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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Philogen S.p.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2024-12-04

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Philogen S.p.A.

External identifiers

EU CT number

2024-515609-25-00

ClinicalTrials.gov

NCT06336291

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Pharmacodynamic, Safety

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.

Secondary objectives 1

1. 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.

Conditions and MedDRA coding

Glioblastoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Male or female, age ≥18
2. Patients with histologically confirmed glioblastoma per 2021 WHO classification progression according to RANO criteria
3. 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 after surgery
4. MGMT promotor status known
5. Karnofsky Performance Status (KPS) ≥ 60%.
6. 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 (HBV-DNA is not required for patients with documented vaccination report). 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
7. 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. *Women of childbearing potential (WOCBP) 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).
8. Male patients: male subjects able to father children must agree to use two acceptable methods of contraception throughout the study and until 6 months after last study drug administration (e.g. condom with spermicidal gel). Double-barrier contraception is required
9. Personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study
10. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures

Exclusion criteria 35

1. Inability to undergo contrast-enhanced MRI
2. Chronically impaired renal function as indicated by creatinine clearance < 60 mL/min/1.73m2 or for patients older than 65 years without albuminuria or proteinuria, creatinine clearance < 45 mL/min/1.73m2
3. Inadequate liver function (ALT, AST, ALP ≥ 2.5 x ULN or total bilirubin ≥ 1.5 x ULN)
4. INR > 1.5 ULN
5. Anti-cancer treatment with radiation therapy, chemotherapy, targeted therapies, immu-notherapy, hormones, tumor treating fields or other antitumor therapies within 4 weeks prior to study treatment start
6. Subjects who participated in an investigational drug or device study within 4 weeks pri-or to study treatment start
7. Grade ≥ 4 myelotoxicity with previous treatment of alkylating agents (e.g., TMZ, CCNU)
8. Previous treatment with Bevacizumab
9. Previous treatment with L19TNF
10. Previous treatment in the PH-L19TNFCCNU-02/20 study
11. Known history of allergy to TNF or lomustine, any excipient in the study medication or any other in-travenously administered human proteins/peptides/antibodies
12. Absolute neutrophil count (ANC) < 1.5 x 10^9/L; platelets < 100 x 10^9/L or hemoglo-bin (Hb) < 9.0 g/dl
13. Any severe concomitant condition which makes it undesirable for the patient to partici-pate in the study or which could jeopardize compliance with the protocol, in the opinion of the investigator
14. Active or history of autoimmune disease that might deteriorate when receiving an im-mune-stimulatory agent, in the judgement of the investigator
15. History within the last year of cerebrovascular disease and/or acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris
16. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria)
17. Clinically significant cardiac arrhythmias or requiring permanent medication
18. LVEF <55% or any other abnormalities observed during baseline ECG and echocardio-gram investigations that are considered as clinically significant by the investigator. Pa-tients with a marked prolongation of QT/QTc interval (e.g., repeated demonstration of QTc >470 milliseconds using Fredricia’s QT correction formula) are excluded
19. Uncontrolled hypertension
20. Known arterial aneurism at high risk of rupture
21. Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine clas-sification)
22. Anxiety ≥ CTCAE Grade 3
23. Severe diabetic retinopathy such as severe non-proliferative retinopathy and prolifera-tive retinopathy
24. Major trauma including major surgery (such as abdominal/cardiac/thoracic surgery) with-in 3 weeks of administration of study treatment
25. Known active or latent tuberculosis (TB)
26. Pregnancy or breast feeding
27. Requirement of chronic administration of high dose corticosteroids or other immuno-suppressant drugs. Subjects must have been either off corticosteroids, or on a stable or decreasing dose ≤ 4 mg daily dexamethasone (or equivalent) for 7 days prior to start of treatment. Limited or occasional use of corticosteroids to treat or prevent acute adverse reactions is not considered an exclusion criterion
28. Presence of active and uncontrolled infections or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or inter-fere with the study
29. Concurrent malignancies unless the patient has been disease-free without intervention for at least 2 years
30. Growth factors or immunomodulatory agents within 7 days prior to the administration of study treatment
31. Serious, non-healing wound, ulcer, or bone fracture
32. Deep vein thrombosis, pulmonary embolism or other acute vascular events within 6 months
33. Anticoagulation therapy with P2Y12 antagonists (e.g., clopidogrel, ticagrelor) and vita-min K antagonists (e.g., phenprocoumon, warfarin)
34. Requirement of concurrent use of other anti-cancer treatments or agents other than study medication
35. Any recent live vaccination within 4 weeks prior to treatment or plan to receive live vac-cination during the study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Safety endpoints: Incidence of adverse Events (AEs), Serious Adverse Events (SAEs) and Drug-Induced Liver Injury (DILI), standard labor-atory assessments, ECG, ECHO and physical examination ac-cording to CTCAE v.5.0
2. Efficacy endpoint: Survival rate at 12 months

Secondary endpoints 9

1. Progression-Free Survival (PFS)
2. Overall Survival (OS)
3. Objective Response Rate (ORR)
4. Disease Control Rate (DCR)
5. Duration of Response (DoR)
6. Incidence of Dose Reductions
7. Incidence of Dose Modifications
8. Pharmacokinetic parameters of L19TNF
9. Assessment of the formation of Human Anti-Fusion protein Antibodies (HAFA) against L19TNF

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Philogen S.p.A.

Sponsor organisation

Philogen S.p.A.

Address

Piazza La Lizza 7

City

Siena

Postcode

53100

Country

Italy

Scientific contact point

Organisation

Philogen S.p.A.

Contact name

Teresa Hemmerle

Public contact point

Organisation

Philogen S.p.A.

Contact name

Teresa Hemmerle

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications