Veliparib + Radiation + Temozolomide for Brain Cancer

Recruiting at 172 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

38 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well veliparib, radiation therapy, and temozolomide work in treating patients with newly diagnosed malignant glioma without H3 K27M or BRAFV600 mutations. Poly adenosine diphosphate (ADP) ribose polymerases (PARPs) are proteins that help repair DNA mutations. PARP inhibitors, such as veliparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving veliparib, radiation therapy, and temozolomide may work better in treating patients with newly diagnosed malignant glioma without H3 K27M or BRAFV600 mutations compared to radiation therapy and temozolomide alone.

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.

What safety data exists for the combination of Veliparib, Radiation, and Temozolomide in treating brain cancer?

The combination of radiation therapy and temozolomide has been studied for brain metastases and high-grade gliomas, showing some common side effects like neutropenia (low white blood cell count), anemia (low red blood cell count), vomiting, fatigue, and dizziness. Serious blood-related side effects were not observed, but skin reactions have been reported in some cases. Overall, the treatment was considered active and improved quality of life in some patients. ^{1 2 3 4 5}

What makes the Veliparib + Radiation + Temozolomide treatment unique for brain cancer?

This treatment combines Veliparib, a drug that may enhance the effects of radiation, with Temozolomide, a chemotherapy drug that can cross the blood-brain barrier and has shown effectiveness in treating brain tumors. The combination aims to improve the effectiveness of radiation therapy by making cancer cells more sensitive to it, potentially leading to better outcomes for patients with brain cancer. ^{6 7 8 9 10}

What data supports the effectiveness of the treatment Veliparib + Radiation + Temozolomide for brain cancer?

Research shows that combining temozolomide (a chemotherapy drug) with radiotherapy can improve survival in patients with brain tumors like glioblastoma compared to radiotherapy alone. This suggests that adding temozolomide to radiation treatments may enhance effectiveness. ^{2 11 12 13 14}

Research Team

Matthias A Karajannis

Principal Investigator

Children's Oncology Group

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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 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]

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]

References

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

Brain Radiotherapy plus Concurrent Temozolomide versus Radiotherapy Alone for Patients with Brain Metastases: A Meta-Analysis. [2018]

2. England 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. [2018]

3. England pubmed.ncbi.nlm.nih.gov

A population-based study on the effect of temozolomide in the treatment of glioblastoma multiforme. [2022]

4. France pubmed.ncbi.nlm.nih.gov

[Radiotherapy of adult glial tumors: new developments and perspectives]. [2008]

5. Ireland pubmed.ncbi.nlm.nih.gov

Oral temozolomide in heavily pre-treated brain metastases from non-small cell lung cancer: phase II study. [2018]

6. Greece pubmed.ncbi.nlm.nih.gov

Intensity-modulated radiation therapy combined with concomitant temozolomide for brain metastases from lung adenocarcinoma. [2020]

7. India pubmed.ncbi.nlm.nih.gov

Feasibility of preirradiation temozolomide in cases of high-grade gliomas: Our experience and review of literature. [2023]

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

Future directions for temozolomide therapy. [2019]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Two cases of cutaneous drug eruption associated with temozolomide therapy for glioblastoma. [2018]

10. Iran pubmed.ncbi.nlm.nih.gov

Radiosensitization of Glioma Cells by Temozolomide (TMZ): A Colony Formation Assay. [2022]

11. Iran pubmed.ncbi.nlm.nih.gov

In Vitro Radiosensitizing Effects of Temozolomide on U87MG Cell Lines of Human Glioblastoma Multiforme. [2020]

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

Temozolomide for treating brain metastases. [2019]

13. Cyprus 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. [2021]

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

Effects of Temozolomide and Radiotherapy on Brain Metastatic Tumor: A Systematic Review and Meta-Analysis. [2018]