Temozolomide + Veliparib for Glioblastoma

Recruiting at 446 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: National Cancer Institute (NCI)

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 9

Duration: 24 weeks

447 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized phase II/III trial studies how well temozolomide and veliparib work compared to temozolomide alone in treating patients with newly diagnosed glioblastoma multiforme. 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. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether temozolomide is more effective with or without veliparib in treating glioblastoma multiforme.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must be on a stable dose of any anti-seizure medication for at least 10 days before joining the trial.

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

Research shows that Temozolomide is effective in treating high-grade gliomas, including glioblastoma, with studies indicating it has meaningful efficacy and an acceptable safety profile. It is often used in combination with other treatments like radiation to improve outcomes for patients with newly diagnosed glioblastoma. ^{1 2 3 4 5}

Is the combination of Temozolomide and Veliparib safe for humans?

Temozolomide is generally well tolerated, with common side effects like fatigue, nausea, and mild blood-related issues. However, rare but serious blood disorders have been reported, such as myelodysplastic syndrome and aplastic anemia. ^{1 3 6 7 8}

What makes the drug combination of Temozolomide and Veliparib unique for treating glioblastoma?

The combination of Temozolomide (TMZ) and Veliparib is unique because Veliparib, a PARP inhibitor, may enhance the effectiveness of TMZ in glioblastoma by potentially overcoming resistance in TMZ-sensitive tumors. This combination aims to improve outcomes by targeting specific mechanisms that contribute to tumor resistance. ^{4 5 9 10 11}

Research Team

Jann N Sarkaria

Principal Investigator

Alliance for Clinical Trials in Oncology

Eligibility Criteria

This trial is for adults with newly diagnosed glioblastoma multiforme or gliosarcoma. Participants must have proper liver function, enough tissue for testing, and their tumor must not be a specific subtype (1p19q codeleted). They should also have normal blood cell counts and kidney function. Those with certain genetic features of the tumor that make it less likely to respond to treatment are excluded.

Inclusion Criteria

My brain tumor is confirmed as grade IV glioblastoma or gliosarcoma.

My condition hasn't worsened outside the treated area after chemoradiation.

I haven't received any treatment before this study except for TMZ with radiation and possibly the Optune device.

Exclusion Criteria

My GBM cancer has specific genetic features (1p19q codeleted).

I haven't had cancer in the last 5 years, except for skin cancer.

I have AML or MDS, possibly caused by previous treatments.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive temozolomide and veliparib or placebo for 6 cycles, each cycle lasting 28 days

24 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

5 years

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

Treatment Details

Interventions

• Temozolomide
• Veliparib

Trial Overview The study is examining if adding Veliparib to Temozolomide chemotherapy improves outcomes in treating brain cancer compared to Temozolomide alone. It's a randomized trial, meaning patients are put into the two different treatment groups by chance.

Participant Groups

Group I: Arm I (temozolomide, veliparib) Experimental Treatment 4 Interventions

Patients receive temozolomide PO QD on days 1-5 and veliparib PO BID on days 1-7. Treatment repeats every 28 days for 6 cycles in the absence of disease progression (confirmed progression) or unacceptable toxicity.

Group II: Arm II (temozolomide, placebo) Placebo Group 4 Interventions

Patients receive temozolomide as in Arm I and placebo PO BID on days 1-7. Treatment repeats every 28 days for 6 cycles in the absence of disease progression (confirmed progression) or unacceptable toxicity.

Temozolomide is already approved in European Union, United States for the following indications:

Approved in European Union as Temodal for:

• Newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment
• Children from the age of three years, adolescents and adults with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy

Approved in United States as Temodar for:

• Newly diagnosed glioblastoma concomitantly with radiotherapy and subsequently as monotherapy treatment
• Newly diagnosed or refractory anaplastic astrocytoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase II trial involving 46 patients with progressive low-grade glioma, Temozolomide (Temodar) demonstrated a 61% objective response rate, with 24% achieving complete response and 37% achieving partial response.

The treatment showed promising safety, with limited toxicity observed; however, one patient experienced severe complications, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with progressive low-grade glioma. Quinn, JA., Reardon, DA., Friedman, AH., 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]

In a study involving 831 patients across 21 French hospitals, temozolomide (TMZ) prescriptions were found to conform to the French summary of product characteristics (SPC) in 51.9% of cases, indicating a moderate level of adherence to official guidelines.

The study revealed high conformity (91.5%) to the prescription guidebook, with specific adherence rates of 62% for newly diagnosed glioblastoma patients receiving combined treatment with radiotherapy, 72% for maintenance therapy, and 66% for patients with progressive disease, highlighting the overall compliance in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter prospective observational study of the conformity of temozolomide prescriptions in France. Tilleul, P., Brignone, M., Hassani, Y., et al.[2018]

In a phase II clinical trial involving 21 patients with newly diagnosed glioblastoma multiforme (GBM), the combination of temozolomide (TMZ) with radiotherapy resulted in a one-year survival rate of 58% and a median survival time of 15.7 months, indicating its efficacy in extending survival.

The treatment regimen was well-tolerated, with only mild to moderate non-hematological side effects and minimal severe hematological toxicity, suggesting that TMZ has a favorable safety profile compared to traditional chemotherapy agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. Lanzetta, G., Campanella, C., Rozzi, A., et al.[2018]

Temozolomide (TMZ) is an effective oral treatment for recurrent glioblastoma multiforme, showing nearly 100% bioavailability and a favorable safety profile, making it a promising option for patients with this aggressive brain cancer.

Research is ongoing to enhance the efficacy of TMZ by combining it with other treatments like chemotherapy, radiation, and immunotherapy, as well as exploring alternative dosing strategies to overcome resistance in gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions in the treatment of malignant gliomas with temozolomide. Prados, MD.[2018]

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) is commonly used as an adjuvant therapy for malignant glioma, but in this case study, a patient developed treatment-related acute myeloid leukemia (t-AML) after receiving 15 cycles of TMZ, highlighting a rare but serious complication.

The case raises questions about the duration of TMZ therapy, as the patient showed no tumor progression but still developed t-AML, suggesting a need for better guidelines to balance treatment benefits and risks in long-term TMZ use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Case of Therapy-Related Acute Myeloid Leukemia Associated with Adjuvant Temozolomide Chemotherapy for Anaplastic Astrocytoma. Kosugi, K., Saito, K., Takahashi, W., 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 20 patients with various types of glioma, the combination of olaparib and temozolomide (TMZ) showed a 50% objective radiographic response rate in patients with recurrent IDH-mutant grade 2-3 gliomas, indicating potential efficacy for this specific group.

While the treatment was generally manageable, common side effects included fatigue and gastrointestinal issues, with 30% of patients requiring dose adjustments due to toxicity, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series. Schaff, LR., Kushnirsky, M., Lin, AL., et al.[2023]

The PARP inhibitor veliparib enhances the effectiveness of temozolomide (TMZ) in treating glioblastoma, particularly in TMZ-sensitive models, but its ability to sensitize TMZ-resistant tumors is limited by achievable drug concentrations in vivo.

In vivo studies showed that while veliparib combined with TMZ significantly delayed tumor growth in sensitive GBM models, it did not have the same effect in resistant models, indicating that higher doses than tolerable are needed for effective sensitization in resistant cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discordant in vitro and in vivo chemopotentiating effects of the PARP inhibitor veliparib in temozolomide-sensitive versus -resistant glioblastoma multiforme xenografts. Gupta, SK., Mladek, AC., Carlson, BL., et al.[2021]

References

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

Phase II trial of temozolomide in patients with progressive low-grade glioma. [2022]

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

Future directions for temozolomide therapy. [2019]

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

A multicenter prospective observational study of the conformity of temozolomide prescriptions in France. [2018]

4. Greece pubmed.ncbi.nlm.nih.gov

Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. [2018]

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

Future directions in the treatment of malignant gliomas with temozolomide. [2018]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Temozolomide-related hematologic toxicity. [2018]

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

A Case of Therapy-Related Acute Myeloid Leukemia Associated with Adjuvant Temozolomide Chemotherapy for Anaplastic Astrocytoma. [2018]

8. England pubmed.ncbi.nlm.nih.gov

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

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

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series. [2023]

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

Discordant in vitro and in vivo chemopotentiating effects of the PARP inhibitor veliparib in temozolomide-sensitive versus -resistant glioblastoma multiforme xenografts. [2021]

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

ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy. [2022]