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

Sponsor

Dawonmedax Co., Ltd. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05737212

Collaborator

(none)

Enrollment

Location

Arms

23.9

Anticipated Duration (Months)

1.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Recurrent High-grade Glioma Recurrent Glioblastoma Recurrent Anaplastic Astrocytoma Recurrent Anaplastic Oligodendroglioma	Radiation: 500mg/kg/3hr followed by neutron irradiation to reach maximum brain dose of 9Gy-Eq Radiation: 500mg/kg/3hr followed by neutron irradiation to reach maximum brain dose of 11Gy-Eq Radiation: 500mg/kg/3hr followed by neutron irradiation to reach maximum brain dose of 13Gy-Eq	Phase 1/Phase 2

Detailed Description

The subject receives the study drug administration and neutron irradiation in the BNCT clinic with all procedures performed under the control by the investigator affiliated to the study site. 500 mg/kg of the study drug is intravenously administered over 3 hours at a constant rate and neutron irradiation starts at 1 hour after the end of the study drug administration according to the previously established neutron irradiation plan.

All patients will be evaluated for response using magnetic resonance imaging (MRI) using RANO and modified RANO criteria.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

39 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

In the Phase I clinical study, the 3+3 dose escalation design is applied to evaluate the dose limiting toxicity (DLT) and 3 study subjects are enrolled to each group (Group 1, Group 2, Group 3). Depending on whether or not DLT occurs, 3 subjects at minimum to 18 subjects at maximum are enrolled. However, in the event a subject assigned a subject number withdraws from the study before starting BNCT or within 90 days from starting BNCT for reasons other than safety, up to 3 additional subjects can be enrolled for each dose group, resulting in 27 subjects at maximum allowed for enrollment for the Phase I clinical study. In the Phase IIa clinical study, up to 12 subjects are enrolled. However, subjects who are included in a group that has received the radiation dose confirmed as the maximum tolerated dose (MTD) in the Phase 1 clinical study AND satisfy all inclusion/exclusion criteria of the Phase IIa are included in the number of subjects of Phase IIa.In the Phase I clinical study, the 3+3 dose escalation design is applied to evaluate the dose limiting toxicity (DLT) and 3 study subjects are enrolled to each group (Group 1, Group 2, Group 3). Depending on whether or not DLT occurs, 3 subjects at minimum to 18 subjects at maximum are enrolled. However, in the event a subject assigned a subject number withdraws from the study before starting BNCT or within 90 days from starting BNCT for reasons other than safety, up to 3 additional subjects can be enrolled for each dose group, resulting in 27 subjects at maximum allowed for enrollment for the Phase I clinical study. In the Phase IIa clinical study, up to 12 subjects are enrolled. However, subjects who are included in a group that has received the radiation dose confirmed as the maximum tolerated dose (MTD) in the Phase 1 clinical study AND satisfy all inclusion/exclusion criteria of the Phase IIa are included in the number of subjects of Phase IIa.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Multi-centered, Radiation Dose Escalation, Open, Exploratory, Phase 1/2a Clinical Trial on the Safety, Efficacy and Pharmacokinetic Characteristics of BNCT(Boron Neutron Capture Therapy) in Patients With Recurrent High-grade Gliomas

Actual Study Start Date :

Dec 5, 2022

Anticipated Primary Completion Date :

Jun 1, 2023

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1 Radiation dose: 9 Gy-Eq Investigational product, boronophenylalanine, DMX-101 500mg/kg/3hr Investigational Device, DM-BTPS, DM-BNCT - neutron irradiation to reach maximum BNCT dose in brain of 9 Gy-Eq	Radiation: 500mg/kg/3hr followed by neutron irradiation to reach maximum brain dose of 9Gy-Eq Patients will be infused DMX-101 intravenously at a dose of 500mg/kg/hr over 3 hours. Thereafter, patient will receive neutron irradiation simultaneously for a certain period of time based on his Boronophenylalanine (BPA) concentration in the blood.
Experimental: Group 2 Radiation dose: 11 Gy-Eq Investigational product, boronophenylalanine, DMX-101 500mg/kg/3hr Investigational Device, DM-BTPS, DM-BNCT - neutron irradiation to reach maximum BNCT dose in brain of 11 Gy-Eq	Radiation: 500mg/kg/3hr followed by neutron irradiation to reach maximum brain dose of 11Gy-Eq Patients will be infused DMX-101 intravenously at a dose of 500mg/kg/hr over 3 hours. Thereafter, patient will receive neutron irradiation simultaneously for a certain period of time based on his Boronophenylalanine (BPA) concentration in the blood.
Experimental: Group 3 Radiation dose: 13 Gy-Eq Investigational product, boronophenylalanine, DMX-101 500mg/kg/3hr Investigational Device, DM-BTPS, DM-BNCT - neutron irradiation to reach maximum BNCT dose in brain of 13Gy-Eq	Radiation: 500mg/kg/3hr followed by neutron irradiation to reach maximum brain dose of 13Gy-Eq Patients will be infused DMX-101 intravenously at a dose of 500mg/kg/hr over 3 hours. Thereafter, patient will receive neutron irradiation simultaneously for a certain period of time based on his Boronophenylalanine (BPA) concentration in the blood.

Arm

Intervention/Treatment

Experimental: Group 1

Radiation dose: 9 Gy-Eq Investigational product, boronophenylalanine, DMX-101 500mg/kg/3hr Investigational Device, DM-BTPS, DM-BNCT - neutron irradiation to reach maximum BNCT dose in brain of 9 Gy-Eq

Radiation: 500mg/kg/3hr followed by neutron irradiation to reach maximum brain dose of 9Gy-Eq

Patients will be infused DMX-101 intravenously at a dose of 500mg/kg/hr over 3 hours. Thereafter, patient will receive neutron irradiation simultaneously for a certain period of time based on his Boronophenylalanine (BPA) concentration in the blood.

Experimental: Group 2

Radiation dose: 11 Gy-Eq Investigational product, boronophenylalanine, DMX-101 500mg/kg/3hr Investigational Device, DM-BTPS, DM-BNCT - neutron irradiation to reach maximum BNCT dose in brain of 11 Gy-Eq

Radiation: 500mg/kg/3hr followed by neutron irradiation to reach maximum brain dose of 11Gy-Eq

Experimental: Group 3

Radiation dose: 13 Gy-Eq Investigational product, boronophenylalanine, DMX-101 500mg/kg/3hr Investigational Device, DM-BTPS, DM-BNCT - neutron irradiation to reach maximum BNCT dose in brain of 13Gy-Eq

Radiation: 500mg/kg/3hr followed by neutron irradiation to reach maximum brain dose of 13Gy-Eq

Outcome Measures

Primary Outcome Measures

Phase I: To explore the adequate radiation dose level of BNCT based on confirmation of the maximum tolerated dose of BNCT [During 90 days post-BNCT]
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
Phase IIa: Proportion of 6-month PFS evaluated by central imaging according to the modified RANO criteria [6 months]
Percentage of patients that are free from progressive disease for 6 months per modified RANO criteria

Secondary Outcome Measures

Proportion of 6-month PFS evaluated by central imaging according to the RANO criteria [Up to 6 months]
Percentage of patients that are free from progressive disease for 6 months per RANO criteria
Proportion of 6-month PFS evaluated by the investigator according to the modified RANO criteria [Up to 6 months]
Percentage of patients that are free from progressive disease for 6 months per modified RANO criteria
Median PFS evaluated by central imaging according to the modified RANO criteria [Up to 6 months]
Median duration of progression free survival according to modified RANO criteria
Median PFS evaluated by central imaging according to the RANO criteria [Up to 6 months]
Median duration of progression free survival according to RANO criteria
Median PFS evaluated by the investigator according to the modified RANO criteria [Up to 6 months]
Median duration of progression free survival according to modified RANO criteria
ORR evaluated by central imaging according to the modified RANO criteria [Up to 6 months]
ORR will be defined as the percentage of patients with complete response (CR) or partial response (PR) according to the modified RANO criteria.
ORR evaluated by central imaging according to the RANO criteria [Up to 6 months]
ORR will be defined as the percentage of patients with complete response (CR) or partial response (PR) according to the RANO criteria.
ORR evaluated by the investigator according to the modified RANO criteria [Up to 6 months]
ORR will be defined as the percentage of patients with complete response (CR) or partial response (PR) according to the modified RANO criteria.
Median OS [Up to 2 years]
Median duration of overall survival for patients that are alive
Proportion of 1-year OS [Up to 2 years]
Percentage of patients that are alive for 1 year
Pharmacokinetic parameters(AUClast) of borono-phenylalanine in subjects with recurrent high-grade glioma [Based on whole blood sample up to 48 hours after the end of infusion]
The analysis is conducted using the Noncompartmental Analysis Method, and the results are summarized for each group in terms of descriptive statistics including the mean, standard deviation, minimum, median, and maximum values.
Pharmacokinetic parameters(AUCinf) of borono-phenylalanine in subjects with recurrent high-grade glioma [Based on whole blood sample up to 48 hours after the end of infusion]
The analysis is conducted using the Noncompartmental Analysis Method, and the results are summarized for each group in terms of descriptive statistics including the mean, standard deviation, minimum, median, and maximum values.
Pharmacokinetic parameters(Cmax) of borono-phenylalanine in subjects with recurrent high-grade glioma [Based on whole blood sample up to 48 hours after the end of infusion]
The analysis is conducted using the Noncompartmental Analysis Method, and the results are summarized for each group in terms of descriptive statistics including the mean, standard deviation, minimum, median, and maximum values.
Pharmacokinetic parameters(Tmax) of borono-phenylalanine in subjects with recurrent high-grade glioma [sampling up to 48 hours after the end of infusion]
The analysis is conducted using the Noncompartmental Analysis Method, and the results are summarized for each group in terms of descriptive statistics including the mean, standard deviation, minimum, median, and maximum values.
Pharmacokinetic parameters(CL) of borono-phenylalanine in subjects with recurrent high-grade glioma [Based on whole blood sample up to 48 hours after the end of infusion]
The analysis is conducted using the Noncompartmental Analysis Method, and the results are summarized for each group in terms of descriptive statistics including the mean, standard deviation, minimum, median, and maximum values.
Pharmacokinetic parameters(Vz) of borono-phenylalanine in subjects with recurrent high-grade glioma [Based on whole blood sample up to 48 hours after the end of infusion]
The analysis is conducted using the Noncompartmental Analysis Method, and the results are summarized for each group in terms of descriptive statistics including the mean, standard deviation, minimum, median, and maximum values.
Pharmacokinetic parameters(Vss) of borono-phenylalanine in subjects with recurrent high-grade glioma [Based on whole blood sample up to 48 hours after the end of infusion]
The analysis is conducted using the Noncompartmental Analysis Method, and the results are summarized for each group in terms of descriptive statistics including the mean, standard deviation, minimum, median, and maximum values.
Pharmacokinetic parameters(t1/2β) of borono-phenylalanine in subjects with recurrent high-grade glioma [Based on whole blood sample up to 48 hours after the end of infusion]
The analysis is conducted using the Noncompartmental Analysis Method, and the results are summarized for each group in terms of descriptive statistics including the mean, standard deviation, minimum, median, and maximum values.
Pharmacokinetic parameters(MRT) of borono-phenylalanine in subjects with recurrent high-grade glioma [Based on whole blood sample up to 48 hours after the end of infusion]
The analysis is conducted using the Noncompartmental Analysis Method, and the results are summarized for each group in terms of descriptive statistics including the mean, standard deviation, minimum, median, and maximum values.

Eligibility Criteria

Criteria

Ages Eligible for Study:

19 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

An adult at the age 19 or above to under 80 at the time of written consent
Individual diagnosed with the following according to the WHO classification (2021)

Astrocytoma, IDH-mutant, WHO grade 3, 4
Oligodendroglioma, IDH-mutant, and 1p/19q-codeleted, WHO grade 3
Glioblastoma, IDH wildtype, WHO grade 4
Anaplastic Astrocytoma, NOS, WHO grade 3
Anaplastic Oligoastrocytoma, NOS, WHO grade 3
Anaplastic Oligodendroglioma, NOS, WHO grade 3
Glioblastoma, NOS, WHO grade 4

Individual who received radiation therapy at the standard level (54 to 66 Gy/25 to 35 fractions) or lower
Individual 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 screening

Individual who is able to lie or sit for 30 minutes to 1 hour using the fixing device of the treatment couch
Individual with no metal implant such as a pacemaker
Individual with KPS (Karnofsky performance score) ≥ 60
Individual with an appropriate kidney function, lung function and bone marrow function based on the laboratory test at the screening visit

Hemoglobin ≥ 10.0 g/dL
WBC (white blood cell) ≥ 3,500/μL
Platelets ≥ 100,000/μL
Serum creatinine ≤ 1.5xULN
AST (aspartate aminotransferase)/ALT (alanine aminotransferase) ≤ 3xULN

Individual 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 glioblastoma
Individual with at least one measurable observed lesion according to the modified RANO criteria

Exclusion 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 oncology
Individual 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 visit
Individual who received radiotherapy within 6 months from the screening visit
Individual who received a radical surgery for high-grade glioma within 4 weeks from the screening visit
Individual who received biopsy within 1 week from the screening visit
Individual confirmed to have a history of the following:

Interstitial brachytherapy
Stereotactic radiosurgery
Reirradiation for a recurrent lesion
Cancer immunotherapy

Individual 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 dissemination
Individual 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 excluded
Individual with hypotonic dehydration or hereditary fructose intolerance
Individual with current or a history of phenylketonuria
Individual with serious infection (e.g., sepsis, HIV) in the opinion of the investigator
Individual 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 Classification
Chronic 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 scale
Hepatic dysfunction of Child-Pugh Classification B or C

Individual with current or a history of hypersensitivity to boron or any component of the study drug
Individual who received or applied other investigational product or device within 4 weeks from the screening visit
Individual who has received prior BNCT
Pregnant 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 period

Women 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 scan
Individual 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