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.
Inclusion Criteria:
1. Male or female, age ≥18.
2. Patients with histologically confirmed glioblastoma at first recurrence.
3. MGMT promotor status known
4. Presence of at least one lesion of measurable disease by MRI of at 10 mm in longest
diameter on baseline MRI.
5. Karnofsky Performance Score (KPS) ≥ 70%
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. 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.
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.
8. Personally signed and dated informed consent document indicating that the subject has
been informed of all pertinent aspects of the study.
9. 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).
Exclusion Criteria:
1. Prior treatment for glioblastoma at recurrence, except surgery.
2. Surgical resection or biopsy of glioma within 4 weeks of the start of study treatment.
3. Inability to undergo contrast-enhanced MRI.
4. Known history of allergy to TNF or lomustine, any excipient in the study medication or
any other intravenously administered human proteins/peptides/antibodies.
5. Absolute neutrophil count (ANC) < 1.5 x 10^9/L; platelets < 100 x 10^9/L or
haemoglobin (Hb) < 9.0 g/dl.
6. Chronically impaired renal function as indicated by creatinine clearance < 60 mL/min
or serum creatinine > 1.5 ULN.
7. Inadequate liver function (ALT, AST, ALP ≥ 2.5 x ULN or total bilirubin ≥ 2.0 x ULN).
8. INR > 1.5 ULN.
9. 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.
10. Active or history of autoimmune disease that might deteriorate when receiving an
immuno-stimulatory agent, in the judgement of the investigator.
11. History within the last year of cerebrovascular disease and/or acute or subacute
coronary syndromes including myocardial infarction, unstable or severe stable angina
pectoris.
12. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).
13. Clinically significant cardiac arrhythmias or requiring permanent medication.
14. 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.
15. Uncontrolled hypertension.
16. Known arterial aneurism at high risk of rupture.
17. Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine
classification).
18. Medically documented history of or active major depressive episode, bipolar disorder
(I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt
or ideation, or homicidal ideation (e.g. risk of doing harm to self or others), or
patients with active severe personality disorders.
19. Anxiety ≥ CTCAE Grade 3.
20. Severe diabetic retinopathy such as severe non-proliferative retinopathy and
proliferative retinopathy.
21. Major trauma including major surgery (such as abdominal/cardiac/thoracic surgery)
within 4 weeks of administration of study treatment.
22. Known history of tuberculosis.
23. Pregnancy or breast feeding.
24. Requirement of chronic administration of high dose corticosteroids or other
immunosuppressant 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.
25. 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
interfere with the study.
26. Concurrent malignancies unless the patient has been disease-free without intervention
for at least 2 years.
27. Growth factors or immunomodulatory agents within 7 days prior to the administration of
study treatment.
28. Serious, non-healing wound, ulcer, or bone fracture.
29. Requirement of concurrent therapy with anticoagulants at therapeutic doses.
30. Requirement of concurrent use of other anti-cancer treatments or agents other than
study medication.
31. Any recent live vaccination within 4 weeks prior to treatment or plan to receive
vaccination during the study.
