Phase II Study of Anlotinib Combined With Sintilimab as First-line Treatment for Advanced Non-liver Metastatic Colorectal Cancer
Phase: PHASE2
Conditions: Colorectal Cancer
Sponsor: Shanghai Changzheng Hospital

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Clinical Research Protocol
Study Title: Phase II Study of Anlotinib Combined with Sintilimab as First-
Line Treatment for Advanced Non-Liver Metastatic Colorectal Cancer
Study ID: APICAL-CRC2
Version: 1.0
Date: 8 December 2025
Sponsoring Institution: Shanghai Changzheng Hospital
Principal Investigator: Yuan-sheng Zang
declaration of secrecy
All information contained in this protocol is owned by the sponsor/lead institution and/or the CRO
company. Therefore, it is provided solely for review by relevant medical institutions such as investigators,
collaborating researchers, ethics committees, and regulatory authorities. Without written approval from the
CRO company, except for necessary explanations during the signing of informed consent forms with
potential study participants, it is strictly prohibited to disclose any information to third parties unrelated to
this study.

2
Plan Signature Page
I agree:
This study was conducted with strict adherence to the protocol, clinical trial regulations, and all
applicable laws and regulations. All resource information provided by Shanghai Changzheng Hospital was
kept confidential in accordance with confidentiality requirements. When submitting these materials to the
institutional review board or independent committee, it must be clearly indicated that the information is
confidential.
I have read the full text of this plan and agree to all its contents.
Signature of the sponsor
date
Statistician's signature
date

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Signature page of the plan
I have reviewed the attached document titled 'Phase II Study of Anlotinib
Combined with Sintilimab as First-Line Therapy for Advanced Non-
Hepatogenous Metastatic Colorectal Cancer' (dated December 8, 2025). I
hereby confirm my consent to participate in this study in accordance with the
protocol.
I agree to comply with the guidelines on Good Clinical Practice (GCP) and
other applicable CFDA regulations/guidelines. I hereby declare that I am
personally responsible for the overall implementation of this study. I consent to
ensure that all assistants and colleagues involved in this study are fully aware of
their responsibilities.
I hereby agree to guarantee that the confidential information contained in
this document will not be used for any purpose other than the evaluation or
implementation of this clinical study without prior written permission from the
Changzheng Hospital affiliated to the Naval Medical University.
Name of the principal investigator at the sub-center:
Signature: Date: Year Month Day
Signature: Date: Year Month Day

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Sponsor/Lead Organization
corporate name
Changzheng Hospital Affiliated to Naval Medical
University
project leader
Yuan-sheng Zang
Contact
address
No.415, Fengyang Road,
Huangpu District, Shanghai
zip code
200003
telephone
021-66540109
cellphone
13816584620
portraiture
021-63526924
E-mail
doctorzangys@163.com
Cooperative Unit
Company/Unit Name
Innovent Biologics (Suzhou) Co., Ltd.
project leader
Contact
address
zip code
telephone
cellphone
portraiture
E-mail
Company/Unit Name
Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
project leader
Contact
address
zip code
telephone
cellphone
portraiture
E-mail

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scenario summary
scenario name
A phase Ⅱstudy of anlotinib plus sintilimab as first-line treatment for
advanced non-liver metastatic colorectal cancer
Program
number
APICAL-CRC2
version number
1.0
date
2025-12-8
Sponsor
Shanghai Changzheng Hospital
indication
Advanced colorectal cancer
Estimated
study duration
The study is scheduled from December 2025 to December 2026. Enrollment
for this research project is planned to commence in December 2025 and is
expected to conclude in December 2026. Data analysis will be completed in
June 2026, with the total trial duration approximately 1.5 years.
purpose of
research
The efficacy of anlotinib combined with sintilimab as first-line therapy for
advanced non-hepatic metastatic colorectal cancer was evaluated using the
investigator-assessed objective response rate (ORR).
Total number
of cases
The sample size calculation was based on the margin of confidence compared
with historical controls, assuming an ORR of 70% in this study and an ORR
rate of 50% in the historical controls. In the ITT analysis set, according to the
Simon two-stage design, with a one-sided α=0.05 and statistical power=0.8,
the calculated sample size was 37 cases.
Case selection
criteria
Inclusion criteria:
• Patients with advanced colorectal adenocarcinoma confirmed by histology
or cytology;
• Patients without liver metastases who have explicitly refused
chemotherapy;
• Patients who have not received systematic therapy or have developed
metastasis or recurrence more than 12 months after the completion of
adjuvant therapy;
• The patient has at least one measurable lesion (per RECIST 1.1 criteria);
• Patients who have undergone local radiotherapy at least 3 weeks prior to
initial drug therapy are eligible for enrollment; however, RECIST-evaluated

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lesions must not be within the radiotherapy field.
• The patient must be at least 18 years of age;
• Physical condition: ECOG score 0-1;
•Life expectancy ≥12 weeks;
•The patient must have the capacity to understand and voluntarily sign a
written informed consent form;
• Women of childbearing age must have a negative pregnancy test result
within 7 days prior to initiating treatment. Both the patient and their spouse
must use contraception during the study period.
Exclusion criteria:
• Patients who underwent major surgery or sustained severe trauma within 4
weeks prior to the initial medication administration;
• Patients with hypersensitivity to any component of the study protocol;
• Patients planning for pregnancy or already pregnant;
• Patients with brain metastases who cannot accurately describe their
condition;
• Patients with autoimmune diseases or organ transplants;
• Received immunosuppressive therapy within 2 weeks prior to treatment
initiation (excluding inhaled corticosteroids or prednisone ≤10 mg/day, or
other steroid hormones at physiologically equivalent doses);
• Planning to receive a live attenuated vaccine within 4 weeks prior to study
initiation or during the study period;
• The patient has received anlotinib or anti-PD-1/PD-L1 monoclonal
antibody therapy, or other treatments targeting T-cell co-stimulatory
receptors or checkpoints;
• Presence of the following conditions within 6 months prior to treatment
initiation: myocardial infarction (MI), severe/unstable angina, NYHA class 2
or higher congestive heart failure, poorly controlled arrhythmias, etc.;
• Abnormal laboratory findings:
-Absolute neutrophil count (ANC) <1,500/mm³;
-Platelet count <75,000/mm³;

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Total bilirubin>1.5 times the upper limit of normal
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)>2.5
times the upper limit of normal;
-Creatinine>1.5 times the upper limit of normal;
• Patients with other cancers (excluding advanced colorectal cancer) within
five years prior to the initiation of treatment in this study. Exclusions include
cervical carcinoma in situ, cured basal cell carcinoma, and bladder epithelial
tumors.
• Patients with operable colorectal cancer (those who explicitly refuse
surgery or are unsuitable for surgery may be enrolled);
• History of drug abuse, substance use, or alcohol dependence
•Lack of legal capacity or limited civil capacity;
• Other circumstances deemed unsuitable for enrollment by the investigator.
Exit criteria:
• Withdrawal requested by the patient or their legal representative;
•According to the investigator's opinion, the patient's continued participation
in the study would be detrimental to their health;
• Patients with severe non-adherence or serious protocol violations;
• The patient is pregnant, and pregnancy should be reported as a serious
adverse event;
• When other diseases occur during the study and the investigator determines
that the condition will significantly affect the assessment of the patient's
clinical status, necessitating discontinuation of the protocol;
• Presence of other malignant tumors requiring treatment;
• Patients who were lost to follow-up;
• Use of prohibited drugs or other medications that the investigator deems
may cause toxic reactions or bias the study results;
• Patient death.
Note: Detailed records of the reasons and dates for withdrawal should be
maintained for participants who withdraw during the study, and the
withdrawal rate should be statistically analyzed upon study completion.
Participants who withdraw from the study will receive appropriate treatment
measures based on the judgment of the investigators at each center.

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Research Phase
and Steps
1) December 2025 – January 2026: Obtain ethical review approval, screen
and identify patients clinically diagnosed with advanced non-hepatic
metastatic colorectal cancer;
2) February 2026 – June 2026: Informed consent was obtained from the
selected population meeting inclusion/exclusion criteria, followed by
treatment and evaluation.
3) July 2026 – December 2026: Complete enrollment of study cases; collect
efficacy and safety data from patients who signed informed consent forms;
4) January 2027 – June 2027: Refine the data, correct errors, and perform
statistical analysis.
statistical
analysis
sample size estimation
The sample size calculation was based on the margin of confidence compared
with historical controls, assuming an ORR of 70% in this study and an ORR
rate of 50% in the historical controls. In the ITT analysis set, according to the
Simon two-stage design, with a one-sided α=0.05 and statistical power=0.8,
the calculated sample size was 37 cases.
Statistical analysis of research data
Statistical analysis was performed using SPSS software. Between-group and
within-group comparisons were conducted using t-tests, with statistical
significance defined as p<0.05.

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Abbreviations
Table
abbreviation
definition
AE
adverse event
ANC
Absolute neutrophil count
BID
twice daily
CBC
CBC
CI
confidence interval
CR
complete remission
CRR
complete remission rate
CT
computerized tomographic scanning
DOR
Duration of relief
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EFS
event-free survival
FDA
U.S. Food and Drug Administration
HBcAb
HBcAb
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
HCV
IEC
independent ethics committee
IHC
immunohistochemical

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IRB
institutional review board
FOLFIRI
5-FU, Iletixan, Lysine Folate
NCI-CTCAE v5.0
National Cancer Institute Common Terminology Criteria
for Adverse Events, Version 5.0
NYHA
New York Heart Association
ORR
overall remission rate
OS
overall survival
PD
PD
PET
Positron Emission Tomography
PFS
progression-free survival
PR
partial remission
PT
Preferred term
QTc
Calibrated QT interval
SAE
Serious adverse events
SD
The disease is stable.
TEAE
Adverse events occurring during treatment
TRAE
adverse events related to treatment
ULN
ULN

1
catalogue
1. Introduction................................................................................................................................3
2. Research Objective.................................................................................................................... 5
3. Research Content.......................................................................................................................5
3.1 Research Design and Planning............................................................................................ 5
3.2 Control.................................................................................................................................5
3.3 Selection of Study Population............................................................................................. 5
3.3.1 Eligibility Criteria.............................................................................................................5
3.3.2 Exclusion Criteria............................................................................................................. 6
3.4 Study Duration.....................................................................................................................7
3.5 Subject Withdrawal from the Study.................................................................................... 7
3.6 Treatment Plan.....................................................................................................................8
3.6.1 Treatment Arrangements.................................................................................................. 8
3.6.2 Delay in Drug Administration and Dose Adjustment.......................................................8
3.6.2.1 Dose Adjustment........................................................................................................... 8
3.6.3 Adjunctive Therapy.......................................................................................................... 9
3.6.3.1 Therapies Not Permitted................................................................................................9
3.6.3.2 Permitted Therapies.......................................................................................................9
3.6.4 Treatment Compliance....................................................................................................10
3.7 Research Indicators............................................................................................................10
3.7.1 Efficacy Indicators..........................................................................................................10
3.7.2 Safety Indicators............................................................................................................. 11
3.7.3 Evaluation Period............................................................................................................11
3.7.3.1 Research Visits............................................................................................................ 11
3.7.3.2 Imaging Evaluation......................................................................................................11
3.8 Research Process............................................................................................................... 12
3.8.1 Screening Period.............................................................................................................12
3.8.2 Treatment Period............................................................................................................ 13
3.8.3 Post-treatment.................................................................................................................13
3.8.4 Temporary Visits............................................................................................................ 13
3.8.5 Follow-up after disease progression...............................................................................13
3.9 Data Quality.......................................................................................................................14
3.10 Archive............................................................................................................................ 14
4. Ethical and Legal Considerations............................................................................................14

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4.1 Ethics Committee (EC) or Institutional Review Board (IRB)...........................................14
4.2 Ethical Guidelines for This Study......................................................................................14
4.3 Subjects' Instructions and Informed Consent.................................................................... 15
4.4 Confidentiality...................................................................................................................15
5. Statistical Methods...................................................................................................................15
5.1 Statistical and Analysis Plan..............................................................................................15
5.1.1 Study Population Analysis..............................................................................................15
5.1.2 Baseline and Demographic Characteristics.................................................................... 15
5.1.3 Efficacy Analysis............................................................................................................15
5.1.3.1 Primary Efficacy Analysis...........................................................................................16
5.1.3.2 Secondary Efficacy Analysis.......................................................................................16
5.1.3.3 Safety Analysis............................................................................................................16
6. Adverse Events........................................................................................................................ 16
6.1 Precautions/Warnings........................................................................................................16
6.2 Detection of Adverse Events............................................................................................. 16
6.3 Definition of Adverse Events............................................................................................ 17
6.3.1 Adverse Events............................................................................................................... 17
6.3.2 Serious Adverse Events.................................................................................................. 18
6.3.3 Unintended Adverse Events........................................................................................... 19
6.3.4 Relationship Between Adverse Events and Study Drug.................................................19
6.3.5 Recording of Adverse Events.........................................................................................20
6.4 Reporting of Serious Adverse Events................................................................................20
7. Appendix..................................................................................................................................22
7.1 General Status (ECOG Score)........................................................................................... 22
7.2 TNM staging......................................................................................................................22
7.3 RECIST Tumor Assessment Criteria.................................................................................24
7.4 New York Heart Association (NYHA) Classification of Heart Function.........................27
7.5 Research Process Table..................................................................................................... 28
8. References................................................................................................................................30

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1. Introduction
Colorectal cancer (CRC) is the third most common malignant tumor globally and the
second leading cause of cancer-related mortality [1]. Despite recent advances in CRC
research, approximately 15%-30% of patients present with metastatic lesions at initial
diagnosis, and an additional 20%-50% of patients with locally advanced CRC will
eventually develop metastatic disease [2]. The standard first-line treatment for metastatic
colorectal cancer (mCRC) is fluorouracil-based chemotherapy combined with anti-
EGFR/VEGF targeted agents, yet the prognosis remains poor, with a median overall
survival of only about 2 years [3,4]. Moreover, some mCRC patients may be ineligible for
standard doublet or triplet chemotherapy combined with targeted therapy due to factors such
as advanced age, poor physical status, comorbidities, or personal preferences [5]. Exploring
novel, highly effective, and low-toxicity treatment regimens holds significant clinical
importance for these patients. In recent years, immune checkpoint inhibitors have emerged
as a promising treatment option for mCRC, particularly for patients with DNA mismatch
repair (dMMR) or high microsatellite instability (MSI-H) characteristics [6-8]. However,
most pMMR/MSS mCRC patients exhibit primary resistance to immune checkpoint
inhibitors due to the presence of immune deserts or immune rejection microenvironments
[9]. To enhance the efficacy of immune checkpoint inhibitors in pMMR/MSS patients, a
highly promising research direction is the combination of immunomodulatory antineoplastic
agents with immunotherapy [10]. Anti-angiogenic drugs can directly or indirectly transform
an immunosuppressive microenvironment into an immunostimulatory one, suggesting that
the combination of immune checkpoint inhibitors with anti-angiogenic agents may produce
synergistic antitumor effects [11,12]. For instance, the REGONIVO trial demonstrated that
the
combination
of
regorafenib
and
nivolumab
exhibited
controllable
safety
and
encouraging antitumor activity in patients with refractory colorectal cancer [13]. However,
in the LEAP-017 study, which compared lenvatinib plus pembrolizumab versus regorafenib
or TAS-102 in previously treated, chemotherapy-resistant metastatic colorectal cancer
patients, the primary endpoint was not met [14]. Patient characteristics (e.g., prior treatment
history), treatment modalities (e.g., subsequent regimens), and performance of the control
group may have influenced the results of the LEAP-017 trial. Although the clinical value of
this regimen in subsequent treatments remains questionable, its potential to provide clinical
benefits for immunocompetent first-line patients warrants further exploration.
Anlotinib is an oral tyrosine kinase inhibitor (TKI) that targets vascular endothelial
growth factor receptors 1/2/3, epidermal growth factor receptors 1/2/3, FDGFR, and c-Kit,

4
demonstrating broad-spectrum antitumor activity in various cancers [15-17]. Multiple
clinical trials have shown therapeutic potential in patients with metastatic colorectal cancer
(mCRC) [18,19]. A retrospective study evaluated the feasibility and tolerability of anlotinib
combined with a PD-1 inhibitor in chemotherapy-resistant mCRC patients, revealing
significant efficacy and favorable safety profile in this patient population [20]. Sintilimab, a
fully humanized IgG4 monoclonal antibody, has demonstrated clinical benefits in non-small
cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC) by blocking the interaction
between PD-1 and its ligand [21,22]. Previous studies have confirmed that the combination
of sintilimab and anlotinib forms a novel chemotherapy-free regimen applicable to diseases
such as cervical cancer and lung cancer [23,24]. Additionally, the combination of sintilimab
and furquintinib has shown promising prospects in patients with refractory colorectal cancer,
further suggesting its potential value when combined with anti-angiogenic TKIs [25].
Based on the aforementioned findings, the combination of immune checkpoint
inhibitors and anti-angiogenic TKIs is expected to generate potent synergistic antitumor
effects. This strategy opens a new avenue for "chemotherapy-free" treatment of mCRC
when the immune system is functional, particularly worthy of exploration in first-line
therapy for mCRC. To preliminarily evaluate the efficacy and safety of anlotinib combined
with sintilimab in first-line treatment of mCRC patients, we conducted the APICAL-CRC
study [26], enrolling a total of 30 patients. The clinical objective response rate (ORR) was
48.3%, the disease control rate was 89.7%, with median progression-free survival (mPFS)
and median overall survival (mOS) of 8.6 months and 22.9 months, respectively. Subgroup
analysis revealed that the ORR in patients without liver metastases reached 70%, with
mPFS of 14.9 months, whereas the ORR in patients with liver metastases was only 36.8%,
significantly lower than that in patients without liver metastases. These results are
consistent with previous studies (in the LEAP-017 study, the ORR for lenvatinib combined
with pembrolizumab in patients with liver metastases was only 4.8% [14], while in the
REGONIVO (USA) study, the ORR in patients with liver metastases was 0% [27]). Patients
with better physical performance scores (ECOG PS 0 – 1) achieved an ORR of 66.7%,
superior to those with ECOG PS 2 (21.4%). Patients carrying ARID1A mutations or those
predicted to have a higher ORR (100% vs. wild-type 40%) also demonstrated better
outcomes. In terms of safety, the incidence of treatment-related adverse events (TRAEs) of
grade ≥3 with anlotinib plus sintilimab was only 13.3% (significantly lower than the 50%-
70% observed with standard chemotherapy regimens). Adverse events such as hand-foot

5
syndrome and hypertension were manageable, with no treatment-related deaths. This
regimen provides a new option for chemotherapy-free treatment in patients with advanced
colorectal cancer. Based on the preliminary results of the APICAL-CRC study, we plan to
further screen the optimal patient population for subsequent research in advanced colorectal
cancer patients. The enrolled patients will be limited to those without liver metastases and
with a PS score of 0-1. Additionally, molecular biomarker analysis will be conducted,
particularly stratified analysis based on ARID1A mutation status, to provide new strategies
and methods for precision treatment of advanced colorectal cancer.
2. Research Objective
To evaluate the efficacy and safety of anlotinib combined with sintilimab as first-line treatment
for non-hepatic metastatic advanced colorectal cancer.
Primary efficacy endpoint: ORR (objective response rate).
Secondary efficacy endpoints: safety, PFS (progression-free survival), OS (overall
survival), and DPR (depth of tumor response).
3. Research Content
3.1 Research Design and Planning
This study is a prospective, single-center clinical trial employing anlotinib combined
with sintilimab. Based on preliminary research findings and statistical analysis of prior
literature, the planned enrollment number is 37 patients.
3.2 Control
Eligible subjects will receive treatment according to the aforementioned protocol, with
historical controls as the reference.
3.3 Selection of Study Population
According to the study protocol definition, all subjects were untreated advanced non-
hepatic metastatic colorectal cancer.
3.3.1 Eligibility Criteria
•
patients with advanced colorectal adenocarcinoma confirmed by
histology or cytology;
•
patients without liver metastases and who have explicitly refused
chemotherapy;
•
those who have not received systematic therapy or have developed
metastasis or recurrence 12 months after the end of adjuvant therapy;
•
The patient has at least one measurable lesion (according to RECIST 1.1
criteria);

6
•
Patients who had received local radiotherapy at least 3 weeks prior to
initial drug therapy were eligible for enrollment; however, RECIST-
evaluated lesions must not be within the radiotherapy field.
•
The patient must be ≥18 years of age;
•
The ECOG physical status score was 0-1;
•
Life expectancy ≥12 weeks;
•
Patients must be able to understand and voluntarily sign a written
informed consent form;
•
Women of childbearing age must have a negative pregnancy test result
within 7 days prior to initiating treatment. Both the patient and their
spouse must use contraception during the study period.
3.3.2 Exclusion Criteria
•
patients who have undergone major surgery or severe trauma within 4
weeks prior to the first dose of the medication;
•
patients with hypersensitivity to the components in the study protocol;
•
patients who are planning to conceive or who are pregnant;
•
patients with brain metastases who cannot accurately describe their
condition;
•
patients with autoimmune diseases or organ transplants;
•
treatment within 2 weeks prior to study;
•
Study of planned vaccination with live attenuated vaccines within 4
weeks before study initiation or during the study;
•
The patient has received anlotinib or anti-PD-1/PD-L1 monoclonal
antibody therapy, or other treatments targeting T-cell co-stimulatory
targets or checkpoints.
•
Within 6 months prior to the initiation of the study, the following
conditions were present: myocardial infarction (MI), severe/unstable
angina pectoris, NYHA class 2 or higher congestive heart failure, poorly
controlled arrhythmias, etc.
•
Abnormal laboratory test results:
-Absolute neutrophil count (ANC) <1,500/mm³;
-Platelet count <75,000/mm³;

7
Total bilirubin>1.5 times the upper limit of normal
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)>2.5
times the upper limit of normal;
-Creatinine>1.5 times the upper limit of normal;
•
Patients with other cancers (excluding advanced colorectal cancer) within
five years prior to the initiation of treatment in this study. Excluded:
cervical carcinoma in situ, cured basal cell carcinoma, and bladder
epithelial tumors.
•
Patients with operable colorectal cancer (those who explicitly refuse
surgery or are unsuitable for surgery may be enrolled);
•
history of drug abuse, substance use, or alcohol dependence;
•
lack of legal capacity or limited civil capacity;
•
Other circumstances deemed unsuitable for enrollment by the
investigators.
3.4 Study Duration
Based on an estimated enrollment of approximately 5 patients per month, the
enrollment period would require approximately 8 months. The total study duration is
estimated to be around 12 months.
3.5 Subject Withdrawal from the Study
Discontinued cases refer to patients who cease medication for various reasons during
clinical studies. Patients meeting the following criteria will be withdrawn from the study:
•
The patient or their legal representative requests withdrawal;
•
According to the investigators 'opinion, continued participation in the
study would be harmful to the patient's health.
•
patients with severe non-adherence or serious protocol violations;
•
The patient is pregnant, and pregnancy should be reported as a serious
adverse event.
•
When other diseases occur concurrently during the study, and based on
the investigator's assessment that the disease will significantly affect the
evaluation of the patient's clinical condition, and when discontinuation
of the current treatment regimen is required;
•
other malignancies requiring treatment;
•
lost to follow-up;

8
•
Use of prohibited drugs or other drugs that the investigator judges may
cause toxic reactions or bias the results of the study;
•
The patient died.
All patients who withdraw from the study should have the reason for withdrawal
recorded in the case report form and the patient's medical record.
All patients who withdrew due to adverse events or abnormal laboratory findings
should be followed up until the adverse event resolved or stabilized, with subsequent
outcomes recorded. If a patient died during the trial or within 30 days after trial completion,
the investigator must be notified by the researchers. The cause of death must be documented
in detail on the Serious Adverse Event (SAE) report form within 24 hours.
3.6 Treatment Plan
3.6.1 Treatment Arrangements
Treatment regimen: Anlotinib, orally, 12 mg once daily, administered from day 1 to
day 14 of each cycle, with each cycle lasting 3 weeks; Sintilimab, 200 mg, intravenous
infusion for 1 hour ± 5 minutes, administered every 3 weeks until disease progression or
intolerable adverse reactions occur.
Treatment should be continued until disease progression or intolerance is achieved.
Due to the inherent limitations of the RECIST criteria used for efficacy evaluation, if
imaging suggests disease progression but the study physician determines that the patient
has clinical benefit, treatment may still be continued.
The efficacy was evaluated every 6 weeks.
3.6.2 Delay in Drug Administration and Dose Adjustment
Patients' toxic reactions should be closely monitored, and dosage adjustments should be
made based on their tolerance. It is recommended to adjust the dosage according to the most
severe toxic reaction or laboratory abnormalities observed during the previous treatment
course or the current treatment course. The severity of toxic reactions should be graded
according to NCI CTC AE 5.0. If multiple toxic reactions occur, the dosage should be
adjusted based on the most severe toxic reaction.
Medication may be reduced or suspended at any stage of the study due to adverse
events.
All adverse events should be graded according to the criteria of NCI CTCAE 5.0.
3.6.2.1 Dose Adjustment
During the treatment phase of this study, the dose of the relevant drug should be

9
reduced or the medication should be suspended if any of the drug-induced severe toxic
reactions occurs.
The dose adjustment for the next cycle will be based on the toxic reactions observed in
the previous cycle.
In the event of any severe hypersensitivity reaction to the relevant medication during
treatment, the injection should be immediately discontinued and documented.
If a patient develops a severe hypersensitivity reaction on day 1 of the first treatment
course, the patient should be excluded from the study.
Imaging evaluation should be performed even if the patient has developed
hypersensitivity to the drug, provided that at least two cycles of chemotherapy have been
completed.
The specific dose adjustment was implemented according to the chemotherapy-related
adverse event management guidelines and drug instructions.
3.6.3 Adjunctive Therapy
3.6.3.1 Therapies Not Permitted
•
No other anticancer drug therapy is permitted except for the prescribed
treatment regimen.
•
Experimental drugs (e.g. experimental antibiotics, antiemetics, etc.)
•
Any herbal medicine with antitumor indication during the treatment
process.
•
Radiotherapy, excluding palliative radiotherapy for existing bone
metastases.
3.6.3.2 Permitted Therapies
•
Unconventional therapies (e.g., non-cancer-related herbal treatments or
acupuncture) and vitamins/microelements may also be administered at
the discretion of the investigator, provided they do not interfere with the
observation of the study endpoint.
•
Patients may receive palliative and supportive care for their underlying
condition, such as bisphosphonate therapy.
•
Radiation therapy for existing bone lesions (bone metastases present at
baseline) with the aim of symptom relief.
•
Patients with known bone metastases at baseline who require
radiotherapy should complete radiotherapy prior to the first
administration of the investigational drug.

10
•
Patients with pre-existing bone metastases at baseline who did not require
radiotherapy prior to the first administration of the investigational drug
but subsequently required radiotherapy during the study were permitted
to receive radiotherapy.
•
Patients who received radiotherapy for bone metastases at baseline and
require subsequent radiotherapy during the study may undergo
additional radiation therapy.
•
Topical corticosteroids for the treatment of rash or cutaneous reactions of
the hands and feet.
3.6.4 Treatment Compliance
The dosage and administration time of each medication used in each treatment course
for every subject should be recorded in the CRF form. Reasons for delayed administration,
dose reduction, or missed doses should also be documented in the CRF.
Subject compliance with treatment and protocol includes voluntary adherence to all
aspects of the protocol, including compliance with all blood draws required for safety
assessment. Subjects who fail to return for follow-up visits or administer medications on
time may be excluded from the study based on the opinion of the principal investigator or
sponsor.
3.7 Research Indicators
The objective of this study was to evaluate the efficacy and safety of anlotinib
combined with sintilimab as first-line treatment for non-hepatic metastatic advanced
colorectal cancer. The primary efficacy endpoint was overall response rate (ORR), while
secondary efficacy endpoints included safety (assessed using CTCAE 5.0), progression-free
survival (PFS), overall survival (OS), and disease progression rate (DPR). Concurrent
biomarker analysis was performed.
3.7.1 Efficacy Indicators
Objective response rate (ORR) refers to the proportion of patients whose tumors shrink
to a certain extent and sustain this reduction for a specified duration (primarily for solid
tumors). It encompasses cases of complete response (CR) and partial response (PR).
Deepness of response (DpR): This refers to the percentage of maximum tumor
shrinkage achieved during treatment compared to baseline. If a complete response (CR) is
observed, the DpR is 100%.
Tumor response and disease progression will be assessed by investigators according to
the RECIST criteria.

11
Progression-free survival (PFS) refers to the time from enrollment until tumor
progression or death.
Overall survival (OS) refers to the time from randomization to death from any cause.
The duration of response maintenance was calculated for all patients who achieved
confirmed RECIST-standardized PR or CR. The response maintenance period was defined
as the time from the first recorded PR or CR until death or disease progression (whichever
occurred first). For patients who were still alive and disease-free as of the analysis date, the
cutoff date was set as the date of their last radiological assessment.
This study also explores the relationship between molecular markers and therapeutic
efficacy and safety.
3.7.2 Safety Indicators
All patients who have received at least one dose of the investigational drug will be
included in the safety analysis as the valid population. The physical examination results,
vital signs, adverse events, and abnormal laboratory test values of the patients will be
summarized. All adverse events should be reported and graded according to the Common
Terminology Criteria for Adverse Events (CTCAE) version 5.0.
3.7.3 Evaluation Period
The study was started on the date of signing the informed consent form.
3.7.3.1 Research Visits

Screening visit should be conducted within 28 days prior to initiation of study drug
therapy.

The treatment period refers to the duration from the initiation of the first study
drug administration until the patient discontinues the study drug therapy.

Patients were evaluated every 8 weeks after discontinuation of study drug therapy
due to non-progressive conditions. If disease progression was confirmed, they
would enter the follow-up period. During this period, contact with patients should
be maintained every 3 months until the patient's death was recorded, to collect data
on overall survival.
3.7.3.2 Imaging Evaluation

Screening period: A CT or MRI scan of the chest and abdomen must be performed
at least 28 days prior to enrollment, and tumor measurements must be recorded in
the CRF according to RECIST criteria.

Treatment phase: CT or MRI scans should be performed at least every 6 weeks ±

12
5 days to evaluate the lesion, and tumor measurements should be recorded in the
CRF according to RECIST criteria. Additional examinations should be conducted
based on symptomatic indications.

At the end of the study: CT or MRI scans were performed to evaluate the lesions,
and tumor measurements were recorded in the CRF according to the RECIST
criteria. Additional examinations were conducted based on symptomatic
indications.
3.8 Research Process
3.8.1 Screening Period
within 28 days prior to initiating the study drug
•
Sign an informed consent form before any research-related procedure is
performed;
•
baseline 12-lead electrocardiogram (ECG) examination;
•
Brain CT or MRI scans should only be performed when neurological
symptoms are present (indicating brain metastases).
•
Tumor assessment at baseline: At least one CT or MRI scan of the target
lesion, which can be performed within 28 days prior to initiating the
investigational drug.
Screening period – within 7 days prior to initiating study drug therapy
•
Record/confirm the tumor stage at the time of diagnosis.
•
Demographic information, complete medical history, and surgical history,
including previous anticancer treatments.
•
A complete physical examination (PE), including the ECOG general
condition score, height, weight, and a detailed systemic examination.
•
Signs and symptoms (including heart rate, blood pressure, respiratory
rate, and body temperature).
•
Record all comorbidities and concomitant medications with their
indications.
•
Complete blood count (CBC): hemoglobin, platelet count, white blood
cell count and differential, including absolute counts of neutrophils and
lymphocytes.
•
Complete blood biochemistry panel: including blood glucose, calcium,
phosphorus, sodium, potassium, chloride, creatinine, blood urea nitrogen

13
(BUN), total protein, albumin, alanine aminotransferase (ALT),
aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin,
etc.
•
Urinary pregnancy tests should be performed for all women of
childbearing age. Women who have been postmenopausal for at least 1
year or have undergone sterilization procedures are not required to
undergo pregnancy testing.
•
Urinalysis: Includes urine leukocytes, urine red blood cells, urine glucose,
urine protein, and occult blood
•
Routine stool examination
3.8.2 Treatment Period
The treatment period is defined as a 21-day cycle. Therapeutic efficacy is evaluated
every 2 cycles. Laboratory tests and imaging assessments during the treatment phase are
detailed in the flowchart.
3.8.3 Post-treatment
After treatment (non-progression end of treatment), examinations should be
performed every 3 months until disease progression (see flowchart).
3.8.4 Temporary Visits
Temporary visits should be conducted based on clinical needs. Corresponding
clinically significant laboratory test abnormalities and adverse events should be recorded
in the CRF and original documentation. If multiple laboratory tests are performed on the
same day, only one set of test values needs to be recorded in the CRF. However, all
abnormal values from repeated laboratory tests should be documented in the CRF.
3.8.5 Follow-up after disease progression
Contact patients every 3 months (via in-person visits or telephone calls) to obtain data
on overall survival and post-study chemotherapy. Follow-up should be conducted every 3
months until the patient's death. During each follow-up visit, the following information
should be collected:
•
Patient survival status.
•
Disease status and progress date (if applicable).
•
Date of death (if applicable).
•
Record all new anticancer therapies.
Note: Patients with tumor progression should be treated as other patients with
advanced colorectal cancer.

14
3.9 Data Quality
In compliance with the guidelines of Good Clinical Practice (GCP), monitors will
conduct regular visits to each center to ensure adherence to the study protocol, GCP, and
relevant regulations. The visits will include on-site inspections of the completeness and
clarity of Case Report Forms (CRFs), cross-verification with original documents, and
clarification of management-related matters.
3.10 Archive
The data entered into the Case Report Form (CRF) must be consistent with the
original documents or recorded directly in the CRF. In cases of direct recording in the
CRF, the recorded content shall be considered as the original data. The parameters of the
original data must be validated, and the source information of the data must be
documented. Both the study documents and all original data should be retained until the
investigator issues a notice for destruction.
4. Ethical and Legal Considerations
4.1 Ethics Committee (EC) or Institutional Review Board (IRB)
In accordance with Good Clinical Practice (GCP), Chinese laws and regulations, and
requirements of relevant organizations, all participating centers must obtain approval
documents from the corresponding ethics committee/institutional review board prior to the
initiation of the study. When necessary, extensions, amendments, or re-evaluations of the
ethics committee approval must be obtained and forwarded to the investigators.
4.2 Ethical Guidelines for This Study
The procedures for operations, evaluations, and documentation in this research
protocol are designed to ensure that researchers adhere to the guidelines of clinical
practice standards and the principles detailed in the Declaration of Helsinki. The
implementation of this study will also comply with relevant laws and regulations in China.
Researchers are not permitted to modify the study protocol without prior consent.
However, in emergency situations to eliminate risk factors for subjects, researchers may
deviate from or alter the protocol without obtaining approval or support from the Ethics
Committee/Institutional Review Board/Principal Investigator. Any deviations or
modifications made, along with their rationale, must be promptly reported to the Ethics
Committee/Institutional Review Board/Principal Investigator. Where appropriate, a
proposal for protocol amendment should also be submitted. Researchers are required to
provide a comprehensive explanation and justification for all deviations or modifications
to the study protocol.

15
4.3 Subjects' Instructions and Informed Consent
The subject must be provided with the key information of the study and the informed
consent form. Prior to the initiation of the study, the investigator must provide the subject
with written approval from the ethics committee/institutional review board (IRB) or
endorsement of the informed consent form, along with all other written information. The
ethics committee/institutional review board approval and the approved informed consent
form must be archived together in the study documentation.
Informed consent must be obtained prior to the implementation of any specific study
procedure. The date of participant enrollment and signing of the informed consent form
shall be recorded in the corresponding subject documentation.
4.4 Confidentiality
All records relating to the identity of the patient are kept confidential and will not be
made publicly available to the extent permitted by applicable laws and/or regulations.
The names of participants will not be provided. Case report forms only record the
participant's number and the initials of their name. If the participant's name appears in any
other documents (e.g., pathology reports), copies of such documents must be redacted.
Computer-stored research reports must comply with local data protection laws. When
research results are published, participant identities will also be kept confidential.
The investigators will keep a list to identify the records of the subjects.
5. Statistical Methods
5.1 Statistical and Analysis Plan
5.1.1 Study Population Analysis
The efficacy analysis will be conducted in the intention-to-treat (ITT) population,
defined as all patients who received at least 2 cycles of study drug therapy. The safety
analysis population includes all patients who received at least one dose of study drug
therapy. The response rate analysis population refers to all patients in the ITT population
who achieved partial or complete response as determined by the RECIST criteria.
5.1.2 Baseline and Demographic Characteristics
Summarize the baseline, demographic characteristics, baseline tumor characteristics,
medical history, previous anticancer therapy, concomitant medications, vital signs, and
trial discontinuation of all patients who underwent randomization according to different
treatment groups. For continuous assessments, calculate the mean, standard deviation,
range, and median; also calculate absolute values, frequencies, and percentages.
5.1.3 Efficacy Analysis

16
The efficacy analysis will be performed in the ITT population.
5.1.3.1 Primary Efficacy Analysis
The primary endpoint was the objective response rate (ORR). The objective response
rate refers to the proportion of patients who achieved tumor shrinkage of a certain size and
maintained it for a specified duration, including cases with complete response (CR) or
partial response (PR). The Kaplan-Meier method was used to derive the expected survival
curves for patients in the treatment group.
5.1.3.2 Secondary Efficacy Analysis
The depth of response (DpR) is defined as the percentage of maximum tumor
shrinkage achieved during treatment compared to baseline. If a complete response (CR) is
observed, the DpR is recorded as 100%.
Tumor response and disease progression will be assessed by investigators according
to the RECIST criteria.
Progression-free survival (PFS) is defined as the time from randomization to tumor
progression or death, with tumor progression recorded promptly.
Overall survival (OS) is defined as the time from randomization to death from any
cause.
5.1.3.3 Safety Analysis
Adverse events and their most severe reaction levels will be summarized according to
the criteria of the 5th edition of the NCI CTCAE. Additionally, adverse events will be
summarized based on their severity and relationship with the investigational drug.
Descriptive summaries of laboratory test values primarily focus on abnormal values.
Laboratory test abnormalities will also be summarized according to the most severe level
specified in the 5th edition of the NCI CTCAE.
6. Adverse Events
6.1 Precautions/Warnings
Treatment must be administered under the supervision and guidance of a specialized
oncologist with experience in the use of relevant medications. Appropriate management of
complications is only possible when adequate diagnostic and therapeutic equipment is
readily available. Common adverse events include cutaneous reactions of the hands and
feet, fatigue, rash, fever, stomatitis, diarrhea, anorexia, hoarseness, arthromuscular pain,
abnormal liver function, leukopenia, and thrombocytopenia.
6.2 Detection of Adverse Events

17
Close monitoring of adverse events occurring in subjects must be conducted. This
monitoring includes clinical laboratory tests. The evaluation should be based on the
severity, seriousness, and relationship to the investigational drug of the adverse event.
The investigator is responsible for evaluating the relationship between all adverse
events and the investigational drug. However, the principal investigator may delegate this
judgment to other investigators participating in the study, while remaining accountable for
the outcome. The investigator must provide a list of qualified personnel who have been
authorized to perform this task.
6.3 Definition of Adverse Events
6.3.1 Adverse Events
Adverse events refer to any adverse medical events occurring in patients or subjects
receiving investigational drug therapy. Adverse events do not necessarily have a causal
relationship with the treatment. Therefore, adverse events may include any adverse and
nonspecific signs (including abnormal laboratory test results), symptoms, or diseases
temporarily associated with the investigational drug, regardless of whether the event is
considered drug-related.
Adverse events occurring in humans (whether or not drug-related) include the
following:
•
adverse events that occur during the use of a drug by a professional;
•
adverse events caused by drug overdose (whether intentional or
accidental);
•
adverse events caused by drug abuse;
•
adverse events caused by discontinuation of medication;
•
Adverse events that may be purely study-related (e.g., those caused by
discontinuation of antihypertensive drugs during the washout period or
serious adverse events) must be reported as adverse events, even if they
are unrelated to the study medication.
Clinical pharmacological effects that do not occur or do not meet the expected
outcomes, and are already recorded in the corresponding section of the CRF, shall not be
recorded as adverse events. However, if they meet the criteria for a 'serious' adverse event,
they must also be recorded and reported as serious adverse events. In this study, the
progression or deterioration of existing tumors that meet the 'serious' criteria must also be
reported as serious adverse events (SAEs). Investigators should also report symptoms and

18
signs arising from the progression or deterioration of existing cancers.
6.3.2 Serious Adverse Events
A serious adverse event refers to any adverse medical event occurring under any
medication condition that meets one of the following criteria:
•
leading to death;
•
threat to life ；
•
resulting in hospitalization or longer hospital stays for patients;
•
resulting in permanent or significant loss of the ability to work or
disability;
•
congenital malformation or congenital defect;
•
Major medical events.
Life-threatening: The term 'life-threatening' is defined as 'severe', indicating that the
subject is at risk of death when the adverse event occurs. It does not refer to adverse
events that may lead to death under more severe hypothetical conditions.
Hospitalization: Any adverse event that results in a patient being hospitalized or that
prolongs the length of hospitalization is considered serious, unless one of the following
exceptions applies:
–
Stay in hospital for no more than 12 hours;
–
perhaps
–
Admission was pre-planned (i.e. pre-scheduled surgery or elective
surgery prior to the start of the study);
–
perhaps
–
Hospitalization was not associated with adverse events (e.g.
hospitalization for convalescence purposes).
–
Note: Any invasive treatment performed during hospitalization may
meet the criteria for a 'major medical event' and may therefore require
reporting as a serious adverse event based on clinical judgment.
Furthermore, if local regulatory authorities require a more stringent
definition, the local regulations shall prevail.
Disability: means that a person has a severely impaired ability to perform daily
activities.
Major Medical Event: Any adverse event that may endanger the subject and may
require intervention to prevent more serious conditions is considered a serious adverse

19
event. The determination of major medical events should be based on the "WHO
Adverse Event Terminology – Main List of Terms". These terms refer to serious
disease states or descriptions of serious disease states.
These events are reported as serious adverse events (SAEs) because they may be
associated with serious disease conditions and, compared to other reporting methods,
reporting them as SAEs ensures heightened attention and facilitates necessary actions.
6.3.3 Unintended Adverse Events
An unexpected adverse event refers to any adverse drug reaction (ADR) whose
characteristics or severity differ from those described in the package insert of the marketed
product. Supplementary information regarding the characteristics or severity of known or
documented adverse events also constitutes part of the unexpected adverse event report.
For instance, events that are more specific or severe than those described in the package
insert should be classified as "unexpected." Specific examples include: (a) acute renal
failure, which has been previously reported as an adverse event, subsequently complicated
by interstitial nephritis; and (b) hepatitis initially reported as acute liver necrosis.
6.3.4 Relationship Between Adverse Events and Study Drug
The evaluation of the relationship between a adverse event and the investigational
drug is a comprehensive clinical judgment made based on all available information when
completing the case report form.
"Not relevant" may include:
1. There are clear alternative explanations, such as traumatic bleeding at the
surgical site;
perhaps
2. Unreasonable, such as when a subject is hit by a car, but there is no
indication that the event was caused by the drug-induced disorientation;
or cancer developing just days after the start of the drug.
A 'yes' evaluation indicates that there are reasonable grounds to suggest a potential
association between the adverse event and the study medication.
The following factors should be considered when assessing the relationship between
adverse events and the investigational drug:
– Short-term occurrence after drug administration: This adverse event should
occur after administration. The duration between medication and the
occurrence of the event should be considered during clinical evaluation.

20
– The event disappeared after discontinuation of administration (cessation of
stimulation) and reappeared after resumption of administration (repeated
stimulation): When analyzing the clinical course of a suspected event, the
response after discontinuation of administration (cessation of stimulation) or
after resumption of administration (repeated stimulation) should be fully
considered.
– Underlying, comorbid and comorbid conditions: Assess the natural course of
the disease, the treatment process and all other conditions the patient may
have in each report;
– Concomitant medications or treatments: The other medications taken by the
subject or other treatments received by the subject should be examined to
determine whether any of them may have caused the adverse event.
– Known response patterns of a specific class of drugs: clinical/preclinical
– Pharmacology and Pharmacokinetics of the Investigational Drug: The
pharmacokinetic characteristics (absorption, distribution, metabolism, and
excretion) of the investigational drug should be considered in conjunction
with the individual pharmacodynamic response of each subject.
6.3.5 Recording of Adverse Events
All adverse events occurring after the subject signs the informed consent form must
be fully documented in the subject's case report form.
Records must be supported by original documentation. Laboratory test abnormalities
deemed clinically relevant (e.g., those leading to early study withdrawal, requiring
treatment, or causing significant clinical manifestations, or those considered clinically
relevant by investigators) should be reported as adverse events. Each event must be
described in detail, including the start and end dates, severity, relationship to the
investigational product, measures taken, and the outcome of the event.
6.4 Reporting of Serious Adverse Events
From the time of informed consent signing until 30 days after the completion of the
last dose, any defined serious adverse event (SAE), including laboratory test abnormalities
meeting the SAE definition, must be immediately reported to the designated personnel in
the study documents (within 24 hours of the investigator's knowledge). The SAE report
form must also be completed and submitted to the designated personnel in the study
documents within 24 hours of the investigator's knowledge.
Each serious adverse event should be followed up until resolution or stabilization,

21
with an updated report submitted to the designated personnel. A simple Level 4 laboratory
test abnormality (according to the CTCAE 5.0 criteria) should not be reported as a serious
adverse event unless the investigator determines that the abnormality meets the
International Conference on Harmonisation (ICH) criteria for serious adverse events (as
defined in Section 6.3.2). A Level 4 laboratory test abnormality that occurs at baseline and
is a manifestation of the disease according to the CTCAE 5.0 criteria should not be
reported as a serious adverse event, particularly if the abnormality is present but the
patient is still allowed to enroll or is not excluded from enrollment. If there is any doubt
about whether the abnormality should be reported as a serious adverse event, the
investigator may consult the study monitor. A Level 4 laboratory test abnormality should
be recorded on the "Laboratory Data" page and regularly cross-checked by the medical
monitor.
According to the requirements of local laws and regulations, serious adverse events
must be reported to the ethics committee and the drug regulatory authority.

22
7. Appendix
7.1 General Status (ECOG Score)
classify
description
0
Full capacity to perform all pre-disease behaviors without restriction.
(Karnofsky 90-100 points)
1
Significant limitation of physical activity, but able to walk and perform
light physical or sedentary work (e.g., housework and office work).
(Karnofsky score 70-80)
2
Capable of walking and performing basic self-care activities, but unable
to complete any work-related activities. The time spent on ambulation
and alertness exceeds 50% of the total. (Karnofsky score 50-60)
3
Only limited self-care is possible. More than 50% of the waking time
requires bed rest or sitting. (Karnofsky score 30-40)
4
Complete disability with loss of mobility. No ability for self-care.
Completely bedridden or sedentary. (Karnofsky score 10-20)
7.2 TNM staging
International Standard for Staging Colorectal Cancer
The American Joint Committee on Cancer (AJCC) stipulates that the staging of colorectal
cancer is performed according to the TNM staging system.
1. Definition of TNM
primary tumor （T）
•
TX: The primary tumor cannot be evaluated.
•
T0: No evidence of primary tumor.
•
Tis: Carcinoma in situ. Limited to the epithelium or invading the mucosal
lamina propria.
•
T1: Tumor invasion into the submucosa.
•
T2: Tumor invasion of the muscularis propria.
•
T3: The tumor penetrates the muscularis propria layer to reach the
subserosal layer, or invades the perirectal tissues without peritoneal
coverage.
•
T4a: Tumor penetrates the visceral peritoneum.
•
T4b: The tumor directly invades or adheres to other organs or structures.

23
Regional lymph nodes (N)
•
NX: Regional lymph nodes cannot be evaluated.
•
N0: No regional lymph node metastasis.
•
N1: Metastasis to 1-3 regional lymph nodes.
•
N1a:1 regional lymph node metastasis
•
N1b: There are 2–3 regional lymph node metastases.
•
N1c: Tumor deposits (TD) in the subserosal, mesenteric, and peritoneally
uncovered perirectal tissues, without regional lymph node metastasis.
•
N2: Metastasis to more than 4 regional lymph nodes.
•
N2a: Metastasis to 4-6 regional lymph nodes.
•
N2b: Metastasis to 7 or more regional lymph nodes.
distant metastasis （M）
•
MX: The distant metastasis status is unknown.
•
M0: No distant metastasis.
•
M1: distant metastasis.
•
M1a: Distant metastasis is confined to a single organ or site (e.g., liver,
lung, ovary, non-regional lymph nodes) but without peritoneal
metastasis
•
M1b: distant metastases are present in more than one organ, but without
peritoneal metastases.
•
M1c: Peritoneal metastasis with or without metastasis to other organs.
American Joint Committee on Cancer (AJCC) staging
Stage 0 Tis, N0, M0
Stage 0 Tis, N0, M0
Stage IA, T1, N0, M0
Stage IA, T1, N0, M0
Stage IB, T2, N0, M0
Stage IB, T2, N0, M0
Stage IIIA, T3, N0, M0 Stage IIIA, T3, N0, M0
Stage IIB, T4a, N0, M0 Stage IIB, T4a, N0, M0
Stage IIIC, T4b, N0, M0
Stage IIIIA, T1-2, N1/N1c, M0 Stage IIIIA, T1-2, N1/N1c, M0
T1, N2a, M0
Stage IIIIB, T3-4a, N1, M0
Stage IIIIB, T3-4a, N1, M0
T2-3, N2a, M0

24
T1-2, N2b, M0
Stage IIIIC, T4a, N2a, M0
Stage IIIIC, T4a, N2a, M0
T3-4a, N2b, M0
T4b, N1-2, M0
Stage IVA, any T, any N, M1a Stage IVA, any T, any N, M1a
Stage IVB: Any T, Any N, M1b
Stage IVB: Any T, Any N, M1b
Stage IVC: Any T, Any N, M1c Stage IVC: Any T, Any N, M1c
7.3 RECIST Tumor Assessment Criteria
In this study, the new international standard proposed by the RECIST (Response
Evaluation Criteria in Solid Tumors) committee will be used to evaluate tumor response
and progression. The only change in the RECIST criteria is the application of the
maximum diameter of the tumor lesion (one-dimensional measurement).
Measurable lesions: Measurable lesions are defined as those that can be accurately
measured in at least one dimension (with the longest diameter recorded), with a maximum
diameter ≥20 mm measured using conventional techniques (PE, CT, XR, MRI) or ≥
10 mm using spiral CT scanning. Spiral CT scans for tumor response evaluation must be
reconstructed with a slice thickness of 5 mm. All tumor measurements must be recorded in
millimeters (or tenths of centimeters).
Unmeasurable lesions: All other lesions (or disease sites) excluding measurable
lesions, including small lesions (measured by conventional techniques with a maximum
diameter <20mm or by spiral CT with a maximum diameter <10mm), are considered
unmeasurable. Lesions in bones, meninges, ascites, pleural/pericardial effusions,
cutaneous lymphangitis/pneumonia, inflammatory breast diseases, abdominal masses
(unfollowable by CT or MRI), and bladder lesions are all deemed unmeasurable.
Target lesions: A maximum of 2 lesions from each organ's measurable lesions may be
selected as target lesions, with up to 5 representative lesions from all affected organs
eligible for selection. All target lesions must be recorded and measured during the baseline
phase. These 5 lesions should be chosen based on their size (longest diameter of the lesion)
and the reproducibility of their precise measurements (whether via imaging techniques or
clinical measurements). The sum of the longest diameters (LD) of all target lesions will
serve as the baseline total LD. The baseline total LD will be used as a reference value to

25
objectively evaluate tumor response by measuring the size of subsequent lesions. If more
than 5 measurable lesions are available, those not selected as target lesions will be
classified as non-target lesions along with unmeasurable lesions.
Non-target lesions: include all non-measurable lesions (or disease sites) and all
measurable lesions outside the selected 5 target lesions. These lesions do not require
measurement but should be recorded as "present" or "absent" at baseline and at each
follow-up.
Efficacy Evaluation: All patients will undergo one of the following efficacy
evaluations:
Complete remission (CR): All clinical and imaging evidence of the tumor (including
target and non-target lesions) is eliminated.
Partial response (PR): A reduction of at least 30% in the sum of LD values at the
target lesion compared to baseline total LD.
Stable Disease (SD): A stable state of the disease. The lesion has not met the PR
criteria for shrinkage or has not met the PD criteria for progression.
Disease progression (PD): Referring to the minimum total LD value recorded from
the start of treatment, the sum of LD in the measured lesions increases by at least 20% or
one or more new lesions appear. The emergence of any new lesions indicates disease
progression. In special cases, unmeasurable lesions with clear progression may also be
accepted as evidence of disease progression.
Evaluation of therapeutic efficacy for target lesions versus non-target lesions
Target
lesion
Non-target
lesions
New
lesion
Overall
response
This type of optimal
response also requires
CR
CR
not have
CR
Confirm after 4 weeks
CR
Non-CR/Non-
PD
not have
PR
Confirm after 4 weeks
PR
Non-PD
not have
PR
SD
Non-PD
not have
SD
At least 4 weeks from the
baseline period
PD
any
Present or
absent
PD
No SD, PR, or CR had
occurred previously.
any
PD
Present or
absent
PD

26
any
any
have
PD
Patients with an overall deterioration in health status requiring treatment
discontinuation should be reported as 'symptom exacerbation' if there is no objective
evidence of disease progression at this time. Objective disease progression should be
observed and documented as closely as possible even after treatment cessation.
Relief time
The duration of remission should be calculated from the time of the first meeting of
the criteria for CR or PR (whichever is recorded first) until the date of the first recorded
disease recurrence or progression.
disease stable time
The duration of disease stability should be calculated from the start of treatment until
disease progression is achieved, with the minimum measured lesion size after treatment
initiation serving as the reference.
measuring method
The same evaluation criteria and measurement techniques should be used to describe
and report each designated lesion during both the baseline and follow-up periods.
Clinical lesions — Clinical lesions are considered measurable only when located on the
body surface (e.g., skin nodules, palpable lymph nodes). For dermatological lesions, it is
recommended to document them with color photographs including the lesion and the
measuring ruler used.
Chest X-ray — When the lesion has well-defined margins and is surrounded by air-filled
lung tissue, the lesion observed on chest X-ray may be considered measurable. However,
CT should still be the preferred modality.
CT/MRI — CT and MRI are currently the most feasible and reproducible methods for
measuring target lesions selected for response evaluation. Conventional CT and MRI
should be performed with continuous scanning at a slice thickness of 10 mm or less. Spiral
CT should be performed with continuous scanning at a slice thickness of 5 mm and
reconstruction. This method is suitable for the chest, abdomen, and pelvis. Scanning of the
head, neck, and limbs often has specific requirements.
When measurable tumor lesions meet the criteria for remission and disease stability,
cytological examination must be performed for any effusion that occurs or worsens during

27
treatment to confirm whether it is tumor-induced (the effusion may be a side effect of
treatment), thereby distinguishing between disease remission/stability and disease
progression.
7.4 New York Heart Association (NYHA) Classification of Heart Function
New York Heart Association (NYHA) functional classification
I level
The patient has a history of heart disease but no restrictions on physical activity.
Normal physical activity does not lead to excessive fatigue, palpitations, dyspnea,
or angina pectoris.
II level
The patient's cardiac condition results in mild limitation of physical activity. No
discomfort is observed at rest. Even mild physical exertion may lead to fatigue,
palpitations, dyspnea, or angina pectoris.
III level
The patient's cardiac condition results in significantly restricted physical activity.
No discomfort is observed during rest. Even mild physical exertion may lead to
fatigue, palpitations, dyspnea, or angina pectoris.
IV level
The patient's cardiac condition renders them incapable of any physical activity.
Even at rest, symptoms of heart failure or angina may occur. Any physical exertion
exacerbates the discomfort.

28
7.5 Research Process Table
Flowchart of Therapy Process
pretherapy
Each 3-week period constitutes one cycle.
Post-treatment
follow-up visit
Follow-up
after
treatment
discontinuatio
n due to non-
progressive
conditions
until disease
progression
Follow-up after
progression 9
Cycle 1
Cycle 2
The 4th and
subsequent cycles
until disease
progression or
treatment
discontinuation
Operation item
Filter period
Day 1
Day 1
Day 1
Within 7 days
Every 8
weeks
Every 3
months
Informed
Consent
Form
X (within 28 days)
Every 2
months,
telephone
follow-up or
outpatient
visit is
conducted to
collect the
following
information:
1. Patient
survival
information;
2. Changes in
cancer
treatment
modalities,
including
all
new therapies
Medical History 1
X (within 7 days)
Complete
physical
examination 2
X (within 7 days)
Inclusion/Exclusio
n Criteria
X
stochastic
X
Life
signs
and
ECOG score
X
X
X
X
X
X
12-lead
electrocardiogram
X (within 28 days)
X
X
X
Brain CT or MRI scan 3
X (within 28 days)
Imaging Evaluation 4
X (within 28 days)
X (every 6 weeks) --------------
Hematological examination 5 X (within 7 days)
X
X
X
Complete Set of Biochemical
Tests 6
X (within 7 days)
X
X
X
Urine test 7
X (within 7 days)
X
X
X
Fecal Test 8
X (within 7 days)
X (every 6 weeks) --------------
Serum
pregnancy
test
X (within 7 days)
Study of drug use
X
X
X
X
Evaluation
of
Adverse
Events
(AEs)
---------------(
comorbidities
and
concomitant
medications
---------------(
1.
Complete medical history, demographic data, surgical history, concomitant medications, comorbidities,
allergy history, and smoking history.
2.
Complete physical examination, ECOG performance status score, height, weight, vital signs, and
detailed examinations of all body systems.

29
3.
Head CT/MRI scans are only required for patients with baseline neurological symptoms to exclude
brain metastases.
4.
Tumor assessment during the treatment phase is required every 6 weeks. After treatment completion,
imaging evaluations are required every 8 weeks until disease progression occurs. If a patient withdraws
from the study due to disease progression, no additional CT scans are required during the final follow-up
at study completion.
5.
Hematological tests include: hemoglobin, hematocrit, platelets, white blood cells, absolute neutrophil
count, and absolute lymphocyte count, which can be performed 1 day prior to the start of each treatment
course.
6.
The complete biochemical panel includes: blood glucose, calcium, phosphorus, sodium, potassium,
chloride, creatinine, blood urea nitrogen, total protein, albumin, alanine aminotransferase (ALT), aspartate
aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin. These tests can be performed
one day prior to the start of each treatment course.
7.
Urinalysis includes: urine specific gravity, pH value, urine glucose, urine protein, and occult blood.
Screening requires laboratory urinalysis, followed by urine test strips during subsequent treatment courses.
Urinalysis can be performed one day before the start of each treatment course.
8.
Fecal examination, also known as routine stool test, includes fecal occult blood, white blood cells, and
red blood cells. It is performed once during the screening phase and can be conducted concurrently with
each subsequent tumor assessment.
9.
Follow-up should be conducted every 3 months after disease progression until 1 year after progression
or death.

30
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