SVZ Radiation + Temozolomide for Glioblastoma

Recruiting at 2 trial locations

Overseen By Kristin Redmond, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must be taking: Temozolomide

Must not be taking: Avastin

Disqualifiers: Pregnancy, Uncontrolled illness, Prior malignancy, others

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: 6

Duration: 6 weeks

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests if giving extra radiation to a specific brain area along with standard cancer treatment can help control glioblastoma for a longer time in newly diagnosed patients. The treatment for newly diagnosed glioblastoma changed when radiation therapy plus temozolomide chemotherapy replaced radiation therapy alone.

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, you cannot use Avastin or another VEG-F inhibitor before the disease progresses.

Is the combination of SVZ Radiation and Temozolomide safe for humans?

Temozolomide, used with radiation for glioblastoma, is generally safe but can cause serious blood-related side effects in some people, like bone marrow failure and severe myelotoxicity (damage to the bone marrow). Rarely, it can also lead to liver damage and aplastic anemia (a condition where the body stops producing enough new blood cells). ^{1 2 3 4 5}

How is the SVZ Radiation + Temozolomide treatment for glioblastoma different from other treatments?

This treatment is unique because it combines radiation specifically targeting the subventricular zone (SVZ) with Temozolomide, a drug that makes cancer cells more sensitive to radiation. This approach aims to improve the effectiveness of the treatment by focusing on a specific brain area that may influence tumor growth. ^{4 6 7 8 9}

What data supports the effectiveness of the drug Temozolomide for treating glioblastoma?

Temozolomide, when used with radiotherapy, has been shown in studies to improve survival in patients with glioblastoma, a type of brain cancer. It is effective in treating various brain tumors and has been used in combination with other therapies to enhance its effectiveness. ^{4 10 11 12 13}

Who Is on the Research Team?

Kristin Redmond, MD, PhD

Principal Investigator

The SKCCC at Johns Hopkins

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed Glioblastoma Multiforme (GBM) who've had surgery but no brain radiation before. They must start treatment within 12 weeks of surgery, have a performance status allowing daily activities with effort or better, and agree to use contraception. Pregnant women, those unwilling to prevent pregnancy, and patients with other serious illnesses or prior cancers (except certain skin cancers and treated cervical cancer) are excluded.

Inclusion Criteria

I am 18 years or older and have been diagnosed with GBM.

I had surgery for my brain tumor and will start radiation within 12 weeks post-surgery.

I can care for myself and am up more than 50% of my waking hours.

Exclusion Criteria

I have not used Avastin or any VEG-F inhibitor before my cancer progressed.

I am not pregnant or breastfeeding and will use birth control during and up to 12 weeks after the study.

I do not have any severe illnesses that could interfere with the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 6 weeks of radiation therapy plus temozolomide chemotherapy. Radiation treatment is modified to deliver a higher dose to the subventricular zone.

6 weeks

5 visits per week (in-person)

Adjuvant Chemotherapy

Participants receive 6 cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle).

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment. MRIs and clinical evaluations are performed at regular intervals.

24 months

Regular visits at 1, 2, 4, 6, 8, 10, 12, and 24 months post-treatment

What Are the Treatments Tested in This Trial?

Interventions

• Neural Progenitor Cell Sparing radiation
• Subventricular Zone radiation
• Temozolomide

Trial Overview The study tests if targeting the subventricular zone (SVZ)—a brain area containing stem cells—with higher-dose radiation alongside standard chemotherapy (Temozolomide), can control GBM longer than standard therapy alone. Patients will receive this modified radiation plan over six weeks to see if it improves outcomes.

How Is the Trial Designed?

Group I: Temozolomide plus radiation therapy to the tumor and SVZ Experimental Treatment 2 Interventions

Patients will be scheduled to receive continuous daily temozolomide (75 mg per square meter of body surface area per day, 7 days per week from the first to the last day of radiation therapy), followed by 6 cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28 day cycle). Patients will receive 60 Gy of radiation therapy in 30 fractions, 5 days per week using IMRT. The target delineation and treatment volumes will be as follows: Initial treatment plan will include the tumor bed and MRI changes based on T1 post gadolinium series and FLAIR series, plus the bilateral subventricular zone Will be prescribed to 46 Gy in 2 Gy fractions Cone down treatment plan will include the tumor bed, areas of contrast enhancement on T1 post gadolinium series MRI plus the ipsilateral subventricular zone Will be prescribed to 14 Gy in 2 Gy fractions

Group II: Temozolomide and neural progenitor cell sparing radiation Active Control 2 Interventions

Patients will receive continuous daily temozolomide (75 mg per square meter of body surface area per day, 7 days per week from the first to the last day of radiation therapy), followed by 6 cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28 day cycle). Patients will receive 60 Gy in 30 fractions, 5 days per week using IMRT. The target delineation and treatment volumes will be as follows: Initial treatment plan will include the tumor bed and MRI abnormalities based on T1 post gadolinium series and FLAIR series. Will be prescribed to 46 Gy in 2 Gy fractions Cone down treatment plan will include the tumor bed and MRI changes based on T1 post gadolinium series. Will be prescribed to 14 Gy in 2 Gy fractions

Subventricular Zone radiation 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?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Reading Health System Foundation

Collaborator

Trials

1

Recruited

60+

Published Research Related to This Trial

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]

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) is the only anticancer drug proven to improve survival in glioblastoma when used with radiotherapy, showing high concentrations in brain tumors and cerebrospinal fluid, which enhances its effectiveness.

Molecular markers like MGMT promoter methylation can predict better responses to TMZ treatment, but side effects such as myelosuppression and nausea are common, necessitating precautions like prophylaxis against Pneumocystis carinii pneumonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Temozolomide: Temodal]. Shinoura, N., Yamada, R., Tabei, Y., et al.[2018]

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 phase 2 clinical trial involving 27 patients with brain metastases from breast cancer and non-small cell lung cancer, a new regimen combining whole-brain radiotherapy (WBRT) with a prolonged low-dose temozolomide (TMZ) treatment showed promising antitumor activity, achieving a 7.4% complete response and a 40.7% partial response.

The treatment was well tolerated, with only 2 patients experiencing grade 3 toxicity, and resulted in a median overall survival of 8.8 months and a median progression-free survival of 6 months, indicating its potential as a viable option for treating brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 trial of temozolomide using protracted low-dose and whole-brain radiotherapy for nonsmall cell lung cancer and breast cancer patients with brain metastases. Addeo, R., De Rosa, C., Faiola, V., et al.[2022]

Temozolomide (TMZ), combined with radiotherapy, is the standard treatment for glioblastoma multiforme, but it can cause hematological side effects in 1-10% of patients.

In a reported case, a patient experienced severe bone marrow failure after just 3 weeks of TMZ treatment, leading to a year-long struggle with the condition and requiring over 100 blood transfusions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Persistent bone marrow depression following short-term treatment with temozolomide. Vandraas, K., Tjønnfjord, GE., Johannesen, TB., et al.[2019]

In a study of 165 glioblastoma patients, the extent of tumor resection was the only factor associated with longer survival, indicating that surgical removal of the tumor is crucial for improving outcomes.

The use of Gliadel wafers significantly increased the risk of adverse events, especially in patients with recurrent tumors, with those receiving eight wafers facing a 3-fold higher risk of adverse events and a 5.6-fold higher risk of site-related complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastoma. De Bonis, P., Anile, C., Pompucci, A., et al.[2018]

In a study of 87 newly diagnosed glioblastoma patients, only 5% experienced severe myelotoxicity during treatment with temozolomide (TMZ) and radiation therapy, indicating that while the risk exists, it is relatively low.

Factors such as female sex, low pretreatment platelet counts, and specific genetic markers were identified as potential predictors of severe myelotoxicity, suggesting that personalized treatment approaches could help mitigate risks in vulnerable patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and Genetic Factors Associated With Severe Hematological Toxicity in Glioblastoma Patients During Radiation Plus Temozolomide Treatment: A Prospective Study. Lombardi, G., Rumiato, E., Bertorelle, R., et al.[2018]

Temozolomide (TMZ) is generally safe with mild to moderate side effects, but this case report highlights a rare instance of severe aplastic anemia (AA) in a 68-year-old female patient following treatment for glioblastoma, indicating a potential serious risk associated with the drug.

The patient's AA was managed successfully with supportive care, including platelet transfusions and growth factor treatment, and her blood counts returned to normal within 38 days, emphasizing the importance of monitoring blood parameters during and after TMZ treatment to detect such rare toxicities early.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-induced aplastic anaemia: Case report and review of the literature. Gilbar, PJ., Pokharel, K., Mangos, HM.[2022]

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 60 glioblastoma patients, higher radiation doses to the contralateral subventricular zone (cSVZ) were linked to poorer progression-free survival (PFS) and overall survival (OS), particularly in those with subtotal resection or biopsy.

The findings suggest that high radiation doses to the ipsilateral subventricular zone also negatively impacted PFS, indicating that increased radiation to these areas may not be beneficial and highlighting the need for more prospective studies to clarify these effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relationship between survival and increased radiation dose to subventricular zone in glioblastoma is controversial. Elicin, O., Inac, E., Uzel, EK., et al.[2022]

The combination of Gliadel wafers with concurrent radio-chemotherapy using temozolomide (TMZ) in 24 patients with glioblastoma multiforme resulted in a median overall survival of 19.2 months and a median progression-free survival of 12.3 months, indicating a potential benefit of this treatment approach.

While the treatment was generally well tolerated, 10 patients experienced significant toxicity leading to premature discontinuation of TMZ, highlighting the need for careful monitoring of hematological and digestive side effects during this multimodal therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of the per-operatory application of GLIADEL wafers (BCNU, carmustine) in combination with temozolomide and radiotherapy in patients with glioblastoma multiforme: efficacy and toxicity. Miglierini, P., Bouchekoua, M., Rousseau, B., et al.[2018]

Temozolomide (TZM) combined with X-ray irradiation significantly inhibits the proliferation and migration of human glioma spheroids, with the most effective results seen at higher concentrations of TZM.

The study found that while the combination of TZM and radiation enhances the effects on glioma cells, the overall impact is less than what would be expected from simply adding the effects of each treatment alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The inhibition of proliferation and migration of glioma spheroids exposed to temozolomide is less than additive if combined with irradiation. Fehlauer, F., Muench, M., Richter, E., et al.[2018]

Citations

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

Future directions for temozolomide therapy. [2019]

2. Germany pubmed.ncbi.nlm.nih.gov

Temozolomide-induced liver damage. A case report. [2021]

3. Japan pubmed.ncbi.nlm.nih.gov

[Temozolomide: Temodal]. [2018]

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

Randomized phase II study of temozolomide and radiotherapy compared with radiotherapy alone in newly diagnosed glioblastoma multiforme. [2018]

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

Phase 2 trial of temozolomide using protracted low-dose and whole-brain radiotherapy for nonsmall cell lung cancer and breast cancer patients with brain metastases. [2022]

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

Persistent bone marrow depression following short-term treatment with temozolomide. [2019]

7. Austria pubmed.ncbi.nlm.nih.gov

Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastoma. [2018]

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

Clinical and Genetic Factors Associated With Severe Hematological Toxicity in Glioblastoma Patients During Radiation Plus Temozolomide Treatment: A Prospective Study. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Temozolomide-induced aplastic anaemia: Case report and review of the literature. [2022]

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

Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma. [2022]

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

Relationship between survival and increased radiation dose to subventricular zone in glioblastoma is controversial. [2022]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Impact of the per-operatory application of GLIADEL wafers (BCNU, carmustine) in combination with temozolomide and radiotherapy in patients with glioblastoma multiforme: efficacy and toxicity. [2018]

13. Greece pubmed.ncbi.nlm.nih.gov

The inhibition of proliferation and migration of glioma spheroids exposed to temozolomide is less than additive if combined with irradiation. [2018]