Inclusion Criteria:
1. Age ≥18. 2. IDH-mutant glioma (according to WHO 2021 classification) at first recurrence or
progression after alkylating chemotherapy:
- - COHORT 1: Grade ≥2 oligodendroglioma or astrocytoma with planned resection,
tumor tissue from prior resection must be available.
- - COHORT 2A: Grade ≥2 oligodendroglioma.
- - COHORT 2B1: Grade ≥2 oligodendroglioma previously treated with lomustine as
monotherapy or in combination.
- - COHORT 2B2: Grade ≥2 oligodendroglioma previously treated with temozolomide as
monotherapy or in combination.
- - COHORT 3A: Grade ≥2 astrocytoma.
- - COHORT 3B1: Grade ≥2 astrocytoma previously treated with lomustine as
monotherapy or in combination.
- - COHORT 3B2: Grade ≥2 astrocytoma previously treated with temozolomide as
monotherapy or in combination.
3. Measurable disease according to RANO 2.0 criteria.
4. Documented IDH1 and/or IDH2 gene mutations detected by immunochemistry or
sequencing.
5. Karnofsky Performance Status (KPS) ≥ 70%.
6. Life expectancy ≥ 3 months.
7. 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.
8. 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 from the screening to 6
months following the last administration of temozolomide, lomustine or L19TNF.
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 scheduled visits, treatment plan, laboratory
tests and other study procedures.
Exclusion Criteria:
1. Any therapy for recurrence/progression after alkylating chemotherapy, except
resection.
2. Therapy for glioma within 4 weeks of start of study treatment.
3. Surgical resection of glioma within 4 weeks of start of study treatment.
4. Stereotactic biopsy of glioma within 2 weeks of start of study treatment.
5. Inability to undergo contrast-enhanced MRI.
6. Known history of allergy to TNF or lomustine or temozolomide, any excipient in the
study medication or any other intravenously administered human
proteins/peptides/antibodies.
7. Absolute neutrophil count (ANC) < 1.5 x 10^9/L; platelets < 100 x 10^9/L or
hemoglobin (Hb) < 9.0 g/dl.
8. 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.
9. Inadequate liver function (ALT, AST, ALP ≥ 2.5 x ULN or total bilirubin ≥ 1.5 x
ULN).
10. INR > 1.5 ULN.
11. 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.
12. Active or history of autoimmune disease that might deteriorate when receiving an
immuno-stimulatory agent, in the judgement of the investigator.
13. History within the last year of cerebrovascular disease and/or acute or subacute
coronary syndromes including myocardial infarction, unstable or severe stable angina
pectoris.
14. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).
15. Clinically significant cardiac arrhythmias or requiring permanent medication.
16. LVEF < 55% or any other abnormalities observed during baseline ECG and
echocardiogram investigations that are considered clinically significant by the
investigator. Patients with a marked prolongation of QT/QTc interval (e.g., repeated
demonstration of QTc >470 milliseconds using Fredricia's QT correction formula) are
excluded.
17. Uncontrolled hypertension, defined by systolic blood pressure ≥ 140 mmHg and
diastolic blood pressure ≥ 90 mmHg.
18. Arterial aneurism at high risk of rupture.
19. Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine
classification).
20. 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.
21. Anxiety ≥ CTCAE Grade 3.
22. Severe diabetic retinopathy, such as severe non-proliferative retinopathy and
proliferative retinopathy.
23. Major trauma including major surgery (such as abdominal/cardiac/thoracic surgery)
within 4 weeks of administration of study treatment.
24. Known history of tuberculosis.
25. Pregnancy or breast feeding.
26. Requirement of chronic administration of high dose steroids or other
immunosuppressant drugs. Subjects must have been either off steroids, 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 steroids to treat or prevent acute
adverse reactions is not considered an exclusion criterion.
27. 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.
28. Concurrent malignancies other than glioma unless the patient has been disease-free
without intervention for at least 2 years.
29. Growth factors or immunomodulatory agents within 7 days prior to the administration
of study treatment.
30. Serious, non-healing wound, ulcer or bone fracture.
31. Deep vein thrombosis, pulmonary embolism or other acute vascular events within 6
months.
32. Anticoagulation therapy with P2Y12 antagonists (e.g., clopidogrel, ticagrelor) and
vitamin K antagonists (e.g., phenprocoumon, warfarin).
33. Requirement of concurrent use of other anti-cancer treatments or agents other than
study medication.
34. Any live vaccination within 4 weeks prior to treatment or plan to receive live
vaccination during the study.
