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Patients will be assigned to the following increasing dose levels of L19TNF: 10 and 13 μg/kg.

L19TNF

Tobias Weiss, MD

Open label, non-randomized, mono-center Phase I/II study in subjects with IDH-wildtype WHO grade III / IV glioma at first relapse.

The purpose of this study is to explore the safety and efficacy profile of the antibody-cytokine fusion protein L19TNF in patients with isocitrate dehydrogenase (IDH) wildtype WHO grade III / IV glioma at first relapse

Phase I:

The primary objective of this phase is to evaluate the safety of L19TNF in patients with IDH-wildtype WHO grade III / IV glioma at first relapse and to establish and confirm the recommended dose (RD) for phase II.

Phase II:

The primary objective of this phase is to evaluate antitumor activity of L19TNF in patients with IDH-wildtype WHO grade III / IV glioma at first relapse.

Safety and Efficacy of L19TNF in Patients With Isocitrate Dehydrogenase (IDH) Wildtype WHO Grade III / IV Glioma at First Relapse

A Study to Evaluate the Safety and Efficacy of the Tumor-targeting Human Antibody-cytokine Fusion Protein L19TNF in Patients With Isocitrate Dehydrogenase (IDH) Wildtype WHO Grade III / IV Glioma at First Relapse

Measurement of neurological function in neuro-oncology

Assessment through a questionnaire of symptom-related restriction of activity, self-sufficiency and self-determination

Philogen S.p.A.

Symptoms and General Pathology

Recurrence

Glioblastoma

Disease Progression

Astrocytoma

Disease Attributes

Antineoplastic Agents

Lomustine

Antineoplastic Agents, Alkylating

Alkylating Agents

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.

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

Teresa Hemmerle, PhD

Marco Taras

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

The present study is a randomized, open-label, non-controlled phase II study in patients with glioblastoma at any progression/recurrence (first and later).

Overall, 90 subjects will be enrolled and parallel assigned in a 1:1 fashion to one of six treatment arms (from A to F) of 15 patients each.

Each arm has a different combination of L19TNF (7 μg/kg or 10 μg/kg or 13 μg/kg) and lomustine at different dose levels (90 or 110 mg/m2).

Treatment is based on a 42-day cycle for up to a maximum of 6 cycles.

This is an open-label study, so there is no blinding.

Patients who successfully complete the screening evaluations and are eligible for participation in the study will be enrolled and randomly assigned (1:1:1:1:1:1) to either of the six parallel treatment arms.

To maintain an appropriate balance between the six treatment arms and avoid undesired confounding effect of different factors, patients will be randomized in accordance with the following strata:

* MGMT status
* Steroid administration
* Previous systemic therapy treatment for progression

A randomization list will be prepared for each stratum using permuted block, the block sizes will be chosen randomly from different, pre-specified sizes with an equal treatment allocation ratio. The labels for the arms are assigned randomly within each block (fixed seed). The obtained final list is sorted by block together with the progressive enrollment number for the patients.

The primary objective of this study is to select the optimal regimen of L19TNF in combination with lomustine, that maximizes effects on clinical parameters and minimizes the probability of moderate to severe adverse events, among six (three L19TNF doses x two lomustine doses) combination schedules for the treatment of patient with progressing or recurrent glioblastoma.

Primary endpoints include Safety (Incidence of adverse Events (AEs), Serious Adverse Events (SAEs) and Drug-Induced Liver Injury (DILI), standard laboratory assessments, ECG, ECHO and physical examination according to CTCAE v.5.0) and Efficacy (Survival rate at 12 months).

The secondary objective of this study is to further evaluate safety, efficacy, exposure, dose-response, pharmacokinetic and pharmacodynamic information of the combination of L19TNF and lomustine at different dose levels to determine the best dose regimen for further studies.

During the conduct of the study the safety information collected will be routinely reviewed by the Data and Safety Monitoring Board (DSMB) in order to identify possible safety concerns.

If the probability in a treatment arm that the development of unacceptable toxicity rate exceeds 33 % is equal or higher than 80%, the recruitment to this treatment arm will be interrupted and the DSMB will be informed to assess the events and relationship to the study treatment. The DSMB may then recommend to re-start recruitment again for the treatment arm or permanently suspend it.

In case of a treatment-related death, recruitment will be suspended for all treatment arms until the Data and Safety Monitoring Board (DSMB) has reviewed the event and recommended to restart

A Study With L19TNF in Combination With Lomustine in Patients With Glioblastoma at Progression or Recurrence

A Dose Optimization Study for L19TNF in Combination With Lomustine in Patients With Glioblastoma at Progression or Recurrence

Occurence of AEs according to CTCAE v.5.0

Occurence of SAEs according to CTCAE v.5.0

Occurence of Unacceptable Toxicity according to CTCAE v.5.0

Occurence of DILI according to CTCAE v.5.0

The rate of patients achieving Complete Response (CR) or Partial Response (PR) defined according to RANO criteria

The rate of patients achieving complete (CR), partial (PR) and stable response (SD)

Pharmacokinetics assessment of L19TNF through blood sampling

Determination of the formation of Human Anti-Fusion protein Antibodies (HAFA) against L19TNF

Phase I part:

Dose Finding Patients will be treated in cohorts according to a traditional 3+3 design with lomustine on Day 1 and L19TNF on Days 1, 3 and 5, and on Days 22, 24 and 26, of a 42-days cycle at different dose levels.

The RD will be confirmed following a traditional 3+3 design.

Cohort 1: 10 µg /kg L19TNF i.v. plus 90 mg/m2 lomustine Cohort 2: 10 µg /kg L19TNF i.v. plus 110 mg/m2 lomustine Cohort 3: 13 µg /kg L19TNF i.v. plus 110 mg/m2 lomustine

The dose of 13 ug/kg L19TNF will be declared the RD in case none of three or not more than one out of 6 patients experienced a DLT. Dose limiting toxicity will be assessed during the dose-escalation from Day 1 through Day 42 after the first administration of lomustine and study drug (Cycle 1). Not more than 2 patients might be treated simultaneously in Cycle 1.

118 Patients will be randomized 1:1 and treated with either lomustine on day 1 and L19TNF on Days 1, 3 and 5, and on Days 22, 24, and 26 of a 42-days cycle at the RD established in the phase I part of the study or with lomustine on day 1 of a 42-days cycle.

* Treatment Arm 1: L19TNF plus Lomustine
* Treatment Arm 2: Lomustine

Cohort 1: 10 µg /kg L19TNF i.v. plus 90 mg/m2 lomustine Cohort 2: 10 µg /kg L19TNF i.v. plus 110 mg/m2 lomustine Cohort 3: 13 µg /kg L19TNF i.v. plus 110 mg/m2 lomustine

François Ducray

Stefania Cuzzubbo

Ahmed Idbaih

Ulrich Herrlinger

Norbert Galldiks

Meike Mitsdörffer

Ghazaleh Tabatabai

Enrico Franceschi

Antonio Silvani

Giuseppe Lombardi

Anna Maria Di Giacomo

Alessia Pellerino

Marc Wehrli

Andreas Hottinger

Glioblastomas are the most common and most aggressive primary brain tumors in adults. The prognosis is poor despite multimodal therapy with surgery, radiotherapy and chemotherapy. Therefore, novel treatments are urgently needed.

L19TNF is a fully human fusion protein consisting of human tumor necrosis factor (TNF)-α fused to the L19 antibody in scFv format, specific to the extra-domain B of fibronectin. TNF not only induces apoptosis or necrosis in certain target cells, but also exerts inflammation and immunity. L19TNF selectively delivers TNF to the tumor site to spare normal tissues from undesired toxicity. Preclinical experiments with L19TNF have demonstrated tumor growth retardation in various mouse tumor models including models of glioma.

Open label phase I/II study in subjects with glioblastoma at first progression.

A Study to Evaluate Safety and Efficacy of L19TNF Plus Lomustine in Patients With Glioblastoma at First Progression

A Study to Evaluate the Safety and Efficacy of the Tumor-targeting Human Antibody-cytokine Fusion Protein L19TNF Plus Lomustine in Patients With Glioblastoma at First Progression

Occurrence of dose limiting toxicity (DLT) assessed by frequency and grade of adverse events (AE) according to CTCAE v.5.0.

Progression-free survival (PFS) based on iRANO criteria and a standardized MRI protocol will be assessed for all enrolled subjects.

Progression-free survival (PFS) based on iRANO criteria and a standardized MRI protocol will be assessed for all enrolled subjects

Safety of administration of L19TNF, through an assessed by Common Toxicity Criteria (version 5.0, CTCAE)

Safety of administration of L19TNF, assessed by Common Toxicity Criteria (version 5.0, CTCAE)

Evaluation of possible Drug Induce Liver Injury, caused by L19TNF, assessed by Common Toxicity Criteria (version 5.0, CTCAE)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety and Efficacy of L19TNF in Patients With Isocitrate Dehydrogenase (IDH) Wildtype WHO Grade III / IV Glioma at First Relapse	NCT03779230	Glioma of Brain	L19TNF	18 Years - 90 Years	Philogen S.p.A.
Safety and Efficacy of L19TNF in Patients With Isocitrate Dehydrogenase (IDH) Wildtype WHO Grade III / IV Glioma at First Relapse	NCT03779230	Glioma of Brain	L19TNF	18 Years - 90 Years	Philogen S.p.A.
A Study With L19TNF in Combination With Lomustine in Patients With Glioblastoma at Progression or Recurrence	NCT06336291	Glioblastoma	L19TNF L19TNF L19TNF Lomustine Lomustine	18 Years -	Philogen S.p.A.
A Study to Evaluate Safety and Efficacy of L19TNF Plus Lomustine in Patients With Glioblastoma at First Progression	NCT04573192	Glioblastoma	L19TNF Lomustine	18 Years -	Philogen S.p.A.

Spots Global Cancer Trial Database for l19tnf

Every month we try and update this database with for l19tnf cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for l19tnf

Every month we try and update this database with for l19tnf cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for l19tnf cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.