Inclusion Criteria:
1. Diagnosed with primary glioblastoma by histopathological examination and confirmed
recurrent glioblastoma by magnetic resonance imaging (MRI) scans after completing
standard of care (Stupp protocol) concomitant temozolomide chemotherapy with
radiotherapy (CCRT)
2. At least one confirmed measurable lesion by RANO criteria. 3. Karnofsky Performance Status (KPS) ≥80. 4. A person who satisfies the following criteria in haematologic, renal, and hepatic
function tests performed within 7 days prior to screening:
1. Haematologic tests.
- - Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
- - Platelets ≥ 100 x 109/L.
- - Haemoglobin ≥ 9.0 g/dL.
2. Blood coagulation tests.
- - Prothrombin time (PT) ≤ 1.5 x Upper limit of normal (ULN)
- Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN.
3. Hepatic function tests.
- - Total bilirubin ≤ 1.5 x UNL.
- - Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 x
ULN (≤ 5 x ULN in case of liver metastasis)
4.
Renal function test.
- - ≤1.5 × ULN or creatinine clearance (CrCl) ≥30 mL/min for patient with
creatinine levels >1.5 × institutional ULN.
5. At least 12 weeks of expected survival time. 6. The patient (or legally acceptable representative if applicable) is able and willing
to provide written informed consent for the trial.
Exclusion Criteria:
1. Has a known additional malignancy that is progressing or has required active
treatment within the past 2 years. (Note: Patients with basal cell carcinoma of the
skin, squamous cell carcinoma of the skin or carcinoma in situ [e.g., breast
carcinoma, cervical cancer in situ] controlled by curative therapy are not excluded)
2. Has received prior radiotherapy within 2 weeks of start of study treatment. Patients
must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is
permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease. 3. Has a history of (non-infectious) pneumonitis/interstitial lung diseases that
required steroids or current pneumonitis/interstitial lung disease. 4. Has an active infection requiring systemic therapy. 5. Uncontrolled hypertension (systolic blood pressure [SBP]> 150 or diastolic blood
pressure [DBP]> 90 mmHg)
6. Uncontrolled seizures. 7. Class III or IV heart failure by New York Heart Association (NYHA) classification. 8. Has oxygen-dependent chronic disease. 9. Active psychiatric disorder (schizophrenia, major depressive disorder, bipolar
disorder etc.). Treated depression with ongoing antidepressant medication is not an
exclusion. 10. History of abdominal fistula or gastrointestinal perforation within 6 months prior
to start of study drug. 11. History of serious gastrointestinal haemorrhage within 6 months prior to start of
study drug. 12. History of severe arterial thromboembolic event within 12 months of start of study
drug. 13. Serious grade 4 venous thromboembolic event including pulmonary embolism. 14. History of hypertensive crisis or hypertensive encephalopathy. 15. History of posterior reversible encephalopathy syndrome. 16. Planned surgery within 4 weeks post last dose. 17. Moderate to severe proteinuria as demonstrated by urine dipstick for proteinuria
≥2+. For patients with ≥2+ proteinuria on dipstick urinalysis, a urine protein:
creatinine (UPC) ratio will be determined, or a 24-hour urine collection will be
done. Patients with a UPC ratio <1 or a 24-hour urine protein <1 gram are eligible. 18. Requiring therapeutic anticoagulation with warfarin at baseline; patients must be
off warfarin or warfarin-derivative anticoagulants for at least 7 days prior to
starting study drug; however, therapeutic or prophylactic therapy with low-molecular
weight heparin is allowed. 19. Not recovered below National Cancer Institute-Common Terminology for Adverse Events
(NCI-CTCAE) grade 1 or baseline from AEs due to previous therapy (patient with ≤
Grade 2 neuropathy or alopecia may be eligible)
20. Treatment with systemic chemotherapy, hormonal therapy, immunotherapy or biologic
therapy within 2 weeks prior to the baseline visit. 21. Undergone major surgery requiring general anaesthesia or a respiratory assistance
device within 4 weeks prior to the baseline visit (within 2 weeks for video-assisted
thoracoscopic surgery [VATS] or open-and-closed [ONC] surgery)
22. Treated with other investigational drugs within 4 weeks prior to the baseline visit
for this study. 23. Pregnant* or lactating females, and females/males of childbearing potential who do
not agree to a reliable and adequate method of contraception. 24. A known history of severe drug hypersensitivity or hypersensitivity to a therapy
similar to the study drugs. 25. Unable to participate in the trial according to the investigator's decision. 26. Previous therapy with vascular endothelial growth factor (VEGF)-targeted agents
including (but not limited to) bevacizumab. 27. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or
with an agent directed to another stimulatory or co-inhibitory T-cell receptor
(e.g., CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade
3 or higher irAE. 28. Has an active autoimmune disease that has required systemic treatment in past 2
years (i.e., with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency) is not considered a form of systemic treatment and is allowed. 29. Known human immunodeficiency virus (HIV) infection. No HIV testing is required
unless mandated by local health authority. 30. Known active hepatitis B or hepatitis C infection. No testing for hepatitis B and
hepatitis C is required unless mandated by local health authority. 31. Have received a live vaccine within 30 days prior to enrollment. Seasonal flu
vaccines that do not contain live virus are permitted. 32. Have had a serious or non-healing wound, ulcer, or bone fracture within 28 days
prior to enrollment
