Vorasidenib + Temozolomide for Brain Tumors

Recruiting at 28 trial locations

Overseen By Institut de Recherches Internationales Servier (I.R.I.S.) Clinical Studies Department

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Institut de Recherches Internationales Servier

Must be taking: Temozolomide

Must not be taking: IDH inhibitors, Bevacizumab

Disqualifiers: Pregnancy, Leptomeningeal disease, Hepatitis, others

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

Compensation: Varies

Number of Visits: 3

42 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for certain brain tumors, specifically gliomas with IDH1 or IDH2 mutations. Researchers are testing the safety and effectiveness of combining two drugs, vorasidenib (a potential new drug) and temozolomide (a chemotherapy drug), to determine the best dose and assess their combined efficacy. Participants who may qualify have documented IDH mutations and a previous diagnosis of certain glioma grades, such as astrocytoma or oligodendroglioma. Joining this trial involves attending regular check-ups, including health assessments like blood tests and questionnaires. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this potential new drug.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on corticosteroids for glioma, you must be on a stable or decreasing dose before starting the study treatment.

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

Research has shown that vorasidenib, when combined with temozolomide (TMZ), is generally safe. In studies, vorasidenib was tested in patients with glioma, a type of brain tumor, and was mostly well-tolerated. However, some patients experienced higher liver enzyme levels at larger doses, making liver health monitoring important.

Temozolomide is commonly used to treat brain tumors and is usually safe, but it can sometimes lower blood cell counts, increasing the risk of infection.

Together, these treatments appear safe for most people, with manageable side effects. The ongoing study aims to determine the optimal dose for this combination to minimize side effects while maintaining effectiveness. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Vorasidenib combined with Temozolomide for brain tumors because it targets cancer cells in a new way. Most treatments for brain tumors focus on killing rapidly dividing cells, but Vorasidenib is designed to specifically inhibit the IDH1 and IDH2 mutations often found in these tumors. This targeted approach means it could be more effective while potentially causing fewer side effects. Additionally, using it together with Temozolomide, a standard chemotherapy drug, could enhance the overall treatment effectiveness, offering new hope for patients.

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

Research shows that vorasidenib, when used alone, positively affects patients with certain brain tumors called IDH-mutant gliomas. In these patients, vorasidenib has been proven to delay cancer progression. Temozolomide (TMZ) is a chemotherapy drug already used to treat brain tumors. In this trial, participants will receive a combination of vorasidenib and TMZ, aiming to enhance the benefits, as vorasidenib blocks the activity of abnormal proteins that can promote tumor growth. Early studies suggest that this combination could more effectively control the growth of these tumors. ^{1 2 5 6 7}

Are You a Good Fit for This Trial?

This trial is for individuals aged 12 and older, weighing at least 40 kg, with IDH-mutant glioma. They must have adequate kidney function, stable blood counts, a life expectancy of over three months, and be on a low or decreasing dose of corticosteroids if they're taking them for glioma. Women who can bear children need to test negative for pregnancy.

Inclusion Criteria

My cancer has an IDH1 or IDH2 mutation.

My hemoglobin level is at least 9 g/dL.

I am expected to live for at least 3 more months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1b Treatment

Participants receive vorasidenib in combination with temozolomide to determine the recommended combination dose (RCD)

Varies by cycle

Visits on day 1 and 22 of each cycle, with additional visits during the first cycle

Phase 2 Treatment

Participants receive vorasidenib at the RCD in combination with temozolomide to assess clinical efficacy

Varies by cycle

Visits on day 1 and 22 of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 30 days after treatment ends, followed by survival follow-up every 3 months

1 safety follow-up visit, then survival follow-up every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Temozolomide
• Vorasidenib

Trial Overview The study aims to find the safest dose combination of vorasidenib with temozolomide (TMZ) and then assess its effectiveness in treating brain tumors with IDH mutations. It starts as Phase Ib to determine the right doses and moves into Phase II for efficacy evaluation.

How Is the Trial Designed?

Group I: Phase 2: Vorasidenib recommended combination dose (RCD) and Temozolomide (TMZ) Experimental Treatment 2 Interventions

Group II: Phase 1b: Vorasidenib and Temozolomide (TMZ) Experimental Treatment 2 Interventions

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?

Institut de Recherches Internationales Servier

Lead Sponsor

Trials

91

Recruited

67,100+

Published Research Related to This Trial

The maximum tolerated dose (MTD) of vorinostat when combined with temozolomide (TMZ) was determined to be 500 mg daily in the first part of the study, with dose-limiting toxicities including severe anorexia and thrombocytopenia.

Vorinostat was found to be well tolerated in patients with high-grade glioma, showing no significant pharmacokinetic interactions with TMZ, and it effectively caused hyperacetylation of histones, indicating its mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of vorinostat in combination with temozolomide in patients with high-grade gliomas: North American Brain Tumor Consortium Study 04-03. Lee, EQ., Puduvalli, VK., Reid, JM., et al.[2021]

In a phase II trial involving 38 patients with recurrent oligodendroglial tumors, temozolomide (TMZ) demonstrated a high response rate, with 52.6% of patients showing a complete or partial response, indicating its efficacy as a first-line chemotherapy.

TMZ was generally well tolerated, with hematologic side effects being the most common, and only one patient discontinuing treatment due to toxicity, suggesting a favorable safety profile for chemotherapy-naive patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. van den Bent, MJ., Taphoorn, MJ., Brandes, AA., et al.[2022]

The TMZ-resistant glioma cell line SF188/TR showed a 6-fold resistance to temozolomide and cross-resistance to various other anticancer agents, indicating a significant challenge in treating resistant tumors.

Increased activity of the enzyme alkylguanine alkyltransferase (AGT) was identified as a primary mechanism of resistance to TMZ, while changes in the balance of pro-apoptotic and anti-apoptotic proteins contributed to broader cross-resistance to other drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. Ma, J., Murphy, M., O'Dwyer, PJ., et al.[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]

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]

In a phase 2 clinical trial involving 27 patients with brain metastases from breast cancer and non-small cell lung cancer, a new regimen combining whole-brain radiotherapy (WBRT) with a prolonged low-dose temozolomide (TMZ) treatment showed promising antitumor activity, achieving a 7.4% complete response and a 40.7% partial response.

The treatment was well tolerated, with only 2 patients experiencing grade 3 toxicity, and resulted in a median overall survival of 8.8 months and a median progression-free survival of 6 months, indicating its potential as a viable option for treating brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 trial of temozolomide using protracted low-dose and whole-brain radiotherapy for nonsmall cell lung cancer and breast cancer patients with brain metastases. Addeo, R., De Rosa, C., Faiola, V., et al.[2022]

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 phase II trial involving 32 patients with recurrent oligodendroglial tumors, temozolomide (TMZ) demonstrated a 25% objective response rate, indicating its potential as an effective second-line treatment after PCV chemotherapy.

TMZ was generally well tolerated, with hematological side effects being the most common, and a median time to progression of 8 months for those who responded, suggesting it could be a viable option for patients who do not respond to initial treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972. van den Bent, MJ., Chinot, O., Boogerd, W., et al.[2020]

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 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]

Citations

1. trials.braintumor.org trials.braintumor.org/trials/NCT06478212

Vorasidenib in Combination With Temozolomide (TMZ) in IDH ... The objective of this study is to determine the safety and tolerability of vorasidenib in combination with temozolomide (TMZ) and to establish the recommended ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06478212

Vorasidenib in Combination With Temozolomide (TMZ) ... The objective of this study is to determine the safety and tolerability of vorasidenib in combination with temozolomide (TMZ) and to establish the ...

3. clinicaltrials.eu clinicaltrials.eu/trial/study-on-the-safety-and-effectiveness-of-vorasidenib-and-temozolomide-for-patients-with-idh1-or-idh2-mutant-glioma/

Study on the Safety and Effectiveness of Vorasidenib ... This study investigates the safety and efficacy of combining vorasidenib and temozolomide in treating patients with IDH1 or IDH2 mutant glioma, a type of ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2304194

Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention.

5. clinicaltrials.servier.com clinicaltrials.servier.com/trial/NCT06478212/vorasidenib-in-combination-with-temozolomide-tmz-in-idh-mutant-glioma

Vorasidenib in Combination With Temozolomide (TMZ) ... Vorasidenib is a drug that blocks the activity of abnormal IDH1 and IDH2 proteins and thus may reduce 2-HG levels in cancer cells. Vorasidenib is approved in ...

6. uclahealth.org uclahealth.org/clinical-trials/vorasidenib-combination-with-temozolomide-tmz-idh-mutant

Vorasidenib in Combination With Temozolomide (TMZ) ... The objective of this study is to determine the safety and tolerability of vorasidenib in combination with temozolomide (TMZ) and to establish the recommended ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8364866/

Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or ... Results: Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg ...