Investigator-initiated phase I trial of an oligonucleotide therapeutic targeting long noncoding RNA TUG 1 for recurrent glioblastoma (2025)

Background

Glioblastoma (GB) is the most common and aggressive primary malignant brain tumor in adults. To date, no effective treatment has been reported for recurrent GB (rGB). Long noncoding RNA taurine upregulated gene 1 (TUG1), which is highly expressed in GB, resolves the formation of R-loops, thereby maintaining tumor growth. TUG1-targeting antisense oligonucleotide (ASO) (TUG1ASO) is a nucleotide therapeutic with drug delivery system that targets TUG1, demonstrating efficacy against GB in mouse models. This multicenter, first-in-human, phase I trial aims to investigate the safety and maximum tolerated dose (MTD) of TUG1ASO.

Methods

This study will enroll patients aged 18–75 years with rGB following postoperative temozolomide plus radiation therapy. The primary endpoints will be the safety and tolerability of TUG1ASO and the MTD. The secondary endpoints will be the response rate, duration of response, progression-free survival, overall survival, and pharmacokinetics of TUG1ASO. Dose escalation will be performed utilizing a 3 + 3 design with four dose levels. Unless the discontinuation criteria are met, four cycles will be administered, with each cycle lasting 7 days. Administration of TUG1ASO will be possible until the discontinuation criteria are met.

Discussion

TUG1ASO is the first oligonucleotide therapeutic with drug delivery system targeting TUG1, expected to show an efficacy in rGB patients. In this first-in-human study, safety, tolerability and MTD of this new targeted therapy will be confirmed to find the recommended dose for the further clinical trial. This study may contribute to develop a new treatment option for rGB patients.

Trial registration

Japan Registry of Clinical Trials (jRCT) 2041230136, registration date May 17, 2024.

Registry

jRCT2041230136.

Registration date

May 17, 2024.

Study dates

January 1, 2024, to present.

Glioblastoma (GB) is the most common and aggressive primary malignant brain tumor in adults. The standard treatment for GB is maximal safe resection or diagnostic biopsy, followed by combined radiotherapy (60Gy) with concomitant daily temozolomide (TMZ), followed by maintenance treatment with TMZ [1]. However, almost all patients with GB experience recurrence even after standard treatment. The period from surgery to recurrence is approximately 7 months [1]. To date, no standard of care has been established for recurrent GB (rGB). Bevacizumab extends progression-free survival (PFS) but does not confer a survival advantage [2]. Nivolumab also fails to demonstrate efficacy against rGB [3]. Treatment for rGB may require drugs with a mechanism different from that of the existing drugs.

Taurine upregulated gene 1-targeting antisense oligonucleotide (TUG1ASO) is an oligonucleotide therapeutic drug delivery system (DDS) that targets the long noncoding RNA (lncRNA) TUG1, which is highly expressed in GB [4]. Unlike messenger RNA, lncRNAs are not translated into proteins. However, as a component of epigenetics, TUG1 has an important function in maintaining GB cells. In tumor cells that continue to have high levels of DNA replication and RNA synthesis, R-loops (structures consisting of three nucleic acid strands: DNA: RNA hybrid and non-template single-stranded DNA) occur owing to the dysregulation of DNA polymerase and RNA polymerase [5]. Accumulation of R-loops causes DNA damage. TUG1 resolves the formation of R-loops, thereby maintaining tumor growth. As the accumulation of R-loops is rare in normal cells, it is reasonable to target TUG1, which is highly expressed in patients with GB. TUG1ASO is a combination of a locked nucleic acid (LNA) gapmer of an ASO against human TUG1 and DDS, which is a branched polyethylene glycol-cationic poly-amino acid block copolymer (YBC polymer). When administered intravenously, it forms a unit poly-ionic complex with a diameter of 17nm and penetrates the blood–brain tumor barrier [6].

TUG1ASO has never been administered in humans, even in clinical trials. A nonclinical efficacy study was conducted using a model in which glioma stem cells derived from patients with GB were transplanted into the brains of immunodeficient mice [4, 6]. TUG1ASO demonstrated complete remission and significant survival benefits. It also demonstrated antitumor activity in a nude mouse subcutaneous transplantation model using two human GB cell lines. In repeated-dose studies using rats and cynomolgus monkeys, somnolence and mild elevation of liver enzymes were observed; however, no serious adverse events (AEs) were noted.

This multicenter, first-in-human, phase I trial aims to investigate the safety and maximum tolerated dose (MTD) of TUG1ASO.

Objectives

The primary objectives are as follows:

• To evaluate the safety and tolerability of TUG1ASO.

• To establish the MTD of TUG1ASO.

The secondary objectives are as follows:

• To evaluate response rate using the Response Assessment in Neuro-Oncology criteria for high-grade gliomas.

• To determine the duration of response (DOR), PFS, and overall survival (OS).

• To assess the pharmacokinetics of TUG1ASO.

Characteristics of participants

Inclusion criteria

1. (1)

   Patients histologically diagnosed with GB (including giant cell GB and gliosarcoma) in a surgically resected or biopsy specimen (regardless of whether it is at the time of initial onset, recurrence, or progression).

2. (2)

   Patients refractory or intolerant to standard treatment or for whom there is no equivalent treatment.

3. (3)

   Patients who have received postoperative (including biopsy by craniotomy or stereotactic surgery) concurrent chemoradiotherapy with TMZ (≥ 54Gy for those aged ≤ 69 years and ≥ 25Gy for those aged ≥ 70 years) as initial treatment at the time of initial onset (including World Health Organization classification grade III), followed by two or more courses of maintenance TMZ therapy (standard dose).

4. (4)

   Patients who have not undergone tumor resection after recurrence or progression: Patients who meet all of the following criteria on head contrast magnetic resonance imaging (MRI) before enrollment:

1. a)

   If steroids are administered after recurrence or progression, contrast MRI of the head must be performed at least 5 days after the start of steroid administration.

2. b)

   Recurrence or progression of GB has been confirmed.

3. c)

   No acute or subacute cerebral hemorrhage has been observed on T1-/T2-weighted images. Asymptomatic patients with hemosiderin and/or intratumoral petechiae are eligible.

4. d)

   Measurable enhanced lesions with qa maximum diameter of ≥ 10mm in both perpendicular directions.

1. (5)

   Patients who have undergone tumor resection after recurrence or progression: Patients who meet all of the following criteria:

1. a)

   GB recurrence or progression has been confirmed via contrast-enhanced head MRI before tumor resection at the time of recurrence or progression.

2. b)

   The amount of residual tumor after tumor resection is confirmed using contrast-enhanced and non-contrast (T1-weighted) head MRI within 3 days of tumor resection (day 0 is the day of tumor resection).

3. c)

   An anaplastic astrocytoma or GB has been histologically confirmed in the resected specimen at the time of reoperation.

4. d)

   Four days after tumor resection, contrast-enhanced head MRI before registration meets all of the following criteria:

   1. i.

      If steroids are administered after recurrence or progression, contrast MRI of the head must be performed at least 5 days after the start of steroid administration.

   2. ii.

      The presence or absence of measurable lesions is not an issue.

   3. iii.

      Head MRI before enrollment showed no worsening of the cerebral hemorrhage compared with head MRI performed within 3 days after tumor resection (no increase in methemoglobin or hemosiderin on T1-/T2-weighted images).

1. (6)

   At the time of registration, the patients had to have received radiation therapy for at least 90 days. In the case of reoperation, patients must be enrolled within 28 days after 21 days after the reoperation.

2. (7)

   Patients aged ≥ 18 years and ≤ 75 years on the day of registration.

3. (8)

   Patients with a Karnofsky Performance Status (KPS) score of ≥ 60 within 14 days prior to registration.

4. (9)

   Patients whose most recent test results within 14 days prior to registration (the same day of 2 weeks prior to the registration date is acceptable) meet all of the following criteria:

1. a)

   Neutrophil count ≥ 1,500 /mm³.

2. b)

   Hemoglobin level ≥ 9.0g/dL.

3. c)

   Platelet count ≥ 10 × 10⁴ /mm³.

4. d)

   Aspartate aminotransferase (AST) (glutamic oxaloacetic transaminase) level ≤ 100 IU/L.

5. e)

   Alanine transaminase (ALT) (glutamic pyruvic transaminase) level ≤ 100 IU/L.

6. f)

   Prothrombin time international normalized ratio < 1.5.

7. g)

   Serum creatinine level ≤ 1.5mg/dL.

8. h)

   Qualitative urine protein: (–) to (+).

1. (10)

   Patients who have provided written consent to participate in this study. If the patient is able to understand and consent to the explanation, but has difficulty signing because of neurological symptoms, a substitute writer may sign the patient’s signature to confirm consent.

Exclusion criteria

1. (1)

   Patients with extracerebral metastases.

2. (2)

   Patients with symptoms due to a marked increase in intracranial pressure.

3. (3)

   Patients with tumors in the cerebellum, brainstem, pituitary gland, optic nerve, or olfactory nerve at the time of initial onset or recurrence/progression.

4. (4)

   Patients with intrathecal dissemination or gliomatosis of the cerebri.

5. (5)

   Patients with active double cancers^{Footnote 1}.

1. (6)

   Patients with a history of chemotherapy, molecular targeted drugs, or radiation therapy in the head and neck region for other cancers.

2. (7)

   Patients with infectious diseases requiring systemic administration of antibiotics or antivirals.

3. (8)

   Patients positive for human immunodeficiency virus (HIV) antibodies.

4. (9)

   Patients positive for hepatitis B surface B (HBs) antigen or hepatitis type C virus C (HCV) antibodies. Patients who are negative for HBs antigen but positive for both HBc and/or HBs antibodies can be enrolled only if they agree to regular quantitative HBV-DNA testing.

5. (10)

   Men with QTcF > 450 ms and women with QTcF > 470 ms on a 12-lead electrocardiogram.

6. (11)

   Patients with severe heart diseases^{Footnote 2}.

1. (12)

   Patients with psychiatric disorders or symptoms that make it difficult to continue participating.

2. (13)

   Patients who received antitumor treatment for GB (including anaplastic astrocytoma at initial onset) within the period prior to the start of the study drug administration:

1. a)

   Temozolomide: within 4 weeks.

2. b)

   Bevacizumab: within 12 weeks.

3. c)

   Systemic drug therapy other than the above: within 4 weeks.

4. d)

   Radiotherapy (including stereotactic radiotherapy), proton therapy, and neutron capture therapy: within 12 weeks.

5. e)

   Alternating current electric field therapy: within 4 weeks.

1. (14)

   Patients who increased their steroid dose within 2 weeks before starting study drug administration.

2. (15)

   Patients who received a study drug in another clinical trial within 4 weeks before starting the administration of the study drug.

3. (16)

   Patients who cannot undergo head MRI examination using gadolinium contrast agents (e.g., patients with drug allergies to contrast agents, pacemakers, or continuous infusion pumps).

4. (17)

   Female patients who are pregnant or possibly pregnant^{Footnote 3} or breastfeeding^{Footnote 4}.

1. (18)

   Patients who cannot agree to complete abstinence or effective contraception for at least 90 days after the last dose of the study drug.

2. (19)

   Patients whose participation in the trial is judged inappropriate by the principal investigator or co-investigator.

Treatment

Dose/administration method

The dose of the study drug will be set at 4 levels: 0.1, 0.3, 0.6 and 1.0mg/kg for TUG1). Dose escalation will be performed using a 3 + 3 design. Unless the discontinuation criteria are met, a total of four cycles will be administered, with each cycle lasting 7 days. If non-progressive disease (PD) is confirmed after four cycles and the investigator determines that continuation is appropriate and the patients’ intention to continue is confirmed (written consent is not required), administration will be possible until the discontinuation criteria are met.

The drug dose escalation plan is described in Fig.1.

Dose escalation plan (Fig.1).

The dose will be escalated in four steps from dose level 1, and the low dose will be gradually increased to the high dose. Dosages will not be increased or decreased in the same patient.

Level 1: 0.1mg/kg, n = 3–6.

Level 2: 0.3mg/kg, n = 3–6.

Level 3: 0.6mg/kg, n = 3–6.

Level 4: 1.0mg/kg, n = 3–6.

The recommended dose will be administered until 24 patients have received the study drug.

Decision on whether to transition to a higher dose level.

(1) Transition procedure.

The dose level will be transitioned to a higher dose level in stages, as described above. The number of patients studied at each dose level will be 3 (maximum 6).

1. 1)

   If none of the three patients experience dose limiting toxicity (DLT), transition to the next dose level.

2. 2)

   If one of the three patients experience DLT, three patients will be added to the same dose level, making the number of six patients.

1. a.

   If one of the six patients experience DLT, there will be a transition to the next higher dose level.

2. b.

   If two or more cases of DLT are observed, enrollment will be interrupted, that dose level will be considered the MTD, and the transition to the next dose level will be halted.

1. 3)

   If two or more of the three patients experience DLT, the dose level will be considered the MTD, and the transition to the next dose level will be halted.

(2) Decision to transition to the next dose level.

The decision to transition to the next dose will be discussed by the Efficacy and Safety Evaluation Committee.

Criteria for administration

Initial administration criteria: All “inclusion criteria” must be met, and none of the “exclusion criteria” must be met.

Criteria for administration from the second cycle onward: In Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, hematological toxicity must be grade 2 (lymphocyte count up to grade 3 is acceptable), and non-hematological toxicity must be grade 1 or less. If any of the above items are present at baseline, there must be no worsening of the grade (a lymphocyte count up to grade 3 is acceptable). In the second cycle onward, if recovery to the above criteria is required, administration may be postponed for up to 14 days after the scheduled administration date. However, if it takes > 15 days, the administration of the study drug will be discontinued.

Criteria for discontinuation of administration

1. (1)

   The patient requests discontinuation of administration.

2. (2)

   If something that should be excluded from the participants is known after registration.

3. (3)

   If PD is determined based on imaging.

4. (4)

   Clearly diagnosed as progressed via clinical diagnosis.

5. (5)

   If an AE occurs, which makes it difficult to continue administration.

6. (6)

   If the administration cannot be completed within 14 days from the administration date.

7. (7)

   If the patient becomes pregnant.

8. (8)

   If the investigator determines that it is inappropriate to continue administration.

Sample size

This trial will be conducted at two academic hospitals and one national cancer center in Japan. No statistical hypotheses were set in this phase I dose escalation study. A 3 + 3 design was used to determine safety and tolerability. We design four dose levels of TUG1ASO. Dose-level transition will be determined based on the incidence of DLT in 3–6 patients at each dose level. The maximum sample size will be 24.

Assessment

The schedule for examinations and assessments is summarized in Table1.

Screening period

The comprehensive information of eligible patients needs to be collected at least 2 week before the registration, which includes medical history, physical examination, KPS score, the test of clinical chemistry, hematology and coagulation, electrolytes, total protein level, albumin level, liver and kidney function, lactate dehydrogenase (LDH), creatine kinase (CK), carbohydrate reactive protein (CRP), HBs antigen, HBs antibody, HBc antibody, HBV-DNA (if both or either of HBc antibody and HBs antibody is positive), HCV antibody, HIV antibody, urinalysis, chest radiography, head MRI (T1-weighted, T2-weighted, or fluid-attenuated inversion recovery [FLAIR] axial, contrast-enhanced T1-weighted axial, coronal images: slice thickness ≤ 5mm), and electrocardiography findings.

First cycle

(1) Physical findings.

Day 1 of the first cycle (day of administration) and day 2 of the first cycle (day after administration).

• signs: blood pressure (systolic/diastolic blood pressure), body temperature, and pulse rate.

• score.

(2) Laboratory tests.

Day 2 of the first cycle (day after administration)

• tests: red blood cell, white blood cell, neutrophil, lymphocyte, hemoglobin, hematocrit, and platelet counts.

• biochemistry tests: total protein, albumin, total bilirubin, direct bilirubin, AST, ALT, alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GTP), LDH, amylase, cholinesterase, blood urea nitrogen (BUN), creatinine, CK, sodium (Na), potassium (K), chlorine (Cl), calcium (Ca), and CRP levels.

• test.

Cycles 2 to 4, day 1

(1) Physical findings on day 1 of each cycle (day of administration).

• signs: blood pressure, body temperature, and pulse rate.

• Weight.

• score.

(2) Laboratory tests at day 1 of each cycle (day of administration).

• tests: red blood cell, white blood cell, neutrophil, lymphocyte, hemoglobin, hematocrit, and platelet counts.

• biochemistry tests: total protein, albumin, total bilirubin, direct bilirubin, AST, ALT, ALP, γ-GTP, LDH, amylase, cholinesterase, BUN, creatinine, CK, Na, K, Cl, Ca, and CRP levels.

• test.

Day 8 of the 4th cycle to before the start of the 5th cycle

(1) Physical findings.

• signs: blood pressure (systolic/diastolic blood pressure), body temperature, and pulse rate.

• Weight.

• score.

(2) Laboratory tests.

• tests: red blood cell, white blood cell, neutrophil, lymphocyte, hemoglobin, hematocrit, and platelet counts.

• biochemistry tests: total protein, albumin, total bilirubin, direct bilirubin, AST, ALT, ALP, γ-GTP, LDH, amylase, cholinesterase, BUN, creatinine, CK, Na, K, Cl, Ca, and CRP levels.

• test.

(3) Imaging tests.

Head MRI (T1-weighted, T2-weighted, or FLAIR axial image, contrast-enhanced T1-weighted axial image, coronal image): slice thickness ≤ 5mm)

Cycle 5 and onward

(1) Physical findings: day 1 of each cycle.

• signs: blood pressure, body temperature, and pulse rate.

• Weight.

• score.

(2) Laboratory tests: day 1 of each cycle.

• tests: red blood cell, white blood cell, neutrophil, lymphocyte, hemoglobin, hematocrit, and platelet counts.

• biochemistry tests: total protein, albumin, total bilirubin, direct bilirubin, AST, ALT, ALP, γ-GTP, LDH, amylase, cholinesterase, BUN, creatinine, CK, Na, K, Cl, Ca, and CRP levels.

• test.

HBV-DNA (only for patients who are positive for both or either HBc antibody and/or HBs antibody during the screening phase and require regular quantitative testing of HBV-DNA, performed every 12 cycles from cycle 13 onward).

(3) Imaging tests.

Regardless of whether the administration of the study drug is postponed, head MRI will be performed every 8 weeks (T1-weighted, T2-weighted, or FLAIR axial, contrast-enhanced T1 weighted axial, coronal images: slice thickness ≤ 5mm).

At the time of discontinuing administration

The following tests will be performed:

(1) Physical findings.

• signs: blood pressure, body temperature, and pulse rate.

• Weight.

• score.

(2) Laboratory tests.

• tests: red blood cell, white blood cell, neutrophil, lymphocyte, hemoglobin, hematocrit, and platelet counts.

• biochemistry tests: total protein, albumin, total bilirubin, direct bilirubin, AST, ALT, ALP, γ-GTP, LDH, amylase, cholinesterase, BUN, creatinine, CK, Na, K, Cl, Ca, and CRP levels.

• test.

(3) Imaging tests.

In principle, MRI will be performed on the day the decision to discontinue administration is made (tolerance range + 14 days). If MR images are obtained before the decision to discontinue administration (tolerance range − 14 days), they may be used.

Pharmacokinetic assessment

Blood samples will be collected for pharmacokinetic analysis, as shown in Table2, and the time of blood sampling will be recorded.

Possible side effects and their countermeasures

In the repeated-dose toxicity studies in rats and cynomolgus monkeys, somnolence was associated with TUG1ASO administration. Changes in the blood biochemical parameters related to liver function, such as increased ALT, total cholesterol, and triglyceride levels, have also been observed. In high-dose studies using rats and cynomolgus monkeys, foam cells have been observed in various organs and tissues; however, these changes do not cause damage to the cells or tissues. Carefully consider administering the study drug to patients with liver dysfunction, and monitor liver function during the administration period. If any symptoms or signs suspected to be related to administration appear, perform careful testing, as necessary.

Monitoring of adverse events

Adverse events will be monitored from the first dose of the study drug until 28 days after the last dose (tolerance range + 14 days). Adverse events will be evaluated using CTCAE version 5.0 for the following:

1. (1)

   Laboratory values: results of hematological, blood biochemistry, and urine tests.

2. (2)

   Clinical changes: physical findings and vital signs.

The evaluation period for DLT will be from the first dose of the study drug until 1 week after the administration of the fourth cycle. During the study, the principal investigator will discuss with Efficacy and Safety Evaluation Committee to monitor participant safety and data assessment procedures. If the investigator determines that continuation is inappropriate, the trial will be discontinued.

Follow-up

All registered patients will be followed up for 3 years after the final administration of the study drug. During the follow-up survey, survival or death and details of the treatment for GB will be investigated approximately once every 6 months. If treatment is discontinued for reasons other than progression, head MRI (T1-weighted, T2-weighted or FLAIR axial, contrast-enhanced T1-weighted axial, coronal images: slice thickness ≤ 5mm) will be performed every 8 weeks from the day of imaging at the time of discontinuation.

Statistical analyses

The treatment and observation periods will be from January 2024 to March 2029. The registration period is scheduled to be completed in March 2026. All patient data will be recorded into case report forms using an electronic data capture system. Safety assessment will include the observation and recording of any grade of AEs according to the CTCAE version 5.0. Researchers will take appropriate measures to prevent AEs and determine the relationship between AEs and the study drug. The overall response rate will be defined as complete response (CR) + partial response (PR) according to the Response Assessment in Neuro-Oncology criteria for high-grade gliomas [7]. PFS will be defined as the time from the beginning of treatment until the first tumor progression or tumor-related death. OS will be evaluated from the start of study drug administration until death from any cause. The DOR will be measured from the date of the first CR or PR to the date of progression or death from any cause, whichever occurred first. The Kaplan–Meier method and two-tailed log-rank test will be used to evaluate PFS and OS. Regarding the pharmacokinetics, we will examine the changes in the blood concentration of TUG1ASO in each patient.

This trial aims to investigate the safety and MTD of TUG1ASO in patients with rGB. To the best of our knowledge, no clinical studies have been conducted on the efficacy and safety of the targeted lncRNAs. Therapies targeting lncRNAs might have two major problems: off-target effects and inefficient drug delivery to lesions. In silico and human GB cell line analyses of TUG1ASO have demonstrated that off-target effects are minimal [4]. In repeated-dose studies using TUG1ASO in rats and cynomolgus monkeys, no serious AEs were observed. Therefore, safety is expected in humans. Drugs targeting brain tumors often have problems with BBB permeability. However, the study drug is a combination of an LNA gapmer of ASO against human TUG1 and a DDS using polymer technology [6], which can penetrate the BBB and reach the brain by intravenous administration.

TUG1 plays a role in creating a favorable environment for tumors by resolving the formation of R-loops [5]. Because pathogenic R-loop formation is strictly regulated at an appropriate level in normal cells, targeting TUG1 may represent a cancer-specific therapeutic strategy. In addition, TUG1 is involved in chemotherapy resistance in ovarian [8] and pancreatic cancers [9]. Targeting TUG1 is a new treatment approach and may shed light on refractory cancers. If safety and MTD are determined in this study, a phase 2 trial for rGB and expansion of its application to other cancers are expected.

In conclusion, in this first-in-human study, safety, tolerability and MTD of this new targeted therapy will be confirmed to find the recommended dose for the further clinical trial. This study may contribute to develop a new treatment option for rGB patients.

1. Synchronous double cancers, metachronous double cancers with a disease-free period of ≤ 5 years, carcinoma in situ, and lesions equivalent to intramucosal cancer that is considered to have been cured by local treatment are not included in active double cancers.

2. Congestive heart failure (New York Heart Association class III or higher), myocardial infarction, or unstable angina within 6 months before the start of study drug administration or arrhythmia requiring treatment.

3. Considering that pregnancy tests may not be positive in patients in the early stages of pregnancy, registration is not possible if a medical interview indicates the possibility of pregnancy.

4. Patients will be eligible to enroll if they discontinue breastfeeding from the first dose of the study drug until 28 days after the final dose of study drug.

ALP:

Alkaline phosphatase

ALT:

Alanine aminotransferase

AMED:

Japan Agency for Medical Research and Development

AST:

Aspartate aminotransferase

BUN:

Blood urea nitrogen

Ca:

Calcium

CK:

Creatine kinase

Cl:

Chlorine

CR:

Complete response

CRP:

Carbohydrate reactive protein

CTCAE:

Common Terminology Criteria for Adverse Events

DDS:

Drug delivery system

DLT:

Dose limiting toxicity

DNA:

Deoxyribonucleic acid

FLAIR:

Fluid attenuated inversion recovery

HBc:

Hepatitis B core

HBs:

Hepatitis B surface B

HBV:

Hepatitis type B virus B

HCV:

Hepatitis type C virus C

HGG:

High-grade glioma

HIV:

Human immunodeficiency virus

jRCT:

Japanese Registry of Clinical Trials

K:

Potassium

KPS:

Karnofsky performance status

LDH:

Lactate dehydrogenase

LNA:

Locked nucleic acid

lncRNA:

Long noncoding RNA

MRI:

Magnetic resonance imaging

mRNA:

Messenger ribonucleic acid

MTD:

Maximum tolerated dose

Na:

Sodium

NE:

Not evaluable

P:

Phosphorus

PD:

Progressive disease

PR:

Partial response

RANO:

Response assessment in neuro-oncology

RNA:

Ribonucleic acid

RT:

Radiotherapy

SD:

Stable disease

TMZ:

Temozolomide

TUG1:

Taurine upregulated gene 1

YBC:

Y-shaped block co-polymer

γ-GTP:

γ-glutamyl transpeptidase

Authors and Affiliations

1. Department of Neurosurgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan

   Shoichi Deguchi,Fumiharu Ohka,Yoshiki Shiba,Junya Yamaguchi,Aya Sato&Ryuta Saito

2. Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

   Keiko Shinjo&Yutaka Kondo

3. Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan

   Yoshiki Arakawa

4. Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan

   Yoshitaka Narita

Contributions

AS, KS, YK and RS developed the study concept and protocol. SD, FO, YS, JY, YA, YN and RS will oversee the implementation of the protocol, data collection and data analysis. SD prepared the first draft of the manuscript. All authors commented on and critically revised the previous drafts of the manuscript and approved the final manuscript.

Corresponding author

Correspondence to Ryuta Saito.

Ethics approval and consent to participate

This study adhered to the ethical standards of the 1964 Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of the Nagoya University Graduate School of Medicine (approval number: 352001). Any modifications to the protocol will be immediately communicated to all responsible authorities. Medical doctors affiliated with the study will give the potential participants information regarding the study. All patients or authorized surrogates must give written informed consent before study.

Consent for publication

Not applicable.

Competing interests

Yutaka Kondo was funded by NANO MRNA Co., Ltd. The other authors declare no competing interests.

Institutional approval

Institutional Review Board of Nagoya University Graduate School of Medicine (approval number: 352001).

Approval date: April 24, 2023.

Protocol version: 4.0, Date: April 4, 2024.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions