A Dose Escalation Study to Estimate MTD, DLTs and Pharmacokinetics After a Single Intracranial Dose of SI-053 as an add-on to the Current Standard of Care, in Adult Patients With Newly Diagnosed GBM

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A Dose Escalation Study to Estimate MTD, DLTs and Pharmacokinetics After a Single Intracranial Dose of SI-053 as an add-on to the Current Standard of Care, in Adult Patients With Newly Diagnosed GBM

Study Purpose

SI-053 is a novel powder formulation containing temozolomide (TMZ), an alkylating chemotherapy agent, in an excipient which forms a viscous gel upon reconstitution in water. SI-053 will be used as an add-on to SoC for newly diagnosed GBM. SoC consists of maximal safe resection followed by radiation therapy (RT) with concomitant TMZ and adjuvant chemotherapy with TMZ. For MGMT promoter methylated GBM, lomustine and TMZ may be administered plus radiation therapy

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years - 70 Years
Gender	All

More Inclusion & Exclusion Criteria

Inclusion Criteria:

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% 9. Women of childbearing potential (WOCBP) and men whose partner is of childbearing potential must use effective contraception 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.

Exclusion Criteria:

- Subjects who fulfil any of the following criteria will be excluded from the trial: 1.

Prior treatment for GBM including resection or radiation therapy. 2. Contraindications to radiation therapy 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. 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

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT04967690
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 1
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Double Bond Pharmaceutical AB
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Manfred Westphal, Prof.Dr.Med.
Principal Investigator Affiliation	Universitätklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Industry
Overall Status	Not yet recruiting
Countries
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Newly Diagnosed Glioblastoma

Arms & Interventions

Arms

Experimental: SI-053

Single arm study. Dose escalation will follow a rule-based 3 + 3 design using increasing doses of SI-053. Subjects will receive a single i.c. dose of room-tempered SI-053 gel, which will be applied onto the walls of the cavity formed after tumor resection using a sterile spatula.This will be followed by chemo-radiotherapy commencing at least 21 and no later than 35 days after SI-053 administration. The dose escalation part of the trial will follow a rule-based 3 + 3 design using a total of six dose levels of SI-053 (optional dose of 50 mg will be used to de-escalate in case of DLT at 75 mg) that consist of increasing amounts of TMZ in a constant amount of excipient and sterile WFI. These dose levels are planned to be tested in 21 subjects, including three more subjects at preliminary RP2D.The dose expansion phase will enroll an additional six subjects,to be treated at the RP2D in order to gather additional safety and preliminary efficacy data at that dose.

Interventions

Drug: - SI-053

SI-053 will be used as an add-on to SoC for newly diagnosed GBM.In conjunction with surgical resection, SI-053 will be applied intracranially (i.c.) into the cavity that is formed after tumor resection. Post-operative chemoradiotherapy (including concomitant and adjuvant TMZ or following the CeTeG protocol) will be initiated at least 21 and no later than 35 days after SI-053 administration.