Study on The Sensitizing Effect of Sonodynamic Therapy on The Treatment of Brainstem Glioma With Radiotherapy and Chemotherapy and Survival Analysis
Phase: PHASE2
Conditions: Glioma (Any Grade) in the Brain
Sponsor: Yingjuan Zheng

Clinical Research on 
SonodynamicTherapy Combined 
with Chemoradiotherapy for 
Brainstem Gliomas 
 
Date：May 1st, 2025 
 
NCT:NCT ID not yet assigned

1. Abstract: Brainstem  
Diffuse midline glioma (DIPG) is difficult to completely resect surgically and 
cannot reach the radical radiotherapy dose. Currently, there is no effective 
treatment method, and the prognosis is extremely poor. Sonodynamic 
therapy (SDT) is a novel treatment technology developed from photodynamic 
therapy (PDT). The results of our Phase I clinical trial have preliminarily 
confirmed the safety and efficacy of SDT in the treatment of brainstem glioma. 
Therefore, we plan to conduct a randomized, open-label, Phase II clinical trial 
of SDT in the treatment of brainstem DIPG. We plan to recruit 216 patients 
with brainstem DIPG and divide them into an experimental group and a 
control group. Patients in the experimental group will receive not only SDT 
treatment but also treatment regimens selected by the researchers, such as 
radiotherapy, temozolomide, and bevacizumab. Patients in the control group 
will only receive the treatment regimens selected by the researchers. The 
follow-up period is 24 months, and brain MRI will be reviewed monthly. The 
treatment effect will be evaluated according to the RANO criteria. The primary 
endpoint is progression-free survival. The planned research period of this 
project is from  
October 1,2024, to May 1, 2028.  
2. Research Background: 
Brainstem gliomas are a type of glioma that occurs in the midbrain, pons, 
medulla oblongata, and even the entire brainstem, and are more common in 

children. Its incidence accounts for 1.3% - 2.2% of intracranial malignant 
tumors and 10% - 15% of pediatric central nervous system tumors[1]. Due to 
the special location of brainstem gliomas, surgical resection is difficult, and 
the radical radiotherapy dose cannot be achieved. The prognosis is very poor, 
with a one-year overall survival rate of only 37%. Especially for diffuse midline 
gliomas (diffuse intrinsic pontine glioma, DIPG), the median survival time is 10 
- 11 months. 90% of children die within 18 months, and the 5-year survival 
rate is less than 1%. In the past few decades, many clinical trials have 
attempted various treatment methods for newly diagnosed brainstem gliomas, 
including targeted drugs, differentiation inhibitors, and radiation sensitizers, 
but none of them have been able to improve the overall survival rate of these 
patients[5]. For the treatment of recurrent brainstem gliomas, the second-line 
treatment options are usually very limited, lacking effective treatment 
methods, and the treatment is often more difficult. Currently, there is no 
unified and effective treatment plan for brainstem gliomas, and the prognosis 
is poor, causing great pain to patients and their families. Therefore, both the 
National Comprehensive Cancer Network (NCCN) in the United States and the 
Chinese Society of Clinical Oncology (CSCO) guidelines advocate giving 
priority to participating in clinical trials of brainstem gliomas, hoping to find 
safe and effective treatment methods through clinical trials, so as to maximize 
the extension of patients' survival time and improve their quality of life. 
Sonodynamic therapy (SDT) is a new technology developed from 

photodynamic therapy (PDT). PDT can selectively eliminate local tumors 
without damaging normal tissues. It is safe, has few side effects, and can be 
reused. It stands out among many malignant tumor treatment options and 
has been included in the clinical treatment guidelines for various tumors such 
as skin cancer, esophageal cancer, biliary tract cancer, and bladder cancer. A 
large number of literatures show that the intraoperative application of PDT in 
the treatment of gliomas can significantly improve the prognosis of gliomas. 
However, due to the invasive surgical operation required by PDT and the poor 
tissue penetration of lasers, with a soft tissue penetration depth of only 1cm, 
PDT is difficult to apply to deep tumors, and its treatment scope is greatly 
limited. Therefore, SDT came into being. SDT uses low-intensity, 
low-frequency focused ultrasound (LILFU), which has strong penetration 
ability into biological tissues (up to 10cm deep). It can non-invasively focus 
acoustic energy on deeper tissues and activate sonosensitizers, thereby 
generating an anti-tumor effect.  
Sonodynamic therapy (SDT) is a new technology developed from 
photodynamic therapy (PDT). PDT can selectively eliminate local tumors 
without damaging normal tissues. It is safe, has few side effects, and can be 
reused. It has stood out among many malignant tumor treatment options and 
has been included in the clinical treatment guidelines for various tumors such 
as skin cancer, esophageal cancer, biliary tract cancer, and bladder cancer[6]. A 
large number of literatures show that the intraoperative application of PDT in 

the treatment of gliomas can significantly improve the prognosis of gliomas. 
However, due to PDT's reliance on invasive surgical procedures and the poor 
tissue penetration of lasers, with a soft tissue penetration depth of only 1 cm, 
PDT is difficult to apply to deep - seated tumors, and its treatment scope is 
greatly limited[7]. Therefore, SDT came into being.SDT utilizes low - intensity, 
low - frequency focused ultrasound (LILFU), which has strong penetrating 
power in biological tissues (up to 10 cm deep). It can non - invasively focus 
acoustic energy in deeper tissues and activate sonosensitizers, thereby 
producing an anti - tumor effect[8][10]. SDT not only has the tumor-treating 
effect of PDT but also has deep-penetrating ability, enabling precise treatment 
of deep-seated lesions. It can selectively eliminate malignant tumors without 
damaging normal tissues, has a definite curative effect, and has few toxic and 
side effects. It is a promising treatment method that has developed rapidly in 
recent years and has attracted the attention of many researchers and clinicians 
at home and abroad. Currently, numerous pre- clinical studies have shown 
that SDT exhibits good effects in the treatment of gliomas[11][15]. Some studies 
have indicated that SDT can induce glioma cell necrosis and enhance the 
therapeutic effect of temozolomide[16]. Some literature has shown that SDT 
can significantly inhibit the tumor growth rate of C6 glioma - bearing mice[17].  
More importantly, in our Phase I clinical trial, SDT was safe and effective in the 
treatment of brainstem gliomas, and the tumors of some patients with 
brainstem gliomas were significantly reduced. However, the patients included 

in the Phase I clinical trial had large heterogeneity, a small sample size, and 
low test efficiency. Therefore, a Phase II clinical trial with a larger sample size is 
urgently needed to further verify the safety and efficacy of SDT in the 
treatment of brainstem gliomas.  
In conclusion, due to the special growth location of brainstem gliomas and 
their diffuse endogenous growth pattern, surgical resection is extremely 
difficult, and it is impossible to deliver a curative radiotherapy dose. Currently, 
there are no effective treatment methods available, resulting in a dismal 
prognosis. This brings great distress to patients and their families. Therefore, 
finding a safe, highly effective, and accessible treatment approach to 
maximize patients' survival time and improve their quality of life has become 
an urgent clinical challenge.  
Sonodynamic therapy (SDT), a novel, effective, safe, and non-invasive 
treatment technology developed from photodynamic therapy (PDT), has 
attracted the attention of many scholars and clinicians. SDT has demonstrated 
promising therapeutic effects in treating gliomas in numerous preclinical 
models. Moreover, the results of our Phase I clinical trial have preliminarily 
confirmed the safety and efficacy of SDT in the treatment of brainstem 
gliomas. However, the Phase I clinical trial has limitations, such as a high 
degree of patient heterogeneity, a small sample size, and low statistical power. 
Therefore, we plan to conduct a single-center, randomized, open-label, Phase 
II clinical trial of sonodynamic therapy for diffuse intrinsic pontine gliomas 

(DIPG) in the brainstem. This study will further verify the efficacy and safety of 
SDT in the treatment of brainstem gliomas. The promotion and application of 
SDT technology will have significant social implications, not only alleviating 
patients' suffering but also improving their quality of life and extending their 
overall survival. 
3. Research Objectives 
To further confirm the effectiveness, safety, and existing clinical problems of 
SDT in the treatment of brainstem gliomas.  
4. Research Design 
This study is a single-center, randomized, open-label, Phase II clinical trial of 
SDT in the treatment of brainstem DIPG, aiming to confirm the efficacy and 
safety of SDT in the treatment of brainstem gliomas.  
This trial plans to recruit 216 newly diagnosed patients with brainstem DIPG. 
Stratification factors such as the basic clinicopathological characteristics of the 
subjects will be used, and they will be randomly divided into an experimental 
group and a control group at a 1:1 ratio.  
Subjects in the experimental group will receive not only SDT but also 
treatment regimens selected by the researchers, such as radiotherapy, 
temozolomide, and bevacizumab. Subjects in the control group will only 
receive the treatment regimens selected by the researchers.  

 
5. Research PopulationInclusion Criteria 
5.1 Inclusion criteria： 
1) All subjects or their legal representatives must voluntarily and in writing 
sign the informed consent form approved by the ethics committee before 
starting the screening process.  
2) Age < 75 years old, gender is not limited.  
3) Newly diagnosed patients with brainstem DIPG. It is confirmed as brainstem 
DIPG by histology or cytology (referring to the WHO Classification of Tumors 
of the Central Nervous System 2016), and there are radiologically evaluable 
lesions.  
4) ECOG score is 0 - 2.  
5) The expected survival period is ≥ 3 months.  

6) The subjects have sufficient organ and bone marrow functions, without 
severe hematopoietic dysfunction and abnormal heart, lung, liver, kidney 
functions or immunodeficiency. The hematological indicators before 
enrollment are basically normal: white blood cell count ≥ 4×10⁹/L, absolute 
neutrophil count ≥ 1.5×10⁹/L, platelet ≥ 100×10⁹/L, hemoglobin ≥ 90 g/L. The 
renal function is basically normal: serum creatinine ≤ 1.2 mg/dL or creatinine 
clearance rate ≥ 60 ml/min. The liver function is basically normal: serum total 
bilirubin ≤ 1.5 × ULN (if there is liver metastasis, then serum total bilirubin 
should ≤ 3.0 × ULN); aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ 2.0 × ULN (if there is liver metastasis ≤ 5.0 × ULN). 
The coagulation function is basically normal: the international normalized 
ratio of prothrombin time (INR) ≤ 2.0, and PT, APTT, and TT are all within the 
normal range. 
7) The toxic reactions of anti-tumor treatment before the administration of 
the test drug have decreased to Grade 1 or below, or the subjects have fully 
recovered from previous surgeries (judged by the researcher).  
8) Women of childbearing age and all male subjects must agree to use highly 
effective contraceptive methods during the trial period and within 12 months 
after the last use of hematoporphyrin injection (such as condoms, 
contraceptive sponges, contraceptive gels, contraceptive membranes, 
intrauterine devices, oral or injectable contraceptives, subcutaneous implants, 
etc.), and the pregnancy test results of women of childbearing age must be 

negative within ≤ 7 days before the administration of the test drug.  
5.2 Exclusion Criteria： 
1) Subjects known to be allergic to hematoporphyrin or other photosensitive 
drugs.  
2) Subjects who participated in any other drug clinical trials or other 
interventional clinical trials within 4 weeks before the administration of the 
test 
drug, 
except 
for 
those 
who 
participated 
in 
observational 
(non-interventional) clinical studies or those who are in the follow-up period 
of interventional studies.  
3) Subjects who have previously received SDT treatment.  
4) Subjects who used other photosensitive drugs (tetracycline antibiotics, 
sulfonamides, phenothiazines, sulfonylurea hypoglycemic drugs, thiazide 
diuretics, and griseofulvin, etc.) within 4 weeks before the administration of 
the test drug.  
5) Subjects with brainstem gliomas in a cachectic state or who are expected to 
be unable to tolerate SDT treatment.  
6) Subjects with uncontrolled infections or clinically significant active 
infectious diseases.  
7) Subjects with positive test results for any one or more of hepatitis C virus 
(HCV) antibody, syphilis antibody, or human immunodeficiency virus (HIV) 
antibody, or subjects with active hepatitis B (defined as HBV DNA ≥ 2000 
IU/mL or HBV DNA ≥ 10⁴ copies).  

8) Difficult-to-control epilepsy and/or increased intracranial pressure and/or 
hypertension and/or hyperglycemia.  
9) Subjects with severe or uncontrolled cardiovascular and cerebrovascular 
diseases and lung diseases (including myocardial infarction, Class III - IV heart 
failure, cardiac insufficiency, Grade 2 or above heart block, severe arrhythmia, 
cerebral infarction, cerebral hemorrhage, asthma attack, or severe respiratory 
failure).  
10) Subjects who have had other malignant tumors in the past 5 years and 
have not been effectively controlled.  
11) Subjects with uncontrolled mental illnesses/social situations that are 
expected to limit their compliance with the research requirements or impair 
the subject's ability to sign the informed consent form in writing.  
12) Pregnant or lactating women.  
13) Subjects with other reasons judged by the researcher to be unsuitable for 
participating in this trial, such as those with large brain tumor lesions.  
5.3 Withdrawal Criteria:  
For effectiveness and/or safety evaluation.  
5.4 Withdrawal/Termination Criteria： 
1) The subject withdraws the informed consent and requests to withdraw.  
2) Other situations where the researcher deems it necessary to withdraw from 
the study.  
6.Trial Procedure: 

Photosensitizer: Hematoporphyrin Injection (Xipofen).  
Machine: Transcranial Ultrasound Therapy Apparatus.  
Treatment method:  
1) After the patient is admitted to the hospital, complete various 
pre-treatment laboratory tests. For those who have not undergone a head 
MRI examination within one month before admission, a reexamination of MRI 
is required.  
2) After completing various examinations and relevant procedures for clinical 
treatment, using stratification factors such as the basic clinicopathological 
characteristics of the subjects, randomly divide them into an experimental 
group and a control group at a 1:1 ratio.  
3) Subjects in the experimental group will receive not only SDT but also 
treatment regimens selected by the researchers, such as radiotherapy, 
temozolomide, and bevacizumab. Subjects in the control group will only 
receive the treatment regimens selected by the researchers.  
4) Treatment regimens selected by the researchers: Radiotherapy combined 
with chemotherapy:  
a) The total radiotherapy dose is 50 - 54 Gy, 1.8 - 2 Gy per day, 5 times a 
week, for a total of 25 times.  
b) When temozolomide is given concurrently with radiotherapy, the dose 
is 75 mg/m²/day, and it is taken daily until the end of radiotherapy. For 
adjuvant chemotherapy with temozolomide, the dose is 150 mg/m²/day, 

taken continuously for 5 days, with a 23 - day rest period, and each cycle is 
28 days. If tolerated, the dose in the 2nd - 6th cycles should be adjusted to 
200 mg/m²/day.  
c) For targeted therapy, bevacizumab is used at a dose of 7.5 - 10 mg/kg, 
once every 3 weeks, for a total of 4 - 6 courses.  
5)SDT  
a) Administer "Xipofen" at a dose of 5 mg/kg body weight. For children, it 
is given intravenously systemically; for adults, it is locally administered by 
percutaneous arterial catheterization drug perfusion. After administration, 
place the patient in a ward with controlled light intensity.  
b) Start sonodynamic therapy 40 hours after administration. Before SDT 
treatment, position the ultrasonic head on the scalp according to the MRI 
image to determine the tumor treatment range. Shave the area where the 
ultrasonic head is placed.  
c) Set the SDT treatment parameters. Acoustic intensity: 1 - 1.25 W/cm²; 
frequency: 800 KHz - 1 MHz; time: 15 min.  
d) After treatment, keep the patient away from light for one month.  
e) Treatment frequency: Treat twice a day at 24h, 48h, and 72h after 
administration. For the handling of relevant adverse reactions and treatment 
adjustments: Systemic symptoms such as phototoxic reactions, fatigue, 
weakness, fever, and pain; skin and mucosal symptoms such as rashes, ulcers, 
and bleeding; digestive tract symptoms such as diarrhea, nausea, vomiting, 

anorexia, and melena; respiratory system symptoms such as cough, asthma, 
hemoptysis, and dyspnea; as well as symptoms of the nervous and 
cardiovascular systems. If photosensitizer allergic reactions, shock, etc. occur, 
immediately stop the drug infusion and carry out anti - allergic and anti - 
shock treatment.  
7.Research Endpoints 
7.1 Efficacy Evaluation Endpoints： Primary research endpoint: Progression - 
free survival (PFS). Secondary research endpoints: 1) Overall survival time. 2) 
Tumor control rate. 3) Incidence of treatment - related adverse events.  
7.2 Safety Evaluation Endpoints: The incidence, severity, and duration of any 
adverse events and drug - related adverse events.  
8.Data Collection  
8.1 Data Source: This study plans to collect data from 216 newly diagnosed 
patients with diffuse midline glioma.  
8.2 Data Collection Content:  
Basic information: Gender, age, height, weight, ethnicity, smoking history, 
drinking history, allergy history, disease history, surgical history.  
Clinical diagnosis and staging: Blood routine, liver and kidney function before 
and after treatment, tumor location, tumor size, TNM staging, clinical staging, 
ECOG score or KPS score, EGFR expression, and the Common Toxicity Criteria 
for Anticancer Drugs of the WHO .  
Information related to previous treatments:  

1) Surgical treatment: Name of the surgery, surgical information.  
2) Radiotherapy: Radiotherapy technique, total radiotherapy dose, irradiation 
site, fractionated dose, and number of times.  
3) Chemotherapy: Chemotherapy drugs, usage and dosage, treatment cycle.  
4) Other information related to anti - tumor treatments. 
 Information related to concurrent treatments: 
 Name of the concurrent treatment, drugs, usage and dosage, start and end 
times, and the reasons for concurrent medications and treatments.  
Imaging data: 
Use MRI. Complete the imaging examinations related to tumor efficacy 
evaluation within 2 weeks before treatment. After the end of treatment, 
perform MRI reexamination once every 4 weeks for evaluation until the 
disease progresses, the subject cannot tolerate it, or withdraws. The 
examination time window is ±7 days.  
Clinical follow - up information:  
1) Conduct a descriptive statistics on all treatment - related adverse events 
that occur, list the events, duration, severity, and the relationship with SDT 
treatment. Calculate the incidence of adverse events and serious adverse 
events.  
2) Short - term efficacy: Collect the imaging data of the included patients. 
After one cycle of SDT treatment, evaluate the efficacy of the patients to 
obtain complete remission (CR), partial remission (PR), stable disease (SD), and 

progressive disease (PD). Calculate the objective remission rate (ORR) and 
disease control rate (DCR) of the tumor based on the best efficacy evaluation 
results within 12 months after the end of treatment.  
3) Long - term efficacy: Collect the survival data of the included patients. 
Record the date of death and the cause of death. Evaluate the survival status 
of the patients 1 year, 2 years, and 3 years after treatment, calculate the 1 - 
year OS rate, 1 - year PFS rate, and safety, and record the median PFS and 
median OS.  
9.Statistical Analysis 
 1) Safety analysis: Conduct a descriptive analysis of the occurrence of all 
adverse events (AE) and serious adverse events (SAE) collected.  
2) Efficacy analysis: Use the Kaplan - Meier method to draw survival curves, 
and use the Log - rank test to evaluate survival differences. Use the Cox 
proportional hazards model for multivariate analysis to evaluate the role of 
prognostic factors. Unless otherwise specified, all statistical tests will use a two 
- sided test with α = 0.05, and calculate the two - sided 95% confidence 
interval.  
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