NMS-03305293 + Temozolomide for Glioblastoma

Recruiting at 17 trial locations

Overseen By Domenico Roberti

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Nerviano Medical Sciences

Must not be taking: Anticancer agents, PARP inhibitors

Disqualifiers: Active infections, Heart failure, others

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

Compensation: Varies

Number of Visits: 2

150 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Multicenter, open-label, single-arm Phase 1/2 study on the safety and efficacy of the combination of NMS-03305293 and temozolomide (TMZ) in adult patients with diffuse gliomas (Phase 1) and isocitrate dehydrogenase (IDH) wild type glioblastoma (Phase 2) at first relapse.

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

The trial protocol does not specify if you need to stop all current medications, but it does mention that you cannot be on certain treatments like enzyme-inducing anti-epileptic drugs and some medications that affect specific liver enzymes. You should discuss your current medications with the trial team to see if any adjustments are needed.

Is the combination of NMS-03305293 and Temozolomide safe for treating glioblastoma?

The combination of Temozolomide and Lomustine (also known as CCNU) has been studied for safety in treating glioblastoma. It is generally well tolerated, though it can cause hematotoxicity (blood-related side effects) and is more frequent with Lomustine than Temozolomide. No severe infections or bleeding were observed in one study, suggesting it is a relatively safe treatment option. ^{1 2 3 4 5}

What makes the drug combination of NMS-03305293, Temozolomide, and Lomustine unique for treating glioblastoma?

This drug combination is unique because it combines Temozolomide and Lomustine, which have shown therapeutic synergy (working better together) in treating glioblastoma, with NMS-03305293, potentially enhancing effectiveness. The combination is administered orally, which is less invasive than some other treatments, and has been shown to be generally well tolerated with a safe dosage schedule. ^{1 2 3 5 6}

What data supports the effectiveness of the drug combination NMS-03305293 + Temozolomide for Glioblastoma?

Research shows that the combination of temozolomide and lomustine (a type of nitrosourea) has been effective in treating glioblastoma, with studies indicating improved survival rates when used together with radiotherapy. Additionally, the combination has shown therapeutic synergy, meaning they work better together than alone, in treating high-grade malignant gliomas. ^{1 2 3 5 7}

Are You a Good Fit for This Trial?

Adults with a specific brain tumor called IDH wild type glioblastoma at first relapse can join this trial. They must have confirmed diagnosis, possibly after surgery, and meet certain lab value criteria. Participants need to be able to swallow capsules, use effective contraception or practice abstinence, and commit to the study schedule.

Inclusion Criteria

I had surgery for cancer recurrence and meet the post-surgery requirements.

I am experiencing my first relapse after initial treatment that included temozolomide.

Phase 1 and Phase 2: Additional criteria including life expectancy, ability to undergo brain MRI scans, absence of intratumoral hemorrhage, availability of tissue for evaluation, age, performance status, informed consent, resolution of prior therapy effects, baseline laboratory values, contraception requirements, ability to swallow capsules intact, willingness to comply with study procedures

Exclusion Criteria

I had standard radiotherapy within the last 3 months before my condition worsened.

Pregnancy or breastfeeding

Current enrollment in another interventional clinical trial

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Participants receive NMS-03305293 and temozolomide (TMZ) to determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Doses (RP2Ds).

4-week cycles

Cycle 1: Days 1, 2, 5, 6, 8; Cycle 2: Days 5, 15

Phase 2 Treatment

Participants receive TMZ daily on days 1-5 in combination with NMS-03305293 at the RP2D on days 1-7 or on days 1-28 every 28 days.

4-week cycles

Cycle 1: Days 1, 5; Cycle 2: Day 5; Cycle 3 or 4: Day 5

Follow-up

Participants are monitored for safety and effectiveness after treatment.

18 months

What Are the Treatments Tested in This Trial?

Interventions

• Lomustine
• NMS-03305293 + TMZ

Trial Overview The trial is testing the safety and effectiveness of combining NMS-03305293 with Temozolomide (TMZ) in treating recurrent glioblastoma. It's an open-label study where all participants receive the same treatment without a comparison group.

How Is the Trial Designed?

Group I: NMS-03305293 +TMZ Experimental Treatment 2 Interventions

Phase 1 Dose Escalation: All patients will receive NMS-03305293 and temozolomide (TMZ) administered orally (NMS-03305293 once or twice daily on days 1-7 or 28 consecutive days from Day 1 to Day 28; TMZ once daily on days 1-5;) in repeated 4-week cycles aimed at defining the Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Doses (RP2Ds) of NMS-03305293 in combination with TMZ. Each cycle is 28 days. Phase 2: Once the RP2D is defined, the patients will receive TMZ daily on days 1-5 in combination with NMS-03305293 at the RP2D on days 1-7 or on days 1-28 every 28 days. Backfill cohorts: additional patients may be treated with TMZ daily on days 1-5 and NMS-03305293 at different dose levels/schedules that have been previously assessed and determined to be safe, in order to properly characterize the exposure relationship over a range of doses/schedules. The backfill cohorts may run in parallel.

Lomustine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Gleostine for:

• Brain tumors
• Hodgkin's disease

Approved in European Union as Gleostine for:

• High-grade gliomas
• Hodgkin's lymphoma

Approved in Canada as Gleostine for:

• Brain tumors
• Breast cancer
• Lung cancer
• Hodgkin's lymphoma
• Melanoma

Who Is Running the Clinical Trial?

Nerviano Medical Sciences

Lead Sponsor

Trials

14

Recruited

770+

Published Research Related to This Trial

In a study involving 97 patients with malignant gliomas, temozolomide (TMZ) demonstrated a significantly higher response rate (35.71%) compared to lomustine (CCNU) (9.09%), indicating its greater efficacy in treating these aggressive brain tumors.

TMZ was found to have an acceptable safety profile, with common side effects being mild nausea and vomiting, suggesting it could be a preferred chemotherapy option for patients with refractory malignant brain gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A multicenter randomized controlled study of temozolomide in 97 patients with malignant brain glioma]. Qian, ZZ., Wang, HQ., Liu, XM., et al.[2018]

In a study of 39 patients with newly diagnosed glioblastoma, the combination of radiotherapy and chemotherapy (lomustine and temozolomide) resulted in a median overall survival of 23.1 months, with 47.4% of patients surviving for 2 years and 18.5% for 4 years.

Patients receiving an intensified dose of chemotherapy showed significantly higher survival rates compared to those on standard doses, with some patients in the intensified group surviving over 56 months, although this came with a higher risk of severe hematotoxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide. Glas, M., Happold, C., Rieger, J., et al.[2022]

In a phase III trial, the combination therapy of temozolomide (TMZ) and lomustine (CCNU) resulted in higher rates of high-grade hematotoxicity (36.4%) compared to TMZ alone (28.6%), indicating a trade-off between efficacy and safety in treating newly diagnosed glioblastoma.

Despite the increased hematotoxicity with CCNU/TMZ, this adverse effect did not correlate with shorter survival rates, suggesting that while monitoring for hematotoxicity is important, it may not impact overall patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial. Weller, J., Schäfer, N., Schaub, C., et al.[2023]

A phase I study involving 10 patients with high-grade malignant glioma demonstrated that the combination of low-dose Temozolomide (TMZ) and Lomustine (CCNU) was generally well tolerated, with no severe side effects like bleeding or infections commonly seen in other chemotherapy combinations.

The treatment regimen, consisting of TMZ at 75 mg/m2 daily for 21 days and CCNU at 100 mg/m2 on day 1 every 6 weeks, showed promising results with one patient achieving a partial response and nine maintaining stable disease for a median duration of 5 to 6 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of temozolomide and lomustine in the treatment of high grade malignant glioma. Tafuto, S., Muto, P., Tortoriello, A., et al.[2019]

Nitrosoureas, such as lomustine, carmustine, and fotemustine, are among the most effective treatments for high-grade gliomas and glioblastoma, highlighting their importance in cancer therapy.

Due to their toxicity and the introduction of temozolomide, nitrosoureas are now primarily used for recurrent cases of gliomas, indicating a shift in their clinical application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrosoureas in the Management of Malignant Gliomas. Brandes, AA., Bartolotti, M., Tosoni, A., et al.[2018]

In a study involving 74 patients with recurrent high-grade glioma, the combination of temozolomide (TMZ) or lomustine (CCNU) with 6-thioguanine, capecitabine, and celecoxib showed a 6-month progression-free survival (PFS) of 14% for glioblastoma patients and a promising 44% PFS for anaplastic glioma patients.

While the treatment was generally well tolerated, hematological toxicity was more common with CCNU compared to TMZ, indicating a need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of 6-thioguanine, capecitabine, and celecoxib with temozolomide or lomustine for recurrent high-grade glioma. Walbert, T., Gilbert, MR., Groves, MD., et al.[2022]

The combination of Tumour Treating Fields (TTFields) with lomustine and temozolomide in patients with MGMT promoter methylated newly diagnosed glioblastoma showed a median progression-free survival of 20 months, indicating promising efficacy.

Safety analysis revealed that while some patients experienced significant adverse events, including hematologic and hepatotoxic effects, the treatment was generally well-tolerated with a high adherence rate of 83%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumour Treating Fields (TTFields) in combination with lomustine and temozolomide in patients with newly diagnosed glioblastoma. Lazaridis, L., Schäfer, N., Teuber-Hanselmann, S., et al.[2020]

Citations

1. China pubmed.ncbi.nlm.nih.gov

[A multicenter randomized controlled study of temozolomide in 97 patients with malignant brain glioma]. [2018]

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

Long-term survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide. [2022]

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

Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial. [2023]

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

Phase I study of temozolomide and lomustine in the treatment of high grade malignant glioma. [2019]

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

Nitrosoureas in the Management of Malignant Gliomas. [2018]

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

Combination of 6-thioguanine, capecitabine, and celecoxib with temozolomide or lomustine for recurrent high-grade glioma. [2022]

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

Tumour Treating Fields (TTFields) in combination with lomustine and temozolomide in patients with newly diagnosed glioblastoma. [2020]