Peposertib + Radiation + Temozolomide for Glioblastoma/Gliosarcoma

Overseen By Nazanin Majd

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Chemotherapy, Immunotherapy, Radiotherapy, others

Disqualifiers: HIV, Psychiatric disorders, Malignancies, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 33

29 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of a new drug, Peposertib (also known as Nedisertib), in combination with radiation therapy and the chemotherapy drug temozolomide for treating certain brain tumors, such as glioblastoma or gliosarcoma. The goal is to determine the optimal dose of Peposertib and assess whether it more effectively stops tumor growth compared to radiation therapy alone. Individuals recently diagnosed with MGMT unmethylated glioblastoma or gliosarcoma, who have undergone brain surgery but received no other treatments, may be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot receive other chemotherapy, immunotherapy, or radiotherapy while participating in the study.

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

Research has shown that combining peposertib with radiation therapy is safe for patients with newly diagnosed glioblastoma. Early results suggest patients tolerated this treatment well, with few reports of serious side effects.

Temozolomide, another drug used in this trial, has undergone extensive study. Previous research found it typically does not cause additional side effects when treating glioblastoma. Some studies noted side effects like a drop in white blood cells, but these were managed by adjusting the dose.

Both treatments have demonstrated safety for humans, based on past and current studies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Peposertib, radiation therapy, and temozolomide for glioblastoma and gliosarcoma because these treatments offer a novel approach compared to the standard options like radiation with temozolomide alone. Peposertib inhibits DNA repair mechanisms in cancer cells, potentially making them more vulnerable to radiation. This could enhance the effectiveness of radiation therapy by preventing the tumor cells from recovering after treatment. Additionally, by integrating surgery in some cases, this approach aims to further reduce tumor size, potentially improving patient outcomes.

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

This trial will evaluate the combination of Peposertib with radiation therapy and Temozolomide for treating glioblastoma. Studies have shown that Peposertib with radiation therapy might improve glioblastoma treatment, a type of brain cancer. Peposertib blocks certain enzymes that cancer cells need to grow, making it a good partner for radiation therapy. Early safety results indicate that this combination is safe for patients with glioblastoma. Additionally, Temozolomide, a chemotherapy drug used in this trial, has been proven to help patients live longer when combined with radiation. Specifically, this combination significantly increases survival rates compared to radiation alone. These findings suggest that using these treatments together could be more effective against glioblastoma. ^{1 3 5 6 7}

Who Is on the Research Team?

Nazanin Majd

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed MGMT unmethylated glioblastoma or gliosarcoma who have had surgery but no other treatments. They must be able to follow the study plan, have proper kidney and liver function, normal blood counts, and a stable condition on low-dose steroids. Women of childbearing age need a negative pregnancy test and agree to use birth control; men also need to use contraception.

Inclusion Criteria

I've had a brain MRI within the last 14 days and am on a low or reducing dose of steroids.

My GBM is MGMT unmethylated according to a certified lab test.

I am a woman who could still become pregnant.

Exclusion Criteria

Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating physician

I do not have any health conditions that would make the treatment risky for me.

I have a condition that increases my risk for side effects from radiation.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Concurrent Treatment (Stage I)

Patients undergo standard of care radiation therapy daily (Monday-Friday) for 30 fractions and receive Peposertib orally on each day of radiation therapy.

6 weeks

30 visits (in-person)

Adjuvant Treatment (Stage I)

Patients receive temozolomide orally once daily on days 1-5, repeating every 28 days for up to 6 cycles.

6 months

Concurrent Treatment (Stage II)

Patients receive Peposertib and undergo standard of care radiation therapy as in Stage I, followed by surgical resection within 1-14 days after completion of radiation therapy.

6 weeks

Adjuvant Treatment (Stage II)

Patients receive temozolomide as in Stage I.

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment.

Up to 3 years

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Nedisertib
• Radiation Therapy
• Temozolomide

Trial Overview The trial tests Peposertib combined with radiation therapy followed by Temozolomide chemotherapy in patients with specific brain tumors. It aims to find the best dose of Peposertib that can be given safely and see if this combination works better than standard treatment alone.

How Is the Trial Designed?

Group I: Stage II (Peposertib, Radiation, Temozolomide, Surgery) Experimental Treatment 4 Interventions

CONCURRENT: Patients receive Peposertib and undergo standard of care radiation therapy as in Stage I. Within 1-14 days after the completion of radiation therapy, patients undergo surgical resection. ADJUVANT: Patients receive temozolomide as in Stage I.

Group II: Stage I (Peposertib, Radiation therapy, Temozolomide) Experimental Treatment 3 Interventions

CONCURRENT: Patients undergo standard of care radiation therapy daily (Monday-Friday) for 30 fractions. Patients also receive Peposertib PO on each day of radiation therapy and given 1-2 hours before each treatment fraction. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. ADJUVANT: Patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

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]

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]

Tipifarnib can be safely administered at a maximum tolerated dose of 300 mg twice daily in combination with conventional radiotherapy for newly diagnosed glioblastoma patients, with manageable side effects like rash and fatigue.

In a specific cohort receiving both tipifarnib and temozolomide, 65% of patients were alive after one year, suggesting potential efficacy that warrants further investigation in a Phase II study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of tipifarnib with radiation therapy, with and without temozolomide, for patients with newly diagnosed glioblastoma. Nghiemphu, PL., Wen, PY., Lamborn, KR., et al.[2021]

The study successfully developed and validated methods for delivering ultra-high doses of radiation (BED10 > 300 Gy) using volumetric modulated arc therapy (VMAT) in a safe manner, achieving high coverage of tumor subvolumes while protecting surrounding organs at risk.

Out of 30 treatment plans evaluated, 12 out of 15 plans using 6FFF beams and 13 out of 15 using 10FFF beams met the primary goal of delivering over 95% of the prescribed dose to the target area, demonstrating the feasibility of this approach for future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation treatment planning study to investigate feasibility of delivering Immunotherapy in Combination with Ablative Radiosurgery to Ultra-High DoSes (ICARUS). Rokni, MB., Pointer, KB., George, J., et al.[2021]

In a Phase 1b/2a trial involving 56 patients with newly diagnosed malignant glioma, the combination of galunisertib (a TGF-β inhibitor) with temozolomide-based radiochemotherapy showed a comparable safety profile to the control group receiving only TMZ/RTX.

While the combination treatment did not significantly improve overall survival (18.2 months vs. 17.9 months) or progression-free survival (7.6 months vs. 11.5 months), it did achieve a higher disease control rate of 80% compared to 56% in the control group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma. Wick, A., Desjardins, A., Suarez, C., et al.[2021]

In a study of 68 patients with advanced solid tumors, the combination of stereotactic body radiotherapy (SBRT) followed by pembrolizumab showed a high one-year treated metastasis control rate of 89.5%, indicating effective tumor response regardless of whether the tumors received complete or partial radiation coverage.

The study found that treated metastasis control (TMC) was significantly associated with improved overall survival, and SBRT altered tumor gene expression by increasing immune-related genes while decreasing those related to cell cycle and DNA repair, suggesting a mechanism for enhanced immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial. Luke, JJ., Onderdonk, BE., Bhave, SR., et al.[2021]

The combination of pembrolizumab, hypofractionated stereotactic irradiation (HFSRT), and bevacizumab was found to be generally safe and well tolerated in 32 patients with recurrent high-grade gliomas, with manageable treatment-related adverse events such as proteinuria and fatigue.

In the bevacizumab-naïve group, 83% of patients showed a complete or partial response, with a median overall survival of 13.45 months, indicating promising preliminary efficacy of this treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypofractionated stereotactic re-irradiation with pembrolizumab and bevacizumab in patients with recurrent high-grade gliomas: results from a phase I study. Sahebjam, S., Forsyth, PA., Tran, ND., et al.[2021]

In a phase II study involving 66 adults with newly diagnosed glioblastoma multiforme or gliosarcoma, the combination of enzastaurin with temozolomide and radiation therapy was well tolerated and resulted in a median overall survival of 74 weeks and median progression-free survival of 36 weeks.

The study found that the treatment outcomes were comparable to those from a previous trial using erlotinib and significantly better than those from trials using thalidomide or cis-retinoic acid, suggesting that enzastaurin may be an effective addition to standard treatment regimens for these types of brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma. Butowski, N., Chang, SM., Lamborn, KR., et al.[2022]

In a phase I study involving 12 patients with newly diagnosed glioblastoma multiforme or gliosarcoma, the oral drug enzastaurin was found to be well tolerated at a dose of 250 mg per day when combined with radiation therapy and temozolomide, with no dose-limiting toxicities observed in the first 6 patients.

At a higher dose of 500 mg, two patients experienced dose-limiting toxicities, but the lower dose of 250 mg is recommended for further studies, indicating a balance between efficacy and safety in this treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzastaurin plus temozolomide with radiation therapy in glioblastoma multiforme: a phase I study. Butowski, N., Chang, SM., Lamborn, KR., et al.[2021]

In a pilot study of 23 patients with high-grade glioma, the addition of estramustine to radiosurgery and/or radiotherapy showed promising results, with a median survival of 16 months for newly diagnosed glioblastoma patients and a 38% two-year survival rate.

While some patients experienced significant survival benefits, such as those with recurrent anaplastic astrocytoma surviving 24 and 48+ months, the treatment was associated with risks, including deep vein thrombosis in four newly diagnosed glioblastoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot study of estramustine added to radiosurgery and radiotherapy for treatment of high grade glioma. Landy, H., Markoe, A., Potter, P., et al.[2019]

In a study of 182 patients with newly diagnosed glioblastoma, those receiving dose-intensified temozolomide experienced greater deterioration in quality of life and increased symptom burden compared to those receiving standard chemoradiotherapy.

The findings suggest that while dose-intensified treatment did not show differences in neurocognitive function, it was associated with worse overall health and motor function, indicating potential risks in terms of patient quality of life and survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Net clinical benefit analysis of radiation therapy oncology group 0525: a phase III trial comparing conventional adjuvant temozolomide with dose-intensive temozolomide in patients with newly diagnosed glioblastoma. Armstrong, TS., Wefel, JS., Wang, M., et al.[2022]

Nivolumab combined with radiotherapy and temozolomide (NIVO+RT+TMZ) is tolerable for patients with newly diagnosed glioblastoma, with no new safety concerns identified; however, higher rates of grade 3/4 treatment-related adverse events were observed compared to Nivolumab with radiotherapy alone (NIVO+RT).

The study found that overall survival (OS) was similar for patients with unmethylated MGMT promoter whether they received NIVO+RT+TMZ or NIVO+RT, indicating that the addition of temozolomide may not significantly improve outcomes in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. Omuro, A., Reardon, DA., Sampson, JH., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04555577

Study Details | NCT04555577 | Peposertib and Radiation ... Giving Peposertib with radiation therapy may work better than radiation therapy alone in treating patients with glioblastoma or gliosarcoma. Detailed ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.2076

Phase I clinical trial of peposertib plus radiation in adults ... Conclusions: The initial safety data of peposertib plus radiation in patients with newly-diagnosed MGMT unmethylated glioblastoma is favorable.

3. academic.oup.com academic.oup.com/neuro-oncology/article/26/Supplement_8/viii119/7890602

DNAR-10. PHASE I CLINICAL TRIAL OF PEPOSERTIB PLUS ... Peposertib, a small molecule inhibitor of DNA-PK, has demonstrated pre-clinical efficacy in sensitizing GBM to RT, resulting in tumor regression ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11565114/

DNA-dependent protein kinase inhibitor as a sensitizer of ... The efficacy of the combination with peposertib and capecitabine-based CRT did not demonstrate a clear clinical benefit for patients with LARC ( ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7954093/

The promise of DNA damage response inhibitors for the ... The effective use of CPIs against GBM has been reported in patients with tumors with a high mutational burden resulting from germline impairment in DNA repair ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10639556/

CTNI-42. PHASE I CLINICAL TRIAL OF PEPOSERTIB ... CONCLUSION. The initial safety data of peposertib plus radiation in newly-diagnosed MGMT unmethylated glioblastoma is favorable. The cases with RN in tumors ...

7. aacrjournals.org aacrjournals.org/mct/article/19/5/1091/92835/Pharmacologic-Inhibitor-of-DNA-PK-M3814

Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates ... M3814 potently inhibits DNA-PK catalytic activity and sensitizes multiple cancer cell lines to ionizing radiation (IR) and DSB-inducing agents.