Chemoradiotherapy vs Biomarker-Guided Therapy for Glioblastoma

Recruiting at 1 trial location

Age: 65+

Sex: Male

Trial Phase: Phase 2

Sponsor: AHS Cancer Control Alberta

Must not be taking: Temozolomide

Disqualifiers: Recurrent gliomas, Prior malignancy, others

Stay on Your Current Meds You can continue your current medications while participating

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 21 days for initial treatment, followed by up to 6 cycles of adjuvant TMZ

121 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the best treatment for elderly patients with newly diagnosed glioblastoma, a type of brain cancer. It compares the standard combined treatment of chemotherapy and radiation (radiotherapy) with a new approach that uses the patient's specific cancer biomarker to guide treatment. The trial aims to determine if this new method can provide similar survival outcomes with fewer side effects. Ideal candidates for the trial are those recently diagnosed with glioblastoma who often feel very tired or weak due to their condition. As a Phase 2 trial, it measures how well the treatment works in an initial, smaller group of people, offering a chance to benefit from a potentially more personalized approach.

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's best to discuss this with the trial coordinators or your doctor to get specific guidance based on your situation.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have shown that the drug temozolomide (TMZ) is safe for patients over 65 with glioblastoma, a type of brain cancer. It can help extend life without causing severe side effects for most. However, some patients, especially those over 70, might experience serious blood issues like neutropenia, a low count of white blood cells, though this occurs in a small number of cases.

Research has shown that radiotherapy is a well-known treatment for glioblastoma. It targets the tumor while protecting healthy brain cells, which helps limit damage and reduce side effects. Studies indicate that combining radiotherapy with TMZ remains safe and effective.

Both treatments have a history of being safe for older patients with glioblastoma. Participants should consult their doctors about possible side effects to understand what to expect during treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer a more personalized approach to managing glioblastoma. Unlike the standard treatment, which combines radiotherapy and temozolomide for all patients, the biomarker-guided therapy tailors treatment based on MGMT methylation status. Patients with MGMT methylation receive temozolomide alone, while those without it undergo radiation monotherapy. This method aims to optimize treatment effectiveness and minimize unnecessary side effects, potentially improving outcomes by matching the therapy to the tumor's specific characteristics.

What evidence suggests that this trial's treatments could be effective for glioblastoma?

Research shows that Temozolomide (TMZ) can extend the lives of glioblastoma patients, particularly when administered post-surgery. In this trial, participants in the standard arm will receive TMZ with concurrent radiotherapy (RT). Studies have found that patients with a specific gene change, called a methylated MGMT promoter, tend to respond better to TMZ, which can increase their average survival time. One study showed that 53.3% of patients taking TMZ experienced disease stabilization or partial improvement.

In the biomarker-based treatment arm of this trial, patients with a methylated MGMT promoter will receive TMZ monotherapy. For patients without this gene change, radiotherapy alone has proven effective. A study found that 56% of these patients lived for at least 12 months with radiotherapy, with an average survival time of 13.1 months. Both treatments in this trial are considered safe and effective, offering options based on the tumor's MGMT status. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for elderly (age ≥ 65) GBM patients with a performance status KPS of 60-70. They must have newly-diagnosed, histologically proven glioblastoma and known MGMT promoter methylation status. Participants need stable organ function and agree to use effective birth control. Exclusions include prior invasive malignancies within 3 years, recent heart issues, active hepatitis B, or severe co-morbidities.

Inclusion Criteria

AST < 120 U/L (ie < 3 times ULN)

My steroid dose has been stable or decreasing for the last 2 weeks.

Platelets ≥ 100 x 109/L

Exclusion Criteria

I have been cancer-free for over 3 years, except for non-melanoma skin cancer.

You have a serious health condition that is currently causing problems or complications.

I have been hospitalized for heart issues recently.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either standard chemoradiotherapy or biomarker-guided therapy based on MGMT promoter methylation status

21 days for initial treatment, followed by up to 6 cycles of adjuvant TMZ

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every 3 months for 2 years, then every 6 months for years 3-5

What Are the Treatments Tested in This Trial?

Interventions

• Radiotherapy
• Temozolomide

Trial Overview The study compares standard chemoradiotherapy (40 Gy radiation with concurrent temozolomide) against biomarker-guided therapy—either temozolomide alone for those with methylated MGMT promoters or just radiotherapy for non-methylated cases—to see which is better for survival without increasing toxicity.

How Is the Trial Designed?

Group I: Biomarker based treatment Experimental Treatment 1 Intervention

MGMT (+) Temozolomide monotherapy: Patients will receive Temozolomide (TMZ) at a dose of 75 mg/m2 daily for 21 consecutive days. This will be followed by six cycles of TMZ according to the standard 5-day schedule (days 1-5) every 28 days. The dose will be 150 mg/m2 for the first cycle and increased to 200 mg/m2 beginning with the second cycle, so long as there are no hematologic adverse events. Dose will be determined using body surface area (BSA) calculation. MGMT methylation (-) RT monotherapy: Participants will receive radiation treatment with 40Gy / 15 fractions over a period of 21 days (3 weeks).

Group II: Standard Arm: TMZ with concurrent RT (combined modality arm) Active Control 1 Intervention

Patients will receive a total of 21 days of Temozolomide (TMZ), with 15 days of TMZ administered daily with concurrent RT. TMZ will be delivered at a dose of 75 mg/m2, given daily with RT for 15 days, one hour before each session of RT. After a 4-week break, patients will receive six cycles of adjuvant TMZ according to the standard 5-day schedule (days 1-5) every 28 days, up to 6 cycles as tolerated by the patient. The dose will be 150 mg/m2 for the first cycle and increased to 200 mg/m2 beginning with the second cycle, so long as there are no hematologic adverse events, intractable nausea or fatigue.

Radiotherapy is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Radiation therapy for:

• Various cancers including breast cancer, lung cancer, prostate cancer, and soft tissue sarcoma

Approved in United States as Radiation therapy for:

• Various cancers including breast cancer, lung cancer, prostate cancer, and soft tissue sarcoma

Approved in Canada as Radiation therapy for:

• Various cancers including breast cancer, lung cancer, prostate cancer, and soft tissue sarcoma

Approved in Japan as Radiation therapy for:

• Various cancers including breast cancer, lung cancer, prostate cancer, and soft tissue sarcoma

Approved in China as Radiation therapy for:

• Various cancers including breast cancer, lung cancer, prostate cancer, and soft tissue sarcoma

Approved in Switzerland as Radiation therapy for:

• Various cancers including breast cancer, lung cancer, prostate cancer, and soft tissue sarcoma

Who Is Running the Clinical Trial?

AHS Cancer Control Alberta

Lead Sponsor

Trials

188

Recruited

26,900+

Published Research Related to This Trial

In a study of 51 patients with newly diagnosed glioblastoma, concurrent treatment with temozolomide (TMZ) and radiotherapy was found to be the new standard of care.

The occurrence of early necrosis in 14% of patients, without signs of tumor recurrence, suggests that TMZ may enhance the effectiveness of radiotherapy by acting as a radiosensitizer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma. Chamberlain, MC., Glantz, MJ., Chalmers, L., et al.[2022]

In a study of 67 patients with newly diagnosed glioblastoma multiforme, the combination of temozolomide, thalidomide, and radiation therapy resulted in a median survival of 73 weeks, indicating a favorable outcome compared to those not receiving adjuvant chemotherapy.

The treatment was generally well tolerated, but the specific benefit of adding thalidomide to temozolomide remains uncertain, as the survival outcomes were similar to those seen with other chemotherapy regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme. Chang, SM., Lamborn, KR., Malec, M., et al.[2018]

Temozolomide is primarily used for treating refractory central nervous system cancers like anaplastic astrocytoma and glioblastoma, but ongoing clinical trials are exploring its efficacy and safety in newly diagnosed gliomas and other types of tumors.

Research is also investigating different dosing schedules and combinations with other treatments, suggesting that temozolomide could be a versatile option in cancer therapy beyond its current approved uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. Yung, WK.[2019]

In a study of 432 glioblastoma patients, those receiving daily temozolomide (TMZ) during radiotherapy (7 days a week) had a median survival of 15.7 months, significantly longer than those receiving TMZ only on radiotherapy days (12.6 months) or no TMZ (9.1 months).

The analysis indicated that continuous TMZ administration not only improved survival rates but also showed a significant influence on hazard rates, confirming that while even a reduced TMZ schedule can extend survival, daily administration is more effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide during radiotherapy of glioblastoma multiforme : Daily administration improves survival. Nachbichler, SB., Schupp, G., Ballhausen, H., et al.[2018]

Temozolomide (TMZ) can cause severe drug-induced toxic hepatitis, as demonstrated in a case where a patient developed significant liver issues after 5 weeks of treatment for glioblastoma, highlighting the importance of monitoring liver function during therapy.

To prevent serious complications, including potentially life-threatening conditions, it is crucial to monitor liver enzyme levels twice weekly during TMZ treatment and to discontinue the drug immediately if hepatitis is suspected.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-induced liver damage. A case report. Becker, F., Hecht, M., Schmidtner, J., et al.[2021]

Temozolomide (TMZ) enhances the effectiveness of radiation therapy in treating glioblastoma cells, leading to a significant reduction in colony formation when combined with irradiation, compared to either treatment alone.

While irradiation was more toxic to glioma cells than TMZ, the combination of both treatments increased the sensitivity of glioma cells to radiation, suggesting a potential strategy for improving glioblastoma treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiosensitization of Glioma Cells by Temozolomide (TMZ): A Colony Formation Assay. Babaloui, S., Najafi, M., Mozdarani, H., et al.[2022]

In a study of 130 patients with newly diagnosed glioblastoma multiforme (GBM), the combination of temozolomide (TMZ) with radiotherapy (RT) significantly improved median overall survival to 13.4 months compared to 7.7 months with RT alone.

The combination treatment also resulted in a longer median time to progression (10.8 months vs. 5.2 months) and a higher one-year progression-free survival rate (36.6% vs. 7.7%), indicating that TMZ enhances the effectiveness of RT in treating GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II study of temozolomide and radiotherapy compared with radiotherapy alone in newly diagnosed glioblastoma multiforme. Athanassiou, H., Synodinou, M., Maragoudakis, E., et al.[2018]

In a study of 1157 glioblastoma multiforme patients, the addition of temozolomide (TMZ) to radiotherapy (RT) significantly improved median overall survival from 9.0 months with RT alone to 16.2 months with RT + TMZ (P < .001).

The two-year survival rate increased from 4% with RT alone to 25% with the combination of RT and TMZ, confirming the efficacy of TMZ in enhancing survival outcomes in GBM patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A population-based study on the effect of temozolomide in the treatment of glioblastoma multiforme. Rønning, PA., Helseth, E., Meling, TR., et al.[2022]

Temozolomide (TMZ) is an effective oral treatment for malignant gliomas, providing significant survival benefits while being generally well tolerated by patients.

While most side effects of TMZ are mild to moderate, there is a risk of severe hematologic adverse events, such as myelodysplastic syndrome and aplastic anemia, which have been documented in the literature.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-related hematologic toxicity. Scaringi, C., De Sanctis, V., Minniti, G., et al.[2018]

Temozolomide (tmz), a common chemotherapy drug for glioblastoma, can cause cutaneous drug eruptions, which are rare side effects that have not been widely reported.

In two cases studied, one patient showed clinical signs of an allergy to tmz without positive tests, while the second case confirmed the allergy through a positive lymphocyte activation test, highlighting the need for awareness of potential dermatologic reactions during tmz treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two cases of cutaneous drug eruption associated with temozolomide therapy for glioblastoma. Deluche, E., Leobon, S., Touraine, F., et al.[2018]

Citations

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Comparative analysis of the prognosis of external beam ... EBRT had universal effects in the treatment of GBM, and EBRT + BT had a more pronounced protective effect in the subgroups of males (HR = 0.81, ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5775505/

Advances in Radiotherapy for Glioblastoma - PMC The study authors concluded that these results showed no significant difference in overall survival, 6-month survival, or quality of life ...

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Breakthrough in treatment approach showing promise in ... Results showed that 56% of participants were alive after 12 months and the median overall survival was 13.1 months. "As compared to prior phase ...

4. practicalradonc.org practicalradonc.org/article/s1879-8500(16)30003-0/fulltext

Radiation therapy for glioblastoma: Executive summary of ... Nonrandomized data in this population suggest hypofractionated RT with TMZ is safe and efficacious (KQ2F). For example, a phase 2 multicenter trial combined 40 ...

5. mdpi.com mdpi.com/2227-9059/13/9/2136

Radiotherapy in Glioblastoma Multiforme: Evolution, ... Tumor Treating Fields (TTFields) extend median overall survival (mOS) to 31.6 months in MGMT-methylated patients and 20.9 months overall in supratentorial GBM ( ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9617255/

Factors affecting the radiation response in glioblastoma - PMC Radiotherapy is the mainstay of GBM treatment, with chemotherapy options being limited partly by adverse pharmacokinetics. TMZ is the only drug clinically ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10227167/

Analysis of safety and efficacy of proton radiotherapy for IDH ... Proton beam radiotherapy (PRT) has been demonstrated to improve neurocognitive sequelae particularly. Nevertheless, following PRT, increased ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2016.70.7562

Radiation Therapy for Glioblastoma: American Society of ... The addition of concurrent and adjuvant temozolomide to hypofractionated radiotherapy seems to be safe and efficacious without impairing quality ...

9. ro-journal.biomedcentral.com ro-journal.biomedcentral.com/articles/10.1186/s13014-022-02141-z

Comparative analysis of the prognosis of external beam ... The therapeutical effect of EBRT + BT treatment is better than that of EBRT alone, especially in male patients or patients who have undergone local resection.

10. hopkinsmedicine.org hopkinsmedicine.org/health/conditions-and-diseases/brain-tumor/brain-tumors-radiation-therapy

Brain Tumors: Radiation Therapy External beam radiation therapy (EBRT) There are several types of EBRT. The goal is to target the tumor and limit damage to nearby healthy brain cells.