Veliparib + Radiation + Temozolomide for Brain Cancer

Not currently recruiting at 182 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anti-cancer agents

Disqualifiers: Diffuse astrocytoma, Oligodendrogliomas, PXA, 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: 33

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of a combination of treatments against malignant glioma, an aggressive brain cancer. It uses veliparib, a drug that prevents cancer cells from repairing themselves, alongside radiation therapy and the chemotherapy drug temozolomide. The aim is to determine if this combination is more effective than using only radiation therapy and temozolomide. Individuals newly diagnosed with high-grade glioma and specific genetic profiles (without H3 K27M or BRAFV600 mutations) may be suitable for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, you must not be currently receiving other anti-cancer agents.

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

Research shows that both veliparib and temozolomide have undergone safety testing in humans. Studies have found that veliparib, when combined with radiation, is well-tolerated in cases involving brain conditions. Specifically, it can be safely used with radiation therapy in patients with brain metastases. Veliparib works by preventing tumor cells from repairing themselves, potentially stopping their growth.

Temozolomide is a well-known chemotherapy drug for treating brain tumors. It has been widely studied and is considered safe, though it can cause side effects. Studies have noted side effects such as issues with blood cells, but it remains in use due to its effectiveness in treating tumors.

Overall, both veliparib and temozolomide have demonstrated safety in human studies, despite some known side effects. Testing the safety of any new combination, such as in this trial, underscores the importance of further studies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of veliparib, radiation, and temozolomide for brain cancer because this treatment approach targets cancer cells in a unique way. Veliparib is a PARP inhibitor, which interferes with cancer cells' ability to repair their DNA, making them more susceptible to damage from radiation. This combination could enhance the effectiveness of radiation therapy and temozolomide, potentially improving outcomes compared to standard treatments. While traditional treatments often focus solely on killing cancer cells directly, this approach weakens cancer cells' defenses, potentially leading to better control of tumor growth.

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

This trial will evaluate the combination of temozolomide, radiation therapy, and veliparib for brain cancer. Studies have shown that combining temozolomide with radiation therapy can extend the lives of brain cancer patients. For instance, one study found that 70% of patients survived for 10 years with this combined treatment, compared to 47% with just radiation. Temozolomide has significantly increased the average survival time for brain tumor patients.

Research on veliparib, a PARP inhibitor, suggests it may prevent tumor cells from repairing themselves, potentially stopping their growth. However, several studies found that adding veliparib to treatments like temozolomide did not significantly increase survival for certain types of brain cancer. While veliparib's method shows promise, its ability to extend life for brain cancer patients remains unproven. Participants in this trial will receive the combination of radiation therapy, temozolomide, and veliparib to further investigate its potential benefits. ^{1 6 7 8 9}

Who Is on the Research Team?

Matthias A Karajannis

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

This trial is for patients with newly diagnosed malignant glioma without certain mutations (H3 K27M or BRAFV600). Eligible participants are between 3-25 years old, have not received prior tumor-directed therapy, and can start treatment within 31 days after surgery. They must have proper organ function and controlled seizures if present.

Inclusion Criteria

My kidney function, measured by creatinine clearance or GFR, is normal or above.

My bilirubin levels are within the normal range for my age.

I am between 3 and 21 years old.

Exclusion Criteria

I have been diagnosed with gliomatosis cerebri type 1 or 2.

I am currently pregnant.

I am sexually active and capable of having children.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemoradiotherapy

Patients receive veliparib orally twice daily and undergo 30 daily fractions of radiation therapy 5 days per week for 6-7 weeks

6-7 weeks

30 visits (in-person)

Maintenance Chemotherapy

Patients receive veliparib orally twice daily and temozolomide orally once daily on days 1-5, repeating every 28 days for up to 10 cycles

Up to 10 months

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Up to 10 years

Every 3 months for year 1, every 4 months for year 2, every 6 months for year 3, then once yearly for years 4-10

What Are the Treatments Tested in This Trial?

Interventions

• Radiation Therapy
• Temozolomide
• Veliparib

Trial Overview

The study tests the effectiveness of veliparib combined with radiation therapy and temozolomide in treating malignant glioma. Veliparib is a PARP inhibitor that may prevent tumor cells from repairing DNA damage, potentially enhancing the effects of chemotherapy and radiation.

How Is the Trial Designed?

Group I: Treatment (radiation therapy, veliparib, temozolomide) Experimental Treatment 3 Interventions

CHEMORADIOTHERAPY PHASE: Patients receive veliparib PO BID and undergo 30 daily fractions of radiation therapy 5 days per week for 6-7 weeks in the absence of disease progression or unacceptable toxicity. MAINTENANCE CHEMOTHERAPY: Beginning 4 weeks after chemoradiotherapy phase, patients receive veliparib PO BID and temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 10 cycles in the absence of disease progression or unacceptable toxicity.

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

Approved in European Union as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in United States as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Canada as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Japan as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in China as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Switzerland as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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 128 patients with brain metastases from non-small cell lung cancer, synchronous stereotactic radiotherapy (SRT) combined with temozolomide (TMZ) and whole brain radiotherapy (WBRT) significantly improved overall survival (OS) and progression-free survival (PFS) compared to SRT with WBRT alone, with median OS of 13.1 months and PFS of 11.2 months in the TMZ group.

While the combination treatment led to a higher incidence of nausea and vomiting (67.2% vs. 43.8%), other adverse reactions were similar between the two groups, indicating that the treatment is generally tolerable despite some side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of synchronous stereotactic radiotherapy with temozolomide combined with whole brain radiotherapy in treating brain metastases originating from non-small cell lung cancer. Liu, P., Ren, R., You, D., et al.[2021]

Temozolomide (TMZ) significantly enhances the effectiveness of gamma irradiation in treating glioma cells, demonstrating a notable increase in radiosensitivity compared to irradiation alone, based on in vitro studies with U87MG cell lines.

The study involved various treatment groups over 24, 48, and 72 hours, and the combination of TMZ and irradiation resulted in significantly lower cell viability, indicating a more effective treatment strategy for gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vitro Radiosensitizing Effects of Temozolomide on U87MG Cell Lines of Human Glioblastoma Multiforme. Borhani, S., Mozdarani, H., Babalui, S., et al.[2020]

In a study of 9 patients with brain metastases from lung adenocarcinoma, the combination of intensity-modulated radiation therapy (IMRT) and temozolomide (TMZ) resulted in a high objective response rate of 77.8%, with one complete response and six partial responses, confirming the efficacy of this treatment approach.

Patients receiving the combination treatment experienced fewer severe adverse effects compared to those who only received IMRT, with no grade ≥3 hematologic toxicities reported, and an improvement in quality of life was noted, indicating that the addition of TMZ is both effective and relatively safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensity-modulated radiation therapy combined with concomitant temozolomide for brain metastases from lung adenocarcinoma. Li, J., Chai, X., Cao, Y., et al.[2020]

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 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]

Combining temozolomide with radiotherapy significantly improves the overall response rate (ORR) in patients with brain metastases, particularly in those with non-small cell lung cancer, with a risk ratio of 1.35.

However, this combination treatment does not lead to significant improvements in progression-free survival (PFS) or overall survival (OS) and is associated with a higher incidence of side effects compared to radiotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Temozolomide and Radiotherapy on Brain Metastatic Tumor: A Systematic Review and Meta-Analysis. Ma, W., Li, N., An, Y., et al.[2018]

Temozolomide is a chemotherapeutic agent that effectively crosses the blood-brain barrier and has shown a good safety profile in treating brain metastases from solid tumors, with clinical activity observed in heavily pretreated patients.

In a randomized phase II trial, temozolomide combined with radiation therapy resulted in a significantly higher objective response rate (96% vs. 67%) compared to radiation alone, particularly benefiting patients with newly diagnosed brain and lung metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide for treating brain metastases. Abrey, LE., Christodoulou, C.[2019]

In a phase II study involving 30 patients with brain metastases from non-small cell lung cancer (NSCLC), temozolomide (TMZ) was found to be an active and safe treatment option, with 10% of patients achieving an objective response, including two complete remissions.

No severe (grade 3 or 4) toxicities were reported, and all treatment-related adverse events were mild to moderate, indicating that TMZ can be administered without significant safety concerns in this heavily pre-treated patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral temozolomide in heavily pre-treated brain metastases from non-small cell lung cancer: phase II study. Giorgio, CG., Giuffrida, D., Pappalardo, A., 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]

Combining brain radiotherapy (RT) with temozolomide (TMZ) significantly improves the objective response rate (ORR) in patients with brain metastases, with an odds ratio of 2.27, indicating a better response to treatment compared to RT alone.

However, this combination treatment does not lead to a significant improvement in overall survival (OS) or progression-free survival (PFS), and it is associated with increased adverse effects, such as severe nausea and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain Radiotherapy plus Concurrent Temozolomide versus Radiotherapy Alone for Patients with Brain Metastases: A Meta-Analysis. Zhao, Q., Qin, Q., Sun, J., et al.[2018]

In a randomized trial involving 144 patients with anaplastic astrocytoma (AA) and glioblastoma (GBM), neoadjuvant temozolomide (NeoTMZ) did not show a survival advantage for the overall population or for GBM patients compared to radiotherapy alone.

However, patients with AA who received NeoTMZ had a significantly longer median survival of 95.1 months compared to 35.2 months for those receiving only radiotherapy, indicating a potential benefit of NeoTMZ specifically for AA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial. Malmström, A., Poulsen, HS., Grønberg, BH., et al.[2018]

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