A Prospective Single Arm Phase II Exploratory Study on the Combination of Whole Brain Radiotherapy and Thiotepa Intrathecal Injection for Systemic Treatment of Primary Diseases in the Treatment of Solid Tumor Leptomeningeal Metastasis
Phase: PHASE2
Conditions: Solid Tumor Leptomeningeal Metastasis
Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University

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A Prospective Single Arm Phase II Exploratory Study
on the Combination of Whole Brain Radiotherapy, Thiotepa
Intrathecal Injection and Systemic Treatment of Primary
Diseases in the Treatment of Solid Tumor Leptomeningeal
Metastasis
Main researcher: Zhang Ting
Plan version number: 2.0 version
Date of formulation: January 06, 2024
Main research unit: Second Affiliated Hospital of Zhejiang University

catalog
1 Research background.........................................................................................3
2 Research Objectives and Endpoints................................................................... 6
2.1 Research Objectives.........................................................................................................6
2.2 Main research endpoints.................................................................................................. 6
2.3 Secondary study endpoints...............................................................................................6
3 Research Plan.....................................................................................................6
3.2 Research Steps...................................................................................................... 7
3.2.1 Screening period.......................................................................................................7
3.2.2 Treatment period.......................................................................................................8
3.2.3 Treatment after leaving the group.............................................................................9
3.2.4 Follow up period.......................................................................................................9
3.2.5 End of Study............................................................................................................. 9
3.3 Case selection...................................................................................................... 10
3.3.1 Selection criteria.....................................................................................................10
3.3.2 Exclusion criteria....................................................................................................10
3.3.3 Study drug discontinuation/withdrawal criteria......................................................11
3.3.4 Follow up on withdrawal cases.............................................................................. 13
4 Concomitant medication...................................................................................13
4.1 Permissible drugs for use.....................................................................................13
4.2 Research drug and dosage...................................................................................13
5 Efficacy evaluation..................................................................................................14
6 Statistical analysis................................................................................................... 14
6.1 Sample size estimation.........................................................................................14
6.2 Analyzing the population.....................................................................................14
6.3 Statistical analysis............................................................................................... 14
6.3.1 Demography and Baseline......................................................................................14
6.3.2 Efficacy analysis.....................................................................................................14
7. Adverse event...................................................................................................16
7.1 Definition.............................................................................................................16
7.2 Content................................................................................................................16
7.3 Record of Adverse Events....................................................................................16
7.4 Criteria for determining the severity of adverse events....................................... 16
7.5 Judgment criteria for the relationship between adverse events and investigational
drugs.........................................................................................................................17
7.6
Serious adverse events and recording and reporting.........................................18
8. Research management.....................................................................................21
8.1 Case Report Form............................................................................................... 21
8.2 Research Documents and Preservation................................................................21
8.3 Regulations on Data Management and Data Traceability....................................22

8.4 Quality control and assurance of clinical trials....................................................22
9. Ethical and regulatory aspects ..............................................................................24
9.1 Responsibilities of Researchers............................................................................24
9.2 Subject Information............................................................................................ 24
9.3 Informed consent form........................................................................................24
9.4 Compensation for subjects.................................................................................. 25
9.5 Ethics Committee................................................................................................ 25
10. Publication and Achievements............................................................................25
11 Treatment process.................................................................................................25

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1 Research background
Tumor meningeal metastasis (LM) refers to the metastasis that occurs when
tumor cells spread to the subarachnoid space and spread to the meninges with the flow
of cerebrospinal fluid (CSF). The occurrence of LM is less common than brain
parenchymal metastasis, but more deadly. LM can occur in non small cell lung cancer
(NSCLC), breast cancer (BC), melanoma and other malignant solid tumors.
Compared to the 20% to 65% incidence of brain metastasis in NSCLC patients, the
proportion of LM occurring in NSCLC patients is only 3% to 5%. However, the
prognosis of LM patients is worse, and for untreated patients, the median overall
survival (mOS) is only 6-8 weeks. With tumor treatment, the survival can be extended
to several months The mOS of LM BC is approximately 3.5 to 4.4 months, LM
NSCLC is 3 to 6 months, and LM melanoma is 1.7 to 2.5 months.
LM can produce clinical manifestations such as brain parenchymal involvement,
meningeal irritation sign, cranial nerve involvement, and increased intracranial
pressure. However, considering that most clinical manifestations of LM are
non-specific and overlap with brain parenchymal metastasis, they are easily
overlooked. The diagnosis and treatment of LM are extremely important but also
challenging. According to the EANO-ESMO guidelines, imaging is one of the
diagnostic criteria, but the positivity rate is low and the patient's condition becomes
severe when imaging features are present. With the development of detection
technology for CSF circulating tumor cell DNA (ctDNA), the early detection rate of
LM has been improved by 2. The treatment of LM includes comprehensive treatment
methods such as intrathecal drug therapy, systemic drug therapy, and local
radiotherapy. The purpose of treating leptomeningeal metastasis is to improve
survival rate and maintain quality of life by delaying the deterioration of the nervous
system. However, due to the presence of the Blood Brain Barrier (BBB), systemic
drugs are unable to exert their effects on the meninges. Although activated T cells can
pass through BBB, the blood brain barrier located in the choroid plexus and

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ependymal epithelial cells restrict T cell infiltration through tight junctions, thus
limiting the action of immune checkpoint inhibitors on tumor cells in cerebrospinal
fluid. In the BLOOM trial, EGFR tyrosine kinase inhibitors (EGFR TKIs),
third-generation TKI ositinib, with its outstanding ability to penetrate BBB, improved
the median progression free survival (mPFS) and mOS (11.0 months) of LM NSCLC
patients with EGFR mutations (EGFRm), demonstrating preliminary potential.
Another retrospective study confirmed that ositinib significantly improved OS in
EGFRm LM NSCLC patients, outperforming first/second generation EGFR-TKIs6.
Local radiotherapy is more suitable for nodular lesions. Therefore, intrathecal
injection of drugs has the advantage of directly acting on the affected area, making it
the best choice for LM. The administration routes include injecting chemotherapy
drugs into the subarachnoid space through lumbar puncture and intraventricular
chemotherapy through the Ommaya reservoir. Repeated lumbar puncture and
intrathecal administration can lead to complications such as infection and bleeding at
the puncture site. At the same time, intracranial hypertension is a contraindication for
lumbar puncture, and these patients cannot receive effective treatment through lumbar
puncture and intrathecal administration. Metastatic and disseminated lesions cannot
be effectively treated. Compared to lumbar puncture, Ommaya fluid sacs can prevent
the delivery of drugs into the epidural or subdural space, resulting in uniform drug
distribution and better patient comfort. The revision rates are less than 7.4%, but in a
study, it was found that the incidence of ventricular infections in reservoir revisions
was as high as 18%. In addition to the difficulties in drug administration, due to the
difficulty in establishing a mouse model of solid tumor meningeal metastasis and the
limited research on drugs for intrathecal injection of LM, the main intrathecal
injection chemotherapy drugs in clinical practice are methotrexate, liposome
cytarabine, and thiotepa. Shandong Cancer Hospital shared a case of HER2 (+) LM
BC patients who achieved a 16 month survival benefit through a regimen of
pyrrolitinib+vinorelbine rhythm chemotherapy+intrathecal injection of methotrexate.
For LM patients whose condition worsens after treatment with methotrexate, Thiotepa
can be used as a salvage treatment. A retrospective study included 30 LM patients

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who failed methotrexate treatment and received 10mg of intrathecal injection twice a
week. Among them, 14 cases (47%) had cytological reactions to intrathecal injection
of cetepete. In addition to chemotherapy drugs, other drugs have also been actively
added to the experimental scope. A prospective phase I/II trial (chiCTr1800016615)
included 30 EGFRm LM NSCLC patients who failed to receive EGFR-TKIs
treatment, proving that such patients can obtain mOS10 up to 9 months through
intrathecal injection of 50mg of the recommended dose of pemetrexed. Trastuzumab
has also been evaluated in the phase I study of LM patients with Her2 positive breast
cancer (NCT01373710). The mOS of patients who received intrathecal injection and
intravenous injection of the PD-1 inhibitor nivolumab (NCT03025256) was 4.9
months. However, it is worth noting that four patients survived to 74 weeks, 115
weeks, 136 weeks, and 143 weeks (i.e. 2.7 years), exceeding the mOS 11 that patients
can achieve in all LM clinical trials. The EANO-ESMO guidelines recommend
intrathecal drug therapy if tumor cells are found in CSF, regardless of MRI findings.
Radiation therapy is also one of the treatment methods, but the bone marrow
suppression caused by whole brain and spinal cord radiation therapy is significant,
with limited dosage, which leads to interruption of systemic treatment and poor
prognosis. The combination regimen in this study can quickly control symptoms by
intrathecal injection of chemotherapy drugs, while opening the blood-brain barrier
through whole brain radiotherapy, combined with systemic treatment for the primary
disease, to achieve better therapeutic effects.
Therefore, studying the effectiveness and safety of comprehensive treatment
mainly consisting of whole brain radiotherapy combined with intrathecal injection of
chemotherapy drugs for LM of different tumors can help guide clinical treatment
decisions. This is a scientific problem that urgently needs to be solved in the field of
cancer. Here, we conduct a single arm prospective exploratory study to provide
treatment opportunities for more patients.

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2 Research Objectives and Endpoints
2.1 Research Objectives
The aim of this prospective study is to evaluate the effectiveness and safety of whole
brain radiotherapy combined with Thiotepa intrathecal injection for systemic
treatment of primary diseases in patients with different solid tumor meningeal
metastases in our hospital.
2.2 Primary endpoints
The primary safety analysis will be conducted based on subjects who experience
toxicity (as defined by CTCAE standards). CTCAE version 5.0 will be used to
evaluate safety through reported adverse events. The relationship between adverse
events and drugs, onset time, duration of events, their resolution, and any concomitant
medication will be recorded. Adverse events (AEs) will be analyzed, including but not
limited to all AEs, SAEs, lethal AEs, and laboratory changes.
2.3 Secondary endpoints
overall survival (OS), progression free survival (PFS), 3-month OS rate, 6-month OS
rate, 9-month OS rate, 12-month OS rate, the disease control rate (DCR), the
objective response rate (ORR) (using RANO-LM criteria)
3 Research Plan
3.1 Research Design
This study is a prospective, one arm clinical study evaluating the efficacy of
intrathecal injection of Thiotepa in patients with leptomeningeal metastases from
different solid tumors in our hospital. This study plans to include 58 subjects in the
intention to analyze (ITT) population for a duration of 2 years. Observe patient safety
indicators and survival data during the research process.

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The study is divided into three stages: screening period, intrathecal injection, and
follow-up period. The screening period is 28 days before the first administration.
Intrathecal injection: Subjects who meet the inclusion criteria but do not meet the
exclusion criteria will undergo intrathecal injection after signing the informed consent
form. The subjects received hippocampal avoiding whole brain radiotherapy
(HA-WBRT). At the same time, the comprehensive treatment plan mainly includes
intrathecal injection of Thiotepa, which is administered by qualified personnel (those
holding training certificates in the radiotherapy department of our hospital). All
eligible patients received intrathecal injection of Thiotepa twice a week for 3 week as
induction treatment, followed by once every week as consolidation therapy for 6 week
and then once bi-weekly as maintenance therapy, until progressive disease was
observed or intolerance or adverse events (AEs) developed. Before each injection,
cerebrospinal fluid pressure should be measured and an equal amount of cerebrospinal
fluid containing the injection drug should be taken to detect cerebrospinal fluid
routine, cerebrospinal fluid biochemistry, tumor markers, IgG and albumin content,
exfoliated cells, and micro single-cell sequencing. After mixing with cerebrospinal
fluid, inject slowly for 5-10 minutes. According to the Neurotumor Response
Evaluation (RANO) - LM criteria for efficacy evaluation, if there is disease
progression or serious adverse events, the study will be immediately withdrawn.
Evaluate the efficacy and safety every 6 cycles according to RANO-LM criteria.
Follow up period: After stopping the study treatment, the subjects enter the follow-up
period. During the follow-up period, MRI enhanced scans will be performed every 3
months to observe PFS. For subjects who have not withdrawn their informed consent
form, survival information (i.e. date and cause of death, subsequent tumor treatment,
etc.) will be collected every month through telephone and/or clinical visits.
3.2 Research Steps
3.2.1 Screening period
The screening period starts from signing the informed consent form and ends with the
start of the research process or the end of screening failure. Participants must sign an

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informed consent form before proceeding with any screening procedures specified in
the study.
Unless otherwise specified, the following screening should be completed within 28
days prior to the start of the study drug:
1) Sign an informed consent form.
2) Medical history collection, including past treatment history, current medical history,
drug allergy history, concomitant diseases, and disease staging.
3) Collect adverse events and concomitant medications.
4) Physical examination, height, weight, vital signs (including body temperature,
blood pressure, heart rate, breathing, blood oxygen saturation, and 5 minutes of sitting
still).
5) ECOG score.
6) Blood, urine, and stool routine.
7) Blood biochemistry (including but not limited to ALT, AST, total bilirubin, direct
bilirubin, indirect bilirubin, ALP, LDH, albumin, urea nitrogen or serum urea,
creatinine, blood sugar, etc.) β 2 microglobulin).
8) Electrolytes (potassium, sodium, chlorine, calcium, magnesium, phosphorus).
9) Coagulation function (PT or INR), thyroid function, myocardial enzyme spectrum,
serum creatine kinase, BNP.
10) Serum pregnancy test (only applicable to women of childbearing age).
11) Virological testing (including HBV, HCV, HDV, HIV, syphilis markers, and
HBV-DNA).
12) Cardiac ultrasound (mainly observing LVEF).
13) 12 lead electrocardiogram (QTc interval time should be indicated).
14) PET/CT or enhanced CT of the neck, chest, abdomen, and pelvic cavity, as well
as head MRI.
15) Cerebrospinal fluid pressure measurement, cerebrospinal fluid biochemistry,
cerebrospinal fluid routine, cerebrospinal fluid shed cells, and cerebrospinal fluid
tumor markers
3.2.2 Treatment period

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Laboratory tests and vital sign measurements specified in the protocol must be
conducted within 72 hours before each cycle of administration (for the first cycle,
laboratory tests can be conducted within 7 days before administration), and adverse
event evaluations must be recorded at each visit.
3.2.3 Treatment after leaving the group
Patients who are excluded from the PD group due to disease should consider
other treatment options, and the specific treatment plan will be determined by the
researcher.
3.2.4 Follow up period
After stopping the study and treatment (whichever occurs first), the subjects
enter the follow-up period, which is divided into three parts:
1) Safety visit: A safety follow-up is required within 30 days after the last
administration.
2) Imaging follow-up: Except for subjects who stopped taking medication due to
disease progression determined by imaging evaluation, imaging evaluation is
conducted every 3 months until imaging disease progression occurs, new anti-tumor
treatment begins, informed consent is withdrawn, death occurs, or the end of this
study (whichever occurs first).
3) Survival follow-up: Within 2 years after the last administration, the subject
receives a survival visit every 3 months. Within 3-5 years after the end of treatment,
the subject receives a follow-up visit every 6 months. For more than 5 years after the
end of treatment, the subject receives a follow-up visit every 12 months until the
subject dies, is lost to follow-up, or terminates the study (whichever occurs first).
Researchers can inquire about the survival status (date and cause of death) of the
subjects, their family members, or local physicians by phone, and collect information
on other anti-tumor treatments after the end of the study treatment. The details of each
survival follow-up should be recorded in the original medical record.
3.2.5 End of Study
The end of the study is defined as the date of the last follow-up. The final
analysis of the main research endpoint will be conducted up to 24 weeks after the last

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participant is enrolled in this study. The study will continue until the last data point of
the last subject is collected. Researchers can terminate the study at any time.
3.3 Case selection
3.3.1 Inclusion criteria
1) Voluntary participation in clinical research: fully understand and be informed of
this study, and sign a written informed consent form; Willing to follow and capable of
completing all experimental procedures.
2) Age: ≥18 years old, both male and female are acceptable.
3) Solid tumor patients diagnosed with leptomeningeal metastasis according to the
EANO-ESMO guidelines
4) Expected survival time is at least 3 months.
5) Adequate organ and bone marrow function, no severe hematopoietic dysfunction,
heart, lung, liver, kidney dysfunction, or immune deficiency (no blood transfusion,
granulocyte colony-stimulating factor, or other related medical support received
within 14 days prior to the use of the study drug):
a) Blood routine: Absolute neutrophil count (ANC) ≥1.5 ´ 109/L (1500/mm3),
platelets ≥75 ´ 109/L, hemoglobin ≥9 g/dL (if bone marrow is involved, platelets ≥
50 ´ 109/L, ANC ≥1.0 ´ 109/L, hemoglobin ≥8 g/dL).
b) Liver function: Serum bilirubin ≤1.5 times the upper limit of normal value,
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 times the
upper limit of normal value (AST is allowed if there is liver involvement, ALT ≤5
times the upper limit of normal value).
c) Renal function: Serum creatinine ≤1.5 times the upper limit of normal value.
d) Coagulation function: INR ≤1.5 times the upper limit of normal value; PT and
APTT are ≤1.5 times the upper limit of normal values (unless the subject is receiving
anticoagulant treatment and PT and APTT are within the expected range of
anticoagulant treatment at the time of screening).
6) Left ventricular ejection fraction (LVEF) ≥50% in cardiac function examination.
7) The serum pregnancy test is negative, and effective contraceptive measures have
been taken from the signing of the informed consent form until 6 months after the last
chemotherapy.
8) Thyroid stimulating hormone (TSH), free thyroxine (FT4), or free triiodothyronine
(FT3) are all within the normal range of ± 10%.

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9) Ophthalmic examination: including dilated pupil fundus examination, slit lamp
examination, and fundus color photography.
3.3.2 Exclusion criteria
1) I am currently participating in other clinical studies, or my first study drug was
administered less than 4 weeks after the end of the previous clinical study treatment.
2) Suffering from other malignant tumors in the past 5 years.
3) Patients who have received CNS guided therapy for prevention.
4) Patients with a known history of human immunodeficiency virus (HIV) infection
and/or acquired immunodeficiency syndrome.
5) Patients with active autoimmune diseases or a history of autoimmune diseases with
a high risk of recurrence, including but not limited to immune related neuropathy,
multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain Barr é syndrome,
myasthenia gravis, systemic
lupus erythematosus, connective tissue diseases,
scleroderma, inflammatory bowel cancer (including Crohn's disease and ulcerative
colitis), autoimmune hepatitis, toxic epidermal necrolysis, or Stevens Johnson
syndrome.
6) Patients with active chronic hepatitis B or active hepatitis C. Patients with positive
hepatitis B surface antigen or hepatitis C virus antibody in screening period must
further pass the hepatitis B virus DNA drop test (not more than 1000 iu/ml) and HCV
RNA test (not more than the lower limit of the test method), and can be included in
the test only after the active hepatitis B or hepatitis C infection requiring treatment is
excluded. Hepatitis B virus carriers, hepatitis B patients who are stable after drug
treatment and cured hepatitis C patients can be included in the group.
7) Suffer from active pulmonary tuberculosis.
8) Currently, there is interstitial lung disease or infectious pneumonia.
9) Active infections that require systematic anti infective treatment, including but not
limited to bacterial, fungal, or viral infections.
10) Patients with heart failure, unstable angina, severe uncontrolled ventricular
arrhythmias, acute ischemia or myocardial infarction as determined by the New York

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Heart Association (NYHA) functional classification within the first 6 months of
screening.
11) QTcF interval>480milliseconds, unless secondary to bundle branch block.
12) Suffering from uncontrollable comorbidities, including but not limited to
uncontrolled hypertension, active peptic ulcers, or bleeding disorders.
13) Individuals with a history of mental illness in the past; Individuals without legal
capacity or with limited legal capacity.
14) According to the researchers' assessment, the patient's underlying condition may
increase their risk of receiving study drug treatment, or cause confusion regarding the
occurrence of toxic reactions and their assessment.
15) Other researchers believe that patients who are not suitable to participate in this
study.
3.3.3 Study drug discontinuation/withdrawal criteria
If any of the following occurs, the subject must discontinue the investigational drug:
1) AE related to treatment that meets the discontinuation criteria specified in the
research protocol.
2) Disease progression.
3) During the study period, receiving any prohibited concomitant therapy may affect
the assessment of safety and efficacy.
4) Any intermittent disease that prevents the subject from continuing to receive study
drug treatment.
5) The subject is unwilling to continue the clinical study and may discontinue the
investigational drug at any time with the consent of the researcher. According to the
Helsinki Declaration and other applicable regulations, participants have the right to
withdraw from this study at any time and for any reason, and researchers may not
have any bias towards their future medical care.
6) The subjects had poor compliance, did not receive treatment on time, and
communication and coordination with the researchers were ineffective, which may
result in significant deviations in the trial results and cannot be remedied.

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7) Other situations where researchers believe it is not appropriate to continue
medication.
In any case, the primary reason for discontinuing the investigational drug will be
recorded in the original medical record.
3.3.4 Follow up on withdrawal cases
Any patient who withdraws from this study for reasons other than progression
should continue to undergo imaging evaluation at a predetermined time to collect
information about disease progression, until imaging disease progression occurs, new
anti-tumor treatment begins, informed consent is withdrawn, death occurs, or the
study ends (whichever occurs first). After recording disease progression, researchers
need to contact patients, their families, or their current treatment physicians by phone
at least once a month to collect long-term follow-up information on survival.
4 Concomitant medication
4.1 Permissible drugs for use
1) Unconventional treatment (such as non anti-cancer Chinese herbal medicine or
acupuncture and moxibustion), vitamins/trace elements are allowed to be used
without affecting the observation of the study endpoint, and are controlled by the
researcher.
2) When clinically significant bone marrow suppression occurs after treatment,
therapeutic treatments such as colony stimulating factor, TPO, and blood transfusion
can be used.
3)
Subjects
can
use
topical,
ocular,
intra-articular,
intranasal,
and
inhaled
corticosteroids.
4) Emergencies that occur during treatment allow patients to undergo surgery or other
targeted treatments.
4.2 Research drug and dosage
In this study protocol, whole brain radiotherapy combined with intrathecal
injection of 10mg of Thiotepa was administered twice a week.

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5 Efficacy evaluation
It is recommended to undergo MRI and CSF testing during the screening period. The
efficacy of intrathecal injection is evaluated every 3 months based on the Neuro
Tumor Response Evaluation (RANO) - LM criteria.
6 Statistical analysis
6.1 Sample size estimation
The main endpoint of this study is safety. 58 patients are expected to be enrolled and
their overall efficacy will be observed.
6.2 Analyzing the population
Full Analysis Set (FAS): An analysis set determined according to the principle of
intention analysis. All subjects who received at least one medication record will be
included in this analysis set. The full analysis set is the main effectiveness analysis
set.
PPS: A subset of the complete analysis set. Subjects who violate the protocol and are
judged to have a significant impact on the therapeutic effect will be excluded from
this episode.
Safety Analysis Set (SS): All subjects who received intrathecal injection medication
and had a post medication safety assessment.
6.3 Statistical analysis
6.3.1 Demography and Baseline
Demographic and baseline characteristics such as age, gender, baseline disease
characteristics, ECOG physical condition, etc. will be summarized in the safety
analysis set. The baseline measurement value refers to the last data obtained before
the first administration of the study drug by the subject. Continuous data will be
subjected to descriptive statistics (mean, median, standard deviation, and range), and
frequency and percentage will be used as categorical data descriptions.
6.3.2 Efficacy analysis
1) Primary efficacy endpoint
Descriptive statistical analysis was used to summarize the exposure levels of the
study drugs, including course of treatment, frequency of administration, etc.

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According to NCI CTCAE v5.0, adverse events are classified. All adverse events that
occurred during or after the first study drug administration will be summarized
according to NCI CTCAE grading. In addition, serious adverse events, severe adverse
events (grades 3 to 5), investigational drug related adverse events, and adverse events
leading to the termination or change of investigational drug treatment will be
summarized accordingly. Multiple occurrences of the same event will be recorded as
one event based on the highest severity. The proportion of subjects who reported at
least one adverse event. We will summarize the deaths reported during the treatment
period and during the follow-up period after treatment completion/termination.
Specific laboratory test results, vital signs, physical examinations, as well as 12 lead
ECG test values and their relative baseline changes will be summarized. When
applicable, the baseline check values and post baseline check values are presented in a
cross tabular form.
2) Secondary efficacy endpoint
PFS refers to the time (in months) from the initial use of medication to the initial
confirmation of disease progression or death (whichever comes first). When
researchers evaluate disease progression analysis based on the 2005 IPCG criteria,
subjects without disease progression or death will be excluded on the last tumor
assessment date. Subjects without baseline tumor evaluation results will be deleted on
the first day of medication plus one day. Use the Kaplan Meier method to obtain
estimates of the survival function and median PFS, and use the Greenwood formula to
estimate the error of the survival function, resulting in a 95% CI of the median PFS
value. And draw the Kaplan Meier survival curve.
OS refers to the time from the initial use of medication to death, with no
limitation on the cause of death. For subjects who did not report death before the data
deadline, the last known survival date will be deleted. If the subjects do not have post
baseline data, they will be deleted on the first day of medication plus one day. The
analysis method is the same as PFS.
6.3.3 Analysis of cerebrospinal fluid indicators

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Record the routine, biochemical, albumin content, IgG content, exfoliated cells,
and micro single-cell detection data of cerebrospinal fluid before and after each
treatment. The discarded cerebrospinal fluid from our laboratory can be used as a
control.
7. Adverse event
7.1 Definition
AE refers to any adverse medical event that occurs 90 days after the last use of
the investigational drug, regardless of whether there is a causal relationship with the
investigational drug, starting from the signing of the informed consent form by the
clinical trial subjects.
7.2 Content
1) The worsening of the original medical condition/disease (including symptoms,
signs, and laboratory abnormalities before entering clinical trials);
2) Any newly occurring adverse medical condition (including symptoms, signs,
newly diagnosed diseases);
3) Abnormal laboratory test values or results with clinical significance.
Researchers should provide detailed records of any adverse events that occurred in the
subjects, including the name of the event and a description of all related symptoms,
time of occurrence, severity, correlation with the investigational drug, duration,
measures taken, and final outcomes and outcomes.
7.3 Record of Adverse Events
Researchers should carefully observe any adverse reactions that occur in subjects
during clinical research, require subjects to truthfully reflect changes in their
condition after medication, avoid inducing questioning, and record in detail in the
case table CRF, including the time of occurrence of adverse reactions, symptoms,
signs, degree, duration, laboratory test indicators, treatment methods, process, results,
etc., as well as the situation of combined medication.
7.4 Criteria for determining the severity of adverse events
Refer to the NCI-CTCAE 5.0 grading criteria for drug AEs.

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7.5 Judgment criteria
for the relationship between
adverse events
and
investigational drugs
AE includes all unexpected clinical manifestations, as long as these events occur
after signing the informed consent form, regardless of whether they are related to the
investigational drug or whether the drug is used, they should be reported as AE.
During the treatment period, any discomfort or abnormal changes in objective
laboratory test indicators reported by the subject should be truthfully recorded, and
the severity, duration, treatment measures, and outcomes of the AE should be
indicated. The research physician should also comprehensively determine the
relationship between the AE and the investigational drug, and evaluate the possible
association between the AE and the investigational drug using the "definitely related,
possibly related, possibly unrelated, definitely unrelated, and unable to determine"
five
level
classification
method
"Definitely
related",
"possibly
related",
and
"undeterminable" are all listed as adverse drug reactions, and the criteria for
determination are shown in the table below:
Table 1
Criteria for Judging the Relationship between AE and investigational
Drugs
Grading
Judging criteria
Definitely
related
The occurrence of the event conforms to a reasonable time sequence
after medication, and the event conforms to the known reaction type of
the suspected drug; Or improve after discontinuation of medication, and
the event may occur again after repeated administration.
May
be
related.
The occurrence of the event conforms to a reasonable time sequence
after medication, and the event does not match the known reaction type
of the suspected drug; The patient's clinical status or other treatment
methods may also contribute to this event.
May
not
be
relevant
The occurrence of the event does not conform to the reasonable time
sequence after medication, the event does not match the known reaction
type of the suspected drug, and the patient's clinical status or other

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treatment methods may have caused the event.
Definitely
unrelated
The occurrence of the event does not conform to the reasonable time
sequence after medication, the event does not match the known reaction
type of the suspected drug, the patient's clinical status or other treatment
methods may cause the event, the event disappears after disease
improvement or cessation of other treatment methods, and the event of
repeated use of other treatment methods occurs.
Unable to
evaluate
The occurrence of the event has no clear relationship with the time
sequence after medication, and is similar to the known reaction type of
the drug. At the same time, the use of other drugs may also cause
corresponding events.
7.6
Serious adverse events and recording and reporting
1) Definition of SAE
SAE refers to medical events that occur during clinical trials that require
hospitalization or prolonged hospitalization, disability, affect work ability, endanger
life or death, and result in congenital malformations.
Including the following unexpected medical events: events leading to death; A
life-threatening event (defined as the risk of immediate death of the subject at the time
of the event); Events that require hospitalization or extended length of stay; Events
that can lead to permanent or severe disability/functional impairment/impact on work
ability; Congenital abnormalities or birth defects; Other important medical events
(defined as events that harm the subject or require intervention to prevent the
occurrence of any of the above situations).
2) Disease progression
Disease progression is defined as the deterioration of the subject's condition
caused by the primary tumor targeted by the study medication. Including the
progression of imaging and clinical symptoms and signs. The appearance of new
metastases relative to the primary tumor or the progression of existing metastases are
considered disease progression. Events that endanger life due to symptoms and signs

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of disease progression, require hospitalization or extended hospital stay, or result in
permanent or severe disability/functional impairment/impact on work ability,
congenital abnormalities or birth defects are not reported as SAE for accelerated
reporting. Death caused by symptoms and signs of disease progression is reported as
accelerated SAE.
3) Perform other anti-tumor treatments
The AE record starts from the signing of the informed consent form until 90 days
after the last use of the study drug. Within 90 days after the last administration, if the
subject begins to use other tumor drugs and experiences serious adverse events, a
report is required.
4) Hospitalization treatment
Adverse events that lead to hospitalization or prolonged hospital stay in clinical
studies should be considered as SAEs. Any initial hospitalization by a medical
institution meets this standard. Hospitalization does not include the following
situations: rehabilitation institutions; Sanatorium; Routine emergency room admission;
Same day surgery (such as outpatient/same day/non bed rest surgery); Hospitalization
treatment or prolonged hospital stay that is not related to the deterioration of AE itself
is not an SAE. For example, if admitted due to an existing disease, there have been no
new adverse events or worsening of the existing disease (such as in order to check for
laboratory test abnormalities that have persisted since the trial); Hospitalization for
management reasons (such as annual routine physical examinations); Hospitalization
specified in the trial protocol during the clinical trial period (such as operating
according to the requirements of the trial protocol); Selective hospitalization unrelated
to the worsening of adverse events (such as elective surgery); The scheduled
treatment or surgery should be recorded in the entire trial protocol and/or individual
baseline data of the subjects.
Diagnostic or therapeutic invasive (such as surgery) and non-invasive procedures
should not be reported as AEs, but when the disease condition that caused this
procedure meets the definition of AE, it should be reported. For example, acute
appendicitis that occurred during the AE reporting period should be reported as AE,

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and the appendectomy performed as a result should be recorded as the treatment
method for that AE.
5) SAE's reporting system
The reporting period for SAE should start from the signing of the informed
consent form by the subject and continue until 90 calendar days (including 90 days)
after the last use of the study drug. If SAE occurs, whether it is the first or follow-up
report, the researcher must immediately fill out the Serious Adverse Event Report
Form for Clinical Research of New Drugs, sign and date it, and report it to the
relevant provincial, autonomous region, or municipality drug regulatory department,
NMPA
(via
EMS),
health
administrative
department
(fax
to
the
Medical
Administration Bureau), and notify the applicant (via email) within 24 hours of the
researcher's knowledge, And report to the ethics committee in a timely manner.
SAE occurring 90 days after the last use of the investigational drug, unless
suspected to be related to the investigational drug, is generally not reported. SAE
should provide detailed records of symptoms, severity, correlation with the
investigational drug, occurrence time, treatment time, measures taken, follow-up time
and method, and outcome. If the researcher believes that a certain SAE is not related
to the investigational drug but potentially related to the study conditions (such as
termination of original treatment or complications during the trial), this relationship
should be detailed in the narrative section of the SAE report form. If the intensity of
an ongoing SAE or its relationship with the test drug changes, a follow-up report
should be submitted immediately.
6）Follow up of SAE
All SAEs should be followed up until disappearance, remission to baseline level,
or ≤level 1, stable.
Researchers should follow up until the end of AE, stable status, reasonable
explanation, loss of follow-up, or death; Follow up information should be provided in
a timely manner according to the requirements of the sponsor.
If there are no special requirements in the protocol, AE/SAE collection and
follow-up usually begin after the subject signs the informed consent form, and each
AE/SAE must be followed up during the study period; At the end of the study, the

21 / 23
principles for collecting and following up on AE/SAE that occurred after the
completion of the last medication by the subjects can be referred to in the table below:
Classify, collect
and record.
Follow up.
Unrelated AE.
90 days after the end of
treatment.
End treatment for 90 days.
Related AEs.
90 days after the end of
treatment.
Until the event is resolved
or the situation stabilizes
when it returns to baseline.
Unrelated SAE.
Unrelated SAE. 90 days
after the end of treatment.
End treatment for 90 days.
Related SAE.
Unlimited.
Until the event is resolved
and the condition or stability
is restored to baseline.
8. Research management
8.1 Case Report Form
The main purpose is to obtain the necessary information for the research plan in
a complete, accurate, clear, and timely manner. The data in the medical record report
form should be consistent with the original file. The filling out of the medical record
report form must be complete and clear (using black or blue ballpoint pens, in
compliance with legal requirements). The medical record report form is a regulatory
document that must be suitable for submission to hospital authorities.
All revisions and corrections must be carried out and confirmed by researchers,
indicating the date of revision/correction. Errors must be clearly preserved and cannot
be covered with corrected information (such as using correction fluid). The researcher
must
indicate
the
reasons
for
his/her
revision
of
important
data.
Missing
information/notes in the medical record should be replaced by underlined spaces in
the medical report form to avoid unnecessary follow-up investigations.
8.2 Research Documents and Preservation
Researchers should have a document regarding the research objectives. This file
should include all relevant documents necessary for conducting research. After the

22 / 23
research is completed, these documents should be archived in accordance with
relevant regulations of the hospital and the country.
8.3 Regulations on Data Management and Data Traceability
The designed CRF is in triplicate (carbon free copy), and the second copy of the
CRF is submitted to the data management personnel participating in this clinical trial
to establish a unified database. After completing at least 5 CRFs, the trial will be
promptly submitted to the data administrator through clinical monitors for the
establishment of the corresponding database. All data will be entered in duplicate
using computer software to develop a data entry program.
During this period, any questions will be forwarded to the researcher for data
review by the clinical monitor, and the researcher should answer and return as soon as
possible. The locked data file cannot be changed again. The database will be handed
over to statistical analysts for statistical analysis in accordance with the requirements
of the statistical plan. The statistical analysis report shall be submitted to the main
researcher of this experiment to write the research report.
Provide training to researchers on relevant regulations and SOPs, and ensure that
all researchers strictly adhere to them, recording truthfully, timely, accurately, and
completely, preventing omissions and arbitrary modifications, and not forging or
fabricating data; The inspector strengthens the verification of various records. The
follow-up medical records of the subjects should be kept together with the CRF as
raw data. Each central laboratory provides a certificate of conformity for participating
in the quality control of the Clinical Laboratory Center of the Ministry of Health, and
the test results are stored in the computer connected to the testing equipment for at
least three years for future reference.
8.4 Quality control and assurance of clinical trials
Applicants and researchers should fulfill their respective responsibilities and
strictly follow the clinical trial protocol, adopting standard operating procedures to
ensure the quality control of the clinical trial and the implementation of the quality
assurance system.

23 / 23
All observations and findings related to clinical trials should be verified, and
quality control must be carried out at each stage of data processing to ensure data
completeness, accuracy, authenticity, and reliability.
This study was commissioned by the drug regulatory department and the sponsor
to conduct a systematic inspection of the activities and documents related to this
clinical trial, in order to evaluate whether the trial was conducted in accordance with
the trial protocol, standard operating procedures, and relevant regulatory requirements,
and whether the trial data was recorded in a timely, truthful, accurate, and complete
manner. The inspection should be carried out by personnel who are not directly
involved in the clinical trial. This study is subject to inspection by the drug regulatory
authorities on the tasks and execution status of the researchers and sponsors during
the implementation of this trial.

24 / 23
9. Ethical and regulatory aspects
9.1 Responsibilities of Researchers
Researchers are responsible for ensuring that clinical studies are conducted according
to the research protocol, ethical and ethical principles are based on the Helsinki
Declaration (the World Medical Association Declaration of Helsinki, current revised
version) and Good Clinical Practice (GCP) for drug trials, and in accordance with
China
Adjust the national conditions appropriately. The above documents must be stated on
the informed consent form of the subjects, which is a basic prerequisite for inclusion
in clinical studies.
9.2 Subject Information
Signing a written informed consent form is a necessary prerequisite for patient
selection. Before signing, researchers must provide sufficient information to the
subjects. If it complies with hospital regulations, information can be provided to the
subject by the designated executor appointed by the subject. In addition to written
information, researchers or practitioners should verbally inform patients. Pay attention
to choosing wording so that the subjects can fully and easily understand. Whenever
important new information is discovered that involves the patient's informed consent
form, the subject information form should be modified.
9.3 Informed consent form
Before engaging in all research related behaviors, a written consent form from the
patient must be obtained to participate in the clinical study. The informed consent
form
needs
to
be
personally
signed
by
the
patient
and
the
designated
executor/researcher, indicating the signing date.
Researchers should confirm again in the CRF whether to sign the consent form. The
signed and dated informed consent form should be stored at the researcher's location
and must be securely archived by the researcher for supervision, review, and
inspection at all times.

25 / 23
The original copy of the informed consent form should be provided to the patient
before conducting the study. If patients or legally recognized representatives are
unable to read the informed consent form, a reliable and independent witness should
attend the entire process of discussing the informed consent form. The selection of
witnesses must ensure the patient's right to confidentiality. Reliable and independent
witnesses should be independent individuals, rather than affiliated with research
institutions or participants in the study. Family members or acquaintances are a
suitable choice for independent witnesses. If possible, after the subject, patient, or
legally recognized representative verbally agrees and signs the informed consent form,
the witness should personally sign and date the informed consent form to prove that
the information is accurate, because only the patient or legally recognized
representative fully understands the content of the informed consent form is the true
informed consent form.
9.4 Compensation for subjects
The drugs used in this study were all domestically marketed drugs. During the
treatment
process
of
the
subjects,
the
researchers
closely
monitored
the
treatment-related adverse reactions and actively handled them according to clinical
routine.
9.5 Ethics Committee
Researchers must provide all documents as required by the hospital ethics committee
before starting the study. Before obtaining approval from the ethics committee,
participants are not allowed to participate in the study.
10. Publication and Achievements
After completing the research summary, researchers can publish papers, participate in
domestic and international academic conferences, and receive awards for clinical
research papers. The first author and corresponding author are enjoyed by the Second
Affiliated Hospital of Zhejiang University School of Medicine.
11. Treatment process

26 / 23
Table 1 Research Process Table
Resear
ch
period
Scree
ning
period
Treatment period
Follow up period
Treatm
ent
cycle
or visit
name.
screen
ing
period
1
2
3
4
5
6
Study
treatme
nt
termina
tion
visit 1
Safety
follow-u
p 2
Imag
ing
follo
w-up
3
Survival
follow-up
4
Visit
time
and
windo
w
period
Day-2
8
to
Day-1
Day
±3
Day
±3
Day
±3
Day
±3
Day
±3
Day
±3
7
30 days ±
3
days
after
the
last
treatment
Every
12
weeks ± 7
days after
the
last
treatment
Research management process
Inform
ed
consen
t form
×
Emissi
on
standar
ds
×
Demo
graphy
and
×

27 / 23
medica
l
history
Previo
us
treatm
ent
and
conco
mitant
medica
tion 5
×
×
×
×
×
×
×
×
×
×
Clinical operation evaluation
Advers
e
Event
6
×
×
×
×
×
×
×
×
×
×
×
Twelv
e lead
electro
cardio
gram 7
×
×
×
×
×
×
×
×
×
Height
,
weight
,
and
vital
signs 8
×
×
×
×
×
×
×
×
×
Physic
×
×
×
×
×
×
×
×
×

28 / 23
al
exami
nation
and
ECOG
score 9
Subseq
uent
anti-tu
mor
treatm
ent
×
×
×
existen
ce
×
×
×
Research treatment
Chemo
therap
y 10
×
×
×
×
×
×
Laboratory operations/evaluations
Blood
routine
,
bioche
mistry,
stool
and
urine
routine
11
×
×
×
×
×
×
×
×

29 / 23
coagul
ation1
2
×
×
×
×
×
×
Infecti
ous
Diseas
es 13
×
EBV--
DNA1
4
×
×
×
×
×
×
×
HBV-
DNA1
5
×
×
×
×
×
×
×
HCV-
RNA1
6
×
thyroid
functio
n
×
×
×
×
×
×
Myoca
rdial
enzym
e
spectru
m,
creatin
e
kinase,
BNP
×
×
×
×
×
×

30 / 23
×
×
×
×
×
×
pathol
ogy
×
Efficacy evaluation
Imagin
g
Exami
nation
17
×
×
×
×
×
Detecti
on
of
circula
ting
tumor
cells in
cerebr
ospinal
fluid
18
×
1. Study treatment termination visit: The date of study treatment termination is
defined as the date on which the researcher confirms that the subject needs to
terminate the study treatment for any reason. The time window for study treatment
termination visit is 7 days from this date.
2. Safety follow-up: The time window for safety follow-up is 30 days+-3 days after
the last study treatment; If the termination of the study treatment visit occurs within
the time window of safety follow-up, the same examination items do not need to be
repeated.

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3. Imaging follow-up: Except for subjects who stopped taking medication due to
disease progression determined by imaging evaluation, imaging evaluation will
continue at the established time until imaging disease progression occurs, new
anti-tumor treatment begins, informed consent is withdrawn, death occurs, or the
study ends (whichever occurs first).
4. Survival follow-up: Follow up the survival status of the subjects by phone in the
12th week after the last study treatment.
5. Combination medication: Record the combination medication within 30 days prior
to the screening visit until imaging follow-up is completed.
6. Adverse events: Starting from the signing of the informed consent form, all AEs
and SAEs are recorded until 90 days after the last study treatment or the start of new
anti-tumor treatment (whichever occurs first), after which only AEs and SAEs related
to the study treatment are recorded. AE after safety follow-up visits can be recorded
through telephone inquiries on the 60th and 90th days after the last treatment.
7. Electrocardiogram: The electrocardiogram will be analyzed during the screening
period, treatment period, study treatment termination visit, and safety follow-up. If
necessary, an electrocardiogram examination can be added.
8. Height, weight, vital signs: will be conducted during the screening period,
treatment period, study treatment termination visit, and safety follow-up.
9. Physical examination and ECOG score: During the screening period, at the end of
the study treatment visit and safety follow-up, a full body physical examination will
be conducted. During the treatment period, a lymphoma specific physical examination
will be conducted.
10. Research treatment: Administration should start on the first day of each cycle after
all clinical and laboratory procedures/evaluations have been completed.
11. Blood routine, blood biochemistry, stool and urine routine: Blood routine
examination must include whole blood cell classification count and hemoglobin; The
blood biochemistry test items must include urea nitrogen, creatinine, sodium,
potassium, magnesium, chlorine, calcium, phosphorus, total bilirubin, direct bilirubin,
indirect bilirubin, ALT, AST, lactate dehydrogenase, total cholesterol, total protein,

32 / 23
and albumin; Screening period (within 7 days prior to initial administration), within 3
days prior to weekly administration, study treatment termination visits, and safety
follow-up will be conducted.
12. Coagulation function: Coagulation function testing should be conducted during
the screening and treatment periods.
13. Infectious disease detection: hepatitis B, hepatitis C, HIV, syphilis and other
antibodies were detected during the screening period.
14. EBV-DNA testing: EBV-DNA testing will be conducted during the screening
period, treatment period, and study treatment termination visit.
15. HBV-DNA test: Regardless of the results of infectious disease test during the
screening period, HBV-DNA test must be carried out during the screening period, the
treatment period, and the termination of the study treatment visit. For patients with
positive hepatitis B B surface antigen or positive hepatitis B core antibody, the
follow-up period should be reviewed once a month.
16. HCV-RNA testing: HCV antibody positive subjects must undergo HCV-RNA
testing during the screening period, followed by monthly follow-up.
17. Imaging examination: PET/CT examination is recommended during the screening
period, after the 4th and 6th cycles of chemotherapy. After the second cycle, it is
recommended to perform CT enhanced examination of the lesion site. During the
follow-up period, except for subjects who stopped taking medication due to disease
progression determined by imaging evaluation, CT enhancement examinations will be
performed every 3 months until imaging disease progression occurs, new anti-tumor
treatment begins, informed consent is withdrawn, death occurs, or the end of this
study (whichever occurs first). If PET/CT examination is not possible, head MRI and
whole body enhanced CT examination should be performed instead.
18.Testing of cerebrospinal fluid tumor markers, protein content, IgG and albumin
content, albumin index, circulating tumor cells, and micro single-cell sequencing.
19. Retain blood samples: for biomarker exploration.