Studying the Safety, Efficacy, and Pharmacokinetic Characteristics of BNCT in Patients With Recurrent High-grade Gliomas

This is a multi-centered, radiation dose escalation, open, exploratory, Phase 1/2a clinical trial on the safety, efficacy and pharmacokinetic characteristics of BNCT in patients with recurrent high-grade gliomas.The Phase I clinical study is to explore the adequate radiation dose level of BNCT based on confirmation of the maximum tolerated dose (radiation dose) of BNCT in patients with recurrent high-grade gliomas and characterize the safety, efficacy and pharmacokinetics.To evaluate the primary objective of tolerability, subject population with history of exposure to a similar treatment recurrent high-grade glioma who received prior standard radiotherapy will be recruited.The Phase IIa is to confirm the efficacy and safety after irradiation of radiation dose confirmed in the Phase I clinical study. To evaluate the primary objective of efficacy, subject population with glioblastoma (The 2021 WHO Classification of Tumors of the Central Nervous System, Glioblastoma IDH-wild type, WHO Grade 4) will be recruited.

Inclusion Criteria:An adult at the age 19 or above to under 80 at the time of written consentIndividual diagnosed with the following according to the WHO classification (2021)Astrocytoma, IDH-mutant, WHO grade 3, 4Oligodendroglioma, IDH-mutant, and 1p/19q-codeleted, WHO grade 3Glioblastoma, IDH wildtype, WHO grade 4Anaplastic Astrocytoma, NOS, WHO grade 3Anaplastic Oligoastrocytoma, NOS, WHO grade 3Anaplastic Oligodendroglioma, NOS, WHO grade 3Glioblastoma, NOS, WHO grade 4Individual who received radiation therapy at the standard level (54 to 66 Gy/25 to 35 fractions) or lowerIndividual confirmed to have disease progression* according to the RANO criteria within 4 weeks from the screening visit (*) At least one lesion with contrast enhancement needs to exist on the contrast enhancement MRI. For a subject who shows no lesion with contrast enhancement, functional imaging such as 18F-FET or 18F-FDOPA PET/CT needs to confirm the existence of at least one clear recurrent lesion.However, in the event differentiation between recurrence and pseudoprogression is unclear, the subject cannot participate in the screeningIndividual who is able to lie or sit for 30 minutes to 1 hour using the fixing device of the treatment couchIndividual with no metal implant such as a pacemakerIndividual with KPS (Karnofsky performance score) ≥ 60Individual with an appropriate kidney function, lung function and bone marrow function based on the laboratory test at the screening visitHemoglobin ≥ 10.0 g/dLWBC (white blood cell) ≥ 3,500/μLPlatelets ≥ 100,000/μLSerum creatinine ≤ 1.5xULNAST (aspartate aminotransferase)/ALT (alanine aminotransferase) ≤ 3xULNIndividual who receives sufficient explanation on the study, agrees to following the study procedures during the study period, and voluntarily decides to participate in the study and provides a written consent[Phase IIa study inclusion criteria]Individual histologically diagnosed with glioblastomaIndividual with at least one measurable observed lesion according to the modified RANO criteriaExclusion Criteria:Individual to which a traditional therapy such as reoperation or reirradiation is effectively applicable based on consultation with a brain tumor multidisciplinary committee or consultation among two or more medical departments, including neurosurgery and radiation oncologyIndividual who received cytotoxic anticancer therapy within 4 weeks from the screening visit (including previous interstitial anticancer therapy, local medication, and convection-enhanced delivery)Individual who received targeted anticancer therapy (e.g., bevacizumab) within 6 weeks from the screening visitIndividual who received radiotherapy within 6 months from the screening visitIndividual who received a radical surgery for high-grade glioma within 4 weeks from the screening visitIndividual who received biopsy within 1 week from the screening visitIndividual confirmed to have a history of the following:Interstitial brachytherapyStereotactic radiosurgeryReirradiation for a recurrent lesionCancer immunotherapyIndividual with uncontrollable brain edema* even with the use of corticosteroid (*) Uncontrollable brain edema: Uncontrolled serious headache, vomiting, dyspnea, consciousness disturbance of NCI CTCAE (Ver. 5.0) grade 3 or above. However, for a patient taking corticosteroid, the patient must at least be on a stable dose or dose reduction for 7 days prior to the MRI scan at the screening visit.Individual confirmed with meningeal disseminationIndividual diagnosed with cancer in another site* in the past at the time of the screening visit and whose disease-free period is less than 3 years (*) Patients with the skin basal cell carcinoma and carcinoma in situ of uterine cervix who received radical treatment are excludedIndividual with hypotonic dehydration or hereditary fructose intoleranceIndividual with current or a history of phenylketonuriaIndividual with serious infection (e.g., sepsis, HIV) in the opinion of the investigatorIndividual who has dysfunction as below or, in the investigator's opinion, who is confirmed to have clinically significant disease (e.g., unstable angina, myocardial infarction) within 6 months from the screening visit:Heart disease of Class II or above according to the New York Heart Association Functional ClassificationChronic obstructive pulmonary disease of moderate or higher severity according to the Chronic obstructive pulmonary disease clinical practice, or Dyspnea of Grade II or above according to the American thoracic society dyspnea scaleHepatic dysfunction of Child-Pugh Classification B or CIndividual with current or a history of hypersensitivity to boron or any component of the study drugIndividual who received or applied other investigational product or device within 4 weeks from the screening visitIndividual who has received prior BNCTPregnant woman, breastfeeding woman, or individual who plans pregnancy or who does not agree to using and does not perform a medically reliable contraceptive method during the study periodWomen of childbearing potential*: Use of 'intrauterine device', 'tubal surgery or tubal ligation', 'chemical barrier method (spermicide) + physical barrier method' or 'subcutaneously implanted contraceptive device + physical barrier method' (*) Woman of any potential of pregnancy, except for those who are before their first period, who received surgical sterilization (hysterectomy or bilateral ovariectomy) or who reached menopause (absence of menstrual periods for 12 months without any specific reason)Male: Vasectomy or use of 'male condom + use of a medically reliable contraceptive method by the partner'Individual not eligible for MRI or PET/CT scanIndividual the investigator otherwise considers ineligible for participating in the study [At the treatment planning visit, the following exclusion criteria will be checked:]Individual not eligible for BNCT implementation according to the treatment plan established with DM-BTPS