An open-label dose escalation study to estimate maximum tolerated dose (MTD), identify dose-limiting toxicities (DLTs) and study pharmacokinetics following a single dose of intracranially administered temozolomide-based SI-053 as an add-on to the current standard of care (SoC), in adult patients with newly diagnosed glioblastoma (GBM).

1) Signed informed consent form (ICF) prior to the start of any trial-related
procedures.
2) Subject age >= 18 years with an upper limit of 70 years.
3) In the Investigator*s opinion, subject is able and willing to comply with
all trial requirements for the duration of the trial.
4) Suspected primary, newly diagnosed supratentorial GBM (Grade IV glioma per
WHO guidelines) based on signs/symptoms and MRI (obtained maximally 10 days
prior to surgery, using the same MRI settings as will be used for post-surgery
MRI; if the MRI is older than 10 days or if it is taken at a local clinic, this
has to be repeated within 10 days before the surgery), needing maximum safe
resection followed by chemoradiotherapy as per institutional guidelines (Stupp
protocol: radiotherapy [60 Gy total; 10 Gy per week for 6 weeks] plus
concomitant TMZ [75 mg/m2 of body surface area per day; 7 days per week from
first to the last day of radiotherapy], followed by six cycles of adjuvant TMZ
[150 to 200 mg/m2] once daily for 5 consecutive days, followed by 23 days of no
treatment prior to the next cycle; or CeTeG protocol for MGMT promoter
methylated GBMs: up to six courses of lomustine [100 mg/m2 on Day 1 plus TMZ
[100-200 mg/m2 per day on Days 2-6 of the 6-week course] in addition to
radiotherapy [59-60 Gy], if preferred by the investigator).
5) Preliminary histological diagnosis of GBM by an intraoperative *frozen
section*, analyzed during surgery is mandatory before administration of SI-053.
A final diagnosis is made by histopathological and molecular analysis of the
resected tumor tissue.
6) It is the surgeon*s estimation that maximum safe resection of the contrast
enhancing part of the tumor with image-guided surgery is possible and it is not
expected that the ventricular system will be opened during surgery. When the
ventricular system is opened during surgery, no SI-053 will be administered.
7) The tumor volume as assessed by pre-surgery MRI is at least 10 mL, and the
actual resection bed volume based on the surgeon*s estimation after surgery
enables complete administration of a single dose of SI-053.
8) Karnofsky Performance Status (KPS) score >=70% (see Appendix II)
9) Women of childbearing potential (WOCBP) and men whose partner is of
childbearing potential must use highly effective contraceptive methods from the
time of screening and for 6 months after receiving SI-053. WOCBP should have a
negative serum pregnancy test β-human chorionic gonadotropin (β-HCG) at trial
enrollment and within <= 72 h before SI-053 administration.
10) Subjects must have following laboratory values obtained within 2 weeks
prior to enrollment.
• Acceptable liver function:
- Total bilirubin <= 1.5 x upper limit of normal (ULN) (except in the case of
Gilbert*s disease)
- Albumin 3.0 - 5.5 g/dL
- Aspartate transaminase (AST) <= 2.5 x ULN
• Alanine transaminase (ALT) <= 2.5 x ULN
• Alkaline phosphatase <= 2.5 x ULN
• Acceptable kidney function:
- Creatinine clearance: <= 30 mL/min (by CKD-EPI formula)
• Acceptable hematologic status:
- Absolute neutrophil count (ANC) >= 1 500 cells/mm3
- Platelet count >= 100 000 cells/mm3
- Hemoglobin >= 10.0 g/dL
11) Subjects should have a suspected life expectancy of at least 6 months.
12) Documented negative test for HBV. For HBV serology, the determination of
HbsAg and anti-HbcAg Ab is required.

1) Prior treatment for GBM including resection or radiation therapy.
2) Contraindications to radiotherapy or TMZ chemotherapy (i.e allergy,
hypersensitivity or other intolerabilities to TMZ and its excipients or
hypersensitivity to dacarbazine).
3) Has a history of another primary malignancy, except for:
• Malignancy treated with curative intent and with no known active disease
within 2 years prior to SI-053 administration
• Adequately treated non-invasive basal skin cancer or squamous cell skin
carcinoma
• Adequately treated uterine cervical cancer stage 1B or less
4) Has clinically significant cardiac disease (as identified by
electrocardiogram [ECG]), including:
• Known congestive heart failure Grade III or IV by the New York Heart Failure
Association;
• Myocardial infarction within 6 months prior to signing the ICF;
• Onset of unstable angina within 6 months prior to signing the ICF.
5) Infratentorial or multifocal glioblastoma.
6) Pre-operative MRI showing ventricular invasion (defined as presence of
intraventricular lesion or of intraventricular tumor mass).
7) Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1.
8) Chronic use of systemic steroid therapy (>1 month of >10 mg prednisone
per day or equivalent, except topical or inhaled).
9) Any significant disease or disorder which, in the opinion of the
Investigator, may either put the participant at risk because of participation
in the trial, or affect the participant*s ability to participate in the trial.
Presence of active and uncontrolled infections or other severe concurrent
disease, which, in the opinion of the Investigator, would place the subject at
undue risk or interfere with the trial.
10) Subjects who have participated in another research trial involving an
investigational product within the past 12 weeks or are currently participating
in another clinical trial (excluding observational studies).
11) Pregnant or lactating women.
12) Subjects unable to undergo MRI during the trial participation.