1. Subjects must have signed and dated an approved written informed consent form in
accordance with regulatory and institutional guidelines. This must be obtained before
the performance of any protocol related procedures that are not part of normal subject
care. 2. Subjects must be willing and able to comply with scheduled visits, treatment schedule,
laboratory tests, tumor biopsies, and other requirements of the study.
3. Histopathological diagnosis of glioblastoma (= IDHwt, WHO grade IV astrocytoma of the
central nervous system (Louis, Perry et al. 2021).
4. Diagnosis of resectable glioblastoma recurrence and/or progression following prior
standard of care treatment (surgery for resectable lesions, radiation therapy and
temozolomide chemotherapy). Recurrence/progression is defined as significant
[according to the investigators assessment] growth and/or recurrence of the
glioblastoma tumor mass on sequential MRI of the brain;
5. The following disease characteristics should be present:
1. Presence of a measurable tumor lesion that is characterized by gadolinium
enhancement on T1-MRI of the brain (with a longest diameter of > 10 mm and a
perpendicular diameter of >5mm).
2. No evidence of clinically relevant spontaneous intra-tumor hemorrhage on baseline
MRI-imaging or in the prior disease history;
6. No ventriculo-peritoneal drain:
7. No contraindication for evaluation by gadolinium enhanced MRI, 18FFET-PET/CT of the
brain or whole-body contrast enhanced CT;
8. ECOG performance status score of 0, 1 or 2;
9. An interval of at least 4 months (: 16 weeks) after the end of postoperative radiation
therapy for glioblastoma unless progression is confirmed on an MRI of the brain
obtained > 4 week after the first observation of progression; and with an interval of
at least 4 weeks after the last administration of temozolomide;
10. Male or female, 18 years of age or older;
11. Resolution of all acute treatment related adverse effects of prior surgical
procedures, radiotherapy and temozolomide to NCI CTCAEv4.0 grade 0 or 1 except for
alopecia;
12. Adequate organ function as defined by the following criteria:
1. Total serum bilirubin < 1.5 x ULN (patients with Gilbert's disease exempt who
should have bilirubin < 2x ULN)
2. AST and ALT < 2.5 x upper limit of normal (ULN);
3. Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min. 4. Absolute neutrophil count (ANC) > 1500/mm³ without growth factor support. 5. Platelets > 75 000 cells/mm³
6. Hemoglobin ≥9 g/dL (which may be obtained by transfusion or growth factor
support)
7. FT4 hormone levels within normal range;
13. No prior treatment on a nivolumab and/or ipilimumab trial;
14. No prior treatment with an anti-CTLA-4 or anti-PD-1/-L1 targeted therapy;
15. No gastrointestinal abnormalities including:
1. Inability to take oral medication.
2. Requirement for intravenous alimentation.
3. Prior surgical procedures affecting absorption including gastric resection.
4. Treatment for active peptic ulcer disease in the past 6 months.
5. Malabsorption syndromes.
6. Active gastrointestinal bleeding, unrelated to cancer, as evidenced by
hematemesis, hematochezia or melena in the past 3 months without evidence of
resolution documented by endoscopy or colonoscopy;
16. No evidence of pre-existing uncontrolled hypertension as documented by baseline blood
pressure reading. The baseline systolic blood pressure reading must be ≤140 mm Hg, and
the baseline diastolic blood pressure readings must be ≤90 mm Hg. If baseline blood
pressure reading exceeds the inclusion values a second blood pressure reading (taken
at least 1 hour apart) must be documented in order to confirm the absence of
uncontrolled hypertension. Patients whose hypertension is controlled by
antihypertensive therapies are eligible;
17. No concurrent treatment:
1. In another therapeutic clinical trial;
2. No requirement for permanent therapeutic anticoagulation therapy.
18. Subjects with active, known, or suspected autoimmune disease are not eligible.
Subjects with type I diabetes mellitus, residual hypothyroidism due to autoimmune
thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo,
psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll;
19. Subjects requiring systemic treatment with either corticosteroids (> 8 mg daily
methylprednisolone equivalent) or other immunosuppressive medications within 14 days
of study enrollment. Inhaled or topical steroids are permitted in the absence of
active autoimmune disease;
20. No active uncontrolled seizure disorder;
21. No myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
graft, symptomatic congestive heart failure or any unstable arrhythmia,
cerebrovascular accident or transient ischemic attack, within the 12 months prior to
study drug administration.;
22. No known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
(AIDS)-related illness;
23. No serious uncontrolled medical disorder or active infection that would impair their
ability to receive study treatment;
24. No history of a malignancy (other than glioma) except those treated with curative
intent for skin cancer (other than melanoma) or in situ breast or cervical cancer or
those treated with curative intent for any other cancer with no evidence of disease
for 5 years;
25. No other severe acute or chronic medical or psychiatric condition, or laboratory
abnormality that would impart, in the judgment of the investigator, excess risk
associated with study participation or study drug administration, or which, in the
judgment of the investigator, would make the patient inappropriate for entry into this
study;
26. No dementia or significantly altered mental status that would prohibit the
understanding or rendering of informed consent and compliance with the requirements of
this protocol;
27. Female patients must be surgically sterile or be postmenopausal, or must agree to use
effective contraception measures during the period of therapy, which should be
continued for at least 5 months following the last dose of nivolumab as indicated in
the SmPC. All female patients with reproductive potential must have a negative
pregnancy test (serum or urine) prior to enrollment and pregnancy testing should be
conducted within 24h prior to the first dose of immune checkpoint inhibitors and
thereafter monthly and at the end of systemic exposure. The definition of effective
contraception will be included in the Informed consent form. Women must not be
breastfeeding at initiation of screening.
