A Study to Evaluate the Safety and Efficacy of L19TNF With Alkylating Chemotherapy for Patients With Recurrent IDH-mutant Astrocytoma or Oligodendroglioma

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.