SVZ Radiation + Temozolomide for Glioblastoma

Recruiting at 3 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 explores a new method to treat glioblastoma, a type of brain cancer, by delivering higher doses of radiation to the subventricular zone, along with standard chemotherapy using Temozolomide. Researchers aim to determine if this approach can control the tumor longer than standard treatment. Individuals recently diagnosed with glioblastoma, who have undergone surgery and have not received prior brain radiation, may qualify for this trial. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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

Research has shown that using temozolomide with radiation therapy is generally safe for treating glioblastoma, a type of brain cancer. One study found that focusing radiation on specific brain areas might help prevent memory and thinking problems without affecting the treatment's effectiveness. This suggests that the adjusted radiation treatment is safe.

Temozolomide may cause side effects like nausea and tiredness, but these are usually manageable. This treatment combination has been tested in other studies with similar patients, supporting its safety. Overall, the evidence suggests that the treatment is quite safe for participants. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they target glioblastoma with a unique approach. Unlike standard treatments that focus solely on the tumor, these therapies incorporate subventricular zone (SVZ) radiation, potentially tackling cancer stem cells that might contribute to recurrence. By combining temozolomide, a well-known chemotherapy drug, with precise radiation techniques, these treatments aim to improve effectiveness and reduce the likelihood of the tumor returning. This dual-target strategy offers hope for better outcomes in glioblastoma patients, a condition notoriously challenging to treat.

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

Research has shown that the chemotherapy drug temozolomide effectively treats glioblastoma, a type of brain cancer. Studies have found that it significantly improves patient outcomes, helping patients live longer compared to using only radiation therapy. In this trial, one group of participants will receive temozolomide alongside neural progenitor cell sparing radiation. Another group will receive temozolomide plus radiation therapy targeting the tumor and subventricular zone (SVZ). Evidence suggests that higher doses of radiation to the SVZ can extend patient survival, as this area contains stem cells that might contribute to cancer recurrence. Together, these treatments aim to improve survival rates and control glioblastoma. ^{5 6 7 8 9}

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 (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 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 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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6347443/

Subventricular Zone Radiation Dose and Outcome for ... Median PFS was 8.9 months (95% CI: 8.3–9.8 months), and OS was 16.5 months (95% CI: 15.2–17.6 months). PFS was significantly lower for older age ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0360301625027816

Assessment of Subventricular Zone Irradiation in ... Mean of ipsilateral SVZ median dose equal to or more than 52.14Gy had increased overall survival (p value: 0.04) in SVZ contacting tumors. Median of bilateral ...

3. nature.com nature.com/articles/s41598-021-97714-5

Subventricular zone involvement is associated with worse ... Subventricular zone involvement may represent a risk factor for worse outcome in glioma WHO grade 2 depending on the molecular tumor signature.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02177578

Study Details | NCT02177578 | Subventricular Zone (SVZ) ... In this study patients will be treated with 6 weeks of radiation therapy plus temozolomide chemotherapy according to the standard of care.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6645358/

High dose vs low dose irradiation of the subventricular zone in ... Increased subventricular zone radiation dose correlates with survival in glioblastoma patients after gross total resection. Int J Radiat ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7293896/

A Prospective Cohort Study of Neural Progenitor Cell-Sparing ... To prospectively evaluate the impact of limiting radiation dose to the NPC niches on tumor progression, survival, and cognition in patients with ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT01478854

Neural Progenitor Cell Sparing Radiation Therapy Plus ... We hypothesize that NPC-sparing RT will reduce neurocognitive decline following treatment for brain tumors, without compromising tumor local control. However, ...

8. redjournal.org redjournal.org/article/S0360-3016(15)00995-5/pdf

Neural Progenitor Cell (NPC) Sparing ... Conclusion: Planned irradiation of potential stem cell niches in the ipsi- lateral cerebral hemisphere resulted in improved survival in glioblastoma. Treatment ...

9. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32497183/

A Prospective Cohort Study of Neural Progenitor Cell-Sparing ... In treating glioblastoma, limiting dose to the NPC niches may reduce cognitive toxicity while maintaining clinical outcomes.