Temozolomide + Veliparib for Glioblastoma

Not currently recruiting at 456 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: National Cancer Institute (NCI)

Must be taking: Temozolomide

Disqualifiers: Uncontrolled seizures, Thromboembolic disease, others

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding veliparib to the standard chemotherapy drug temozolomide can more effectively treat individuals with newly diagnosed glioblastoma, an aggressive brain tumor. Temozolomide disrupts tumor cell growth, and veliparib may enhance this effect by blocking certain enzymes necessary for tumor growth. Participants will receive either temozolomide with a placebo or with veliparib to compare outcomes. Individuals with a confirmed diagnosis of glioblastoma or gliosarcoma, who have completed specific prior treatments and meet certain test criteria, may qualify for this trial. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to significant advancements in glioblastoma treatment.

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.

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

Research has shown that using temozolomide with veliparib has generally been well-tolerated. In previous trials, adding veliparib to temozolomide proved safe for patients, though some side effects, such as nausea and tiredness, were noted.

Temozolomide is already used to treat glioblastoma and has FDA approval, indicating a known safety record. Veliparib is still under study, but earlier research found it safe when combined with temozolomide. Notably, when both drugs were combined with radiation therapy, patients experienced more side effects; however, this trial does not include radiation.

Overall, while side effects exist, past studies have shown that the combination is usually manageable for patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for glioblastoma because they explore the potential of combining temozolomide with veliparib to enhance treatment effectiveness. Temozolomide is a well-known chemotherapy drug that works by damaging the DNA of cancer cells, but veliparib introduces a new mechanism by inhibiting PARP, an enzyme that helps cancer cells repair themselves. By combining these two, there's hope that the treatment could make cancer cells more vulnerable to damage and improve outcomes for patients. This combination targets cancer cells more aggressively than the standard treatments, offering a promising new approach for a tough-to-treat cancer.

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

In this trial, participants will be assigned to one of two treatment arms. Arm I involves treatment with temozolomide and a placebo, while Arm II involves treatment with temozolomide and veliparib. Research has shown that adding veliparib to temozolomide for treating glioblastoma does not significantly improve patient survival or delay disease progression. Several studies have consistently found that this combination does not extend survival times compared to using temozolomide alone. Temozolomide is a chemotherapy drug that stops tumor cells from growing and dividing. The idea was that veliparib might enhance this effect by blocking certain enzymes needed for tumor growth, but the evidence so far does not support this. Therefore, while temozolomide remains an important treatment, adding veliparib has not been shown to be more effective. ^{2 6 7 8 9}

Who Is on the Research Team?

Jann N Sarkaria

Principal Investigator

Alliance for Clinical Trials in Oncology

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Patients receive temozolomide as in Arm I 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 I (temozolomide, placebo) Placebo Group 5 Interventions

Patients receive temozolomide PO QD on days 1-5 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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2825373

Efficacy of Adding Veliparib to Temozolomide for Patients ... This randomized clinical trial did not demonstrate a significant overall survival benefit for patients with MGMT-hypermethylated GBM treated ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39480453/

Efficacy of Adding Veliparib to Temozolomide for Patients With ... This trial found that adding veliparib to adjuvant temozolomide did not significantly extend OS in patients with newly diagnosed, MGMT-hypermethylated ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02152982

NCT02152982 | Temozolomide With or Without Veliparib in ... This randomized phase II/III trial studies how well temozolomide and veliparib work compared to temozolomide alone in treating patients with newly diagnosed ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.2001

Randomized phase II/III trial of veliparib or placebo in ... Conclusions: Veliparib combined with adjuvant TMZ therapy was not associated with significant extension in OS or PFS in newly diagnosed, MGMT ...

5. cancertherapyadvisor.com cancertherapyadvisor.com/news/glioblastoma-veliparib-temozolomide-does-not-improve-survival/

Adding Veliparib to Temozolomide Does Not Improve ... These results, from a phase 3 trial, showed that veliparib plus temozolomide did not improve overall survival (OS) or progression-free survival ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11528341/

Efficacy of Adding Veliparib to Temozolomide for Patients With ... To evaluate the combination of veliparib and temozolomide in glioblastoma based on preclinical data demonstrating significant ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8206461/

Temozolomide: An Updated Overview of Resistance ... However, conventional therapy using surgery, radiation, and TMZ in glioblastoma results in a median patient survival of 14.6 months. Treatment failure has been ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT01026493

Veliparib and Temozolomide in Treating Patients With ... To characterize the safety profile of the combination of temozolomide and veliparib. · To determine the adverse event profile and tolerability of the combination ...

9. asco.org asco.org/abstracts-presentations/ABSTRACT261961

A randomized phase II trial of veliparib (V), radiotherapy ... V is synergistic with both RT and TMZ in preclinical models, safe when combined with either RT or TMZ clinically, but the triplet (V+RT+TMZ) is poorly tolerated ...