Debio 0123 + Temozolomide for Glioblastoma

Recruiting at 18 trial locations

Overseen By Debiopharm International S.A

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Debiopharm International SA

Must be taking: Anti-epileptic drugs

Must not be taking: Monoclonal antibodies, Biologics

Disqualifiers: Other malignancies, LVEF below 55%, others

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

Compensation: Varies

Number of Visits: 84

116 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dosage and assess the safety of a new drug, Debio 0123, when combined with the chemotherapy drug temozolomide (TMZ) and sometimes with radiation therapy. The study targets glioblastoma (GBM), a fast-growing brain tumor, and will compare the effectiveness of the new treatment against the current standard treatment. Individuals whose GBM has returned or worsened after standard treatment might be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding the treatment's effects in people, offering participants the chance to be among the first to receive this new treatment.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, participants with seizures must have their condition controlled on a stable regimen of anti-epileptic drugs, and those on corticosteroids must be on a stable or decreasing dose. It's best to discuss your specific medications with the trial team.

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

Research has shown that Debio 0123, when combined with temozolomide, is generally safe for most patients at certain doses, meaning serious side effects were uncommon at these levels. However, combining Debio 0123 with both temozolomide and radiotherapy led to safety issues for some participants, causing one part of the study to stop due to safety concerns.

In summary, using Debio 0123 with only temozolomide has proven relatively safe, but adding radiotherapy increased the risks. Potential participants should consider these findings when deciding to join a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Debio 0123 in combination with temozolomide for glioblastoma because it offers a novel approach compared to standard treatments like surgery, radiation, and chemotherapy with temozolomide alone. Debio 0123 is designed to enhance the effectiveness of temozolomide by potentially making cancer cells more sensitive to treatment. This combination could improve outcomes by targeting the cancer more precisely and effectively. Moreover, the addition of radiotherapy in some treatment arms might work synergistically with Debio 0123 and temozolomide, providing a multifaceted attack on the tumor. This innovative approach holds promise for improving patient survival and quality of life.

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

Research has shown that Debio 0123 could be a promising treatment for glioblastoma, a type of brain cancer. In animal studies, Debio 0123 effectively worked with temozolomide, a common chemotherapy drug, to shrink tumors. Participants in this trial will receive Debio 0123 combined with temozolomide, with some also receiving radiotherapy. Debio 0123 is a selective WEE1 inhibitor, targeting a specific protein that helps cancer cells survive. Lab tests demonstrated that using Debio 0123 with radiation increased cancer cell death, enhancing the treatment's effectiveness. These early results suggest that Debio 0123 might improve current treatments for glioblastoma. ^{1 2 6 7 8}

Who Is on the Research Team?

Study Director

Principal Investigator

Debiopharm International SA

Are You a Good Fit for This Trial?

Adults with recurrent or newly diagnosed glioblastoma who've had limited prior treatments can join this trial. They must have a performance status indicating they're mostly independent, stable minor symptoms like seizures, and their major organs should be functioning well. Participants need to commit to the study schedule and agree to use effective birth control.

Inclusion Criteria

My seizures are under control with stable medication.

I am mostly able to take care of myself.

Signed written informed consent approved before undertaking any study-specific procedures

Exclusion Criteria

I have never been treated with a WEE1 inhibitor.

Patient is living outside the US

I have been frequently exposed to a lot of sunlight.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Dose Escalation

Participants receive Debio 0123 with temozolomide, with dose escalation to identify dose-limiting toxicities and characterize safety

Up to 2 years

Multiple visits per 28-day cycle

Phase 1 Dose Expansion

Participants receive Debio 0123 with temozolomide at selected doses for further investigation

Up to 2 years

Multiple visits per 28-day cycle

Phase 2

Participants receive Debio 0123 at the recommended dose with temozolomide to assess efficacy compared to standard of care

Up to 2 years

Multiple visits per 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 66 months

What Are the Treatments Tested in This Trial?

Interventions

• Debio 0123
• Radiotherapy
• Temozolomide

Trial Overview

The trial is testing Debio 0123 in combination with Temozolomide (TMZ), both alone and alongside radiotherapy for glioblastoma patients. Phase 1 determines the safest dose while Phase 2 compares its effectiveness against standard care.

How Is the Trial Designed?

Group I: Phase 2: Debio 0123 RD + Temozolomide Experimental Treatment 2 Interventions

Participants will receive intermittent Debio 0123 RD along with TMZ in each 28-day cycle for up to 2 years.

Group II: Phase 1 (Dose Expansion): Debio 0123 + Temozolomide Experimental Treatment 2 Interventions

Participants will receive Debio 0123, escalating doses along with temozolomide (TMZ) in each 28-day cycle for up to 2 years. Participants will receive one of the 2 selected doses for further investigation.

Group III: Phase 1 (Dose Escalation): Arm C - Debio 0123 + Temozolomide + Radiotherapy Experimental Treatment 3 Interventions

Participants will receive intermittent Debio 0123, escalating doses along with TMZ and concomitant administration of radiotherapy (RT) for up to 6 weeks.

Group IV: Phase 1 (Dose Escalation): Arm B - Debio 0123 + Temozolomide + Radiotherapy Experimental Treatment 3 Interventions

Participants will receive intermittent Debio 0123, escalating doses along with TMZ and concomitant administration of radiotherapy (RT) for up to 6 weeks. As per Protocol \_V4.0 Arm B has been permanently halted.

Group V: Phase 1 (Dose Escalation): Arm A - Debio 0123 + Temozolomide Experimental Treatment 2 Interventions

Participants will receive intermittent Debio 0123, escalating doses along with temozolomide (TMZ) in each 28-day cycle for up to 2 years.

Who Is Running the Clinical Trial?

Debiopharm International SA

Lead Sponsor

Trials

53

Recruited

7,300+

Published Research Related to This Trial

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 432 glioblastoma patients, those receiving daily temozolomide (TMZ) during radiotherapy (7 days a week) had a median survival of 15.7 months, significantly longer than those receiving TMZ only on radiotherapy days (12.6 months) or no TMZ (9.1 months).

The analysis indicated that continuous TMZ administration not only improved survival rates but also showed a significant influence on hazard rates, confirming that while even a reduced TMZ schedule can extend survival, daily administration is more effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide during radiotherapy of glioblastoma multiforme : Daily administration improves survival. Nachbichler, SB., Schupp, G., Ballhausen, H., 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]

In a study of 103 glioblastoma patients treated with standard temozolomide and radiotherapy, the median overall survival was found to be 13.7 months, highlighting the effectiveness of this treatment regimen.

Three key prognostic factors were identified that negatively impacted overall survival: age over 65 years, a Medical Research Council (MRC) scale score of 3-4, and the occurrence of postoperative complications, suggesting that these factors can help predict patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Age, Neurological Status MRC Scale, and Postoperative Morbidity are Prognostic Factors in Patients with Glioblastoma Treated by Chemoradiotherapy. Verlut, C., Mouillet, G., Magnin, E., et al.[2020]

In an in vitro study of glioblastoma multiforme (GBM) cells, the TMZ-resistant subline (U251/TMZ-R) showed increased resistance to temozolomide (TMZ) but was more sensitive to the chemotherapy drug CCNU, suggesting CCNU could be a better treatment option for resistant cases.

The study found that the effectiveness of radiotherapy remained intact in TMZ-resistant GBM cells, and combining CCNU with TMZ overcame resistance, indicating a potential strategy for treating recurrent GBM and preventing resistance development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acquired temozolomide resistance in human glioblastoma cell line U251 is caused by mismatch repair deficiency and can be overcome by lomustine. Stritzelberger, J., Distel, L., Buslei, R., 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 study of 87 newly diagnosed glioblastoma patients, only 5% experienced severe myelotoxicity during treatment with temozolomide (TMZ) and radiation therapy, indicating that while the risk exists, it is relatively low.

Factors such as female sex, low pretreatment platelet counts, and specific genetic markers were identified as potential predictors of severe myelotoxicity, suggesting that personalized treatment approaches could help mitigate risks in vulnerable patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and Genetic Factors Associated With Severe Hematological Toxicity in Glioblastoma Patients During Radiation Plus Temozolomide Treatment: A Prospective Study. Lombardi, G., Rumiato, E., Bertorelle, R., et al.[2018]

The study confirmed that the generic temozolomide capsules (TOZ039) are bioequivalent to the brand Temodal® capsules, with pharmacokinetic parameters falling within the acceptable range for both 20-mg and 100-mg doses in 29 patients with brain tumors.

The treatment was found to be safe, with no treatment-related severe adverse events or mortality reported, although 82.8% of patients experienced some adverse effects, highlighting the importance of monitoring patient responses during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal&#174;) in glioma patients in China. Hu, C., Lin, Q., Liu, C., et al.[2021]

In a study of 51 patients with newly diagnosed glioblastoma, concurrent treatment with temozolomide (TMZ) and radiotherapy was found to be the new standard of care.

The occurrence of early necrosis in 14% of patients, without signs of tumor recurrence, suggests that TMZ may enhance the effectiveness of radiotherapy by acting as a radiosensitizer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma. Chamberlain, MC., Glantz, MJ., Chalmers, L., et al.[2022]

In a study of 31 patients with melanoma that had spread to the brain, the combination of whole brain irradiation (WBI) and temozolomide (TMZ) showed limited antitumor activity, with only one complete response lasting 4.5 months and two partial responses lasting 2 and 7 months.

While the treatment was generally safe, with only a few instances of significant toxicity, the median survival was only 6 months, indicating that WBI combined with TMZ may not be effective for improving outcomes in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group. Margolin, K., Atkins, B., Thompson, A., et al.[2018]

Temozolomide (TMZ) is the only anticancer drug proven to improve survival in glioblastoma when used with radiotherapy, showing high concentrations in brain tumors and cerebrospinal fluid, which enhances its effectiveness.

Molecular markers like MGMT promoter methylation can predict better responses to TMZ treatment, but side effects such as myelosuppression and nausea are common, necessitating precautions like prophylaxis against Pneumocystis carinii pneumonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Temozolomide: Temodal]. Shinoura, N., Yamada, R., Tabei, Y., et al.[2018]

Citations

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In efficacy studies, Debio 0123 administered at 30 or 60mg/kg every day for 28 days displayed significant anti-tumor activity in a GBM xenograft ...

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debio 0123 is a selective wee1 inhibitor that effectively ...

Glioblastoma (GBM) is one of the most aggressive and hard-to- treat cancers with a 5-year survival rate of 6.8%, in part due to the presence of the blood brain.

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A Study of Debio 0123 in Combination With Temozolomide ...

This study is to identify the dose-limiting toxicities (DLTs) of Debio 0123 combined with temozolomide (TMZ) (Arm A) and with TMZ and radiotherapy (RT) (Arms B ...

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debiopharm.com/wp-content/uploads/2023/06/Debio-0123_ASCO2023_poster_Final.pdf

Debio 0123-101, A PHASE 1 TRIAL OF ...

Debio 0123, in combination with CP, is well tolerated up to 520 mg and demonstrates a manageable safety profile like that for CP monotherapy.

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Preclinically, Debio 0123 has been shown to effectively penetrate the brain and demonstrated improved response to radiotherapy (RT) in vitro and ...

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A study on the use of Debio 0123 in combination ...

The main goal of Phase II is to determine the efficacy of the combination of Debio 0123 and TMZ in the treatment of GBM in a group of participants, the “trial ...