Gossypol Acetate Combined With Bevacizumab and FOLFIRI as Second-Line Therapy for Metastatic Colorectal Cancer With TP53 Mutation and LRPPRC Positivity: A Single-Center, Single-Arm Clinical Study
Phase: PHASE2
Conditions: Patients With Metastatic Colorectal Cancer Who Were TP53-mutant and LRPPRC-positive and Had Previously Failed Prior First-line Treatment
Sponsor: Guiying Wang

Gossypol acetate Combined with Bevacizumab and
FOLFIRI as Second-Line Therapy for Metastatic
Colorectal Cancer with TP53 Mutation and LRPPRC
Positivity: A Single-Center, Single-Arm Clinical Study
Principal Investigator: Guiying Wang
Undertaking Department: Gastrointestinal Surgery
Project Contact Person: Haisong Xin
Contact Number: 16630159968
Study Duration: February 1, 2026 - February 1, 2028
Protocol Version Number: V1.0
Protocol Version Date: January 4, 2026

I. Study Background
Globally, colorectal cancer (CRC) ranks third in incidence and fourth
in mortality among malignant tumors. Approximately 900,000 individuals
die from colorectal cancer annually, accounting for about 10% of all
cancer-related deaths, posing a severe threat to human health [1].
Chemotherapy resistance in colorectal cancer is a complex multifactorial
biological process. Recent studies indicate that mutations in tumor
suppressor genes are also key contributors to chemotherapy resistance,
with tumor protein p53 (TP53) gene being the most representative example
[2]. Whole-genome analyses reveal that 60% of colorectal cancer patients
harbor TP53 gene mutations [2], rising to 80% among Stage IV colorectal
cancer patients with distant metastases. TP53 mutations not only abolish
the protein's transcriptional activation of tumor suppressor genes but also
confer
novel
pro-oncogenic
and
chemotherapy-resistant
functions.
Multiple previous studies have reported that TP53 gene mutations promote
chemotherapy resistance in colorectal cancer by facilitating tumor cell
DNA damage repair, chemotherapeutic drug efflux and inactivation, and
apoptosis resistance [3]. Over recent decades, restoring TP53 protein
function has become a highly attractive strategy for developing novel
antitumor drugs [4]. However, as a nuclear transcription factor, the TP53
protein lacks typical druggable characteristics. Regrettably, few TP53-
targeted drug development programs have advanced to late-stage clinical

trials
[5].
Therefore,
identifying
novel
therapeutic
targets
and
corresponding agents to reverse TP53-induced chemotherapy resistance
holds significant importance for improving the prognosis of patients with
TP53-mutant colorectal cancer.
In
our
recent
study,
we
first
reported
that
Leucine-Rich
Pentatricopeptide Repeat Containing protein (LRPPRC) serves as a critical
functional downstream effector and therapeutic target in TP53 mutation-
induced chemotherapy resistance in colorectal cancer. Wild-type TP53 and
mutant TP53 oppositely regulate LRPPRC expression. In wild-type TP53
cells, the TP53-miR-34a-LRPPRC-MDR1 signaling pathway is activated,
leading to reduced LRPPRC and MDR1 protein levels. Conversely, in
mutant P53 cells, this pathway is activated in reverse, resulting in
accumulation of LRPPRC and MDR1 proteins that mediate chemotherapy
resistance
in
colorectal
cancer.
Silencing
LRPPRC
demonstrates
substantial potential for reversing TP53 mutation-driven chemotherapy
resistance [6]. In previous research, Professor Fang Xiaohong from the
Institute of Chemistry, Chinese Academy of Sciences and Professor Song
Yongmei from the Cancer Hospital of the Chinese Academy of Medical
Sciences discovered that Gossypol Acetate (GAA), a clinically approved
established gynecological drug, can specifically target and degrade
LRPPRC [7]. This finding provides a potential approach to reverse TP53-
mediated chemotherapy resistance by targeting LRPPRC. Our further

experiments demonstrate that combining GAA with chemotherapeutic
agents can reverse chemotherapy resistance caused by TP53 mutations.
In second-line treatment for advanced unresectable metastatic
colorectal cancer, FOLFIRI (irinotecan + 5-FU/LV) or FOLFOX
(oxaliplatin + 5-FU/LV) with or without targeted therapy drugs constitute
standard regimens. For patients who received first-line oxaliplatin-based
chemotherapy,
second-line
irinotecan-based
chemotherapy
is
recommended [8].
Based on our preliminary basic research findings and previous studies,
gossypol acetate (GAA) demonstrates synergistic effects with conventional
chemotherapy in TP53-mutated colorectal cancer cells. It is worthwhile to
clinically investigate whether this combination strategy can yield superior
therapeutic outcomes in metastatic colorectal cancer patients with both
TP53 mutation and LRPPRC positivity. Therefore, this study aims to
evaluate the efficacy and safety of Gossypol Acetate Tablets combined
with Bevacizumab and FOLFIRI as second-line treatment for metastatic
colorectal cancer with TP53 mutation and LRPPRC positivity.
II. Study Objectives
To investigate the efficacy and safety of Gossypol Acetate Tablets
combined with Bevacizumab and FOLFIRI as second-line treatment for
metastatic colorectal cancer with TP53 mutation and LRPPRC positivity
in the Chinese population.

III. Study Design
(I) Study Population
Patients meeting all criteria: TP53 mutation and LRPPRC positivity;
metastatic colorectal cancer patients with failure of first-line treatment.
Patients with metastatic colorectal cancer who meet the inclusion criteria
without meeting any exclusion criteria.
Inclusion Criteria:
1. Female patients aged ≥18 years;
2. Histopathologically or cytologically confirmed colon or rectal
adenocarcinoma;
3. Imaging-confirmed unresectable metastatic disease;
4. At least one measurable lesion (per RECIST v1.1);
5. Previously received first-line oxaliplatin-based therapy;
6. ECOG score 0-2;
7. Expected survival time ≥3 months;
8. Bone marrow function: Neutrophils (ANC) ≥1.5×10⁹/L, Platelets
(PLT) ≥100×10⁹/L, Hemoglobin (Hb) ≥90 g/L, White blood cells (WBC)
≥3.0×10⁹/L;
9.
Liver
function: Alanine
aminotransferase
(ALT),
aspartate
aminotransferase (AST), and alkaline phosphatase (ALP) ≤2.5×ULN
(upper limit of normal); ≤5×ULN in cases with liver metastases; total
bilirubin ≤1.5×ULN;

10. Renal function: Serum creatinine (Cr) ≤1.5×ULN or creatinine
clearance ≥60 ml/min (calculated by Cockroft-Gault formula); urine
protein <2+;
11. Coagulation function: Normal coagulation function (International
Normalized Ratio INR ≤1.5);
12. Capable of comprehending the study details. Patients and/or their
legal guardians voluntarily agree to participate in this trial and sign the
Informed Consent Form.
Exclusion criteria:
1. Patients diagnosed with other malignancies within the past 5 years
(except cured carcinoma in situ and basal cell carcinoma of the skin);
2. Previous chemotherapy based on irinotecan/liposomal irinotecan;
3. Massive pleural effusion or ascites requiring interventional
treatment;
4. Active, uncontrolled bacterial, viral, or fungal infections requiring
systemic therapy, defined as persistent signs/symptoms related to infection
without improvement despite appropriate antibiotic, antiviral, and/or other
therapies;
5. Known active HIV infection (i.e., positive for HIV-1/2 antibodies);
Untreated active HBV infection (defined as positive for HBsAg/HBcAg
with HBV-DNA copies exceeding the upper limit of normal at the central
laboratory) and active HCV infection (positive for HCV antibodies with

HCV-RNA levels above the upper limit of normal);
6.
Uncontrolled
systemic
diseases,
including
cardiovascular
conditions such as unstable angina, myocardial infarction, congestive heart
failure, severe unstable ventricular arrhythmias, or history of severe
pericardial disease; Uncontrolled hypertension (defined as systolic blood
pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg after
standardized antihypertensive
therapy),
or
history
of
hypertensive
crisis/hypertensive encephalopathy; uncontrolled diabetes mellitus;
7. Presence of severe gastrointestinal disorders (including active
bleeding, obstruction of Grade >1, diarrhea of Grade >1, or gastrointestinal
perforation);
8. History of laparotomy, thoracotomy, or intestinal resection within
28 days prior to enrollment;
9. Presence of interstitial pneumonia or pulmonary fibrosis;
10. Known allergy or intolerance to the investigational drugs or their
excipients;
11. History of pulmonary hemorrhage/hemoptysis ≥Grade 2 (defined
as ≥2.5 mL of bright red blood) within one month prior to enrollment;
12.
History of arterial
thromboembolism,
severe
hemorrhage
(excluding
surgical
bleeding),
or
existing
predisposition
to
thromboembolism/severe hemorrhage within 6 months prior to enrollment;
13. Presence of central nervous system metastases;

14. Serum albumin ≤3 g/dL;
15. Concomitant use of strong inhibitors or inducers of CYP3A4,
CYP2C8, and UGT1A1;
16. Women who are pregnant or breastfeeding, as well as patients of
childbearing potential who refuse to use adequate contraception during the
trial;
17. Participation in other investigational studies within 30 days prior
to the first dose of study drug;
18. Patients with allergies to Bevacizumab, irinotecan, fluorouracil,
calcium folinate, or Compound Gossypol Acetate Tablets;
19. Patients deemed unsuitable for participation by the Investigator's
judgment.
(II) Patient Grouping
This single-arm, single-center clinical study does not involve patient
grouping.
（三）Study Content
3.1 Study Content

3.2 Follow-up Plan (Schedule and Components)
Visit Point
Visit
Screening
Period 1
Treatment
Period 2
End of
Treatment
3
Follow-up
4
Informed Consent Form
×
Inclusion/Exclusion
Criteria
×
Medical History Collection
5
×
Demographic Data 6
×
Height and Weight
×
×
Vital Signs 7
×
×
×
Physical Examination 8
×
×
×
ECOG score
×
×
×
Complete Blood Count 9
×
×
×
Blood Biochemistry 10
×
×
×
Urinalysis 11
×
×
×
Coagulation Function 12
×
×
×
Biomarker 13
×
×
×
Electrocardiogram
×
×
Pregnancy Test 14
×
HIV/HBV/HCV Testing
×
UGT1A1*28 Testing
×
RAS
and
TP53
Status
Testing,
and
LRPPRC
Immunohistochemical
Testing 15
×
Histopathological
or
Cytological Testing
×
Tumor Assessment 16
×
×
×
×
Chemotherapy/Targeted
Therapy Drugs 17
×
Concomitant
Medication/Treatment 18
×
×
×
Adverse Event 19
×
×

Subsequent
Anti-tumor
Therapy 20
×
Survival Follow-up
×
Note:
1. Screening Period: Data requiring documentation includes: Medical History,
Demographic Data, Height and Weight, Vital Signs, Physical Examination, ECOG
Score, Complete Blood Count, Blood Biochemistry, Urinalysis, Coagulation Function,
Biomarker, Electrocardiogram, Pregnancy Test, HIV/HBV/HCV Testing, UGT1A1
Testing, RAS and BRAF Gene Testing, Histopathological or Cytological Testing, and
Tumor Assessment. Imaging examinations conducted within 28 days prior to subject
enrollment are acceptable; Historical histopathological/cytological examination results
and genetic testing results (including but not limited to sequencing, microarray, or
qPCR) are acceptable, provided they are confirmed by the Investigator; other
examination items must have been performed within 14 days prior to enrollment.
2. Treatment period: Data requiring documentation includes: height/weight, vital
signs, physical examination, ECOG score, Complete Blood Count, Blood Biochemistry,
Urinalysis, Coagulation function,
Biomarker testing, Tumor Assessment, and
chemotherapy/targeted therapy drugs. If screening assessments were completed within
7 days prior to Cycle 1 Day 1 (C1D1), they need not be repeated on C1D1. Imaging
examinations will be conducted every 8 weeks (±7 days; approximately every 4
treatment cycles); Coagulation function and Biomarker testing will be performed every
4 weeks (±7 days; approximately every 2 treatment cycles); other examination items
will be conducted within 5 days prior to each cycle administration.
3. End of Treatment: Data to be recorded includes vital signs, physical
examination, ECOG score, complete blood count, blood biochemistry, urinalysis,
coagulation
function,
biomarkers,
electrocardiogram,
and
tumor
assessment.
Examinations shall be conducted within 28 days after treatment cessation. If imaging
results within 28 days are available, additional imaging examination will not be
required.
4. Follow-up: Data to be recorded includes tumor assessment, subsequent anti-
tumor therapy, and survival follow-up. After entering the follow-up period,
examinations shall be performed every 12 weeks (±10 days); Until death, loss to follow-
up, informed withdrawal, or completion of 1-year follow-up (whichever occurs first).
5. Medical history collection: Past medical history (colorectal adenoma,
inflammatory bowel disease, and other colorectal cancer-related conditions without
time window restriction; myocardial infarction and other bevacizumab-related histories
without time window; other past medical histories recorded within 28 days) and present
illness history. Colorectal cancer-related history (including date of diagnosis,
histological type, tumor assessment scan results, disease stage, multidisciplinary team
consultation outcomes, prior antitumor therapy, primary tumor site, and metastatic sites)
will be documented.
6. Demographic data: Date of birth, gender, and ethnicity will be recorded.
7. Vital signs: including blood pressure, pulse, respiration, and temperature
(axillary/forehead).

8. Physical examination: encompassing skin and mucous membranes, lymph
nodes, head and neck, chest, abdomen, spine and limbs, nervous system, general
condition, and others.
9. Complete Blood Count: including white blood cell count, red blood cell count,
hemoglobin, platelet count, neutrophil count, and lymphocytes.
10. Blood
Biochemistry:
including
Alanine
Aminotransferase,
Aspartate
Aminotransferase, Alkaline Phosphatase, Total bilirubin, Direct bilirubin, Indirect
bilirubin, Total protein, Albumin, Lactate Dehydrogenase, Urea or Blood Urea Nitrogen,
Serum Creatinine, Uric acid, Phosphorus, Magnesium, Potassium, Sodium, Chloride,
and Calcium.
11. Urinalysis: including urine protein, red blood cells, and white blood cells.
12. Coagulation function: prothrombin time, International Normalized Ratio,
activated partial thromboplastin time, thrombin time, fibrinogen.
13. Biomarkers: CEA, CA199.
14. Pregnancy test: Women of childbearing potential must undergo blood/urine
human chorionic gonadotropin (hCG) testing during the screening period.
15. RAS and TP53 status testing, LRPPRC immunohistochemical testing: Genetic
testing and immunohistochemical testing.
16. Tumor Assessment: CT or MRI is recommended for evaluation, with
consistent imaging modality maintained for each patient throughout the study.
17. Chemotherapy/Targeted Therapy Drugs: Record the generic drug name,
administration date, dosage, and reasons for any chemotherapy delays or regimen
modifications.
18. Concomitant Medication/Treatment: Document all concomitant therapies
from the signing of the Informed Consent Form through the end-of-treatment visit,
including medications used for preventive and therapeutic management of adverse
events, treatment of comorbid conditions, or enhancement of immune function.
19. Adverse Events: Record from the first dose administration until 28 days after
the last dose. Record the adverse event name, cycle of occurrence, severity (according
to NCI-CTCAE v5.0), relationship to study treatment, relationship to investigational
product, action taken with investigational product, outcome, start and end dates,
whether symptomatic treatment was administered, and whether it was a Serious
Adverse Event (SAE).
20. Subsequent anti-tumor therapy: Record any antitumor therapy received by
subjects after the end-of-treatment visit, including generic drug names, dosage and
administration, start date, and end date.
3.3 Selection and Confirmation of Primary Measures or Outcome
Indicators
3.3.1 Primary Endpoint
Objective Response Rate (ORR), defined as the percentage of patients

achieving Complete Response (CR) and Partial Response (PR) among the
Intent-to-Treat (ITT) analysis set population.
3.3.2 Secondary Endpoints
Secondary Endpoint 1: Progression-Free Survival (PFS), defined as
the time from the date of first dose of Study Treatment to the first
documented disease progression (PD) or death from any cause, whichever
occurs first.
Secondary Endpoint 2: Clinical Benefit Rate (CBR), calculated as the
percentage of patients in the ITT analysis set who achieve complete
response (CR), partial response (PR), or stable disease (SD) for at least 24
weeks.
Secondary Endpoint 3: Duration of Response (DoR), defined as the
time from the first documented CR or PR to disease progression or death
from any cause.
Secondary Endpoint 4: Time to Response (TTR), defined as the time
from the date of first dose of Study Treatment to the first documented
objective tumor response of CR or PR.
Secondary Endpoint 5: Overall Survival (OS), defined as the time
from the first administration of Study Treatment until death from any cause.
Secondary Endpoint 6: Adverse Events (AE), assessed using the
National Cancer Institute (NCI) Common Terminology Criteria for
Adverse Events (CTCAE) version 5.0.

IV. Data Management
4.1 Data Entry (selection of paper/electronic record forms,
whether double data entry will be performed, whether electronic data
capture system will be used, etc.)
The Investigator will be responsible for data management in this
study. All case report forms (CRF) will be completed by designated,
trained trial site personnel, with the Investigator reviewing CRFs and
signing with name and date.
To ensure data accuracy, completeness, and consistency,
Investigators shall maintain source documents including but not limited
to: hospitalization records, clinical and outpatient charts, laboratory
records, memoranda, patient-reported outcomes, assessment inventories,
pharmacy dispensing logs, automated instrument data records, verified
accurate and complete transcript copies, patient files, and records
maintained by pharmacies, laboratories, or medical technical departments
participating in the clinical trial.
4.2 Scope and Methods of Data Verification and Management
After all case report forms undergo double-entry and verification,
the data manager will generate a database audit report. This report shall
include: study completion status (with a list of discontinued subjects),
eligibility/exclusion criteria verification, completeness verification,

logical consistency verification, outlier data verification, time window
verification, concomitant medication verification, and adverse event
verification.
4.3 Statistical Analysis
4.3.1 Analysis Populations
Full Analysis Set (FAS): Includes all subjects who pass screening and
are enrolled, with at least one treatment record. FAS serves as the primary
analysis set.
Per Protocol Set (PPS): Comprises datasets from subjects sufficiently
compliant with the trial protocol, including adherence to treatment,
availability of primary endpoint measurements, and absence of major
protocol violations. PPS is used for efficacy analyses.
Safety Set (SS): Consists of actual data from subjects receiving at
least one treatment with recorded post-treatment safety indicators. Adverse
reaction incidence rates are calculated using the number of cases in the SS
as the denominator.
4.3.2 Statistical Methods
(1) General Principles
Generally, continuous data will undergo normality testing. Based on
distribution type, we will report mean ± standard deviation or median
(minimum value, maximum value). Categorical data will present counts
and percentages for each category. For continuous variables, report

maximum/minimum/mean/median/standard deviation with one decimal
place. For categorical variables, report subject counts and percentages (to
one decimal place). If a percentage becomes 0.0% after rounding to one
decimal, retain it as 0.0%. For survival data, report median time to two
decimal places unless otherwise specified. Confidence intervals and p-
values retain two decimal places.
(2) Case Enrollment Analysis
List the total number of enrolled cases and those completing treatment
to determine the analysis datasets (FAS, PPS, SS).
(3) Demographic Data and Baseline Analysis
Demographic data and baseline characteristics were analyzed based
on the FAS set by group and for all subjects.
According to data type: categorical and ordinal data were described
by case counts and percentages (%); Continuous data were described with
case counts, mean, standard deviation, minimum value, and maximum
value. Baseline characteristics included: gender, age, ECOG score, CA19-
9 level, histological type, disease stage, primary tumor site, metastatic sites,
UGT1A1 test result, RAS and BRAF gene test results.
(4) Medication Compliance
Based on the FAS set, analyses will be performed on the number of
treatment cycles, average unit dose of liposomal irinotecan, and reasons for
treatment discontinuation. Categorical variables will be described using

number and percentage, while continuous data will be presented as number,
mean, standard deviation, minimum value, and maximum value.
(5) Efficacy Analysis
For Objective Response Rate (ORR), analyses will be conducted
based on the FAS set and PPS set, reporting the number of patients
achieving response and calculating the response rate with its 95%
confidence interval.
Disease Control Rate (DCR) will be analyzed based on the FAS set,
reporting the number of patients achieving disease control and calculating
the control rate with its 95% confidence interval.
Overall Survival (OS),
Progression-Free Survival
(PFS), and
Duration of Response (DoR) will be analyzed based on the FAS set using
the Kaplan-Meier method to calculate median time with its 95%
confidence interval.
(6) Safety Analysis
Statistical analysis of adverse events will be performed based on the
Safety Set (SS).
Adverse events during the treatment period, Grade 3 or higher adverse
events, and serious adverse events will be summarized by treatment group
and for the overall population, with calculation of occurrences, number of
cases, and incidence rates. Detailed listings of all adverse events, adverse
events related to the investigational product (adverse reactions), serious

adverse events, and adverse events leading to discontinuation will be
provided.
(7) Subgroup Analysis
Subgroup analyses will be conducted based on baseline characteristics
including gender, age, ECOG score, CA19-9 level, histological type,
disease stage, primary tumor site, metastatic sites, and UGT1A1 test results
to explore efficacy differences among subgroups.
(8) Statistical Software
Primary statistical analysis and graphing will be performed using
SPSS 25.0 and Graphpad Prism 7.0 or later versions.
V. Safety Evaluation
The number of subjects and occurrences of adverse events (graded per
NCI CTCAE v5.0) will be calculated separately.
'Number of subjects' refers to the total count of individuals
experiencing adverse events. If a single subject experiences more than one
adverse event during the study, it is counted only once.
'Number of occurrences' refers to the total count of all adverse event
incidents.
Adverse event incidence rates will be calculated using the number of
subjects as the numerator and the total number of participants in the safety
analysis set as the denominator.

5.1 Definition of Adverse Events (AE) and Serious Adverse Events
(SAE)
An adverse event (AE) is defined as any untoward medical occurrence
in a patient or clinical trial subject administered a pharmaceutical product,
which does not necessarily have a causal relationship with this treatment.
Thus, an AE may be any unfavorable or unintended sign (including
clinically significant abnormal laboratory findings), symptom, or disease
temporally associated with the use of an investigational product, regardless
of whether it is considered related to the investigational product. Adverse
events may include newly emergent conditions and exacerbations of pre-
existing conditions.AEs may include adverse medical conditions occurring
at any time (including during baseline or washout periods), even when no
study treatment has been administered.
Treatment-emergent adverse events (TEAEs) are defined as any new
AE commencing after at least one dose of Study Treatment, or any
worsening or exacerbation of a pre-existing condition.
Serious adverse events (SAEs) are defined as any untoward medical
occurrence that fulfills one of the following criteria at any dose:
(1) Results in death.
(2) Is life-threatening, where the patient was at immediate risk of
death during the event occurrence. This does not imply an outcome that
might hypothetically cause death if more severe.

(3) Requires inpatient hospitalization or prolongation of existing
hospitalization. Any AE prolonging hospitalization shall be considered an
SAE. However, planned hospitalizations (e.g., for observation, protocol
compliance, elective procedures, social reasons, etc.) are not considered
SAEs; the reason for planned hospitalization should be documented in the
Medical History.
(4) Resulting in permanent or significant disability/incapacity.
(5) Congenital anomaly or birth defect.
(6) Important medical events that may not be immediately life-
threatening or result in death/hospitalization, but may jeopardize the
patient or require intervention to prevent one of the outcomes above.
Examples include allergic bronchospasm requiring intensive treatment in
emergency rooms or at home, blood dyscrasias, convulsions not requiring
hospitalization, or development of drug dependency/abuse.
5.2 Reporting of Adverse Events
During the clinical study, regardless of whether adverse events are
related to the investigational product, the Investigator must truthfully and
comprehensively complete the Adverse Event Record Form. This
includes documenting clinical manifestations, time of onset, severity,
duration, measures taken, and outcomes of adverse events. Additionally,
concomitant medication usage must be meticulously recorded to facilitate

analysis of the relationship between adverse events and the
investigational product.
Except for serious adverse events specified in the study protocol or
other documents (e.g., Investigator's Brochure) as not requiring
immediate reporting, the Investigator shall immediately submit a written
report of all serious adverse events to the Sponsor. This must be followed
by timely provision of detailed written follow-up reports. The Sponsor
and Investigator shall promptly investigate the serious adverse event and
take necessary measures to ensure subject safety and rights.
The Investigator must complete the 'Serious Adverse Event Report
Form'. The source documents shall record when, in what manner, and to
whom the serious adverse event was reported. The Sponsor guarantees
that all reporting procedures required by laws and regulations are
fulfilled.
VI. Subject Protection
6.1 Informed Consent
In accordance with local regulatory requirements, each subject (or
their legal representative) must provide written informed consent after
being fully informed of the nature of the study. Subjects must sign the
informed consent form before any study-related procedures are performed.
The informed consent form used must be approved by the Sponsor, the
Independent Ethics Committee, and the Institutional Review Board, and

must be written in a language understandable to the subject.
Prior to subject enrollment, the investigator or authorized research
personnel must explain the study purpose, methodology, potential benefits,
inherent risks, and possible discomforts associated with participation to
potential subjects or their legal representatives. Subjects shall be informed
that participation is voluntary and they may withdraw informed consent to
discontinue the study at any time without affecting the treatment of their
disease. Subjects shall be advised that alternative treatment options remain
available if they choose not to participate, and this decision will not impact
their future medical care. Finally, subjects shall be informed that
investigators will retain their registration information for potential long-
term follow-up when necessary. Drug regulatory authorities or authorized
sponsor personnel may review relevant subject records as permitted by
applicable laws and regulations, without infringing upon their privacy. By
signing
the
Informed
Consent
Form,
the
subject
or
their
legal
representative authorizes such access, permitting their research physician
to: (1) recontact the subject; (2) obtain consent for additional safety
assessments and subsequent disease-related treatment information if
required; and (3) acquire information regarding survival status.
Subjects or their legal representatives shall be given sufficient time to
read the Informed Consent Form and opportunities to ask questions. After
explanations are provided and before enrollment, written informed consent

with the signature and date of the subject or legal representative must be
documented. Upon obtaining informed consent, a copy of the Informed
Consent Form shall be provided to the subject.
If the subject or legal representative is unable to read or write, an
impartial witness must be present throughout the entire informed consent
process (including the reading and explanation of all written materials).
After obtaining oral consent from the subject or legal representative, the
witness shall also sign and date the written informed consent form.
6.2 Personal Information
This study will only collect and process subjects' data strictly
necessary for investigating drug efficacy, safety, quality, and application.
The confidentiality of such data shall be fully ensured during
collection and usage, with strict adherence to relevant laws and regulations
protecting subjects' privacy.
The Sponsor shall ensure that:
(1) The data collection process is fair and lawful;
(2) The purposes of data collection are specific, explicit, and
legitimate; No further processing incompatible with these purposes shall
occur, nor shall data be processed through other methods contrary to these
purposes;
(3) The collected data shall be sufficient, relevant and not excessive
in relation to the research purpose, with no collection of data unrelated to

the research objectives;
(4) The collected data shall be accurate and kept up-to-date with
necessary updates.
The Investigator shall obtain the Subject's consent prior to collecting
personal information. This consent shall include explicit notification
regarding potential transfer of data to other institutional entities and
countries.
Subjects have the right to access their personal information through
the Investigator and may request rectification of erroneous or incomplete
data. Such requests shall receive an appropriate response, taking into
account their content and purpose, the status of the trial, and applicable
laws. Consideration shall be given to the nature of requirements, the status
of the trial, and relevant laws and regulations.
Appropriate technical procedures and organizational management
measures must be implemented to protect subjects' personal information
from unauthorized access or disclosure, accidental or unlawful destruction,
and accidental loss or alteration. Throughout the study, sponsor personnel
authorized
to
access
subjects'
personal
data
shall
maintain
its
confidentiality.
VII. Protocol Amendments
Prior to study initiation, the study protocol and/or other relevant
documents must obtain approval from ethics committees and other

authorities in accordance with local legal requirements. Any protocol
amendments must be accompanied by detailed modification records,
including signatures, version numbers, and dates. The amended protocol
must be submitted to the Ethics Committee for approval before
implementation.
Section VIII: Early Termination
8.1 Treatment Termination:
Patients reserve the right to voluntarily discontinue treatment at any
time for any reason. Permanent discontinuation of all study treatment will
occur if any of the following conditions arise:
• Enrollment error, i.e., the patient fails to meet the study's
inclusion/exclusion criteria.
• The Investigator and/or Sponsor determines that the patient's
medical condition may compromise their safety.
• The Investigator and/or Sponsor determine that continued study
treatment is not in the patient's best interest.
• The Investigator and/or Sponsor deem the patient to have poor
compliance with the protocol.
• The patient has concurrent medical conditions unrelated to cancer,
where continued treatment would pose safety risks or make regular study
visits unfeasible.
• Occurrence of intolerable toxicity or serious adverse event (SAE).

• The patient withdraws informed consent.
• Disease progression (PD) assessed per RECIST 1.1 criteria.
• Lost to follow-up.
• Patient death.
• Pregnancy in female patients.
• Termination of the entire study or this study site by the Sponsor or
regulatory authorities.
Patients may withdraw informed consent at any time. Following
withdrawal, no additional patient data will be collected, though
previously collected data will be retained and continue to be utilized.
8.2 Study-Wide Termination or Site-Specific Termination:
The Sponsor reserves the right to terminate this study at any time.
Reasons for termination include, but are not limited to, the following
circumstances:
• The incidence or severity of Adverse Events (AEs) in this study
indicates potential health hazards to patients from the Investigational
Product.
• Patient recruitment lags significantly, with overall enrollment
progress severely below expectations.
• Study completion (i.e., all patients have concluded participation
and relevant obligations have been fulfilled).
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