UMIN-CTR Clinical Trial

Basic information
Public title	Boron neutron capture therapy using cyclotron-based epithermal neutron source for squamous cell carcinoma of the head and neck refractory to standard treatments: An open-label phase II trial
Acronym	REBIVAL study
Scientific Title	Boron neutron capture therapy using cyclotron-based epithermal neutron source for squamous cell carcinoma of the head and neck refractory to standard treatments: An open-label phase II trial
Scientific Title:Acronym	REBIVAL study
Region	Japan

Condition
Condition	unresectable squamous cell carcinoma of the head and neck refractory to standard treatments
Classification by specialty	Oto-rhino-laryngology Radiology Adult
Classification by malignancy	Malignancy
Genomic information	YES

Objectives
Narrative objectives1	The purpose of study is to evaluate effect of squamous cell carcinoma of the head and neck refractory to standard treatments on long-term tumor control by Boron neutron capture therapy using cyclotron-based epithermal neutron source.
Basic objectives2	Safety,Efficacy
Basic objectives -Others
Trial characteristics_1	Confirmatory
Trial characteristics_2
Developmental phase

Assessment
Primary outcomes	Locoregional progression-free survival within 2 years after BNCT
Key secondary outcomes	1. Response rate Evaluate tumor response within 180 days. 2. Duration of response From the time that the measurement criteria are first met for CR or PR until the first date that recurrent or the progressive disease is objectively documented. 3. Disease control rate Evaluate tumor response within 180 days. 4. Overall survival The time to death from any cause. 5. Progression-free survival The time to the date of first documented PD. 6. QOL assessment based on EORTC-QLQ-C30 and HN35. QOL assessment in the post-treatment observation period. 7. Quality-adjusted life year (QALY) To calculate the QALY, QOL assessment is used in EQ-5D-5L Japanese version. 8. Adverse events The occurrence of acute adverse events within 90 days after BNCT, and the occurrence of late adverse events 90 days after BNCT. 9. 18F-FDG-PET If available before the start of BNCT, and Day 90 or 180, evaluate changes in SUV. 10. 18F-FBPA-PET If available before the start of BNCT, and Day 90 or 180, evaluate changes in SUV. 11. Boron concentration change in whole blood and blood plasma Two hours later after the administration of Borofalan (10B), right after neutron irradiation, 30 minutes later after the administration, evaluate boron concentration in whole blood and blood plasma. 12. Immune responsiveness in the tumor tissue assessments If available, perform a biopsy before the start of BNCT and Day 3-5. Evaluate PD-L1 IHC and immune responsiveness on single staining protocol. 13. Changes cytokine level in blood If available, evaluate changes cytokine level in blood before the start of BNCT, Day 1, 3, 14, 30, 90. 14. Genetic mutation and expression analysis If available, perform a biopsy before the start of BNCT and Day 3-5, then extract neoplasm DNA and RNA, and miRNA from blood specimen and analysis tumor gene mutation and gene expression. 15. Metabolome analysis If available, evaluate changes metabolic product in blood before the start of BNCT, Day 1, 3.

Base
Study type	Interventional

Study design
Basic design	Single arm
Randomization	Non-randomized
Randomization unit
Blinding	Open -no one is blinded
Control	Uncontrolled
Stratification	NO
Dynamic allocation	NO
Institution consideration	Institution is not considered as adjustment factor.
Blocking	NO
Concealment	No need to know

Intervention
No. of arms	1
Purpose of intervention	Treatment
Type of intervention	Medicine Device,equipment
Interventions/Control_1	Patients will be administered borofalan(10B) intravenously at 200 mg/kg/h for 2 h. The blood boron concentration will be measured after 2 h, and will be used to calculate the optimized thermal neutron flux based on the mucosal tolerable dose renewed by the previous observational study. Neutrons are irradiated to the target site from the accelerator-based neutron generator to the specified charge while borofalan(10B) is administered at a moderated dose of 100 mg/kg/h.
Interventions/Control_2
Interventions/Control_3
Interventions/Control_4
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10

Eligibility
Age-lower limit	20 years-old <=
Age-upper limit	Not applicable
Gender	Male and Female
Key inclusion criteria	1. Document consent by his/her own free will. 2. 20 years old or older. 3. ECOG performance status of 0-2. 4. The primary lesion is histologically head and neck cancer. 5. Any participant who meets any of the following criteria refractory to standard treatments. - Patients with locally recurrent head and neck squamous cell carcinoma after chemoradiotherapy or radiation. - Patients with primary locally recurrent head and neck squamous cell carcinoma refractory to standard treatments such as radical chemoradiotherapy, and prior radiation therapy. 6. Patients who have at least one measurable lesion in the target lesion site based on RECIST (version 1.1) 7. Patients with unilateral local recurrent lesion(s). 8. Patients with radiation therapy, fractionation around 2Gy/day, total dose within the range of 40 Gy and Radiation therapy, over 40 Gy of total biologically effective dose; 2Gy/day. 9. 50 days or more have passed since the last irradiation date of prior radiation therapy for the evaluation target lesion site to the scheduled date of BNCT. 10. Over 90 days of survival is expected after BNCT. 11. Patients that able to receive at least 20 Gy-Eq (expected tumor minimum dose) for the evaluation target lesion site on the prior simulation with the CT images at screening test. 12. Any participant who meets any of the following criteria. Supportive therapies (G-CSF and blood transfusion), which might affect the following tests within 14 days before the screening tests are prohibited. - Kidney function Serum creatinine level <= 1.2mg/dL for male; serum creatinine level <= 1.0mg/dL for female) - Liver function AST <= 5 x ULN ALT <= 5 x ULN - Hemoglobin >= 8.0 g/dL - Platelet count >= 80,000/microL - White blood cell count >= 2,500/microL - Neutrophil count >= 1,500/microL
Key exclusion criteria	1. Patients (Pts) with active multiple cancers, not including lesions equivalent to carcinoma in situ or skin cancer considered healed 2. Pts with distant metastasis 3. Pts with active infections requiring systemic treatment 4. Pts with significant complications - Poorly uncontrolled diabetes - Poorly uncontrolled hypertension - Chronic lung disease - Kidney disease - Heart disease - Serious complications 5. Pts with phenylketonuria 6. Pts with hereditary fructose intolerance 7. Pts who have complications and a medical history with severe hypersensitivity reactions in drugs and contrast agents 8. Pts with myocardial infarction, unstable angina, uncontrolled arrhythmia within 6 months 9. Pts with over Grade 3 (CTCAE v4.0) in the target lesion site 10. Pts with the tumors invade the carotid artery or adjacent to more than halfway through the carotid artery, and considered not to manage the normal tissue between the carotid artery and membrane mucosa or skin by the treatments 11. Pts with decayed and untreated teeth 12. Pts with the administration of antineoplastic drug within 3weeks prior to the scheduled date of BNCT 13. Pts who were enrolled in unapproved drugs clinical study except for 18F-FBPA-PET/CT or who are participating in this clinical study within 4 weeks prior to the scheduled date of BNCT. Or patients will participate in unapproved drugs clinical study except for 18F-FBPA-PET/CT other clinical study during this study 14. Pts who have a cardiac pacemaker and auxiliary artificial heart 15. Pts who are considered unable to be fixed position during irradiation 16. Pts who complicated with psychiatric disorder or mental manifestation 17. Pts with poorly uncontrolled epilepsy 18. Pts who unable to comply with this clinical protocol and receive follow-up care 19. Other conditions that in the opinion of the investigator would preclude the subject's participation in a clinical study
Target sample size	120

Research contact person
Name of lead principal investigator	1st name Katsumi Middle name Last name Hirose
Organization	Southern Tohoku BNCT Research Center
Division name	Department of Radiation Oncology
Zip code	963-8052
Address	7-10 Yatsuyamada, Koriyama, Fukushima
TEL	81-24-934-5330
Email	khirose@hirosaki-u.ac.jp

Public contact
Name of contact person	1st name Katsumi Middle name Last name Hirose
Organization	Southern Tohoku BNCT Research Center
Division name	Department of Radiation Oncology
Zip code	963-8052
Address	7-10 Yatsuyamada, Koriyama, Fukushima
TEL	81-24-934-5330
Homepage URL
Email	khirose@hirosaki-u.ac.jp

Sponsor
Institute	Department of Radiation Oncology, Southern Tohoku BNCT Research Center
Institute
Department

Funding Source
Organization	Japan Society for the Promotion of Science
Organization
Division
Category of Funding Organization	Japanese Governmental office
Nationality of Funding Organization

Other related organizations
Co-sponsor
Name of secondary funder(s)

IRB Contact (For public release)
Organization	Southern Tohoku General Hospital
Address	7-115 Yatsuyamada, Koriyama, Fukushima
Tel	81-24-934-5322
Email	bnct.irb@mt.strins.or.jp

Secondary IDs
Secondary IDs	NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions	脳神経疾患研究所附属南東北BNCT研究センター

Other administrative information
Date of disclosure of the study information	2021 Year 05 Month 10 Day

Related information
URL releasing protocol
Publication of results	Unpublished

Result
URL related to results and publications
Number of participants that the trial has enrolled
Results
Results date posted
Results Delayed
Results Delay Reason
Date of the first journal publication of results
Baseline Characteristics
Participant flow
Adverse events
Outcome measures
Plan to share IPD
IPD sharing Plan description

Progress
Recruitment status	Preinitiation
Date of protocol fixation	2021 Year 03 Month 11 Day
Date of IRB	2021 Year 03 Month 12 Day
Anticipated trial start date	2021 Year 05 Month 10 Day
Last follow-up date	2030 Year 03 Month 31 Day
Date of closure to data entry
Date trial data considered complete
Date analysis concluded

Other
Other related information

Management information
Registered date	2021 Year 05 Month 06 Day
Last modified on	2021 Year 05 Month 06 Day

Link to view the page
URL(English)	https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000050375