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

NCT04573192 | Recruiting Phase 1

• 1 other identifier: PH-L19TNFCCNU-02/20
• Study Type: interventional
• Target: 142
• Locations: 4 countries
• Sites: 15

Brief Summary

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.

Conditions

Glioblastoma

Outcome Measures

Primary Outcomes (2)

• For Phase 1: DLT

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

  For Cohort 1 to Cohort 3 from Day 1 to Day 42 after the first administration of lomustine and study drug (Cycle 1)

• For Phase 2: Overall Survival

  Overall survival (OS) rate

  From beginning of treatment to 12 months

Secondary Outcomes (6)

• PFS

  From the date of enrollment to the date of progression or death for any cause, whichever came first, assessed up to 52 weeks

• PFS-rate at 6 months

  From the date of enrollment to the date of progression or death for any cause, whichever came first, assessed up to 6 months

• OS-rate at 12 months

  From beginning of treatment to 12 months

• Adverse Events (AE)

  Throughout study completion for each patient, a maximum of 52 weeks for each patient

• Serious Adverse Events (AE)

  Throughout study completion for each patient, a maximum of 52 weeks for each patient

Study Arms (2)

Phase 1 part: Dose Finding

EXPERIMENTAL

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.

Drug: L19TNF; Drug: Lomustine

Phase II part: Signal Seeking

EXPERIMENTAL

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

Drug: L19TNF; Drug: Lomustine

Interventions

L19TNF DRUG

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

Also known as: onfekafusp alfa

Phase 1 part: Dose Finding; Phase II part: Signal Seeking

Lomustine DRUG

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

Phase 1 part: Dose Finding; Phase II part: Signal Seeking

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female, age ≥18.
• Patients with histologically confirmed glioblastoma at unequivocal first recurrence or progression according to RANO criteria.
• MGMT promotor methylation status known
• IDH wildtype.
• Patients may have undergone surgery for recurrence.
• 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 before study treatment start). Study treatment will need to start minimum 4 weeks to maximum 6 weeks after surgery.
• Karnofsky Performance Status (KPS) ≥ 70%.
• Documented negative test for HIV-HBV-HCV. For HBV serology, the determination of HBsAg and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV, negative serum HBV-DNA is required. For HCV, HCV-RNA or HCV antibody test is required. Subjects with a positive test for HCV antibody but no detection of HCV-RNA indicating no current infection are eligible.
• Female patients: female patients must be either documented not Women Of Childbearing Potential (WOCBP)\* or must have a negative pregnancy test within 14 days of starting treatment. Additionally WOCBP must agree to use, from the screening to 6 months following the last study drug administration, highly effective contraception methods, as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group (www.hma.eu/ctfg.html) and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion or vasectomized partner.
• Male patients: male subjects able to father children must agree to use two acceptable methods of contraception throughout the study (e.g. condom with spermicidal gel). Double-barrier contraception is required.
• Personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
• Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.
• Women of childbearing potential are defined as females who have experienced menarche, are not postmenopausal (12 months with no menses without an alternative medical cause) and are not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy, or bilateral salpingectomy).

You may not qualify if:

• Prior treatment for glioblastoma at recurrence, except surgery.
• Surgical resection or biopsy of glioma within 4 weeks of the start of study treatment.
• Inability to undergo contrast-enhanced MRI.
• Prior treatment with lomustine.
• Known history of allergy to TNF or lomustine, any excipient in the study medication or any other intravenously administered human proteins/peptides/antibodies.
• Absolute neutrophil count (ANC) \< 1.5 x 10\^9/L; platelets \< 100 x 10\^9/L or haemoglobin (Hb) \< 9.0 g/dl.
• Chronically impaired renal function as indicated by creatinine clearance \< 60 mL/min or serum creatinine \> 1.5 ULN.
• Inadequate liver function (ALT, AST, ALP ≥ 2.5 x ULN or total bilirubin ≥ 2.0 x ULN).
• INR \> 1.5 ULN.
• Any severe concomitant condition which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol, in the opinion of the investigator.
• Active or history of autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent, in the judgement of the investigator.
• History within the last year of cerebrovascular disease and/or acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
• Heart insufficiency (\> Grade II, New York Heart Association (NYHA) criteria).
• Clinically significant cardiac arrhythmias or requiring permanent medication.
• LVEF \<55% or any other abnormalities observed during baseline ECG and echocardiogram investigations that are considered as clinically significant by the investigator. Subjects with current or a history of QT/QTc prolongation are excluded.

Sponsors & Collaborators

• Philogen S.p.A.: lead

Study Sites (15)

Hôpital Neurologique Pierre Wertheimer

Bron, France

NOT YET RECRUITING

Hôpital Saint Louis

Paris, France

NOT YET RECRUITING

Sorbonne University, AP-HP, Paris brain institute

Paris, France

NOT YET RECRUITING

University Hospital Bonn

Bonn, Germany

RECRUITING

University Hospital Köln

Cologne, Germany

NOT YET RECRUITING

Klinikum rechts der Isar

München, Germany

RECRUITING

Universitatsklinikum Tubingen

Tübingen, Germany

RECRUITING

Azienda USL di Bologna IRCCS delle Scienze Neurologiche di Bologna

Bologna, Italy

RECRUITING

Fondazione IRCCS Istituto Neurologico Carlo Besta

Milan, Italy

RECRUITING

Istituto Oncologico Veneto IRCCS

Padua, Italy

RECRUITING

Azienda Ospedaliero-Universitaria Senese Policlinico Le Scotte

Siena, Italy

NOT YET RECRUITING

AOU Città della Salute e della Scienza di Torino

Torino, Italy

NOT YET RECRUITING

Inselspital Universitätsklinik für Medizinische Onkologie Bern

Bern, Switzerland

RECRUITING

Centre Hospitalier Universitaire Vaudois (CHUV)

Lausanne, Switzerland

RECRUITING

Universitatspital Zurich - Klinik fur Neurologie & Hirntumorzentrum

Zurich, CH-8091, Switzerland

RECRUITING

Related Publications (1)

• Look T, Puca E, Buhler M, Kirschenbaum D, De Luca R, Stucchi R, Ravazza D, Di Nitto C, Roth P, Katzenelenbogen Y, Weiner A, Rindlisbacher L, Becher B, Amit I, Weller M, Neri D, Hemmerle T, Weiss T. Targeted delivery of tumor necrosis factor in combination with CCNU induces a T cell-dependent regression of glioblastoma. Sci Transl Med. 2023 May 24;15(697):eadf2281. doi: 10.1126/scitranslmed.adf2281. Epub 2023 May 24.

  PMID: 37224228 DERIVED

MeSH Terms

Conditions

Glioblastoma

Interventions

Lomustine

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Nitrosourea Compounds; Urea; Amides; Organic Chemicals; Nitroso Compounds

Central Study Contacts

Teresa Hemmerle, PhD

CONTACT

+390577017816; regulatory@philogen.com

Marco Taras

CONTACT

regulatory@philogen.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

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

Study Record Dates

• First Submitted: September 25, 2020
• First Posted: October 5, 2020
• Study Start: February 19, 2021
• Primary Completion: March 1, 2025
• Study Completion: December 1, 2025
• Last Updated: April 8, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

FR (3); CH (3); IT (5); DE (4)