L19TNF + Lomustine for Glioblastoma

(GLIOSTELLA Trial)

Recruiting at 7 trial locations

Overseen By Marco Taras

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Philogen S.p.A.

Must not be taking: Anticoagulants, Immunosuppressants

Disqualifiers: Autoimmune disease, Heart disease, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

Duration: 36 weeks

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for people with glioblastoma, a type of brain cancer that has returned or worsened. Researchers are testing L19TNF, an experimental treatment, and lomustine, a chemotherapy drug, to assess their safety and effectiveness together. The trial includes several groups, each receiving the treatments on a specific schedule. This trial might suit someone with glioblastoma confirmed through biopsy and whose disease has progressed again. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had anti-cancer treatments, certain investigational drugs, or specific medications like high-dose corticosteroids within a certain period before starting the trial. It's best to discuss your current medications with the trial team.

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

Research has shown that L19TNF, when combined with lomustine, has been studied for safety in patients with glioblastoma, a type of brain cancer. L19TNF is a special protein designed to target tumors, and studies have assessed its safety and optimal dosage. These studies generally found that the treatment is well-tolerated, meaning most people did not experience serious side effects.

Lomustine, approved by the FDA for treating various cancers, including brain tumors, works by damaging the DNA of cancer cells, stopping their growth. However, it can cause side effects like nausea and low blood cell counts, which require close monitoring.

Testing of the combination of these two treatments indicates it is reasonably safe. Participants should be aware of possible side effects and discuss any concerns with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about L19TNF combined with Lomustine for glioblastoma because it offers a novel approach to treatment. Unlike traditional chemotherapy, which generally targets rapidly dividing cells, L19TNF works by harnessing the body's immune system to attack the tumor, specifically targeting tumor blood vessels. This targeted action potentially leads to fewer side effects compared to standard treatments like Temozolomide. Additionally, the combination with Lomustine, an established chemotherapy, could enhance overall effectiveness, providing a new hope for patients with this aggressive brain cancer.

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

Research has shown that L19TNF, a special protein combining an antibody and a cytokine, has potential in early studies to slow tumor growth in various cancers, including glioma. This trial will explore the combination of L19TNF with lomustine, a known treatment for glioblastoma. Lomustine can improve outcomes such as overall survival and progression-free survival when used with other drugs like bevacizumab. However, lomustine alone may not be very effective, with progression-free survival typically ranging from 1 to 3 months. The trial aims to enhance these effects by combining L19TNF with lomustine, offering better results for patients with glioblastoma. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults over 18 with confirmed glioblastoma that has progressed or recurred. They must have a Karnofsky Performance Status of at least 60%, known MGMT promoter status, and no HIV, HBV, or HCV infections. Women must not be able to bear children or use effective contraception; men also need to agree to use contraception.

Inclusion Criteria

My glioblastoma diagnosis is confirmed and has progressed.

I know my cancer's MGMT promoter status.

My recent surgery confirmed glioblastoma recurrence, and I will have an MRI 3-5 weeks after, with treatment starting 4 weeks post-surgery.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive L19TNF and lomustine in a 42-day cycle for up to 6 cycles

36 weeks

6 cycles with multiple visits per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• L19TNF
• Lomustine

Trial Overview The study tests the combination of L19TNF and lomustine in various doses on patients with recurrent or progressing glioblastoma. It aims to assess safety, effectiveness, how the body processes the drugs (pharmacokinetics), and their impact on the disease (pharmacodynamics).

How Is the Trial Designed?

Group I: Arm F Experimental Treatment 2 Interventions

Patients will be treated with L19TNF on Days 1, 3 and 5, and on Days 22, 24 and 26 and Lomustine on Day 1 (in the evening after L19TNF infusion) of a 42-day cycle for up to a maximum of 6 cycles.

Group II: Arm E Experimental Treatment 2 Interventions

Patients will be treated with L19TNF on Days 1, 3 and 5, and on Days 22, 24 and 26 and Lomustine on Day 1 (in the evening after L19TNF infusion) of a 42-day cycle for up to a maximum of 6 cycles.

Group III: Arm D Experimental Treatment 2 Interventions

Patients will be treated with L19TNF on Days 1, 3 and 5, and on Days 22, 24 and 26 and Lomustine on Day 1 (in the evening after L19TNF infusion) of a 42-day cycle for up to a maximum of 6 cycles.

Group IV: Arm C Experimental Treatment 2 Interventions

Patients will be treated with L19TNF on Days 1, 3 and 5, and on Days 22, 24 and 26 and Lomustine on Day 1 (in the evening after L19TNF infusion) of a 42-day cycle for up to a maximum of 6 cycles.

Group V: Arm B Experimental Treatment 2 Interventions

Patients will be treated with on Days 1, 3 and 5, and on Days 22, 24 and 26 and Lomustine on Day 1 (in the evening after L19TNF infusion) of a 42-day cycle for up to a maximum of 6 cycles

Group VI: Arm A Experimental Treatment 2 Interventions

Patients will be treated with L19TNF on Days 1, 3 and 5, and on Days 22, 24 and 26 and Lomustine on Day 1 (in the evening after L19TNF infusion) of a 42-day cycle for up to a maximum of 6 cycles.

L19TNF is already approved in European Union for the following indications:

Approved in European Union as Onfekafusp alfa for:

• Soft tissue sarcoma

Who Is Running the Clinical Trial?

Philogen S.p.A.

Lead Sponsor

Trials

42

Recruited

2,400+

Published Research Related to This Trial

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]

A meta-analysis of four randomized controlled trials found that adjuvant lomustine does not significantly improve overall treatment outcomes, such as objective response, complete response, or overall survival, for patients with recurrent glioblastoma.

However, lomustine was associated with a statistically significant increase in 6-month progression-free survival, and it did not lead to a higher incidence of severe adverse events compared to control treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Efficacy and Safety of Adjuvant Lomustine to Chemotherapy for Recurrent Glioblastoma: A Meta-analysis of Randomized Controlled Studies. Fu, X., Shi, D., Feng, Y.[2022]

Lomustine, particularly when combined with procarbazine and vincristine in the PCV regimen, has shown improved survival in newly diagnosed glioblastoma patients with isocitrate dehydrogenase-mutant tumors, highlighting its efficacy in specific genetic contexts.

In recurrent glioblastoma, lomustine remains a standard treatment option, especially for patients with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation, although its use is often limited by hematological toxicity like thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How did lomustine become standard of care in recurrent glioblastoma? Weller, M., Le Rhun, E.[2020]

Fotemustine is an alkylating agent that has shown an objective response rate of 26% to 70% in treating recurrent malignant gliomas, with a reported median survival time of about 10 months.

Common side effects of fotemustine include myelosuppression, leucopenia, and thrombocytopenia, and it is currently used in Europe as a salvage therapy, often in combination with angiogenesis inhibitors like bevacizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fotemustine: a third-generation nitrosourea for the treatment of recurrent malignant gliomas. Beauchesne, P.[2021]

In a study of 28 patients treated for malignant brain tumors, 50% exhibited signs of restrictive lung disease (RLD), with a significant association found between spinal irradiation and the development of RLD.

Patients who received spinal irradiation were 4.3 times more likely to develop RLD compared to those who did not receive this treatment, highlighting spinal irradiation as a potential risk factor for lung complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Restrictive lung disease following treatment for malignant brain tumors: a potential late effect of craniospinal irradiation. Jakacki, RI., Schramm, CM., Donahue, BR., et al.[2017]

In the CeTeG/NOA-09 trial, the combination of lomustine and temozolomide (CCNU/TMZ) showed superior overall survival compared to temozolomide alone in patients with MGMT promoter-methylated glioblastoma, although progression-free survival rates were similar between the two treatments.

Analysis of MRI features at progression revealed that patients treated with CCNU/TMZ who had long postprogression survival exhibited a significant increase in mean ADC values, suggesting potential pseudoprogression, which may not have been detected by standard mRANO criteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Undetected pseudoprogressions in the CeTeG/NOA-09 trial: hints from postprogression survival and MRI analyses. Zeyen, T., Paech, D., Weller, J., et al.[2023]

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 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]

Fotemustine (FM) demonstrated promising efficacy in treating melanoma, including brain metastases, with an overall response rate of 12% in a multicenter phase II trial involving 144 patients, confirming earlier phase I and II studies with response rates around 40%.

The treatment was associated with manageable toxicity, primarily affecting blood cell production and causing gastrointestinal symptoms, with significant grade III or IV toxicities observed in 30% of patients for platelets and 25% for granulocytes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palliative therapy of melanoma patients with fotemustine. Inverse relationship between tumour load and treatment effectiveness. A multicentre phase II trial of the EORTC-Melanoma Cooperative Group (MCG). Kleeberg, UR., Engel, E., Israels, P., et al.[2019]

In a study of 166 brain tumor patients treated with CCNU, there was no significant overall change in lung function, but a notable decrease in vital capacity was observed in patients with prior lung diseases and smokers.

The results suggest that lung function monitoring during CCNU treatment should be focused on patients with existing pulmonary risk factors, while all patients should be monitored for clinical symptoms of lung issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lung toxicity of lomustine in the treatment of progressive gliomas. Seliger, C., Nürnberg, C., Wick, W., et al.[2022]

Citations

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NCT04573192 | A Study to Evaluate Safety and Efficacy of ... Preclinical experiments with L19TNF have demonstrated tumor growth retardation in various mouse tumor models including models of glioma. Official Title. A Study ...

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Philogen Publishes New Data on a Fibromun-based ... The product is currently investigated in multiple clinical trials for the treatment of soft tissue sarcoma and glioblastoma, both in Europe and ...

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NCT04443010 | Safety and Efficacy of L19TNF Plus ... The purpose of this study is to explore the safety profile and establish a recommended dose (RD) for phase II of the antibody-cytokine fusion protein L19TNF ...

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Targeted delivery of tumor necrosis factor in combination ... We investigated combination therapies based on L19TNF, an antibody-cytokine fusion protein based on tumor necrosis factor that selectively localizes to cancer ...

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A Study With L19TNF in Combination With Lomustine ... For operated patients, the histological report must document glioblastoma recurrence and a new MRI will need to be done at 3-5 weeks after surgery (directly ...