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

Trial Summary

What is the purpose of this trial?

The trial aims to collect safety, efficacy, exposure, dose- response, pharmacokinetic and pharmacodynamic information of the combination of L19TNF and lomustine at different dose levels in patients with Glioblastoma at progression or recurrence

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.

What data supports the effectiveness of the drug L19TNF + Lomustine for Glioblastoma?

Research shows that lomustine, a component of the treatment, is effective in treating high-grade gliomas and glioblastoma, especially when combined with other drugs like temozolomide, as it improved overall survival in certain trials. However, the effectiveness of L19TNF specifically for glioblastoma is not directly addressed in the available research. ^{1 2 3 4 5}

Is the combination of L19TNF and Lomustine safe for humans?

Lomustine, a part of the treatment, can cause lung issues like pulmonary fibrosis (scarring of lung tissue) and hematotoxicity (blood-related side effects). These side effects have been observed in treatments for brain tumors, indicating potential safety concerns. ^{4 5 6 7 8}

What makes the drug L19TNF + Lomustine unique for treating glioblastoma?

The combination of L19TNF and Lomustine is unique because it pairs a targeted therapy (L19TNF) with a chemotherapy agent (Lomustine), potentially enhancing the treatment's effectiveness against glioblastoma by targeting tumor blood vessels and cancer cells simultaneously. This approach differs from standard treatments that typically involve surgery, radiation, and temozolomide chemotherapy. ^{1 4 5 9 10}

Eligibility Criteria

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.

I am 18 years old or older.

Timeline

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

Treatment Details

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).

Participant Groups

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+

Findings from Research

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 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]

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 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 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]

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 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 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]

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 (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]

References

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

Nitrosoureas in the Management of Malignant Gliomas. [2018]

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

Undetected pseudoprogressions in the CeTeG/NOA-09 trial: hints from postprogression survival and MRI analyses. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

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

4. 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]

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

The Efficacy and Safety of Adjuvant Lomustine to Chemotherapy for Recurrent Glioblastoma: A Meta-analysis of Randomized Controlled Studies. [2022]

6. China pubmed.ncbi.nlm.nih.gov

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

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

Restrictive lung disease following treatment for malignant brain tumors: a potential late effect of craniospinal irradiation. [2017]

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

Lung toxicity of lomustine in the treatment of progressive gliomas. [2022]

9. Netherlands pubmed.ncbi.nlm.nih.gov

How did lomustine become standard of care in recurrent glioblastoma? [2020]

10. England 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). [2019]