study are to see how this adaptive, two-phase RT approach compares to standard RT in terms of: * Local control * Overall and progression-free survival * Patterns of failure * Toxicity, Neurological Function, and Quality of Life

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It might be best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Adaptive Radiotherapy for Glioblastoma?

Research shows that combining radiotherapy with temozolomide (a chemotherapy drug) is effective for treating glioblastoma, as studies have found that different forms of radiotherapy with temozolomide can be safely administered and may improve outcomes for patients. ^{1 2 3 4 5}

Is adaptive radiotherapy with temozolomide safe for humans?

Research shows that combining radiotherapy with temozolomide (a chemotherapy drug) has been studied for safety in patients with glioblastoma. These studies aimed to find the maximum dose that patients can tolerate, indicating that safety is a key focus in this treatment approach. ^{1 3 4 5 6}

How is the Adaptive Radiotherapy for Glioblastoma treatment different from other treatments?

Adaptive Radiotherapy for Glioblastoma is unique because it combines advanced radiotherapy techniques, like intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT), with temozolomide (a chemotherapy drug), allowing for higher radiation doses to the tumor while minimizing damage to healthy tissue. This approach aims to improve treatment effectiveness by adjusting the radiation dose based on the tumor's response, which is not typically done in standard treatments. ^{1 2 3 5 7}

Eligibility Criteria

This trial is for adults with newly diagnosed glioblastoma or grade 4 astrocytoma. They must have had a biopsy or surgery within the last 12 weeks, good blood counts and organ function, an expected survival of at least 12 weeks, and be in fair to good physical condition. Participants need to understand English for questionnaires and commit to treatment follow-up.

Inclusion Criteria

Completed written informed consent

My doctor thinks it's suitable for me to have radiation and medication treatment together.

I had a biopsy or surgery for my condition within the last 12 weeks.

Exclusion Criteria

I cannot have MRI contrast dyes due to an allergy or other health issue.

My cancer has spread to the lining of my brain and spinal cord.

Contraindications to MRI examination

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase 1

Participants receive adaptive radiation therapy with a smaller margin using MR-Linac technology

3 weeks

Daily visits for radiation therapy

Treatment Phase 2

Continuation of adaptive radiation therapy with adjustments based on daily MRI scans

3 weeks

Daily visits for radiation therapy

Follow-up

Participants are monitored for safety, effectiveness, and quality of life after treatment

6-24 months

Treatment Details

Interventions

• Adaptive, two-phase RT

Trial Overview The study tests an adaptive two-phase radiation therapy (RT) against standard RT in patients with glioblastoma. It aims to see if this new method improves tumor control, survival rates without disease progression, failure patterns, toxicity impact on neurological functions, and life quality.

Participant Groups

Group I: Adaptive, two-phase RT Experimental Treatment 1 Intervention

Adaptive, two-phase RT is already approved in United States, European Union for the following indications:

Approved in United States as Temodar for:

• Glioblastoma multiforme
• Anaplastic astrocytoma

Approved in European Union as Temodal for:

• Glioblastoma multiforme
• Anaplastic astrocytoma
• Malignant glioma

Who Is Running the Clinical Trial?

Sunnybrook Health Sciences Centre

Lead Sponsor

Trials

693

Recruited

1,569,000+

Findings from Research

In a phase I clinical trial involving nine patients with glioblastoma, simultaneous integrated-boost intensity-modulated radiotherapy (SIB-IMRT) combined with temozolomide was found to be feasible and well tolerated up to a maximum dose of 80Gy.

No dose-limiting toxicities were observed at the highest dose level, indicating that this treatment combination may be safe for patients with malignant glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I dose escalation study using simultaneous integrated-boost IMRT with temozolomide in patients with unifocal glioblastoma. Truc, G., Bernier, V., Mirjolet, C., et al.[2018]

In a study of 126 newly diagnosed glioblastoma patients, both standard dose radiotherapy (SDRT) and escalated dose radiotherapy (EDRT) combined with temozolomide (TMZ) showed similar overall survival (OS) and local progression-free survival (LPFS), with no statistically significant differences between the two treatments.

While the EDRT group had a median OS of 22 months compared to 14.9 months for SDRT, this difference was not statistically significant, indicating that further research with larger populations is needed to determine the true efficacy of EDRT in combination with TMZ.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective comparison of standard and escalated doses of radiotherapy in newly diagnosed glioblastoma patients treated with concurrent and adjuvant temozolomide. Guler, OC., Yıldırım, BA., Önal, C., et al.[2019]

In a study of 46 patients with newly diagnosed glioblastoma multiforme, hypofractionated high-dose intensity modulated radiation therapy (IMRT) combined with temozolomide (TMZ) resulted in a median overall survival of 20 months, indicating its efficacy in prolonging life for these patients.

No acute toxicity from the IMRT was observed, but radiation necrosis occurred in 20 patients, particularly in the subventricular zone, which was linked to longer survival, although it also negatively impacted the quality of life for some long-term survivors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 trial of hypofractionated high-dose intensity modulated radiation therapy with concurrent and adjuvant temozolomide for newly diagnosed glioblastoma. Iuchi, T., Hatano, K., Kodama, T., et al.[2018]

In a study of 78 patients with gliomas, combining 3-dimensional conformal radiotherapy with temozolomide resulted in a significantly higher 3-year survival rate of 41.38% compared to 20.83% for temozolomide alone and 20.00% for radiotherapy alone.

The combination therapy also improved progression-free survival time to 23.29 months and overall survival time to 25.75 months, while adverse reactions were reported to be mild and tolerable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of 3-dimensional conformal radiotherapy combined with temozolomide for glioma]. Wang, L., Tu, Q., Zhou, W., et al.[2018]

In a Phase I clinical trial involving 19 patients with glioblastoma, the maximum tolerated dose of fractionated intensity-modulated radiotherapy (IMRT) combined with temozolomide (TMZ) was determined to be 65 Gy, delivered in 25 fractions over 5 weeks, without any dose-limiting toxicities observed.

The treatment was well tolerated, with only mild to moderate (Grade 1-2) neurologic and skin toxicities reported, and no severe late neurologic toxicities, indicating a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I dose-escalation study (ISIDE-BT-1) of accelerated IMRT with temozolomide in patients with glioblastoma. Morganti, AG., Balducci, M., Salvati, M., et al.[2018]

In a trial involving 40 glioblastoma patients, the maximum tolerated dose (MTD) of intensity-modulated radiotherapy (IMRT) was determined to be 70 Gy, delivered in 25 fractions, without unacceptable acute toxicity.

The study demonstrated that this high dose of radiation, combined with standard doses of temozolomide (TMZ), did not result in significant late neurological toxicity after a median follow-up of 25 months, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated intensity-modulated radiotherapy plus temozolomide in patients with glioblastoma: a phase I dose-escalation study (ISIDE-BT-1). Massaccesi, M., Ferro, M., Cilla, S., et al.[2022]

In a Phase I clinical trial involving 37 patients with resected glioblastoma multiforme (GBM), the maximum tolerated dose (MTD) of volumetric modulated arc radiotherapy (VMAT-SIB) combined with standard dose temozolomide (TMZ) was determined to be 80 Gy delivered in 25 fractions over 5 weeks.

The trial identified dose-limiting toxicities at higher doses (82.5 Gy), with 29.7% of patients experiencing mild acute neurological toxicity and 8.1% experiencing severe toxicity, indicating that while the treatment can escalate doses, careful monitoring for side effects is crucial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-Operative Accelerated-Hypofractionated Chemoradiation With Volumetric Modulated Arc Therapy and Simultaneous Integrated Boost in Glioblastoma: A Phase I Study (ISIDE-BT-2). Ferro, M., Ferro, M., Macchia, G., et al.[2022]

References

1. France pubmed.ncbi.nlm.nih.gov

A phase I dose escalation study using simultaneous integrated-boost IMRT with temozolomide in patients with unifocal glioblastoma. [2018]

2. India pubmed.ncbi.nlm.nih.gov

Retrospective comparison of standard and escalated doses of radiotherapy in newly diagnosed glioblastoma patients treated with concurrent and adjuvant temozolomide. [2019]

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

Phase 2 trial of hypofractionated high-dose intensity modulated radiation therapy with concurrent and adjuvant temozolomide for newly diagnosed glioblastoma. [2018]

4. China pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of 3-dimensional conformal radiotherapy combined with temozolomide for glioma]. [2018]

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

A phase I dose-escalation study (ISIDE-BT-1) of accelerated IMRT with temozolomide in patients with glioblastoma. [2018]

6. Japan pubmed.ncbi.nlm.nih.gov

Accelerated intensity-modulated radiotherapy plus temozolomide in patients with glioblastoma: a phase I dose-escalation study (ISIDE-BT-1). [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Post-Operative Accelerated-Hypofractionated Chemoradiation With Volumetric Modulated Arc Therapy and Simultaneous Integrated Boost in Glioblastoma: A Phase I Study (ISIDE-BT-2). [2022]