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  Title	Investigator-initiated phase I trial of an oligonucleotide therapeutic targeting long noncoding RNA TUG 1 for recurrent glioblastoma
  ID	6921626
  External ID	7547962809
  Author	Unknown
  Published Date	Feb. 13, 2025, 7:55 a.m.
  Summary	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 respons
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  URL	https://bmccancer.biomedcentral.com/articles/10.1186/s12885-025-13623-0
  Sentiment	Negative: 0.03067    Neutral: 0.93767    Positive: 0.03166
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  Content ID	4319407
  Key	9eef984b-9db9-40e2-8505-923364b00ea5
  Content	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) 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) Patients refractory or intolerant to standard treatment or for whom there is no equivalent treatment. (3) Patients who have received postoperative (including biopsy by craniotomy or stereotactic surgery) concurrent chemoradiotherapy with TMZ (≥ 54 Gy for those aged ≤ 69 years and ≥ 25 Gy 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) 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: 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. b) Recurrence or progression of GB has been confirmed. 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. d) Measurable enhanced lesions with qa maximum diameter of ≥ 10 mm in both perpendicular directions. (5) Patients who have undergone tumor resection after recurrence or progression: Patients who meet all of the following criteria: a) GB recurrence or progression has been confirmed via contrast-enhanced head MRI before tumor resection at the time of recurrence or progression. 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). c) An anaplastic astrocytoma or GB has been histologically confirmed in the resected specimen at the time of reoperation. d) Four days after tumor resection, contrast-enhanced head MRI before registration meets all of the following criteria: 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. ii. The presence or absence of measurable lesions is not an issue. 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). (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. (7) Patients aged ≥ 18 years and ≤ 75 years on the day of registration. (8) Patients with a Karnofsky Performance Status (KPS) score of ≥ 60 within 14 days prior to registration. (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: a) Neutrophil count ≥ 1,500 /mm3. b) Hemoglobin level ≥ 9.0 g/dL. c) Platelet count ≥ 10 × 104 /mm3. d) Aspartate aminotransferase (AST) (glutamic oxaloacetic transaminase) level ≤ 100 IU/L. e) Alanine transaminase (ALT) (glutamic pyruvic transaminase) level ≤ 100 IU/L. f) Prothrombin time international normalized ratio < 1.5. g) Serum creatinine level ≤ 1.5 mg/dL. h) Qualitative urine protein: (–) to (+). (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) Patients with extracerebral metastases. (2) Patients with symptoms due to a marked increase in intracranial pressure. (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) Patients with intrathecal dissemination or gliomatosis of the cerebri. (5) Patients with active double cancersFootnote 1. (6) Patients with a history of chemotherapy, molecular targeted drugs, or radiation therapy in the head and neck region for other cancers. (7) Patients with infectious diseases requiring systemic administration of antibiotics or antivirals. (8) Patients positive for human immunodeficiency virus (HIV) antibodies. (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. (10) Men with QTcF > 450 ms and women with QTcF > 470 ms on a 12-lead electrocardiogram. (11) Patients with severe heart diseasesFootnote 2. (12) Patients with psychiatric disorders or symptoms that make it difficult to continue participating. (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: a) Temozolomide: within 4 weeks. b) Bevacizumab: within 12 weeks. c) Systemic drug therapy other than the above: within 4 weeks. d) Radiotherapy (including stereotactic radiotherapy), proton therapy, and neutron capture therapy: within 12 weeks. e) Alternating current electric field therapy: within 4 weeks. (14) Patients who increased their steroid dose within 2 weeks before starting study drug administration. (15) Patients who received a study drug in another clinical trial within 4 weeks before starting the administration of the study drug. (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). (17) Female patients who are pregnant or possibly pregnantFootnote 3 or breastfeedingFootnote 4. (18) Patients who cannot agree to complete abstinence or effective contraception for at least 90 days after the last dose of the study drug. (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 1.0 mg/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. Fig. 1 Dose escalation plan for the study drug ※ If the level is 1, the recommended dose will not be determined and the clinical trial will be discontinued. If the patient is at level 2 or above, registration will continue at the next lower dose level Full size image 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: 0.1 mg/kg, n = 3–6. Level 2: 0.3 mg/kg, n = 3–6. Level 3: 0.6 mg/kg, n = 3–6. Level 4: 1.0 mg/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) If none of the three patients experience dose limiting toxicity (DLT), transition to the next dose level. 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. a. If one of the six patients experience DLT, there will be a transition to the next higher dose level. 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. 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) The patient requests discontinuation of administration. (2) If something that should be excluded from the participants is known after registration. (3) If PD is determined based on imaging. (4) Clearly diagnosed as progressed via clinical diagnosis. (5) If an AE occurs, which makes it difficult to continue administration. (6) If the administration cannot be completed within 14 days from the administration date. (7) If the patient becomes pregnant. (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 Table 1. Table 1 Schedule for examinations and assessments Full size table 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 ≤ 5 mm), 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 ≤ 5 mm) 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 ≤ 5 mm). 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 Table 2, and the time of blood sampling will be recorded. Table 2 Pharmacokinetics testing schedule Full size table 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) Laboratory values: results of hematological, blood biochemistry, and urine tests. (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 ≤ 5 mm) 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.
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  Publisher Name	Bmccancer.biomedcentral (#12733)
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