Debio 0123 + Temozolomide for Glioblastoma

Recruiting at 15 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

Trial Summary

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.

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

Research shows that Temozolomide, when used with radiotherapy, improves survival in patients with glioblastoma, making it a standard treatment. It has been effective in treating various brain tumors and is known to work well when certain genetic markers are present. ^{1 2 3 4 5}

Is the combination of Debio 0123 and Temozolomide safe for humans?

Temozolomide, often used with radiation therapy for brain tumors like glioblastoma, is generally considered safe but can cause blood-related side effects such as myelosuppression (a decrease in bone marrow activity), which can be severe in some cases. Other common side effects include fatigue, nausea, and vomiting. There is no specific safety data available for Debio 0123 in combination with Temozolomide. ^{1 6 7 8 9}

What makes the Debio 0123 + Temozolomide treatment for glioblastoma unique?

The Debio 0123 + Temozolomide treatment is unique because it combines a new drug, Debio 0123, with the standard treatment of Temozolomide and radiotherapy, potentially enhancing the effectiveness of the existing regimen by targeting different pathways in cancer cells. ^{3 4 5 10 11}

What is the purpose of this trial?

This trial is testing a new drug called Debio 0123 combined with standard treatments for adults with aggressive brain cancer. It aims to find the best dose, ensure safety, and check if it works better than current treatments.

Research Team

Study Director

Principal Investigator

Debiopharm International SA

Eligibility Criteria

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.

I am willing to provide a tumor sample if I have one.

Exclusion Criteria

Patient is living outside the US

I have been frequently exposed to a lot of sunlight.

I have never been treated with a WEE1 inhibitor.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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 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 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]

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 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]

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 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]

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]

References

1. Japan pubmed.ncbi.nlm.nih.gov

[Temozolomide: Temodal]. [2018]

2. England pubmed.ncbi.nlm.nih.gov

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

3. Germany pubmed.ncbi.nlm.nih.gov

Temozolomide during radiotherapy of glioblastoma multiforme : Daily administration improves survival. [2018]

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

Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma. [2022]

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

Age, Neurological Status MRC Scale, and Postoperative Morbidity are Prognostic Factors in Patients with Glioblastoma Treated by Chemoradiotherapy. [2020]

6. Germany 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. [2018]

7. Germany pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal&#174;) in glioma patients in China. [2021]

8. United States 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. [2018]

9. England pubmed.ncbi.nlm.nih.gov

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

10. Italy 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. [2018]

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

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