UMIN-CTR Clinical Trial

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

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

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

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.

Study type

Interventional

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

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

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

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

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

Institute

Department of Radiation Oncology,
Southern Tohoku BNCT Research Center

Institute

Department

Personal name

Organization

Japan Society for the Promotion of Science

Organization

Division

Category of Funding Organization

Japanese Governmental office

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

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

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

脳神経疾患研究所附属南東北BNCT研究センター

Date of disclosure of the study information

2021

Year

05

Month

10

Day

URL releasing protocol

Publication of results

Unpublished

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

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 related information

Registered date

2021

Year

05

Month

06

Day

Last modified on

2021

Year

05

Month

06

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000050375