Vorasidenib + Temozolomide for Brain Tumors

Recruiting at 31 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

Trial Summary

What is the purpose of this trial?

The objective of this study is to determine the safety and tolerability of vorasidenib in combination with temozolomide (TMZ) and to establish the recommended combination dose (RCD) of vorasidenib. The study will begin as a Phase Ib study to determine the RCD and then will transition to a Phase II study to assess the clinical efficacy of vorasidenib at the RCD in combination with TMZ. During the treatment period participants will have study visits on day 1 and 22 of each cycle, with additional visits occurring during the first cycle of the Phase 1b study. Approximately 30 days after treatment has ended, a safety follow-up visit will occur and then participants will be followed for survival every 3 months. Study visits may include questionnaires, blood tests, ECG, vital signs, and a physical examination.

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.

What data supports the effectiveness of the drug Vorasidenib + Temozolomide for brain tumors?

Temozolomide has shown effectiveness in treating various brain tumors, including gliomas and brain metastases, and has demonstrated high response rates in patients with recurrent anaplastic astrocytoma. It is also being evaluated in combination with other agents for its potential to treat a variety of cancers. ^{1 2 3 4 5}

Is the combination of Vorasidenib and Temozolomide safe for treating brain tumors?

Temozolomide is generally well tolerated and safe, with common side effects like fatigue, nausea, and vomiting. However, it can cause serious blood-related issues like myelodysplastic syndrome and aplastic anemia, though these are rare. Vorasidenib's safety in combination with Temozolomide is still being studied. ^{3 6 7 8 9}

What makes the drug Vorasidenib + Temozolomide unique for treating brain tumors?

The combination of Vorasidenib and Temozolomide is unique because Vorasidenib targets specific genetic mutations in brain tumors, potentially enhancing the effectiveness of Temozolomide, which is already used to treat various gliomas. This combination aims to improve outcomes by addressing tumor resistance and targeting specific tumor biology. ^{1 3 6 7 10}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. [2022]

2. United States 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. [2022]

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

Future directions for temozolomide therapy. [2019]

4. United States 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. [2022]

5. England 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. [2020]

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

Phase II trial of temozolomide in patients with progressive low-grade glioma. [2022]

7. United States 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. [2021]

8. England pubmed.ncbi.nlm.nih.gov

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

9. Switzerland pubmed.ncbi.nlm.nih.gov

Temozolomide-related hematologic toxicity. [2018]

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

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series. [2023]