Conditions: NSCLC
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 450
Healthy volunteers: no

Brief summary:
A randomized, double blind, multicenter phase3 study .

Detailed description:
A randomized, double blind, multicenter phase3 study in chemotherapy naive patients with stage IIIB,IV or recurrent NSCLC of non-squamous. the study will randomize about 436 patients at a 1:1 ratio to 2 treatment arms. The study is divided 4 phase, screening, combination treatment, maintenance and follow up.

Arms:
arm 1: Drug Bevacizumab15mg/kg in combination with Paclitaxel/Carboplatin 6 cycles then maintains at 7.5 mg/kg arm 2: Drug IBI305 15mg/kg in combination with Paclitaxel/Carboplatin 6 cycles then maintains at 7.5 mg/kg

Interventions: intervention 1: Bevacizumab in Combination With Paclitaxel/Carboplatin intervention 2: IBI305 in Combination with Paclitaxel/Carboplatin
Intervention descriptions: intervention 1: Drug Bevacizumab15mg/kg in combination with Paclitaxel/Carboplatin 6 cycles then maintains at 7.5 mg/kg intervention 2: Drug IBI305 15mg/kg in combination with Paclitaxel/Carboplatin 6 cycles then maintains at 7.5 mg/kg

Protocol document:
Prot_001.pdf: 
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CLINICAL STUDY PROTOCOL
Study Title:
A randomized, double-blinded, multi-center phase III study
comparing the efficacy and safety of IBI305 plus paclitaxel/carboplatin
versus bevacizumab plus paclitaxel/carboplatin in treatment-naive
subjects with advanced or relapsed non-squamous non-small cell
lung cancer
Protocol No.:
CIBI305A301
Version and Date:
Nov. 5, 2018/Version 3.2
Product Name:
Recombinant anti-VEGF humanized monoclonal antibody
injection (IBI305)
Study Phase:
Phase III
Sponsor:
Innovent Biologics (Suzhou) Co., Ltd.
No. 168 Dongping Street, Suzhou Industrial Park, Jiangsu, China
Sponsor Contact:
Zhou Hui (Senior Medical Director)
Tel: (+86) 21-31652896
E-mail: hui.zhou@innoventbio.com
NCT Number
NCT02954172
Confidentiality Statement
This document is the confidential information of Innovent Biologics (Suzhou) Co., Ltd.
The content of this document shall not be disclosed to any person other than the investigators, research consultants
or related personnel, and Institutional Review Board/Independent Ethics Committee.
The information contained in this document must not be used for any purpose, except for the evaluation or
conduction of this study, without the written consent of the sponsor.


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SIGNATURE PAGE
Protocol Title: A randomized, double-blinded, multi-center phase III study comparing the efficacy
and safety of IBI305 plus paclitaxel/carboplatin versus bevacizumab plus paclitaxel/carboplatin in
treatment-naive subjects with advanced or relapsed non-squamous non-small cell lung cancer
Protocol No.: CIBI305A301
Title
Name
Signature
Date
Senior
Medical
Director
Zhou Hui
Senior
Director of
Biostatistics
Zhang Nan


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PROTOCOL SYNOPSIS
Sponsor/Company:
Innovent Biologics (Suzhou) Co., Ltd.
Investigational drug:
IBI305
Active Ingredient:
Recombinant anti-VEGF humanized monoclonal antibody
Study Title:
A randomized, double-blinded, multi-center phase III study comparing the efficacy
and safety of IBI305 plus paclitaxel/carboplatin versus bevacizumab plus
paclitaxel/carboplatin in treatment-naive subjects with advanced or relapsed non-
squamous non-small cell lung cancer
Protocol No.:
CIBI305A301
Coordinating Investigator:
Zhang Li
Coordinating Center:
Sun Yat-Sen University Cancer Center
Expected study duration: Each subject will receive treatment every 3-week
until progressive disease (PD), unacceptable toxicity, withdrawal of informed
consent, lost to follow-up or death (whichever comes first).
The end of the study is defined as the 18th month after the randomization of
the last subject.
Phase: III
Study Objectives:
Primary Objective:

To compare the objective response rate (ORR) of IBI305 plus paclitaxel/carboplatin versus bevacizumab
plus paclitaxel/carboplatin for the treatment of advanced or relapsed non-squamous non-small cell lung
cancer (NSCLC)
Secondary Objectives:

To compare the duration of response (DOR), progression-free survival (PFS), disease control rate (DCR),
and overall survival (OS) of IBI305 plus paclitaxel/carboplatin versus bevacizumab plus
paclitaxel/carboplatin for the treatment of advanced or relapsed non-squamous NSCLC

To compare the safety and immunogenicity of IBI305 plus paclitaxel/carboplatin versus bevacizumab
plus paclitaxel/carboplatin for the treatment of advanced or relapsed non-squamous NSCLC
Exploratory objectives:


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
To compare the population pharmacokinetics (PPK) of IBI305 and bevacizumab in subjects with
advanced or recurrent non-squamous NSCLC

To compare the PD of IBI305 and bevacizumab in subjects with advanced or recurrent non-squamous
NSCLC
Study design:
This is a randomized, double-blinded, multi-center phase III study. The study planned to enroll and randomize 436
subjects with non-squamous NSCLC in a 1:1 ratio to IBI305 plus paclitaxel/carboplatin group or bevacizumab plus
paclitaxel/carboplatin group. Stratifying factors include age (< 60 vs. ≥60 years old) and EGFR status (wild type vs.
unknown type).
Each treatment cycle is 3 weeks for both groups. 15 mg/kg IBI305 or bevacizumab is administered on D1 of each
cycle along with paclitaxel/carboplatin. Subjects will receive up to 6 treatment cycles of combination therapy until
PD, unacceptable toxicity, withdrawal of informed consent, loss to follow-up, or death (whichever comes first).
Then subjects receive maintenance monotherapy, that is, discontinuing paclitaxel/carboplatin while continuing
therapy with IBI305 or bevacizumab. The maintenance monotherapy continues every 3 weeks. On D1 of each
treatment cycle, subjects will be administered 7.5 mg/kg of either IBI305 or bevacizumab until PD, unacceptable
toxicity, withdrawal of informed consent, loss to follow-up, death, or end of study (whichever comes first).
During the study, a CT or an MRI will be performed every 6 weeks (± 7 days) and be determined whether the study
treatment will be continued by investigators at each site through tumor assessments until PD, withdrawal of
informed consent, lost to follow-up, death, start of other anti-tumor therapies, or end of study. If subjects discontinue
the study treatment for reasons other than PD, tumor assessments will be continued until PD, withdrawal of
informed consent, loss of follow-up, death, start of other anti-tumor therapies, or end of study. If subjects discontinue
the study treatment for PD, the investigators will make telephone follow-up every 12 weeks (± 7 days) to collect
information of subsequent anti-tumor therapies and survival until withdrawal of informed consent, lost to follow-up,
death, or end of study.
Number of Subjects:
436
Diagnosis and main inclusion
criteria:
Inclusion Criteria:
Subjects must meet all of the following inclusion criteria to be enrolled in the study:
1)
Sign the formed consent form
2)
Male or female ≥18 and ≤75 years old
3)
Histologically or cytologically confirmed unresectable locoregionally
advanced (stage IIIB), metastatic (stage IV), or relapsed non-squamous
NSCLC; mixed tumors should be categorized according to the main cell
types
4)
Histologically or cytologically confirmed EGFR wild type or non-
sensitive mutation type


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5)
Must have at least one measurable target lesion (as per RECIST 1.1)
6)
Eastern Cooperative Oncology Group Performance Status (ECOG PS)
score of 0–1
7)
Expected survival ≥6 months
8)
Laboratory results during screening:
a)
Routine blood test: WBC ≥3.0 × 109/L, ANC ≥1.5 × 109/L, platelets ≥
100 × 109/L, and hemoglobin ≥90 g/L
b)
Hepatic function: TBIL < 1.5 × ULN; ALT and AST < 2.5 × ULN for
subjects without liver metastasis, or ALT and AST < 5 × ULN for subjects with
liver metastasis
c)
Renal function: SCr ≤1.5 × ULN or CrCl ≥50 mL/min, and urine
protein < 2+ in routine urinalysis. Subjects with urine protein ≥2+ from
urinalysis dipstick at baseline, a 24-h urine should be collected with total protein
content < 1 g
d)
INR ≤1.5 and PTT or aPTT ≤1.5 × ULN within 7 days prior to the
study treatment
9)
Able to comply with study protocol
10)
Female and male subjects of childbearing age, and partners of these male
subjects must agree to use effective contraceptive measures (such as
abstinence, sterilization, oral contraceptives, medroxyprogesterone
injections or contraceptive implants) during the study and for 6 months
after the infusion of the study drug
Exclusion Criteria:
Subjects meeting any of the followings will not enrolled in the study:
1)
Prior systemic chemotherapy or targeted therapy (such as monoclonal
antibody or tyrosine kinase inhibitor) for the treatment of the current
stage of disease (Stage IIIB not suitable for multidisciplinary treatment,
stage IV or relapsed disease). Prior surgery and radiotherapy are
permitted, provided that the criteria outlined in the study protocol are met.
Subjects who received prior adjuvant therapy and relapsed within 6 months
are not eligible
2)
Mixed non-small cell and small cell carcinoma, or mixed adenosquamous
carcinoma predominantly containing squamous cell carcinoma component
3)
Histologically or cytologically confirmed EGFR-sensitive mutation type
(including exon 18-point mutation (G719X), exon 19 deletion, and exon
21-point mutations (L858R and L861Q)). Subjects with unknown EGFR
status for various reasons might enroll.


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4)
History of hemoptysis within 3 months prior to screening, with a volume
of blood greater than 2.5 mL each time
5)
Radiographic evidence of tumor invasion in great vessels. The
investigator or the radiologist must exclude subjects with tumors that are
fully contiguous with, surrounding, or extending into the lumen of a great
vessel (such as pulmonary artery or superior vena cava)
6)
Symptomatic CNS metastasis; subjects with asymptomatic brain
metastasis or subjects who are symptomatically stable after treatment for
brain metastasis might enroll if the following criteria are met: measurable
lesions outside the CNS; no midbrain, pons, cerebellum, medulla or
spinal cord metastasis; no history of intracranial hemorrhage;
7)
Subjects who received radical thoracic radiotherapy within 28 days prior
to enrollment; subjects who received palliative radiation for non-thoracic
bone lesions within 2 weeks prior to the first dose of the study drug
8)
Subjects with severe skin ulcers or fracture, or having major surgery
within 28 days prior to randomization or expecting to have major surgery
during the study
9)
Subjects who received minor surgery within 48 hours prior to the first
dose of the study treatment (Outpatient/inpatient surgery requiring
locoregional anesthetics, including central line insertion)
10)
Currently or recently (within 10 days prior to the first dose of the study
treatment) used aspirin (> 325 mg/day) or other known NSAIDs to
inhibit platelet function for 10 consecutive days
11)
Currently or recently (within 10 days prior to the first dose of the study
treatment) received treatment with full dose oral or parenteral
anticoagulant or thrombolytic agents for 10 consecutive days. However,
anticoagulants for prophylaxis are accepted
12)
Subjects with inherited hemorrhagic tendency or coagulopathy, or history
of thrombosis
13)
Uncontrolled hypertension after treatment (systolic greater than 140
mmHg and/or diastolic greater than 90 mmHg), history of hypertensive
crisis or hypertensive encephalopathy
14)
Any unstable systemic disease including but not limited to: active
infection, unstable angina, cerebrovascular accident or transient cerebral
ischemia (within 6 months prior to screening), myocardial infarction
(within 6 months prior to screening), cardiac failure congestive (NYHA
Class ≥II), severe arrhythmia requiring medication, and liver, kidney or
metabolic disease


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15)
History of the following diseases within 6 months prior to screening:
gastrointestinal ulcers, gastrointestinal perforation, corrosive esophagitis
or gastritis, inflammatory bowel disease or diverticulitis, abdominal
fistula, or intra-abdominal abscess
16)
Subjects with tracheoesophageal fistula
17)
Clinically significant third spacing (such as ascites or pleural effusion
that are uncontrollable by drainage or other treatments)
18)
Subjects with current interstitial lung disease or CT showing active
pneumonia during screening
19)
History of malignant tumors other than NSCLC within 5 years prior to
randomization, except for adequately treated cervical carcinoma in situ,
basal or squamous cell skin cancer, locoregional prostate cancer after
radical surgery, ductal carcinoma in situ after radical surgery, or papillary
thyroid carcinoma
20)
Subjects with active autoimmune disease
21)
Subjects who were HBsAg-positive, and peripheral blood HBV DNA
titer ≥1 × 103 copies/L or ≥200 IU/mL; subjects who were HBsAg-
positive and peripheral blood HBV DNA titer < 1 × 103 copies/L or <
200 IU/mL might be eligible if the investigator determines that the
subject's chronic hepatitis B infection is stable and participation in the
study would add no further risks to the subject
22)
Subjects who are tested positive for HCV antibody, HIV antibody or
syphilis
23)
Subjects with known history of allergic diseases or allergic physique
24)
Received treatment with other investigational drugs or participated in
another interventional study within 30 days prior to screening
25)
History of alcohol or drug abuse
26)
Female subjects who are pregnant or breastfeeding, or expected to be
pregnant or breastfeeding during the study
27)
Known allergies to bevacizumab or any of its excipients, or any
chemotherapeutic agents
28)
Other conditions unsuitable for the inclusion as determined by the investigator
Investigational Drug, Dosage,
and Route of Administration:
IBI305: 15 mg/kg in combination chemotherapy and 7.5 mg/kg maintenance
monotherapy, administered via intravenous infusion on D1 of every 3-week
treatment cycle until PD, unacceptable toxicity, withdrawal of informed consent,
lost to follow-up, death, or end of study (whichever comes first)


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Control Drug, Dosage, and
Route of Administration:
Bevacizumab: 15 mg/kg in combination chemotherapy and 7.5 mg/kg
maintenance monotherapy, administered via intravenous infusion on D1 of
every 3-week treatment cycle until PD, unacceptable toxicity, withdrawal of
informed consent, lost to follow-up, death, or end of study (whichever comes
first)
Chemotherapy:
Paclitaxel: 175 mg/m² administered via intravenous infusion on D1 of every
3-week treatment cycle for up to 6 cycles until PD, unacceptable toxicity,
withdrawal of informed consent, loss of follow-up, or death.
Carboplatin: Areas under the concentration-time curve (AUC) = 6.0 administered
via intravenous infusion on D1 of every 3-week treatment cycle for up to 6 cycles
until PD, unacceptable toxicity, withdrawal of informed consent, loss of follow-up,
or death.
Evaluation criteria:
Efficacy endpoints:
Primary efficacy endpoint:

Objective response rate (ORR)
Secondary efficacy endpoints:

Duration of response (DOR)

Progression-free survival (PFS)

Disease control rate (DCR)

Overall survival (OS)
Safety endpoints:

Vital signs

Physical examination

Laboratory tests (routine blood test, blood chemistry, and urinalysis)

12-Lead ECG

Adverse event (AE, including treatment-emergent AE (TEAE)), AE of special interest (AESI)
(hypertension, proteinuria, gastrointestinal perforation, hemorrhage [cerebral hemorrhage, hematuria and
upper gastrointestinal hemorrhage], cardiotoxicity, and thrombosis), and serious adverse event (SAE)

Immunogenicity: Positive rates of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs)
PK/PD Endpoints:

Population PK parameters, including steady-state trough concentrations after repeated doses


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
Changes of serum VEGF at different time points
Statistical methods:
Sample size calculation:
A number of 218 subjects for each group (436 subjects in total) can provide 80% test power to confirm the clinical
equivalence between the treatments of IBI305 in combination with paclitaxel/carboplatin and bevacizumab in
combination with paclitaxel/carboplatin. Estimation parameters for sample size: The significance level of the two-
sided test is 0.05, the ORR of subjects in the IBI305 and bevacizumab groups is about 50.0%, and the equivalence
margin for the ratio of ORR is taken as (0.75, 1/0.75). Based on the above hypothesis, each group requires 218
subjects (436 subjects in total).
Efficacy analysis:
Clinical equivalence will be determined by whether the 90% confidence interval (CI) of the ratio of ORR between
the IBI305 and bevacizumab arms falls within the preset margin of (0.75, 1/0.75). The ORR and 95% CI of two
groups, ORR difference and 90% CI, and ORR ratio and 90% CI will be estimated using the generalized linear
model (GLM, including groups and stratification factors).
Median survival (OS) and survival curves will be estimated using the Kaplan-Meier method. The hazard ratio (HR)
and 95% CI of two groups will be estimated using the Cox model. DORs and PFSs will be analyzed by the same
method as the median survivals. DCR will be analyzed using the same method for primary efficacy endpoints, but
an equivalence test will not be conducted.
Safety analysis:
All adverse events (AE) will be coded using MedDRA and graded according to CTCAE v4.03. All treatment-
emergent adverse events (TEAEs), Grade 3 or greater TEAEs, serious adverse events (SAEs), investigational drug-
related TEAEs, investigational drug-related SAEs, TEAEs leading to treatment discontinuation, TEAEs leading
to study termination, and adverse events of special interest (AESIs) will be listed based on system organ class,
preferred terms, and groups and the numbers of corresponding subjects and percentages will be summarized.
In addition, the severity of TEAEs and the correlation with the study drug will also be summarized by system
organ class, preferred terms, and treatment groups.
Measured values and changes from baseline for vital signs, physical examination, laboratory tests and 12-lead ECG
will be analyzed using descriptive statistics. Baseline results and worst results during the study will be presented in
cross tabulation.
The number and percentage of subjects who developed anti-drug antibodies and neutralizing antibodies during the
study will be summarized by treatment group.
PK/PD exploratory analysis:
Mainly based on description, and inter-group comparison will be carried out if necessary


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Table 1. Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
a.
After completing the on-site end-of-treatment visit 28 days after the last dose, subjects who discontinue the
investigational drug treatment due to reasons other than PD should continue to undergo tumor assessments once
every 6 weeks (±7 days) until PD (and begin post-PD follow-up thereafter), withdrawal of consent, start of another
antineoplastic treatment, loss to follow-up, death, or study completion.
b.
For subjects with PD, collect survival information once every 12 weeks (84 days, ±7 days) by phone until death,
loss to follow-up, withdrawal of informed consent, or study completion. Subsequent antineoplastic treatments
should be documented in the eCRF.
c.
Only measure weight.
d.
Clinical laboratory tests are carried out at the laboratory of each hospital. If screening laboratory tests (routine
blood test, blood chemistry, and urinalysis) are performed within 7 days prior to the first dose, the screening
results may be used as baseline data. For subsequent visits, all laboratory tests have to be completed within 3
days prior to the dose administration.
e.
A urinalysis is required before each IBI305/bevacizumab infusion to test urine protein.
f.
Women of childbearing age should undergo a serum/urine pregnancy test.
g.
Immunogenicity tests will be performed in all subjects at 3 blood sampling time points: Within 1 hour prior to
the first dose of the study treatment (IBI305/bevacizumab) in C1, within 1 hour prior to the administration of
the study treatment in C4, and during the end-of-treatment visit. Blood specimens that are positive for anti-drug
antibodies (ADA) after dosing will be further tested for neutralizing antibodies (NAb). Samples will be tested
at the designated central laboratory.
h.
Image assessments (CT or MRI) of the brain, chest, abdomen, and pelvis should be completed at baseline. If
these tests are performed within 28 days prior to the first dose of the study drug, they do not need to be repeated
unless the investigator believes that there have been changes in the subject's tumor burden. After the start of
treatment, imaging tests are performed once every 6 weeks (±7 days) and have to be completed within 7 days
prior to the scheduled visits, until progressive disease, start of other treatment, withdrawal of informed consent,
loss to follow-up, death, or study completion. The same method of imaging test is used at baseline and during
follow-up. Imaging evaluations of the chest, abdomen, and pelvis are required.
i.
All subjects should undergo tumor tissue EGFR testing.


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j.
Each treatment cycle of the investigational product contains 3 weeks. The dose of IBI305 or bevacizumab is 15
mg/kg when used in combination with chemotherapeutic drugs and 7.5 mg/kg in the maintenance monotherapy,
given on D1 of every treatment cycle until progressive disease (PD), unacceptable toxic reactions, withdrawal
of informed consent, loss to follow-up, death, or end of study, whichever occurs first. After all assessments
were completed, the study drug was administered followed by chemotherapy. The first dose of study drug was
completed within 24 h after randomization.
k.
Each treatment cycle is 3 weeks long. Chemotherapy (paclitaxel + carboplatin) is administered on D1 of each
cycle for up to 6 cycles, or until disease progression (PD), unacceptable toxicity, withdrawal of informed
consent, loss to follow-up, or death. Paclitaxel is administered after the infusion of study drug is completed,
followed by carboplatin.


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TABLE OF CONTENTS
SIGNATURE PAGE..................................................................................................................... 2
PROTOCOL SYNOPSIS..............................................................................................................3
TABLE OF CONTENTS............................................................................................................ 13
LIST OF ABBREVIATIONS AND DEFINITIONS................................................................18
1
INTRODUCTION............................................................................................................... 20
1.1 Study Background........................................................................................................... 20
1.1.1 Disease background............................................................................................... 20
1.1.2 Investigational drug................................................................................................22
1.1.2.1 Description of investigational drug..............................................................22
1.1.2.2 Preclinical studies........................................................................................ 23
1.2 Study Principles and Risk/Benefit Assessment...............................................................25
1.2.1 Study principles and dose selection....................................................................... 25
1.2.2 Risk/benefit assessment......................................................................................... 26
2
STUDY OBJECTIVES....................................................................................................... 27
2.1 Primary Objective............................................................................................................27
2.2 Secondary Objectives......................................................................................................27
2.3 Exploratory Objectives....................................................................................................27
3
STUDY PLAN......................................................................................................................28
3.1 Overview of Study Design.............................................................................................. 28
3.2 Study Design Discussion.................................................................................................29
4
STUDY POPULATION...................................................................................................... 30
4.1 Inclusion Criteria.............................................................................................................30
4.2 Exclusion Criteria............................................................................................................31
4.3 Screening Failure.............................................................................................................33
4.4 Subject Restrictions.........................................................................................................33
4.5 Subject Withdrawal and Replacement............................................................................ 33
5
STUDY TREATMENT.......................................................................................................36
5.1 Therapies by Study Drugs............................................................................................... 36
5.2 Chemotherapy................................................................................................................. 36
5.3 Dose Adjustment of Each Study Drug............................................................................ 36


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5.3.1 General principles.................................................................................................. 36
5.3.2 Dose adjustments of study drugs........................................................................... 39
5.3.3 Dose adjustments of chemotherapy....................................................................... 44
5.4 Study Drug Properties..................................................................................................... 47
5.6 Packaging, Labeling, and Storage................................................................................... 48
5.7 Subjects Allocation..........................................................................................................48
5.8 Blinding...........................................................................................................................50
5.9 Concomitant Medications and Treatments......................................................................50
5.9.1 Prohibited treatment...............................................................................................50
5.9.2 Permitted treatment................................................................................................50
5.9.3 Treatment after study treatment............................................................................. 51
5.10 Treatment Compliance.................................................................................................. 51
5.11 Drug Return and Destruction........................................................................................ 51
5.12 Study Drug-Related Records.........................................................................................51
6
STUDY PROCEDURE....................................................................................................... 52
6.1 Screening Visits (D -28 to D -1)..................................................................................... 53
6.2 Baseline Visits (D1 of cycle 1)........................................................................................54
6.3 Cycle 2 (week 4 ± 3 days)...............................................................................................55
6.4 Cycle 3 (week 7 ± 3 days)...............................................................................................55
6.5 Cycle 4 (week 10 ± 3 days).............................................................................................56
6.6 Cycle 5 (week 13 ± 3 days).............................................................................................56
6.7 Cycle 6 (week 16 ± 3 days).............................................................................................57
6.8 Cycle 7 and Subsequent Treatment Cycles (±3 Days)....................................................57
6.9 End-Of-Treatment Visit.................................................................................................. 58
6.10 Disease Progression Visit..............................................................................................58
6.11 Survival Follow-Up.......................................................................................................59
6.12 Study Completion..........................................................................................................59
6.13 Tumor Assessment........................................................................................................ 60
6.14 Clinical Laboratory Evaluations....................................................................................60
6.15 Vital Signs, Physical Examinations, and Other Safety Assessments............................62
6.15.1 Vital signs............................................................................................................ 62


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6.15.2 Height and weight................................................................................................ 64
6.1.5.3 Physical examinations.........................................................................................64
6.15.4 12-Lead ECG....................................................................................................... 65
6.15.5 Immunogenicity assessment.................................................................................66
6.15.6. Pharmacokinetics/pharmacodynamics................................................................ 66
6.15.6.1 Pharmacokinetics.............................................................................................. 66
6.15.6.2 Pharmacodynamics........................................................................................... 66
6.15.7 EGFR testing........................................................................................................66
7
STUDY ASSESSMENTS.................................................................................................... 68
7.1 Efficacy Assessment........................................................................................................68
7.1.1 Primary efficacy endpoint......................................................................................68
7.1.2 Secondary efficacy endpoints................................................................................ 68
7.2 Safety Assessments......................................................................................................... 69
7.2.1 Adverse events....................................................................................................... 69
7.2.1.5 Management and follow-up of adverse events............................................ 72
7.2.1.6 Adverse event of special interest and expedited reporting.......................... 72
7.2.1.7 Pregnancy.....................................................................................................73
7.2.1.8 Time limits of documenting and reporting AEs.......................................... 73
8
STATISTICS........................................................................................................................76
8.1 Sample Size Determination.............................................................................................76
8.2 Statistical Population.......................................................................................................76
8.3 General Principles for Statistical Analyses..................................................................... 77
8.4 Statistical Methods.......................................................................................................... 77
8.4.1 Adjustments for covariates.....................................................................................77
8.4.2 Managing dropouts and missing data.....................................................................77
8.4.3 Multi-center study..................................................................................................77
8.4.4 Multiple comparisons and adjustments to multiplicity..........................................77
8.5 Statistical Analyses..........................................................................................................78
8.5.1 Subject distribution................................................................................................ 78
8.5.2 Demographics and other baseline characteristics.................................................. 78
8.5.3 Compliance and drug exposure..............................................................................78


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8.5.4 Efficacy.................................................................................................................. 78
8.5.4.2 Secondary efficacy endpoints...................................................................... 79
8.5.4.3 Sensitivity analysis...................................................................................... 79
8.5.4.4 Antibody and efficacy analysis....................................................................79
8.5.5 Exploratory analysis...............................................................................................80
8.5.6 Interim analysis......................................................................................................80
8.5.7 Stratified analysis...................................................................................................80
8.5.8 Safety analysis........................................................................................................80
8.5.8.2 Laboratory tests............................................................................................80
8.5.8.3 ECG examinations.......................................................................................80
8.5.8.4 Vital signs, physical examinations, and other safety examinations.............81
8.5.8.5 Concomitant medications............................................................................ 81
9
QUALITY ASSURANCE AND QUALITY CONTROL.................................................81
9.1 Clinical Monitoring......................................................................................................... 81
9.2 Data Management/Coding...............................................................................................82
9.3 Audits and Inspections.................................................................................................... 83
10
ETHICS................................................................................................................................ 84
10.1 Independent Ethics Committee..................................................................................... 84
10.2 Implementation of Ethical Principles............................................................................84
10.3 Subject Information and Informed Consent.................................................................. 85
10.4 Protection of Subject Data.............................................................................................85
11
STUDY MANAGEMENT...................................................................................................86
11.1 Organizational Structure................................................................................................86
11.1.1 Independent review committee............................................................................ 86
11.2 Archiving of Study Documents.....................................................................................86
11.3 Access to Source Data/Documents................................................................................87
11.4 Protocol Revisions.........................................................................................................87
11.5 Investigator's Responsibilities.......................................................................................87
11.6 Study Termination.........................................................................................................88
11.7 Publishing Policies........................................................................................................ 88
11.8 Finance and Insurance...................................................................................................88


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12
REFERENCES.................................................................................................................... 89
13
APPENDIX...........................................................................................................................90
13.1 Appendix I.....................................................................................................................90
13.2 Appendix II....................................................................................................................91
13.3 APPENDIX 3................................................................................................................ 93
14
INVESTIGATOR SIGNATURE PAGE......................................................................... 107
LIST OF TABLES
Table 1. Schedule of follow-up visits............................................................................................10
Table 2. Hypertension severity grades and interventions in CTCAE v4.03..................................41
Table 3. Dose adjustments of paclitaxel and carboplatin (febrile neutropenia and
thrombocytopenia)...........................................................................................................44
Table 4. Dose adjustment of paclitaxel (hepatotoxicity)............................................................... 45
Table 5. Dose adjustment of paclitaxel (neurotoxicity).................................................................46
Table 6. Study drugs......................................................................................................................48
Table 7. Correlation between AEs and investigational drugs............................................................. 70
Table 8. Reporting and follow-up of adverse events.....................................................................74
Table 9. Organizational structure...................................................................................................86
LIST OF FIGURE
Figure 1. Study design schematic.................................................................................................. 29


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LIST OF ABBREVIATIONS AND DEFINITIONS
Abbreviations
Definitions
AE
Adverse event
AESI
Adverse event of special interest
ADA
Anti-drug antibody
ALT
Alanine aminotransferase
AUC
Area under the curve
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
CFDA
China Food and Drug Administration (now National Medical
Products Administration)
CQA
Clinical quality assurance
CR
Complete response
CRA
Clinical research associate
CRO
Contract research organization
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DCR
Disease control rate
DOR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data collection
EGFR
Epithelial growth factor receptor
FAS
Full analysis set
GCP
Good Clinical Practice
HBsAg
Hepatitis B surface antigen
HBV-DNA
Hepatitis B virus deoxyribonucleic acid
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Hazard ratio
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
INR
International normalized ratio
ITT
Intention-to-treat


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NCCN
National Comprehensive Cancer Network
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PK
Pharmacokinetics
PP
Per-protocol
PR
Partial response
PRES
Posterior Reversible Encephalopathy Syndrome
PTT
Partial thromboplastin time
SAE
Serious adverse event
SD
Stable disease
SOP
Standard operating procedure
SS
Safety set
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
VEGF
Vascular endothelial growth factor


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1 INTRODUCTION
1.1 Study Background
1.1.1 Disease background
Lung cancer has the highest incidence and mortality globally among all cancers. According to
the 2012 Global Cancer Statistics (GLOBOCAN 2012) published by International Agency for
Research on Cancer, there were approximately 1.8 million new lung cancer cases worldwide,
which accounted for 13% of the global newly-diagnosed cancers, and 58% of these cases
occurred in underdeveloped areas1. According to the data released by the National Central
Cancer Registry of China in 2015, lung cancer was the most prevalent malignancy in China in
2011, with about 650,000 new cases every year. Lung cancer was also the leading cause of death,
with about 520,000 deaths per year2. The limited clinical treatment of lung cancer is the main
reason for its poor prognosis. There is a huge demand for new types of lung cancer treatment
drugs.
Approximately 85–90% of lung cancers are non-small cell lung cancer (NSCLC) and patients
with NSCLC are usually in the advanced stages when diagnosed3. According to the Chinese
guidelines for the diagnosis and treatment of primary lung cancer, anatomic pulmonary resection
is the mainstay of treatment for early stage lung cancers4. However, despite surgery, some
patients develop distance metastases that eventually lead to death5. Surgery is not possible for
most patients with clearly diagnosed stage IIIB and IV as well as some patients with stage IIIA
NSCLC4. Comprehensive treatment based on systemic therapy is used to maximize patient
survival, control progressive disease, and improve the quality of life6.
In recent years, anti-tumor therapies have entered a new era with the emergency of targeted
drugs. Some of these targeted drugs have demonstrated satisfactory efficacy in the treatment of
advanced NSCLC. These targeted drugs include monoclonal antibodies and tyrosine kinase
inhibitors (TKIs), mostly targeting epidermal growth factor receptors (EGFRs) and vascular
endothelial growth factor (VEGF), such as bevacizumab, cetuximab, gefitinib, erlotinib, and
icotinib. Monoclonal antibodies have become the drugs of choice in various treatment guidelines
due to the good targeting ability, low drug resistance, and good patient tolerability. Bevacizumab
combination chemotherapy is a first-line therapy of NSCLC recommended by the National
Comprehensive Cancer Network (NCCN)7. Additionally, bevacizumab in combination with
paclitaxel/carboplatin has also been approved as the first-line therapy of unresectable advanced,
metastatic, or relapsed non-squamous NSCLC by China Food and Drug Administration (CFDA)
on Jul. 9, 20156.


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Compared with traditional chemotherapy that directly inhibit or kill tumor cells, anti-angiogenic
drugs have the following unique advantages8:

The targets are genetically stable vascular endothelial cells (VECs) rather than highly
heterogeneous tumor cells, thus leading to lower drug resistance;

The number of tumor-induced VECs is far less than that of tumor cells, and the efficacy
is preferable targeting on VECs and their cytokines;

Normal VECs are quiescent, whereas tumor VECs are active in proliferation. Anti-
angiogenic therapy targets activated cells and avoids damage to normal VECs, thus
leading to better targeting ability;

Anti-angiogenic therapy can normalize the tumor vessels and thereby reduce the
pressure in tumor tissues. This enhances the delivery of chemotherapeutic agents into
tumor tissues, thus increasing the efficacy of chemotherapy.
Angiogenesis is a basic biological characteristic of tumors. The growth of both solid and
hematologic tumors are depended on angiogenesis regardless of the nature of tumor cells.
Therefore, anti-angiogenic therapy is broad-spectrum and applicable to various tumors.
Bevacizumab is a recombinant humanized monoclonal antibody that selectively binds to human
VEGF and blocks its biological activity. Bevacizumab consists of a framework region of a
human antibody and a humanized murine antigen binding region that can inhibit the binding of
VEGF to its receptors on epithelial cells, Flt-1 and KDR. By blocking the activity of VEGF and
reducing tumor angiogenesis, tumor growth is inhibited9.
In a study conducted by the Estern Cooperative Oncology Group (ECOG), compared with
chemotherapy alone (paclitaxel/ carboplatin), bevacizumab in combination with paclitaxel/carboplatin
significantly increased the overall survival (OS) (median: 12.3 vs. 10.3 months), progression-free
survival (PFS) (median: 6.2 vs. 4.5 months), and overall response rate (ORR) (35% vs. 15%) in
patients with advanced, metastatic, or relapsed non-squamous NSCLC10. In another foreign
AVAiL study, different doses of bevacizumab (7 and 15 mg/kg) in combination with
chemotherapy (cisplatin and gemcitabine) and placebo combine with chemotherapy were
compared for the treatment of non-squamous NSCLC. The study found that the two
bevacizumab groups had significantly increased the PFS (median: 6.7 months (7.5 mg/kg
combination chemotherapy group) vs. 6.5 months (15 mg/kg combination chemotherapy group)
vs. 6.1 months (placebo combination chemotherapy group)) and the ORR (37.8% (7.5 mg/kg
combination chemotherapy group) vs. 34.6% (15 mg/kg combination chemotherapy group) vs.
21.6% (placebo combination chemotherapy group)) in patients with locally advanced, metastatic,
or relapsed non-squamous NSCLC11. In a BEYOND study conducted in China, compared with


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placebo in combination with paclitaxel/carboplatin, bevacizumab in combination with
paclitaxel/carboplatin significantly increase the PFS (median: 9.2 vs. 6.5 months), OS (median:
24.3 vs. 17.7 months), and the ORR (54% vs. 26%) in patients with advanced or relapsed non-
squamous NSCLC12.
In China, the antibodies and fusion proteins targeting VEGF are research hotspots. However,
since 2006, the clinical efficacies of various drugs have not been verified and no products have
been marketed. Considering the complexity of macromolecular drugs and the limitations of drug
development capability in China, advanced technologies in antibody development, production,
and quality control is required to develop high-quality VEGF inhibitors that are safe and
effective. IBI305 has showed high similarity to bevacizumab in various pharmaceutical and
nonclinical studies (refer to Investigator's Brochure [IB]). Besides, the efficacy and safety of
bevacizumab for treatment of locally advanced, metastatic or relapsed lung cancer have been
verified. The relevant domestic and external pivotal clinical studies are referable for the protocol
design of IBI305 clinical study. In summary, the clinical study of IBI305 for treatment of
NSCLC has a solid foundation and relatively low risks. The successful development of IBI305
indicates an additional first-line targeted drug for lung cancer in China, providing doctors and
patients with more therapeutic options.
1.1.2 Investigational drug
1.1.2.1 Description of investigational drug
IBI305 is a recombinant humanized anti-VEGF monoclonal antibody injection developed by
Innovent Biologics (Suzhou) Co., Ltd. (hereafter as sponsor) that specifically binds human
VEGF. The molecular weight of IBI305 is 149 KDa. IBI305 specifically binds to VEGF-A,
inhibits the binding of VEGF-A to VEGF-R1 and VEGF-R2, blocks the signaling pathways such
as PI3K/Akt/PKB and Ras-Raf-MEK-ERK. IBI305 also inhibits the growth, proliferation, and
migration of VECs and angiogenesis, decreases the vascular permeability, blocks blood supply to
tumor tissues, inhibits the proliferation and metastasis of tumor cells, and induces the apoptosis
of tumor cells, thereby generates anti-tumor effects. The main active ingredient is recombinant
humanized anti-VEGF monoclonal antibody and excipients include sodium acetate, sorbitol, and
polysorbate 8013. Refer to the Investigator's Brochure for the detailed structure and
physicochemical properties of IBI305.


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1.1.2.2 Preclinical studies
Pharmaceutical studies
The pharmaceutical studies showed that stability, primary structure, higher-order structure,
oligosaccharide distribution, charge variant, and product-related impurities of IBI305 are highly
similar to those of bevacizumab, and the process-related impurities meet the proposed
specification. Therefore, IBI305 is considered to have highly similar protein properties and
product quality to bevacizumab13.
Pharmacodynamic studies
In vitro and in vivo pharmacodynamic (PD) studies of IBI305 showed the following findings:
1)
Target: IBI305 displayed specifically high-affinity binding to recombinant human
VEGF-A with an affinity constant same as that of bevacizumab, indicating that IBI305,
the same as bevacizumab, is a specific human VEGF blocker with a clear target.
2)
Specificity: IBI305 displayed specifically high-affinity binding to recombinant human
VEGF-A, medium-affinity binding to canine VEGF-A, but low-affinity binding to
human VEGF-B, VEGF-C, VEGF-D, PlGF, suggesting that IBI305 recognizes specific
targets and has low off-target toxicity risk; no obvious affinity to mouse VEGF-A164
and rat VEGF-A164, suggesting that IBI305 has high species specificity.
3)
Mechanism of action: IBI305 specifically binds to VEGF-A and inhibits the activation
of VEGFR-2 and ERK1/2, blocks the proliferation and migration of HUVEC, and
inhibits the sprouting from rat aortic ring, suggesting that IBI305 antagonizes VEGF-
A-induced signaling pathway to block the proliferation and migration of VECs and
inhibit angiogenesis, which leads to the reduction of nutritional supply and metastasis
of tumor.
4)
Anti-tumor effects: IBI305 significantly inhibits the growth of human colon cancer
Ls174t and lung cancer NCI-H460 cells in xenografts in nude mice, indicating that
IBI305 has significant anti-tumor effects.
Results from in vitro and in vivo studies of IBI305 showed highly similarity with that of
bevacizumab designed simultaneously, demonstrating that the target, mechanism of action,
and anti-tumor effects of IBI305 are highly similar to bevacizumab13.


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Pharmacokinetic studies
In vitro and in vivo pharmacokinetic (PK) studies of IBI305 showed the following findings:
1)
IBI305 showed no significant cross-reactivity with normal human tissues and
cynomolgus monkey tissues, and only cross-reacted with the positive-control. i.e.
human angiosarcoma tissue, suggesting that IBI305 is highly specific to cancer tissues
rather than normal human tissues and has very low on-target toxicity.
2)
Linearity: With single dose or repeated doses of IBI305 (2-50 mg/kg) vis intravenous
injection in cynomolgus monkeys, the test showed significant PK, thus reducing the
suddenly rising toxicity risks with increased clinical doses.
3)
Immunogenicity: With single dose or repeated doses of IBI305 or bevacizumab via
intravenous injection in cynomolgus monkeys, the test showed abnormal changes of
drug concentration-time curves in several animals. The anti-drug antibody (ADA) test
results showed that IBI305 has a medium immunogenicity.
4)
Accumulation: With repeated doses of IBI305 or bevacizumab via intravenous
injection in cynomolgus monkeys, the test showed that drug exposure of the last
dose was significantly higher than that of the first dose, and the steady-state drug
concentration after repeated doses was higher than that after a single dose, suggesting
that the drug may be accumulated in body.
The results of tissue cross-reactivity and PK/toxicokinetic studies in cynomolgus monkeys
indicated that IBI305 and bevacizumab have similar characteristics in tissue cross-reactivity and
PK/toxicokinetics13.
Toxicological studies
Toxicological studies of IBI305 showed the following findings:
1)
Single dose: With single dose of IBI305 (up to 300 mg/kg) via intravenous injection in
cynomolgus monkeys, the test showed good tolerability without any abnormal clinical
symptoms and toxicity. The dose was about 48 times the proposed clinical dose for
human based on body surface area. In the safety pharmacology test, with single dose of
IBI305 (50 mg/kg) via intravenous injection in cynomolgus monkeys, the test showed
no significant effects on the central nervous system, respiratory system, and
cardiovascular system, suggesting that the single dose of IBI305 via intravenous
injection has a high safety.


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2)
Repeated doses: With repeated doses of IBI305 (up to 50 mg/kg) via intravenous
injection twice weekly for 9 consecutive doses in cynomolgus monkeys, equivalent to
20 times the proposed clinical dose for humans (based on the weight), the test showed
extremely mild to mild linear growth arrest of metaphyseal lines at knee joint and
disordered chondrocyte proliferation, extremely mild increases in macrophage count
in white pulp of spleen, pulmonary (including bronchial) hemorrhage, and deposits of
hemosiderin in lymphoid tissue of bronchial mucosa, indicating that the target organ
toxicities are mainly in the bone, spleen, and lungs.
3)
Immunotoxicity and immunogenicity: With repeated doses of IBI305 via intravenous
injection twice weekly for 9 consecutive doses in cynomolgus monkeys, the test
showed medium immunotoxicity to the spleen. Different doses of IBI305 may result in
the production of ADAs, a portion of which are neutralizing antibodies (NAbs),
indicating that IBI305 has medium immunotoxicity and immunogenicity.
4)
Local irritation test: With repeated dose of IBI305 via intravenous injection in
cynomolgus monkeys, the test showed no irritation at the injection site, suggesting that
administration of IBI305 via intravenous injection is safe and feasible.
5)
In vitro hemolysis assay: With maximum proposed clinical concentration of IBI305
(9 mg/mL), the assay showed no hemolysis, suggesting that IBI305 is suitable for
intravenous injection.
IBI305 has high similarity with bevacizumab in safety pharmacology, long-term toxicity,
immunotoxicity, immunogenicity, local irritation, and hemolysis13.
1.2 Study Principles and Risk/Benefit Assessment
1.2.1 Study principles and dose selection
A biosimilar drug refers to a therapeutic biological product that is similar in quality, safety and
efficacy with an approved reference drug14. IBI305, developed and sold in the market by the
sponsor, is a bevacizumab biosimilar, and has the same administration method and indications
as bevacizumab.


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This study is conducted in accordance with the "Guidelines on Development and Evaluation of
Bosimilars (for Trial Version)" issued by the NMPA (formerly CFDA)14. The doses of IBI305
selected in this study are based on the preclinical studies that showed highly similarity between
IBI305 and bevacizumab in pharmacology, PD, PK and toxicology (refer to the Investigator's
Brochure for details). Besides, the efficacy and safety of bevacizumab for treatment of advanced,
metastatic or relapsed non-squamous NSCLC have been verified, and the indications have also
been approved in China. Therefore, the dose and administration of IBI305 is similar to
bevacizumab in this study, that is, 15 mg/kg intravenously on D1 of every 3-week cycle
when used in combination with chemotherapy (paclitaxel and carboplatin). In the subsequent
maintenance monotherapy therapy, IBI305 will be given intravenously at a dose of 7.5 mg/kg on
the first day of every 3-week cycle. This design of this study is to further demonstrate that
IBI305 is similar to bevacizumab in clinical efficacy, safety, and immunogenicity in subjects
with advanced, metastatic or relapsed non-squamous NSCLC.
1.2.2 Risk/benefit assessment
IBI305 is a bevacizumab biosimilar developed by the sponsor. Based on the clinical pharmacology
and toxicology characteristics of IBI305, the risks and benefits of IBI305 are expected to be similar
to bevacizumab.
The treatment-related risks of bevacizumab are detailed in its prescribing information. This study
is the first human study of IBI305 so that unexpected adverse reactions will be possible. The
design of this study ensures the minimized subject risks by close monitoring of the adverse
events (AEs) before, during, and after the infusion of the investigational drugs. Once an adverse
reaction occurs, the investigator will immediately take appropriate action for the subject safety.
The platinum-based therapy is the standard first-line regimen of advanced NSCLC4. This study
uses the combination of paclitaxel/carboplatin, ensuring the basic anti-tumor therapy for subjects.


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2 STUDY OBJECTIVES
2.1 Primary Objective
The primary objective of this study is to compare the objective response rate (ORR) of IBI305
plus paclitaxel/carboplatin versus bevacizumab plus paclitaxel/carboplatin for the treatment of
advanced or relapsed non-squamous NSCLC.
2.2 Secondary Objectives
Secondary objectives include:

To compare the duration of response (DOR), progression-free survival (PFS), disease
control rate (DCR), and overall survival (OS) in subjects with advanced or relapsed
non-squamous NSCLC treated by IBI305 plus paclitaxel/carboplatin versus
bevacizumab plus paclitaxel/carboplatin

To compare the safety and immunogenicity of IBI305 plus paclitaxel/carboplatin
versus bevacizumab plus paclitaxel/carboplatin for the treatment of advanced or
relapsed non-squamous NSCLC
2.3 Exploratory Objectives

To compare the population pharmacokinetics (PPK) characteristics of IBI305 and
bevacizumab in subjects with advanced or relapsed non-squamous NSCLC

To compare the pharmacodynamics (PD) characteristics of IBI305 and bevacizumab in
subjects with advanced or relapsed non-squamous NSCLC


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3 STUDY PLAN
3.1 Overview of Study Design
This is a randomized, double-blind, active-controlled, and multi-center phase III study. A total of
436 subjects across 35 study sites with non-squamous NSCLC will be planned, randomized in a
1:1 ratio into the IBI305 plus paclitaxel/carboplatin group or bevacizumab plus paclitaxel/carboplatin
group, and stratified according to age (< 60 vs. ≥60 years old) and epidermal growth factor
receptor (EGFR) status (wild type vs. unknown type). Each treatment cycle is 3 weeks for both
groups. 15 mg/kg IBI305 or bevacizumab is administered on D1 of each cycle along with
paclitaxel/carboplatin. Subjects will receive up to 6 treatment cycles of combination therapy until
PD, unacceptable toxicity, withdrawal of informed consent, loss of follow-up, or death
(whichever comes first). Then subjects received maintenance monotherapy, that is, discontinuing
paclitaxel/carboplatin while continuing maintenance therapy with IBI305 or bevacizumab. The
maintenance monotherapy continues every 3 weeks. On D1 of each treatment cycle, subjects will
be administered 7.5 mg/kg of either IBI305 or bevacizumab until PD, unacceptable toxicity,
withdrawal of informed consent, lost to follow-up, death, or end of study (whichever comes first).
After discontinuing the study drug, subjects will return to the study site 28 days (± 7 days) after
the last dose for an end-of-treatment visit. If the subjects discontinue the study treatment for
reasons other than PD, subsequent follow-up will be continued until PD, withdrawal of informed
consent, start of other anti-tumor therapies, loss of follow-up, death, or end of study. If the
subjects discontinue the study treatment for PD, the investigator will make telephone follow-up
every 12 weeks (± 7 days) to collect information of subsequent anti-tumor therapies and survival.
A CT or an MRI will be performed every 6 weeks (± 7 days) until PD, withdrawal of informed
consent, start of other anti-tumor therapies, loss of follow-up, death, or end of study. The method
for subsequent imaging examination should be consistent with that at baseline, and the chest,
abdomen and pelvis of the subject must be scanned. Each assessment must be completed within
7 days from the most recent visit. The investigators then perform the evaluation based on the
RECIST v1.1 criteria to determine whether the subject can continue receiving the next cycle of
treatment. Furthermore, the independent tumor evaluation committee (Section 11.1.1) will also
evaluate tumor response according to the RECIST v1.1. If the subjects discontinue the study
treatment for reasons other than PD, subsequent tumor evaluation should be continued according
to the study procedures until PD, withdrawal of informed consent, start of other anti-tumor
therapies, loss of follow-up, death or, end of study.
The study design is shown in Figure 1.


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Figure 1. Study design schematic
3.2 Study Design Discussion
This is a randomized, double-blind study, and bias in treatment groups is avoided. Furthermore,
the CT/MRI images of each subject will be evaluated by an independent tumor evaluation committee
according to the RECIST v1.1 to ensure consistency in evaluation.
Screening
period
Combination therapy (once every 3 weeks)
IBI305 or bevacizumab plus
Paclitaxel + carboplatin
Follow-
up
Monotherapy
(once every 3 weeks) IBI305 or
Bevacizumab
End-of-treatment visit
(28 days (±7 days) after
last dose)
Cycle n
D-28
to
D-1
Cycle 1
randomiz
ation
(D1)
Cycle 2
Cycle 3
Cycle 6
Cycle 7
Post-treatment follow-up


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4 STUDY POPULATION
4.1 Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be enrolled in the study:
1)
Sign the informed consent form
2)
Male or female ≥18 and ≤75 years old
3)
Histologically or cytologically confirmed unresectable locoregionally advanced (stage
IIIB), metastatic (stage IV), or relapsed non-squamous NSCLC; mixed tumors should
be categorized according to the main cell types
4)
Histologically or cytologically confirmed EGFR wild type or non-sensitive mutation
type
5)
Must have at least one measurable target lesion (as per RECIST 1.1)
6)
Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0–1
7)
Expected survival ≥6 months
8)
Laboratory results during screening:
a)
Routine blood test: WBC ≥3.0 × 109/L, ANC ≥1.5 × 109/L, platelets ≥100 × 109/L,
and hemoglobin ≥90 g/L
b)
Hepatic function: TBIL < 1.5 × ULN; ALT and AST < 2.5 × ULN for subjects
without liver metastasis, or ALT and AST < 5 × ULN for subjects with liver
metastasis
c)
Renal function: SCr ≤1.5 × ULN or CrCl ≥50 mL/min, and urine protein < 2+ in
routine urinalysis. Subjects with urine protein ≥2+ at baseline urinalysis must
have undergone 24 h urine collection with total protein content < 1 g
d)
INR ≤1.5 and PTT or aPTT ≤1.5 × ULN within 7 days prior to the study treatment
9)
Able to comply with study protocol
10) Female and male subjects of childbearing age, and partners of these male subjects must
agree to use effective contraceptive measures (such as abstinence, sterilization, oral
contraceptives, medroxyprogesterone injections or contraceptive implants) during the
study and for 6 months after the infusion of the study drug


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4.2 Exclusion Criteria
Subjects meeting any of the followings are not enrolled in the study:
1)
Prior systemic chemotherapy or targeted therapy (such as monoclonal antibody or
tyrosine kinase inhibitor) for the treatment of the current stage of disease (Stage IIIB
not suitable for multidisciplinary treatment, stage IV or relapsed disease). Prior surgery
and radiotherapy are permitted, provided that the criteria outlined in the study protocol
are met. Subjects who received prior adjuvant therapy and relapsed within 6 months are
not eligible
2)
Mixed non-small cell and small cell carcinoma, or mixed adenosquamous carcinoma
predominantly containing squamous cell carcinoma component
3)
Histologically or cytologically confirmed EGFR-sensitive mutation type (including
exon 18 point mutation (G719X), exon 19 deletion, and exon 21 point mutations
(L858R and L861Q)). Subjects with unknown EGFR status for various reasons might
enroll.
4)
History of hemoptysis within 3 months prior to screening, with a volume of blood
greater than 2.5 mL each time
5)
Radiographic evidence of tumor invasion in great vessels. The investigator or the
radiologist must exclude subjects with tumors that are fully contiguous with,
surrounding, or extending into the lumen of a great vessel (such as pulmonary artery or
superior vena cava)
6)
Symptomatic CNS metastasis; subjects with asymptomatic brain metastasis or subjects
who are symptomatically stable after treatment for brain metastasis might enroll if the
following criteria are met: measurable lesions outside the CNS; no midbrain, pons,
cerebellum, medulla or spinal cord metastasis; no history of intracranial hemorrhage;
7)
Subjects who received radical thoracic radiation therapy within 28 days prior to
enrollment; subjects who received palliative radiation for non-thoracic bone lesions
within 2 weeks prior to the first dose of the study drug
8)
Subjects with severe skin ulcers or fracture, or having major surgery within 28 days
prior to randomization or expecting to have major surgery during the study
9)
Subjects who received minor surgery within 48 hours prior to the first dose of the study
treatment (Outpatient/inpatient surgery requiring locoregional anesthetics, including
central line insertion)


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10) Currently or recently (within 10 days prior to the first dose of the study treatment) used
aspirin (> 325 mg/day) or other known NSAIDs to inhibit platelet function for 10
consecutive days
11) Currently or recently (within 10 days prior to the first dose of the study treatment)
received treatment with full dose oral or parenteral anticoagulant or thrombolytic
agents for 10 consecutive days. However, anticoagulants for prophylaxis are accepted
12) Subjects with inherited hemorrhagic tendency or coagulopathy, or history of thrombosis
13) Uncontrolled hypertension (systolic greater than 140 mmHg and/or diastolic greater
than 90 mmHg), history of hypertensive crisis or hypertensive encephalopathy
14) Any unstable systemic disease including but not limited to: active infection, unstable
angina, cerebrovascular accident or transient cerebral ischemia (within 6 months prior
to screening), myocardial infarction (within 6 months prior to screening), cardiac
failure congestive (NYHA Class ≥II), severe arrhythmia requiring medication, and
liver, kidney or metabolic disease
15) History of the following diseases within 6 months prior to screening: gastrointestinal
ulcers, gastrointestinal perforation, corrosive esophagitis or gastritis, inflammatory
bowel disease or diverticulitis, abdominal fistula, or intra-abdominal abscess
16) Subjects with tracheoesophageal fistula
17) Clinically significant third spacing (such as ascites or pleural effusion that are
uncontrollable by drainage or other treatments)
18) Subjects with current interstitial lung disease or CT showing active pneumonia during
screening;
19) History of malignant tumors other than NSCLC within 5 years prior to randomization,
except for adequately treated cervical carcinoma in situ, basal or squamous cell skin
cancer, locoregional prostate cancer after radical surgery, ductal carcinoma in situ after
radical surgery, or papillary thyroid carcinoma
20) Subjects with active autoimmune disease
21) Subjects who were HBsAg-positive, and peripheral blood HBV DNA titer ≥1 × 103
copies/L or ≥200 IU/mL; subjects who were HBsAg-positive and peripheral blood
HBV DNA titer < 1 × 103 copies/L or < 200 IU/mL might be eligible if the investigator
determined that the subject's chronic hepatitis B infection was stable and participation
in the study would add no further risks to the subject


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22) Subjects who are tested positive for HCV antibody, HIV antibody or syphilis
23) Subjects with known history of allergic diseases or allergic physique
24) Received treatment with other investigational drugs or participated in another
interventional study within 30 days prior to screening
25) History of alcohol or drug abuse
26) Female subjects who are pregnant or breastfeeding, or expected to be pregnant or
breastfeeding during the study
27) Known allergies to bevacizumab or any of its excipients, or any chemotherapeutic
agents
28) Other conditions unsuitable for the inclusion as determined by the investigator
4.3 Screening Failure
Screening failure is that the subject who has signed the informed consent form fails to meet the
inclusion criteria. Subjects with screening failure will not get a randomization number. The
reasons of screening failure will be documented in the electronic case report forms (eCRFs).
4.4 Subject Restrictions
Female subjects of childbearing age must take effective contraceptive measures during the study
and 6 months after the last dose.
Male subjects must take effective contraceptive measures during the study and 6 months after the
last dose to avoid the pregnancy of their partners.
Restrictions on the use of medication during the study are shown in Section 5.9.
4.5 Subject Withdrawal and Replacement
All subjects may withdraw from this study at any time, with or without a reason. Subjects who
withdraw from the study will not be subjected to discrimination or retaliation, and their medical
treatment will not be affected.
Subjects may discontinue the study treatment or withdraw from the study under the following
circumstances:

Unacceptable toxicity

Progressive disease


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
Investigator believes that the subject should withdraw from the study. If an unacceptable
adverse event (AE) occurs and the investigator believes that the subject should
withdraw from the study, the study treatment should be discontinued and appropriate
measures should be taken. In addition, the sponsor or personnel designated by the
sponsor should be notified.

Withdrawal of informed consent form by the subject

Serious protocol deviation determined by the investigator and/or sponsor

Poor protocol compliance

Study termination by the investigator or sponsor for any reason

Enrollment error* (enrollment of subjects who have violated the inclusion/exclusion
criteria)

Use of prohibited concomitant medications or other medications that the investigator
believes that it may result in toxicities or may affect study results

Subject lost to follow-up

Death of subject
* If the subject is determined by the investigator and the sponsor's doctor to be medically suitable
to continue with the study drugs without any risk or inconvenience, the mistakenly enrolled or
randomized subject will continue with the study treatment and assessments.
In any cases, reasons for withdrawal must be documented in the eCRFs. If the subject withdraws
from the study prematurely for any reason, the investigator should make every effort to persuade
the subject to receive the corresponding assessment, and continue the follow-up of all unresolved
AEs based on the AE reports and follow-up requirements (Table 2):

If the subject withdraws during the study, the series of assessments listed under the End
of Treatment Visit (Section 6.9) should be performed

If the subject withdraws after the end of the treatment visit and has not experienced PD,
the series of assessments listed under the Follow-Up for PD (Section 6.10) should be
performed (tumor assessment is not required to be repeated if it has been performed
within 6 weeks prior to this follow-up)

If the subject withdraws during the follow-up for survival, the information of subsequent
anti-tumor therapies and survival should be collected by telephone follow-up only


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Subjects who withdraw their informed consent are not to be contacted again unless they clearly
indicate the willingness to be contacted. The sponsor may use the clinical study data obtained
before the withdrawal of informed consent.
Subjects who have been randomized will not be replaced.


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5 STUDY TREATMENT
5.1 Therapies by Study Drugs
The study drugs of this study are IBI305 and bevacizumab.
In this study, the dose of IBI305 or bevacizumab during combination therapy with chemotherapy
is 15 mg/kg, while the dose during maintenance monotherapy is 7.5 mg/kg. The study drugs are
administered intravenously on D1 of each 3-week cycle until PD, unacceptable toxicity,
withdrawal of informed consent, loss to follow-up, death, or end of study (whichever comes first).
The duration of the first dose of IBI305 or bevacizumab should be 90 min (± 15 min). If the
first infusion is well-tolerated by the subject, then the duration of the second infusion can be
shortened to 60 min (± 15 min). If the 60 min infusion is also well-tolerated by the subject, then
the subsequent infusions can be completed within 30 min (± 15 min).
5.2 Chemotherapy
Paclitaxel will be administered after the IBI305 or bevacizumab infusion is completed, then
followed by carboplatin:
Paclitaxel: 175 mg/m² administered via intravenous infusion for 3 h (may be adjusted according
to clinical practice of each study site) on D1 of every 3-week cycle for up to 6 cycles until PD,
unacceptable toxicity, withdrawal of informed consent, loss of follow-up, or death.
Carboplatin: AUC 6.0, the infusion time is based on the standard practice of each study site,
administered on D1 of every 3-week cycle for up to 6 cycles until PD, unacceptable toxicity,
withdrawal of informed consent, loss of follow-up, or death.
The chemotherapeutic agents are supplied by the sponsor.
Formulas for calculating surface area, creatinine clearance and carboplatin dose are shown in
Section 13.2.
5.3 Dose Adjustment of Each Study Drug
5.3.1 General principles
The reasons for dose adjustments or delayed administration, measures taken, and
results should be documented in the medical records and eCRFs


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If the concomitant symptoms exist at baseline, the investigator will determine whether
the dose should be adjusted according to the change in severity of toxicity. For example,
if the subject has Grade 1 "weakness" at baseline and Grade 2 "weakness" during the
study treatment, the dose should be adjusted based on Grade 1 toxicity since the
severity has increased by one grade
If several toxic reactions of different grades or severity occur simultaneously, the dose
will be adjusted according to the highest observed grade/severity
If a dose adjustment is required solely due to abnormal lab test results, then the dose
should be adjusted based on the measured values obtained prior to the start of the
treatment cycle
If the investigator determines that the toxicity is unlikely to further develop into a
serious or life-threatening event, the current dose will be continued without any
adjustments or treatment interruptions. In addition, dose adjustments or treatment
interruptions will not be performed for non-hemolytic anemia as the symptoms can be
alleviated through blood transfusions.
If the investigator determines that a toxicity is caused by a specific therapeutic drug,
then the dose adjustments of other drugs are not required
Discontinuation of one or two therapeutic drugs before PD will not affect the continued
treatment with other drugs
Dose reductions or adjustments of IBI305 or bevacizumab are not permitted.
Subsequent therapeutic dose will not be adjusted according to weight change, unless
the subject weight has changed by ≥10% from baseline
Once the dose of any chemotherapeutic agents is reduced, the original dose should no
longer be adopted
If any but not all of the therapeutic drug (IBI305, bevacizumab or chemotherapeutic
agents) treatments is interrupted due to toxicity, then this treatment will be considered
as a treatment cycle
If the administration of any one of the chemotherapeutic agents is delayed for more
than 3 weeks, the subject should permanently discontinue that chemotherapeutic agent


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If IBI305/bevacizumab is continued/infused after a delay for more than 3 weeks, the
investigator must discuss with the sponsor


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5.3.2 Dose adjustments of study drugs
Dose adjustments of IBI305 or bevacizumab are not permitted except for the adjustments
(adjusted to 7.5 mg/kg for maintenance monotherapy) specified in the study protocol. The dose
of IBI305 or bevacizumab is calculated according to the subject weight at baseline (prior to the
first dose), and remains unchanged throughout the study, unless the subject weight has changed
by ≥10% from baseline.
If an infusion reaction occurs during a 60-minute infusion, the infusion time should be extended
to 90 minutes for all subsequent infusions. Likewise, if an infusion reaction occurs during a 30-
minute infusion, the infusion time should be extended to 60 minutes for all subsequent infusions.
IBI305 or bevacizumab in combination with paclitaxel/carboplatin will be administered every
3-week treatment cycle for 6 cycles. If PD is not observed in subject during treatment, then the
subject will continue to receive IBI305 or bevacizumab as maintenance monotherapy every 3-
week treatment cycle until PD, unacceptable toxicity, withdrawal of informed consent, loss of
follow-up, death, or end of study (whichever comes first).
If IBI305 or bevacizumab is permanently discontinued due to unacceptable toxicity or subject
refusal to continue the study drugs during the combination therapy, then the subject will continue
to receive the chemotherapy (paclitaxel/carboplatin) until 6 treatment cycles are completed as
determined by the investigator. If any one of the chemotherapeutic agents (paclitaxel or carboplatin)
is prematurely discontinued due to unacceptable toxicity, the subject can continue to receive
IBI305 or bevacizumab treatment until PD, unacceptable toxicity, withdrawal of informed
consent, loss of follow-up, or death (whichever comes first).
When a Grade 3 or 4 IBI305- or bevacizumab-related toxicity is observed, the investigators
should determine whether to continue or terminate IBI305 or bevacizumab treatment according
to the followings:
First occurrence:
IBI305 or bevacizumab administration should be interrupted until toxicity symptoms return to
baseline level or are at least reduced to the Common Terminology Criteria for Adverse Events
(CTCAE) Grade 1 or lower (except for the special circumstances listed below)
Note that when Grade 4 febrile neutropenia and/or thrombocytopenia occur(s), IBI305
or bevacizumab administration should be interrupted until the symptoms return to
baseline levels or at least reduced to CTCAE Grade 1 or lower, since these events
increase the risk of hemorrhage.


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Re-occurrence in re-administration:
If Grade 3 IBI305- or bevacizumab-related toxicity occurs again, the investigator
should assess the risk/benefit of study drug continuation for the subject. If such toxicity
re-occurs again after re-administration, IBI305 or bevacizumab should be permanently
discontinued
If Grade 4 IBI305- or bevacizumab-related toxicity occurs again, IBI305 or
bevacizumab should be permanently discontinued
Measures should be taken in the following special circumstances (classified based on CTCAE
version 4.03):
Hemorrhage
Subjects with Grade 3 or 4 hemorrhages should be treated accordingly and permanently
discontinue the study treatment
Thrombosis/embolism

Subjects with arterial thrombosis of any severity grades should permanently
discontinue the study treatment

Subjects with Grade 4 venous thrombosis should permanently discontinue the
study treatment

Subjects with Grade 3 venous thrombosis should interrupt the study treatment. If
the anticoagulant therapy at the planned therapeutic dose is < 2 weeks, the study
treatment should be interrupted until the anticoagulant therapy is completed. If
the anticoagulant therapy at the planned therapeutic dose is > 2 weeks, IBI305
or bevacizumab administration should be interrupted for 2 weeks, and the study
treatment can be restarted during the anticoagulant therapy if the following criteria
are met:
- INR is within the target range (usually 2-3) prior to restarting of study treatment
- Subjects must not have experienced Grade 3 or 4 hemorrhage since enrollment
- No signs of great vessel invasion or adjacency to great vessels from previous
tumor assessments
Note: Therapeutic dose of anticoagulant therapy is defined as the escalating dose of
warfarin or other anticogulants until INR is maintained at no less than 1.5 (usually


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2-3). The warfarin dose should be documented in the eCRFs, and the INR of
subjects receiving anticoagulant therapy should be monitored during the treatment.
Hypertension
BP should be measured frequently to monitor the occurrence and exacerbation of hypertension.
Subjects should remain at resting position for at least 5 min before BP measurement.
Definition of hypertension: pathologically increased BP with repeated measurements persistently
over 140/90 mmHg
Table 2. Hypertension severity grades and interventions in CTCAE v4.03
CTCAE
Interventions
Grade 1
Pre-hypertension (systolic blood pressure of
120–139 mmHg, diastolic blood pressure of 80–
89 mmHg)
Intervention not indicated
Grade 2
First-stage hypertension (systolic blood pressure
of 140–159 mmHg, diastolic blood pressure of
90–99
mmHg;
repeated
or
persistent
hypertension of ≥24 h), a symptomatic increase
of > 20 mmHg in systolic blood pressure, or an
increase of > 140/90 mmHg from the previous
normal range
Antihypertensive
monotherapy.
drug interruption. The treatment
with the investigational product can
be
continued
once
the
blood
pressure
is
lower
than
140/90
mmHg.
Grade 3
Second-stage
hypertension
(systolic
blood
pressure of ≥160 mmHg, diastolic blood
pressure of ≥100 mmHg)
Multiple-agent
antihypertensive
therapy. Study treatment should be
interrupted in case of persistent or
symptomatic
hypertension;
study
treatment should be permanently
discontinued
for
uncontrollable
hypertension.
Grade 4
Life-threatening consequences (e.g. malignant
hypertension, transient or permanent
neurological deficit, and hypertensive crisis)
Urgent intervention and permanent
study
treatment
discontinuation
indicated
The dose of antihypertensive agents used should be documented during each visit. If the subject
remains hypertensive despite treatment discontinuation, BP and antihypertensive agents used
should be monitored every 3 months until BP returns to normal or end of study.


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Posterior reversible encephalopathy syndrome (PRES)
There have been a few reports of subjects with signs and symptoms consistent with PRES after
study treatment. This is a rare neurological disease and its signs and symptoms include epilepsy,
headache, altered mental status, visual impairment, or cortical blindness, with or without
hypertension. Subjects with PRES should permanently discontinue the study treatment.
Proteinuria
Urinalysis should be performed prior to each dose of IBI305/bevacizumab unless a 24-hour
urinary protein test has already been done.
First occurrence of proteinuria:
After carrying out the urinalysis, if:
Urine protein is < 2+, continue study treatment as scheduled, no additional tests are
required.
≥2+ (urinalysis): perform 24-hour urinary protein test within 3 days prior to
administration:
•
24-hour urinary protein ≤2 g: continue study treatment as scheduled. and perform
urinalysis dipstick test before each scheduled dose.
•
24-hour urinary protein > 2 g: delay study treatment until 24-hour urinary protein ≤2 g.
and a 24-h urine protein test prior to each subsequent dose is performed until urine protein is
reduced to ≤1 g/24 h. Interrupt study treatment only when 24 h urine protein is > 2 g.
Second and subsequent occurrence of proteinuria:
< 3+ (urinalysis): continue study treatment as scheduled, no additional tests indicated.
≥3+ (urinalysis): perform 24-hour urinary protein test within 3 days prior to
administration:
• 24-hour urinary protein ≤2 g: continue study treatment as scheduled.
• 24-hour urinary protein > 2 g: delay study treatment until 24-hour urinary protein ≤2 g.
and a 24-h urine protein test prior to each subsequent dose is performed until urine protein is
reduced to ≤1 g/24 h. Interrupt study treatment only when 24 h urine protein is > 2 g.
Nephrotic syndrome (Grade 4): Study treatment is permanently discontinued
Gastrointestinal perforation


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If gastrointestinal perforation occurs, appropriate measures should be taken and the study
treatment should be permanently discontinued.
Wound healing complications
The study treatment should not begin within 28 d after a major surgery, or before the surgical
wound is fully healed. If a complication of wound healing occurs during study treatment, the
study treatment should be interrupted until the wound is fully healed. If an elective surgery is
required, the study treatment should be interrupted.
Abdominal abscess or fistula
If abdominal abscess or fistula occurs, the study treatment should be discontinued. However, the
investigator will determine whether study treatment will be continued if the above AE is resolved.
Infusion-related and allergic reactions:
Infusion-related reactions after first dose of the study drug is uncommon (< 3%), and the incidence
of a severe reaction is only 0.2%.
If a mild (grade 1 or 2) reaction (such as fever, chills, headache, and nausea) occurs, pretreatment
prior to subsequent administration should be performed and infusion time should not be reduced.
If the subject is well-tolerated during infusion after pretreatment, the infusion time can be
reduced by 30 minutes (+10 minutes) for subsequent administration with pretreatment. If an
infusion-related AE occurs during a 60-minute infusion, the subsequent infusion should be
completed within 90 minutes (+15 minutes) with pretreatment. Likewise, if an infusion-related
AE occurs during a 30-minute infusion, the subsequent infusion should be completed in 60 minutes
(+10 minutes) with pretreatment. If a subject has a grade 3 infusion-related reaction, the study
treatment should be interrupted and not be restarted on the same day. However, since there lacks
the dose adjustment method for grade 3 infusion-related reactions, the investigators may decide
to either discontinue the study drug or perform pretreatment, and complete the infusion within
90 minutes (+15 minutes). If an adverse reaction still occurs during a 90-minute infusion, the
infusion should be continued at a slower rate and then gradually returned to a 90-minute infusion.
If the investigator is uncertain about the handling, the study treatment should be discontinued.
When the study treatment is restarted, the subject should be closely monitored based on routine
clinical practice until the possible time of adverse reaction has passed. If a subject has a grade 4
infusion-related reaction, the study treatment should be discontinued.
An allergic reaction is defined as the vascular collapse or shock (systolic BP < 90 mmHg,
unresponsive to rehydration) that occurs within 30 minutes of a study drug infusion caused by
an allergy, with or without respiratory distress. Skin reactions include pruritus, urticaria, and
angioedema. Subjects with allergic reactions should discontinue the study treatment.


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5.3.3 Dose adjustments of chemotherapy
Paclitaxel and carboplatin should be administered according to the study site guidelines and local
prescribing information. For the specific information for use, preparation, and storage of
paclitaxel and carboplatin, refer to the prescribing information and local dosing information.
Carboplatin-based chemotherapies have a relatively high incidence of emesis. Therefore,
antiemetics for prophylaxis can be used.
Hematological toxicity:
Absolute neutrophil count (ANC; dose can only be reduced when febrile neutropenia occurs.
ANC must be ≥1.5 × 109/L and platelet count must be ≥100 × 109/L on D1 of each treatment
cycle). Once the chemotherapeutic dose is reduced due to febrile neutropenia or
thrombocytopenia (platelet count < 25 × 109/L or 50 × 109/L with hemorrhage or blood
transfusion required), the original dose should no longer be adopted. If the dose reduction is
required for the third time, the chemotherapy should be immediately discontinued.
Table 3. Dose adjustments of paclitaxel and carboplatin (febrile neutropenia and
thrombocytopenia)
Dose Adjustments of Paclitaxel/Carboplatin
First Occurrence Re-Occurrence After
Dose Adjustment
Re-occurrence After Two Dose
Adjustments
Febrile neutropenia
(regardless of duration)
Paclitaxel = 150 mg/m2
Carboplatin = AUC 4.5
Paclitaxel = 100 mg/m2
Carboplatin = AUC 3
Chemotherapy discontinuation
Lowest Level After
Last Dose
<25 × 109/L or
<50 × 109/L with
hemorrhage or requires
blood transfusion
Paclitaxel = 150 mg/m2
Carboplatin = AUC 4.5
Paclitaxel = 100 mg/m2
Carboplatin = AUC 3
Chemotherapy discontinuation
If the dose adjustment is required when ANC and thrombocytopenia occur concurrently, the low-
dose chemotherapy should be adopted.


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Chemotherapy may be delayed for up to 3 weeks. If after the chemotherapy has been delayed for
3 weeks, ANC does not reach ≥1.5 × 109/L and platelet count does not reach ≥100 × 109/L on
D1 of the scheduled chemotherapy, the chemotherapy should be permanently discontinued. If the
above values have been reached, the next course of chemotherapy should be continued.
The investigator should monitor the subject closely for toxicity with particular attention to early
and evident signs of myelosuppression, infection, or febrile neutropenia to timely and
appropriately treat the complications.
Subjects should be informed to pay attention to these signs and receive treatment as soon as possible.
If the chemotherapy must be interrupted due to hematological toxicity, the complete blood count
should be performed regularly (including WBC differentials) until all the counts reach the minimum
requirements for treatment continuation. Thereafter the scheduled treatment plan will be performed.
Dose adjustments are not required for anemia. However, treatment based on guidelines of each
clinic should be performed.
Gastrointestinal toxicity
Antiemetics will be used to control nausea and/or emesis. If grade 3 or 4 nausea and/or emesis
occur(s) despite of antiemetics, the chemotherapeutic dose should be reduced by 20% for the
next treatment cycle. The dose should be returned to the initial level as possible if the subject is
tolerated.
If the subject experiences stomatitis on D1 of any treatment cycle, the chemotherapy should be
interrupted until the symptoms resolve. If the stomatitis has not resolved after 3 weeks, the
chemotherapy should be permanently discontinued (refer to CTCAE version 4.03). If an acute
Grade 3 stomatitis occurs, the chemotherapeutic dose should be reduced to 75% of the proposed
dose when symptoms resolve.
Hepatotoxicity (Paclitaxel)
The paclitaxel dose should be determined based on the lab values measured on D1 of each
treatment cycle.
Table 4. Dose adjustment of paclitaxel (hepatotoxicity)
AST
Total bilirubin
Paclitaxel Dose
≤5 x UNL
and
WNL
175 mg/m2
> 5 x UNL
or
> UNL ~ 1.5 x UN
150 mg/m
> 1.5 x UN
0


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If paclitaxel is interrupted due to hepatotoxicity, carboplatin should also be interrupted until
paclitaxel is restarted. Paclitaxel will be interrupted for up to 3 weeks. If the subject's hepatic
function does not return to the acceptable ranges in 3 weeks, paclitaxel should be permanently
discontinued. The carboplatin dose will not be adjusted when hepatotoxicity occurs.
The investigators should avoid PD due to abnormal hepatic enzyme levels as possible. If PD
occurs, all the study drugs should be permanently discontinued, including chemotherapy.
Cardiovascular toxicity (paclitaxel)
The arrhythmia in subjects was infrequent in previous clinical studies. However, most subjects
were asymptomatic and electrocardiographic monitoring was not required. Asymptomatic
transient bradycardia was observed in 29% of subjects, but significant atrioventricular block was
rare. Cardiac events should be treated as follows:
Asymptomatic bradycardia: no intervention indicated
Symptomatic arrhythmia during infusion: Discontinue paclitaxel infusion and perform
routine treatment of arrhythmia. Discontinue subsequent paclitaxel treatment.
Document this AE in the AE Report Form of eCRF.
Chest pain and/or symptomatic hypotension (< 90/60 mmHg or rehydration therapy
required): discontinue the paclitaxel infusion. Perform electrocardiography (ECG). If
hypersensitivity reaction is suspected, administer diphenhydramine and dexamethasone
via intravenous infusion. If the chest pain is not considered as cardiogenic, epinephrine
or bronchodilators will be administered. Document this AE in the AE Report Form of
eCRF. Discontinue subsequent paclitaxel treatment and provide symptomatic treatment.
Consult a cardiologist if needed.
Neurotoxicity (paclitaxel)
The dose of paclitaxel should be adjusted according to Table when neuropathy occurs. The dose
adjustment of carboplatin is not needed when neurotoxicity occurs.
Table 5. Dose adjustment of paclitaxel (neurotoxicity)
Toxicity Grade (CTCAE version 4.03)
Paclitaxel dose adjustment
Grade 1 or below
175 mg/m2
2
Interrupt treatment until return to grade 1, then reduce dose to 140 mg/m2
(20% of reduction) and restart infusion


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Grade 3 or above
Interrupt treatment until return to grade 1, then reduce dose to 125 mg/m2
(30% of reduction) and restart infusion.
Once the dose is reduced due to neurotoxicity, the original dose should no longer be adopted.
If the neurotoxicity does not return to grade 1 after paclitaxel interruption for 3 weeks, paclitaxel
should be permanently discontinued.
Allergic reactions/hypersensitivity reactions (paclitaxel)
Note: Prophylaxis for hypersensitivity reactions (see below) and close monitoring of vital signs
are recommended for subjects with history of mild to moderate hypersensitivity reactions when
hypersensitivity reactions reoccur.
Mild symptoms: complete paclitaxel infusion. Close monitoring; no treatment indicated.
Moderate symptoms: Interrupt paclitaxel infusion, administer diphenhydramine 25–
50 mg and dexamethasone 10 mg via intravenous infusion. Once symptoms have
resolved, resume paclitaxel infusion at a slower rate (20 mL/hour for 15 minutes, then
at 40 mL/hour for 15 minutes, and if no further symptoms develop, continue at original
rate until infusion is complete). Document this AE in the AE Report Form of eCRF. If
symptoms reoccur, interrupt the paclitaxel infusion and permanently discontinue
subsequent paclitaxel infusion.
Severe and life-threatening symptoms: Interrupt paclitaxel infusion, administer
diphenhydramine and dexamethasone via intravenous infusion (as above). Use
epinephrine or bronchodilators if indicated. Document this AE in the AE Report Form
of eCRF. Subsequent courses of paclitaxel infusion should be permanently
discontinued.
Moderate or severe hypersensitivity reactions should be documented as AEs.
Other toxicities
If other unmentioned grade 3–4 toxicities occur, the chemotherapy should be interrupted until
symptoms resolve or return to grade 1. Thereafter restart the infusion at 50% of the original dose
(which should no longer be adopted). If the toxicity does not return to grade 1 after an
interruption for 3 weeks, the chemotherapy should be permanently discontinued. Dose
adjustments are not recommended for grade 1 and 2 toxicities.
5.4 Study Drug Properties


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IBI305 is a bevacizumab biosimilar. The active ingredient of both drugs is recombinant humanized
anti-VEGF monoclonal antibody; Bevacizumab is the standard commercially available drug, provided
by the sponsor.
Detailed information on the study drugs is shown in Table .
Table 6. Study drugs
Study Drugs
Dosage Form and
Strength
Excipient
Appearance
Manufacturer
IBI305
4 mL: 100 mg
Sodium acetate,
sorbitol, and
polysorbate 80
Sterile solution for
intravenous injection
pH 5.2
Clear, colorless liquid, no
foreign matters, no floc
or precipitation
Innovent Biologics (Suzhou)
Co., Ltd.
Bevacizumab 4 mL: 100 mg
α,α-trehalose
dihydrate, sodium
dihydrogen phosphate
monohydrate,
disodium hydrogen
phosphate,
polysorbate 20, and
sterile water for
injection
Sterile solution for
intravenous injection
pH 5.9–6.3
Clear to slight
opalescent, colorless to
light brown
Roche Pharma (Schweiz)
Ltd.
5.5 Preparation and Distribution
IBI305 or bevacizumab is diluted in 0.9% sodium chloride solution by the pharmacist or research
nurse before infusion. Check the particles and discoloration prior to administration.
The investigator should ensure that the pharmacist or research nurse administers the study drugs
according to study protocol.
5.6 Packaging, Labeling, and Storage
The sponsor should package and label the study drugs according to appropriate local regulations.
All study drugs (IBI305 and bevacizumab) must be stored at 2–8 °C away from light. The study
drugs should be stored in a safe zone only accessible by authorized staff prior to dispensation to
the subjects.
5.7 Subjects Allocation
After confirming that the subject meets all of the inclusion and exclusion criteria, the study site
will log in the Interactive Web Response System (IWRS) and enter the subject information into
the IWRS. The IWRS will allocate a random number to the subject and provide a medication


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number. Stratified randomization is used in this study. Stratifying factors include age (< 60 vs.
≥60 years old) and EGFR status (wild vs. unknown type).


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5.8 Blinding
This is a randomized, double-blind, and active-controlled study, and only relevant study
personnel had access to the randomization numbers. A non-blinded pharmacist or research nurse
will prepare the medications since IBI305 and bevacizumab do not have an identical appearance.
The pharmacist or research nurse who is responsible for preparing the study drugs is not allowed
to disclose any information regarding treatment allocation to the subject, the subject's family
members, or other personnel including the physician and the relevant study staff.
Unblinding: Subject unblinding should only be performed after database locking.
Emergency unblinding: In case of an emergency where the investigator must know the
medication given to a particular subject, the investigator will unblind the subject via the IWRS
and immediately inform the sponsor and CRO. The reasons for unblinding, date, and outcomes
should be documented in the source document and eCRF of the subject.
5.9 Concomitant Medications and Treatments
All medications except for the study drugs, including other chemotherapies not specified in the
study, Chinese herbal medicines, and other non-traditional therapies, are considered concomitant
medications. All concomitant medications used within 30 days prior to screening should be
documented in the eCRFs, including the information of generic name, route of administration,
start date, end date, and indication.
5.9.1 Prohibited treatment
No other anti-tumor therapies or medications with anti-tumor indications, including Chinese
herbal medicine, radiotherapy, or other investigational drugs, are allowed during this study other
than IBI305, bevacizumab, paclitaxel, and carboplatin.
Severe myelosuppression is possible after chemotherapy. Granulocyte colony-stimulating factor
or granulocyte-macrophage colony-stimulating factor are not allowed to be used prophylactically
in the first treatment cycle.
5.9.2 Permitted treatment
Prophylactic use of anti-emetics, glucocorticoids, or other treatments targeting toxicities is permitted
during the study. Unconventional treatments (such as acupuncture) and vitamins/microelements are
permitted if their use does not affect the study endpoints as determined by the investigators.
Starting from the 2nd chemotherapy cycle, granulocyte colony-stimulating factor or granulocyte-
macrophage colony-stimulating factor are allowed to be used prophylactically to prevent severe
myelosuppression.


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Anti-viral therapy was permitted whenever necessary.
Stable doses of anti-epileptic drugs were permitted.
Radiotherapy for bone metastasis was permitted provided that the radiotherapy field did not
include the target lesion
5.9.3 Treatment after study treatment
Subsequent therapy after the end of study treatment should be determined by the subject's
attending doctor.
5.10 Treatment Compliance
Subjects should receive treatment at the study site. The dose and time of administration of
IBI305 or bevacizumab and paclitaxel/carboplatin should be documented in the source records
and eCRFs during each treatment cycle. Reasons for dose adjustments, therapy delay, and
therapy discontinuation should be documented. Treatment compliance is monitored by
medication dispensing and return records, medical records, and eCRFs.
5.11 Drug Return and Destruction
The containers, vials, infusion bags, and syringes of used and partially used drugs can be
destroyed on-site according to the appropriate guidelines and operating procedures established
by study sites and local agencies.
Unless the contents have significant safety issues requiring immediate destruction in accordance
with local regulations, all the unused drugs should be returned and destroyed based on the
requirements of sponsor.
5.12 Study Drug-Related Records
The designated personnel of the study sites should make timely records of receiving, dispensing,
using, storing, returning, and destroying the study drugs in accordance with the relevant
regulations and guidelines.


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6 STUDY PROCEDURE
The detailed procedures of this study are shown in Table 1. Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
.
6.1 Screening Visits (D -28 to D -1)
Complete the screening visits within 28 days prior to study treatment commencement. The
following procedures must be completed during screening to ensure that subject meets the
requirements for participating in this study:

Sign the ICF

Record the demographics, including age, ethnicity, and gender

Record the past medical history, including smoking history

Record the history of anti-tumor therapies

Record the concomitant medications (within 30 days prior to screening)

Record the vital signs

Measure the height and weight (including BMI)

ECOG score

Physical examination

12-Lead ECG

Hepatitis B panel, anti-HCV, anti-HIV, and syphilis tests

Clinical laboratory tests (routine blood test, coagulation test, blood chemistry, and
urinalysis)


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
Blood/urine pregnancy test (for female subjects of childbearing age only)

Imaging examinations (CT or MRI: Head, chest, abdomen, and pelvis cavity)*

EGFR test#

Review the inclusion/exclusion criteria

Record the AEs and concomitant medications
* Retests are not required if the tests have been performed within 28 days prior to the first dose,
unless the investigators suspect changes in tumor burden. Imaging results during screening will
be used as the baseline data. The same method of imaging test is used at baseline and during
follow-up. Imaging evaluations of the chest, abdomen, and pelvis are required.
# If the subject has been tested for EGFR of tumor sample at the study site with documentation,
the subject will not be required for retest.
6.2 Baseline Visits (D1 of cycle 1)
D1 refers to the day of receiving the first dose of the study drugs. Eligible subjects meeting the
inclusion criteria will return to the study site and complete the following procedures:

Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests * (routine blood test, blood chemistry, and urinalysis)

Confirm the inclusion/exclusion criteria
* If clinical laboratory screening tests (routine blood test, blood chemistry, urinalysis) are
performed within 7 days prior to the first dose, then the results of the screening test can be
used as baseline.
If the subject meets the inclusion criteria, the following procedures should be complete:

Randomization and grouping

Immunogenicity test (within 1 h prior to the study drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Pharmacokinetic (PK) blood sampling (within 1 h prior to the study drug infusion,


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immediately after the study drug infusion [+5 min])

VEGF blood sampling (within 1 h prior to the study drug infusion)

Record the AEs and concomitant medications
6.3 Cycle 2 (week 4 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study drug infusion)

VEGF blood sampling (within 1 h prior to the study drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
6.4 Cycle 3 (week 7 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)


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
Record the AEs and concomitant medications
Imaging tests (CT or MRI) should be done every 6 weeks (±7 days), and tumor assessment
should be completed within 7 days prior to this visit to determine whether the study treatment
should be continued.
6.5 Cycle 4 (week 10 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study drug infusion)

Immunogenicity test (within 1 h prior to the study drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
6.6 Cycle 5 (week 13 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study drug infusion)


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
Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
Imaging tests (CT or MRI) should be done every 6 weeks (±7 days), and tumor assessment
should be completed within 7 days prior to this visit to determine whether the study treatment
should be continued.
6.7 Cycle 6 (week 16 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study drug infusion)

VEGF blood sampling (within 1 h prior to the study drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
6.8 Cycle 7 and Subsequent Treatment Cycles (±3 Days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Maintenance monotherapy will start from week 7 and the dose of study drug will be adjusted to
7.5 mg/kg. Subjects should complete the following procedures during each visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG


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
Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Study drug infusion (IBI305 or bevacizumab)

Record the AEs and concomitant medications
Imaging tests (CT or MRI) should be done every 6 weeks (±7 days), and tumor assessment
should be completed within 7 days prior to this visit to determine whether the study treatment
should be continued.
6.9 End-Of-Treatment Visit
The end of treatment visit in study sites will be conducted in 28 days (±7 days) after the last dose
of study drug. Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Immunogenicity test

PD blood sampling

Blood/urine pregnancy test (for female subjects of childbearing age only)

Tumor assessment (CT or MRI, completed within 7 days prior to this visit; not required
to be repeated if it has been performed within 6 weeks prior to this visit)

Subsequent anti-tumor therapy

Record the AEs and concomitant medications
If the subject has not experienced PD, the subsequent follow-up for PD will be performed
(Section 6.10). If the subject has experienced PD, the subsequent follow-up for survival will be
performed (Section 6.11).
6.10 Disease Progression Visit
If the study drugs are discontinued for reasons other than PD, the end of treatment visit in study
sites will be conducted in 28 days after the last dose of study drug, and tumor assessments should
be conducted every 6 weeks (±7 days) until PD if possible (after which, follow-up for survival
will be conducted [Section 6.11]), withdraw of informed consent, loss to follow-up, death,


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start of other anti-tumor therapies, or end of study. During the visit, vital signs and weight
measurements will be performed, and any subsequent anti-tumor therapies will be documented.
6.11 Survival Follow-Up
The investigator will make telephone follow-up every 12 weeks (±7 days) to collect the
information of subsequent anti-tumor therapies and survival until withdrawal of informed
consent, loss to follow-up, death, or end of study.
6.12 Study Completion
The end of this study will be the18th month after randomization of the last subject. If the subjects
continue to receive the study drug treatment before this cut-off time, the treatment should be
discontinued and the end of treatment visit should be completed (Section 6.9).


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6.13 Tumor Assessment
Imaging tests (CT or MRI) of the brain, chest, abdomen, and pelvis are required at baseline. If
these tests are performed within 28 days prior to the first dose of the study drug, they do not need
to be repeated unless the investigator believes that there have been changes in the subject's tumor
burden. After the start of treatment, imaging tests are performed once every 6 weeks (±7 days)
and have to be completed within 7 days prior to the scheduled visits, until progressive disease,
start of other treatment, withdrawal of informed consent, loss to follow-up, death, or study
completion. The same method of imaging test was used at baseline and during follow-up.
Imaging evaluations of the chest, abdomen, and pelvis are required.
The investigator should perform a tumor assessment based on RECIST v1.1 (Section 13.3) prior
to each dose to determine whether the subject should continue with the next round of treatment.
An independent review committee will also assess the tumor response (Section 11.1.1). Imaging
tests will not be rescheduled if the study drugs or chemotherapeutic agents are interrupted due to
toxicities. Every effort should be made to continue the schedule for imaging tests even for
subjects who discontinue one or two study treatment(s) due to drug-related toxicities.
If subject experience PD according to the RECIST v1.1 criteria, the attending doctor should
discuss with the subject regarding subsequent routine cancer therapies.
6.14 Clinical Laboratory Evaluations
Clinical laboratory tests will be conducted at the laboratories of each study site. Sample collection
and analysis should be performed according to the requirements of each laboratory.
The following laboratory tests should be conducted according to the study procedures (Table 1.
Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
):
Routine blood test: hemoglobin, hematocrit, WBC and differentials (including


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absolute neutrophil and lymphocyte counts), platelets, and RBC
Routine coagulation test (baseline test): INR, aPTT, or PTT
➢
Blood chemistry: Creatinine, blood urea, total protein, albumin, total bilirubin,
alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase
(ALT), fasting blood glucose, sodium, potassium, chloride, calcium, phosphorus, and
magnesium
➢
Urinalysis: Specific gravity, pH, glucose, protein, occult blood, and leukocytes
➢
Pregnancy test: Serum/urine pregnancy tests are performed on women of
childbearing age during screening and the end-of-treatment visit.
These tests are carried out at the laboratory of each trial site.
For subsequent visits, all laboratory tests need to be completed within 3 days prior to the
administration. During the study, the frequency of these laboratory tests will be increased if
safety is a concern. The investigator should review the laboratory test results throughout the
study to determine whether the results are clinically significant. The investigator should assess
the changes in laboratory test results. If the investigator considers a laboratory test result to be
abnormal and of clinical significance, it is considered as an AE.
6.15 Vital Signs, Physical Examinations, and Other Safety Assessments
6.15.1 Vital signs
Vital signs include pulse, BP, temperature, and respiratory rate. The subject must rest for at least
5 minutes prior to each vital sign assessment.
Vital signs will be assessed according to the Schedule of Activities (Table 1. Schedule of follow-
up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
). During the study, the investigator may increase the frequency of vital sign measurement if


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safety is a concern.
6.15.2 Height and weight
Height is only measured during screening. Weight is measure during each visit.
6.1.5.3 Physical examinations
The following organs/systems will be examined according to the Schedule of Activities (Table 1.
Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
x
x
x
x
x
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
(IBI305 or
bevacizumab) j
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
): general condition, head (eyes, ears, nose, and throat), neck and thyroid, respiratory system,
cardiovascular system, abdomen, nervous system, skeletal muscles and limbs, as well as
lymphatic system and skin.
6.15.4 12-Lead ECG
12-lead ECG will be performed during screening. During the study, each medication visit
requires an ECG examination. The following ECG parameters should be documented: HR, PR-
interval, QRS-complex, QT-interval, and QTc-interval. The subject must be in the supine
position for at least 5 minutes prior to undergoing the 12-lead ECG. All ECG are evaluated by
qualified physicians. All clinically significant abnormal findings should be reported as AEs.


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6.15.5 Immunogenicity assessment
Immunogenicity tests will be performed in all subjects at 3 blood sampling time points: Within 1
hour prior to the first dose of the study treatment (IBI305/bevacizumab) in C1, within 1 hour
prior to the administration of the study treatment in C4, and during the end-of-treatment visit.
Blood specimens that are positive for anti-drug antibodies (ADA) after dosing will be further
tested for neutralizing antibodies (NAb). Samples were tested at the designated central laboratory.
6.15.6. Pharmacokinetics/pharmacodynamics
6.15.6.1 Pharmacokinetics
Study sites that are implementing version 2.0 and subsequent versions of the study protocol
should collect PK samples until 140 subjects in this study meet the requirements for PPK
assessment (based on the written notice of the sponsor). There are 6 PK sampling time points:
Within 1 h prior to the first dose of the study treatment (IBI305/bevacizumab) in C1,
immediately after the first infusion (within 5 minutes), within 1 h prior to the dose in C2, within
1 hour prior to the dose in C4, within 1 h prior to the dose in C5, and within 1 h prior to the dose
in C6. Serum will be separated from the samples at the study site and the serum samples will be
analyzed at the designated central laboratory.
6.15.6.2 Pharmacodynamics
Study sites that are implementing version 2.0 and subsequent versions of the study protocol
should collect PD samples until 140 subjects in this study meet the requirements for VEGF
testing (based on the written notice of the sponsor). There are 4 VEGF sampling time points:
within 1 h prior to the first dose of the study treatment (IBI305/bevacizumab) in C1, within 1 h
prior to the dose in C2, within 1 h prior to the dose in C6, and during the end-of-treatment visit.
Samples were tested at the designated central laboratory.
6.15.7 EGFR testing
EGFR mutation testing histologically or cytologically will be performed in all subjects (if the
subject has been tested for EGFR at the study site histologically or cytologically with
documentation, the subject will not be required to be retested). The testing will be conducted at
the laboratory of each study site or a qualified third-party laboratory.


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7 STUDY ASSESSMENTS
7.1 Efficacy Assessment
7.1.1 Primary efficacy endpoint

Objective response rate (ORR)
ORR will be assessed using RECIST v1.1. ORR is defined as the proportion of subjects with
tumor size reduction of a predefined amount and for a minimum time period, including patients
who achieved complete response (CR) and partial response (PR). The cut-off date for data
included in the primary efficacy evaluation is the 18th week after the last subject is randomized.
7.1.2 Secondary efficacy endpoints

Duration of response (DOR)

Progression-free survival (PFS)

Disease control rate (DCR)

Overall survival (OS)
Each endpoint will be assessed using RECIST v1.1.
DOR is defined as the time from initial tumor response (CR or PR) to PD or death before PD;
Subjects with CR or PR who do not progress or die will be censored on the date of the last tumor
assessment.
PFS is defined as the time from the date of randomization to the date of PD or death; Subjects
who do not progress or die will be censored on the date of the last tumor assessment.
DCR is defined as the proportion of patients whose tumor volume has reduced to a
predetermined value for a minimum time limit, including patients who achieved CR, PR, and SD.
OS is defined as the time from the date of randomization to the date of death of any cause. For
subjects that are alive on the date of study completion or are lost to follow-up, their survival time
will be censored at the date of last contact.


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7.2 Safety Assessments
7.2.1 Adverse events
7.2.1.1 Definition
Adverse event
An AE refers to any untoward medical occurrence in a subject after signing the informed consent
form, and does not necessarily have a causal relationship with the treatment. Thus, an AE can be
any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or
disease, whether considered drug related.
Abnormalities resulting from PD are not considered as AEs.
Serious adverse event
A SAE refers to an AE meeting at least one of the followings:
(1)
Lead to death, except for deaths caused by PD.
(2)
Life-threatening (a "life-threatening event" is defined as an AE when the subject is at
immediate risk of death at the time, but does not include the case that may lead to death
only when the event worsens).
(3)
Requires hospitalization or prolonged hospitalization, excluding an emergency or
outpatient visit. Subjects with existing diseases or conditions prior to the enrollment
that do not worsen during the study, and having hospitalization and/or surgery that was
scheduled before the study or during the study do not meet the SAE criterion.
Hospitalizations resulting from PD are not considered as SAEs.
(4)
Results in permanent or severe disability/incapacity.
(5)
Results in congenital anomalies/birth defects.
(6)
Other important medical events: The event that does not result in death, is not life-
threatening or does not require hospitalization, but may jeopardize the health of subjects
and require medical intervention to prevent the SAEs above, is considered as an SAE
7.2.1.2 Severity of adverse events
The severity of AEs is evaluated using the 5-level criteria of NCI CTCAE v4.03.
For AEs not included in CTCAE v4.03, use the following CTCAE general guidelines:

Grade 1: Mild; asymptomatic or mild signs; clinical or diagnostic observations only;
medical intervention not indicated.


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
Grade 2: Moderate; minimal/local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily life (such as cooking, shopping, using the
phone, financial management, etc.).

Grade 3: Severe or clinically significant but not immediately life-threatening;
hospitalization or prolonged hospitalization indicated; disability; limited ability of self-
care (such as bathing, dressing, undressing, eating, using the toilet, taking medication),
but not bedridden.

Grade 4: Life-threatening consequences; urgent intervention indicated.

Grade 5: Death related to AE
7.2.1.3 Relationship between adverse events and the investigational drug
The relationship between the study drugs and AEs can be determined using the followings:
Table 1. Correlation between AEs and investigational drugs
Correlation
CRITERIA
Related

The occurrence of the AE is reasonably related to the time sequence of
dosing;

The investigational drug can more reasonably explain the AE than the other
causes (such as the pre-existing disease of the subject, environment,
toxicity, or other treatment received);

The AE resolves or is alleviated after treatment interruption or dose
reduction;

The AE is consistent with the known type of AEs of the suspicious drug or
similar drugs;

The AE occurs again after the drug administration is resumed.
Possibly related

The occurrence of the AE is reasonably related to the time sequence of
dosing;

The investigational drug can be used to explain the AE with the same level
of rationality as other reasons (such as the pre-existing disease of the
subject, environmental or toxic factors, or other treatments received by the
subject);

The AE resolves or is alleviated after treatment interruption or dose
reduction (if applicable).
Possibly not related

Other reasons can more reasonably explain the AE than the investigational
drug (such as the pre-existing disease of the subject, environmental or toxic
factors, or other treatments received by the subject);

The AE does not resolve or be alleviated after treatment interruption or
dose reduction (if applicable), or the situation is unclear;

The AE does not occur again or the situation of the AE is unknown after
the drug administration is resumed.


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Correlation
CRITERIA
Unrelated

The occurrence of the AE is not reasonably related to the time sequence of
dosing, or

The AE has other obvious causes (such as the pre-existing disease of the
subject, environmental or toxic factors, or other treatments received by the
subject).
Cannot be determined

The above information is unclear and cannot be determined based on the
available information. Further follow-up information is not accessible to
the investigator.
7.2.1.4 Serious adverse event reporting
SAEs that occur from the signing of informed consent form until 90 days (inclusive) after the last
dose should be reported. The investigator must fill out the "CFDA SAE Report Form", regardless
of whether it is the initial report or a follow-up report, and sign and date the form. The
investigator must report the SAE to the sponsor, CFDA, and ethics committee within 24 hours of
noticing the event. The contact information for reporting is shown in the table below.
For SAEs occurring outside of the above-mentioned period, those considered related to the
investigational drug shall also be reported to the sponsor.
The investigator must submit the completed SAE report form to the sponsor within 24 hours of
noticing the event. The investigator shall urgently perform visit on missing information and
provide a complete SAE report for events that result in death or are life-threatening.
The investigator should also report the event to the CFDA, health administration departments,
and ethics committees in accordance with the regulations.
When submitting the SAE report by email, it is recommended for the investigator to encrypt the
report file and send the report file and password in separate emails.
Table. SAE report contacts
Unit
Contact
Fax/Telephone/Address
Hospital Name
Ethics committee
Hospital Fax/Telephone
Innovent Biologics (Suzhou) Co.,
Ltd.
Clinical Study Department PV
Fax: 021-31652800
Email:
drugsafety@innoventbio.com


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Office of Drug Research and
Supervision, Department of Drug
and Cosmetics Registration,
China Food and Drug
Administration
Address: Building 2, No. 26,
Xuanwumen
West
Street,
Xicheng District, Beijing
Post Code: 100053
Tel: 010-88330732
Fax: 010-88363228
Medical Administrative
Department, Health
Administration
Address: No. 38, Lishi Road,
Xicheng District, Beijing
Tel: 010- 68792001
Fax: 010-68792734
Province, Autonomous Region,
Municipality Food and Drug
Administration
Based on the requirements of the food and drug administration
department of each province, autonomous region or municipality
7.2.1.5 Management and follow-up of adverse events
The investigator is responsible for providing appropriate medical treatment for all AEs (Indicate
the actions taken, such as suspension/termination of the investigational drug, dose modification,
drug therapy, etc.). When an AE occurs, the investigator should actively take appropriate
measures to ensure the safety of the subject. All AEs observed from the signing of the ICF
to the time specified in the protocol (Table 2) must be followed.
The investigator should report any SAE that occurs after the time specified in the protocol (Table 2)
and is suspected of being related to the investigational drug to the sponsor.
7.2.1.6 Adverse event of special interest and expedited reporting
The AESI for this study include:

Gastrointestinal perforation

Procedural and wound healing complications

Hemorrhage

Fistula

Hypertension

Thrombotic event

Posterior reversible encephalopathy syndrome (PRES)


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
Proteinuria

Infusion-related reaction

Ovarian failure

Cardiac failure congestive
If the criteria for SAE is met, the SAE report should be submitted to the sponsor within the
specified time limit (see 7.2.1.4 for details)
7.2.1.7 Pregnancy
Bevacizumab may be harmful to the fetus. Subjects or female partners of male subjects must use
an effective form of contraception during the 6 months after the last dose.
During the study, if a female subject exposed to the study drug becomes pregnant, she must
discontinue study treatment. The investigator must report to the sponsor within 24 hours of
noticing the event and submit the "Innovent clinical Study Pregnancy Report/Follow-Up Form".
During the study, if a female partner of a male subject exposed to the study drugs becomes
pregnant, the subject will continue in the study. The investigator must report to the sponsor
within 24 hours of noticing the event and submit the "Innovent Clinical Study Pregnancy
Report/Follow-Up Form".
The investigator must continuously monitor and visit on the outcome of the pregnancy until 8
weeks after the subject gives birth. The outcome should be reported to the sponsor.
If the outcome of the pregnancy is stillbirth, spontaneous abortion, fetal malformation (any
congenital anomaly/birth defect), or medical abortion, it should be considered as an SAE and the
event is required to be reported in accordance with SAE procedures and time limits.
If the subject also experiences a SAE during the pregnancy, the CFDA SAE Report Form should
also be filled out and reported according to SAE's procedures.
7.2.1.8 Time limits of documenting and reporting AEs
All AEs occurring from the time the subject signs the informed consent form to the time
specified in the protocol (Table 2) (including SAEs and non-SAEs), regardless of their severity,
must be collected and recorded on the AE page of the eCRF.
The investigator must fill out all the required information, including the description of the AE,
start date, end date, severity, measures taken, outcome, seriousness, and causality with the
investigational drug. Each AE should be documented separately.


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Table 2. Reporting and follow-up of adverse events
Reporting time limit
Visit time limit
AEs
From signing the informed consent form to 90 days
after the last dose (if the subject begins other anti-
tumor therapies, only AEs related to the study drugs
should be collected)
Until resolved or explainable stable
determined by the investigator
Pregnancy
From the first dose until 6 months after the last dose
of the study treatment
Until the outcome of the event is
available, and the health conditions of
the newborn should be followed up
for at least 2 months according to the
protocol
7.2.1.9 Precautions for AE documentation
Diagnosis, signs, and symptoms
If a diagnosis is already made, the eCRF should record the diagnosis instead of individual
symptoms and signs (such as hepatic failure rather than jaundice, transaminase increased, and
asterixis). However, if the signs and symptoms cannot be attributed to a definitive diagnosis, each
independent event should be documented in the eCRFs as an AE or SAE. Update the report with
visit information if a diagnosis is confirmed later.
AEs secondary to other events
Generally, AEs secondary to other events (such as result of another event or clinical sequelae)
should be documented as the primary event, unless the event is severe or an SAE. However,
clinically significant secondary events should be recorded as independent adverse events in the
eCRFs if they occur at different times than the primary event. If the relationship between events is
unclear, document them as separate events in the eCRFs.
Ongoing or recurrent AEs
An ongoing AE refers to an event that does not resolve and is ongoing between two assessment
time points. These AEs should only be documented once in the eCRFs. The initial severity should
be documented, and the information should be updated if the event exacerbates.
Recurring AEs refer to AE that have resolved between the two time points of assessment but
subsequently occur. These events should be independently documented in the eCRFs.
Abnormalities in laboratory tests/vital signs
All clinically significant laboratory test abnormalities should be reported as AEs. It is the
responsibility of the investigator to review all abnormal laboratory test results, and to make
medical judgments as whether each abnormal laboratory test result should be reported as an AE.


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Death
During the entire course of the study, all the deaths that occurred within 90 days after the last dose
were documented in the Death Report Form in the eCRFs, regardless of the causality with the
investigational drug.
When recording a death event, if the cause of death is clear, the cause of death is recorded as an
adverse event with the result of the adverse event being death, and the event is reported as an SAE;
if the cause of the death is unknown at the time of reporting , "Death with Unknown Cause" should
be recorded on the Adverse Event Form of the eCRF and the "Death with Unknown Cause" should
be reported as an SAE first before further investigation is carried out to find the exact cause of
death.
Pre-existing medical conditions
Symptoms/signs presenting during the screening period will be recorded and reported as AEs only
if their severity, frequency, or property becomes aggravated (except for worsening of the studied
disease). The relative change should be documented, such as "increased frequency of headaches".
Hospitalization and prolonged hospitalization, or surgery
Any AE that results in hospitalization or prolonged hospitalization should be documented and
reported as an SAE, except for the following situations:

Hospitalization or prolonged hospitalization as required by study protocol (such as for dose
administration, efficacy evaluation, etc.)

Hospitalization due to a pre-existing medical condition that remains stable, e.g. elective
surgery/therapy scheduled prior to the study.
However, elective surgery/therapy required because of the exacerbated condition during the study
(e.g. surgery/therapy required earlier than scheduled) should be considered as an AE.
The investigator should fill in all required information, including AE terms
(diagnostic terms, or the record of symptoms and signs including laboratory test abnormalities if
there is no diagnosis), start date, end date, severity level, whether it is an AESI, measures taken for
the investigational product, treatment given for the AE, outcome, seriousness, and relationship with
the investigational product. If the signs and symptoms cannot be attributed to a definitive diagnosis,
each AE should be documented independently.


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Progressive disease
A progressive disease is defined as the worsening of subject condition caused by the primary tumor
that the investigational drug is targeting, the appearance of new lesions, or the progression of the
primary lesion. Expected progressive disease should not be reported as an AE. Any deaths, life-
threatening events, hospitalization or prolonged hospitalization, permanent or significant
disability/incapacity, congenital anomaly/birth defects, or other important medical events caused
by progressive disease should not be reported as an SAE
8 STATISTICS
8.1 Sample Size Determination
A number of 218 subjects for each group (436 subjects in total) can provide 80% test power to
confirm the clinical equivalence between the treatments of IBI305 in combination with
paclitaxel/carboplatin and bevacizumab in combination with paclitaxel/carboplatin.
The sample size is estimated based on the following assumptions:

The ORRs between IBI305 and bevacizumab group are equivalent

The ORR of subjects in the bevacizumab groups is set to 50.0%

The equivalence margin for the ratio of ORR is taken as (0.75, 1/0.75))

The significance level of the two one-side test is 0.05

1:1 randomization
Based on the above hypotheses, a number of 218 subjects for each group is required (436
subjects in total). The sample size was estimated using PASS 2013.
8.2 Statistical Population
Intention-to-Treat (ITT): All randomized subjects.
Full Analysis Set (FAS): All randomized and evaluable subjects who received at least one dose
of the study treatment. This dataset is used as the primary analysis set for efficacy assessment.
Per-Protocol (PP): Based on the FAS, subjects with the predetermined minimum drug exposure
and without any predetermined major protocol deviations. This dataset is used as the secondary
analysis set for efficacy assessment.


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Safety set (SS): Includes all randomized subjects who received at least one dose of the study
treatment and have safety evaluation data. This data set is used for the safety evaluation of this
study.
PK analysis set (PKAS): Includes subjects in the FAS with at least one PPK measured value.
Pharmacodynamic analysis set (PDAS): Includes all subjects in the FAS set with at least one PD
measured value.
8.3 General Principles for Statistical Analyses
For continuous variables, descriptive statistics should include the count, mean, standard
deviation, median, maximum, and minimum. For categorical variables, descriptive statistics will
include the number and percentage of each category. Statistical analyses will be carried out using
SAS 9.4.
8.4 Statistical Methods
8.4.1 Adjustments for covariates
The stratification factors of randomization in this study include age and EGFR status, and the
stratification factors will be considered in the model analysis (GLM or Cox) of primary and
secondary efficacy parameters
8.4.2 Managing dropouts and missing data
The handling of dropout and missing data will be detailed in the statistical analysis plan
8.4.3 Multi-center study
Since this is a multicenter study, the primary endpoint (ORR) will be listed according to study
sites and treatment groups. However, individual equivalence analysis will not be conducted.
Trial sites with fewer than 5 ITT subjects per treatment group will need to be combined for
analysis. Details will be discussed in the data review meeting.
8.4.4 Multiple comparisons and adjustments to multiplicity
The α adjustment for multiple comparisons is not considered.


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8.5 Statistical Analyses
8.5.1 Subject distribution
Refer to Figure 1: Study design schematic for the schedule of activities. The number and
percentage of patients who have completed or dropped out of the study (including the reason for
dropouts such as loss to follow-up, AEs, and poor compliance) are summarized based on
treatment groups.
The number and percentage of subjects in each analysis set are calculated based on treatment groups.
The number and percentage of protocol deviations are calculated based on treatment groups.
8.5.2 Demographics and other baseline characteristics
Demographic information such as age, height, sex, and weight, and other baseline characteristics
such as disease history (including NSCLC diagnosis, staging, previous cancer treatment, and
target and nontarget lesions) are summarized using descriptive statistics.
8.5.3 Compliance and drug exposure
The required dose and the actual dose must be documented in the eCRF. Subject compliance is
calculated based on the ratio of the actual dose (number of doses) to the required dose (number
of doses). Subject compliance is classified into the following categories: < 80%, 80–120%, and >
120%. The number and percentage of subjects in each category will be summarized.
8.5.4 Efficacy
The efficacy analysis will be based on the FAS. Results of the PP set will also be presented.
8.5.4.1 Primary efficacy endpoint
The primary objective of this study is to determine the clinical equivalence between IBI305 +
paclitaxel/carboplatin and bevacizumab + paclitaxel/carboplatin for the treatment of advanced or
relapsed non-squamous non-small cell lung cancer (NSCLC). The primary endpoint is objective
response rate (ORR). ORR is defined as the incidence of confirmed complete response (CR) or
partial response (PR), using a validated imaging method to evaluate target lesions and non-target
lesions according to RECIST v1.1. Subjects without tumor assessments after baseline will be
considered as not assessable. Subjects qualified for the evaluation of CR or PR must have at least
one measurable lesion according to RECIST v1.1. The evaluation of clinical equivalence will be
based on the ORR provided by the independent review committee (IRC). Results provided by the


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investigator will be used for sensitivity analysis.
Clinical equivalence will be determined by whether the 90% CIs of ORR ratio for subjects in
both IBI305 and bevacizumab groups falls within the equivalence margins of (0.75, 1/0.75).
The ORR and corresponding 95% confidence interval of the two treatment groups, the ORR
difference and the 90% confidence interval, as well as the ORR ratio between the two groups and
the 90% confidence interval will be estimated using the generalized linear model (GLM, which
includes treatment groups and stratification factors).
8.5.4.2 Secondary efficacy endpoints
The secondary endpoints for this study include DOR, DCR, progress-free survival (PFS), and
overall survival (OS).
DCR is defined as the incidence of patients with confirmed complete response (CR), partial
response (PR), and stable disease (SD), when a validated imaging method and RECIST v1.1 are
used to evaluate target and non-target lesions.
DOR is defined as the time from initial tumor response (CR or PR) to PD or death; Subjects with
CR or PR who do not progress or die will be censored on the date of the last tumor assessment.
OS refers to the time from the date of randomization to the date of death (of any cause). For
subjects who are still alive at the time of the analysis, their survival time is censored on the last
known alive date. PFS refers to the time from the date of randomization to the date of first
documented PD or death, whichever occurs first. Subjects who do not progress or die will be
censored on the date of the last tumor assessment. Subjects without tumor assessments after
baseline are censored on their date of randomization.
Median OS and its 95% CI will be estimated using the Kaplan-Meier method. The survival curve
will be plotted. The hazard ratio (HR) between the two groups and its 95% CI will be estimated
using a Cox model. The Cox model includes treatment groups and stratification factors. DOR
and PFS will be analyzed using the same method as for OS. DCR will be analyzed using the
same method for primary efficacy endpoints, but an equivalence test will not be conducted.
8.5.4.3 Sensitivity analysis
The center effect (fixed or random) will be considered in the primary and secondary endpoints
analysis models (GLM or Cox).
8.5.4.4 Antibody and efficacy analysis
Subjects who produce antibodies during the study will be listed. The difference in efficacy
between subjects with and without antibodies will be compared if necessary.


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Changes in PK parameters and steady-state trough concentrations of subjects with positive ADA
are analyzed.
8.5.5 Exploratory analysis
Pharmacodynamic parameters: The changes in the serum VEGF level at different time points are
described, and inter-group comparisons are carried out when necessary (based on the PD dataset)
Steady-state trough concentrations of the drug: The level of trough concentration is described
and inter-group comparisons are carried out when necessary (based on the PPK dataset)
8.5.6 Interim analysis
No interim analysis is planned for this study.
8.5.7 Stratified analysis
Efficacy analysis of different levels of subjects is conducted based on the random stratification
factors
8.5.8 Safety analysis
The safety analysis is based on the safety analysis set.
8.5.8.1 Adverse events
All adverse events (AE) will be coded using MedDRA and graded using CTCAE v4.03. All
TEAEs, TEAEs ≥grade 3, SAEs, drug-related TEAEs, drug-related SAEs, TEAEs resulting in
the termination of study drugs, TEAEs resulting in the termination of study, and AESIs will be
listed based on system organ class, preferred terms, and groups and the corresponding numbers
and percentages of subjects will be summarized. In addition, the severity of TEAEs and
relevance to the study drugs will also be summarized system organ class, preferred terms, and
treatment groups.
8.5.8.2 Laboratory tests
All laboratory test results and changes relative to baseline will be summarized by scheduled time
point and treatment group using descriptive statistics. Laboratory abnormalities will be listed.
8.5.8.3 ECG examinations
Results of ECG and changes relative to baseline will be summarized using descriptive statistics.


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8.5.8.4 Vital signs, physical examinations, and other safety examinations
Descriptive statistics of vital signs and relative changes from baseline are shown.
Results of physical examinations are listed by treatment groups.
8.5.8.5 Concomitant medications
Concomitant medications are non-study medications that meet one of the followings:
(1)
Any drug therapy started during or after the first dose of the study treatment;
(2)
Any drug therapy started before the first dose of the study treatment and continued after
the first dose of the study treatment. Concomitant medications are listed by treatment
groups.
9 QUALITY ASSURANCE AND QUALITY CONTROL
According to GCP principles, the sponsor is responsible for implementing and maintaining
quality assurance and quality control systems based on standard operating procedures (SOP),
to ensure that the implementation of the clinical trial and the collection, documentation, and
reporting of trial data is in accordance with the protocol, GCP, and applicable regulatory
requirements.
To ensure that the data is reliable and processed correctly, there should be quality control for
every step during the data processing.
In addition, the Clinical Quality Assurance (CQA) Department of the sponsor and/or CRO may
conduct regular audits of the study process, including but not limited to auditing the study site,
on-site visits, central laboratory, suppliers, clinical database, and the final clinical study report.
Regulatory authorities may also conduct inspections during the trial or at any time after the trial
is completed. The investigator and the research institution must allow the sponsor's representative
and regulatory authorities to review source data.
9.1 Clinical Monitoring
The sponsor has authorized Wuxi Clinical Co., Ltd. to conduct clinical monitoring for this study.
The clinical research associate (CRA) should follow the SOPs of Wuxi Clinical Co., Ltd. when
carrying out monitoring, and has the same rights and responsibilities as the sponsor's monitor.
The CRA should maintain regular communication with the investigator and the sponsor.
Before the start of the study, the associate monitor assess the qualifications of each study site,
and report issues related to facilities, technical equipment, or medical staff to the sponsor. During


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the study, the CRA will be responsible for confirming whether written informed consent is
obtained from all subjects, and whether data documentation is accurate and complete. At the
same time, the CRA will compare data entered in to the eCRF with source data, and notify the
investigator of any errors or omissions. The CRA will also verify protocol compliance of the
study site, as well as the dispensing and storage of investigational drugs to ensure protocol
requirements are met.
The monitoring visit will be conducted in accordance with applicable statutes and regulations.
Each site receives regular monitoring visits from the time the subjects are enrolled. The CRA
should submit a written report to the sponsor after each monitoring visit to the study site.
9.2 Data Management/Coding
The Data Management and Biostatistics Department of Wuxi Clinical Co., Ltd will process data
generated from this study in accordance with relevant SOPs.
This study will use an electronic data capture (EDC) system. Trial data will be entered into the
eCRF by the investigator or authorized study personnel. Prior to launching of the study site or
data entry, the investigator and authorized study personnel will receive appropriate training, and
appropriate safety measures will be taken.
All data are input in Chinese. The eCRF should be completed during or soon after each visit, and
should be constantly updated to ensure that it reflects the latest status of the subject. To avoid
discrepancies in outcome assessments between different evaluators, ensure that baseline and all
subsequent efficacy and safety assessments for the same subject are performed by the same
person. The investigator must review trial data to ensure the accuracy and correctness of all data
entered into the eCRF. During the study, the investigator should document any evaluations that
are not conducted, or any information that is not available, applicable, or known. The
investigator needs to sign all verified data electronically.
The CRA will review the eCRF, and evaluate its completeness and consistency. The CRA will
also compare the eCRF with the source documents to ensure the consistency of critical data. Data
entry, corrections, or modifications are completed by the investigator or designated staff. The
CRA do not have access to data entry. The data in eCRF is submitted to the data server, and any
changes to the data will be documented in the audit trail, including the reason for the change, the
name of the operator, as well as the time and date of the change. The roles and permissions of
study personnel responsible for data entry will be predetermined. The CRA or data manager will
submit data queries in the EDC system, and study personnel shall respond to the queries. The
EDC system will record the audit trail of each query, including the name of the investigator, as
well as the time and date.


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Unless otherwise specified, the eCRF should be considered simply as a form for data collection
and not a source document. A source file is used by the investigator or hospital, relevant to the
subject, and can prove the existence of the subject, inclusion criteria, and all records of
participation in the study, including laboratory records, ECG results, memorandum, pharmacy
dispensing records, and subject folders.
The investigators are required to maintain all source documents and to offer the documents to the
CRA for review during each visit. In addition, the investigator must submit a complete eCRF for
each subject, regardless of the duration of the subject's participation in the study. The study
number and subject number in all supporting documents (such as laboratory records or hospital
records) submitted along with the eCRF should be carefully verified. All personal privacy
information (including the name of the subject) should be deleted or be made indecipherable in
order to protect subject privacy.
The investigator could be automatically added to the eCRF with his/her user ID. The investigators
verify that the record have been reviewed and that the data are accurate with an electronic
signature. The electronic signature is completed with the investigator's user ID and password.
The system automatically attaches the date and time of the signature. The investigator could not
share the user ID and password with other personnel. If data in the eCRF need to be modified,
the procedures defined by the EDC system have to be followed. All modifications and reasons
for the changes are recorded in the audit trail.
Training on the EDC system will be provided to study personnel at the study site.
Adverse events, and concurrent diseases/medical history will be coded. The medical dictionary
used for coding will be described in the Clinical Study Report (CSR).
9.3 Audits and Inspections
The sponsor or its representative (WuXi Clinical Co., Ltd) may conduct quality assurance audits
on the study site, database, and relevant study-related documents. Also, regulatory authorities
may also decide to inspect the study site, database, and relevant study-related documents at its
own discretion. The aim of audits and inspections is to systematically and independently check
all study-related procedures and documents to ensure that the clinical study is being carried out
in accordance with requirements of the trial protocol, GCP, Declaration of Helsinki, and
applicable regulations. The investigator must inform the sponsor immediately when an
inspection notice is received from the regulatory authorities.


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10 ETHICS
10.1 Independent Ethics Committee
The sponsor and its designated personnel will prepare all documents to be submitted to the
independent ethics committee (IEC) of each study site. The trial protocol, informed consent form
(ICF), investigators brochure, subject recruitment material or advertisements (if applicable), as
well as other documents required by regulations must be submitted to the IEC for approval. Prior
to the start of the study, written approval from the IEC must be obtained and provided to the
sponsor. The IEC approval must clearly state the title, number, and version of the study protocol
as well as the version of other documents (e.g. ICF) and the date of approval. The investigator
must notify the sponsor of the IEC's written comments concerning delays, suspension and re-
approval.
The study site must follow the requirements of the IEC. IEC requirements may include
submitting the revised protocol, ICF, or subject recruitment material to the IEC for approval,
local regulatory requirements for safety reports, and regular reports, updates, and submitting the
final report as per IEC requirements. The above documents as well as the IEC approval must be
provided to the sponsor or its designated personnel.
10.2 Implementation of Ethical Principles
The study process and the acquisition of informed consent should comply with the Declaration of
Helsinki, relevant GCP requirements (CPMP/ICH/135/95), and applicable statutes and
regulations related to drugs and data protection in the country in which the study is conducted.
The GCP is an international ethical and scientific quality standard for designing, conducting,
recording and reporting clinical trials that involve the participation of human subjects. To protect
the rights, safety, and healthy of subjects, this study will be carried out in accordance with GCP
and applicable national regulations, as well as ethical principles outlined in the Declaration of
Helsinki.
The investigator is required to follow the procedures specified in this protocol and must not
change the procedures without the permission from the sponsor. Protocol deviations will be
reported in accordance with the requirements of each ethics committee.


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10.3 Subject Information and Informed Consent
Prior to undergoing any study procedure, the ICF should be used to explain to potential participants
the potential risks and benefits of this study. The informed consent form should be in a language
that is simple and be easy to understand. The ICF should state that informed consent is voluntary,
emphasize the potential risks and benefits of participating in this study, and that the subject may
withdraw from the study at any time. The investigator may only enroll a subject after fully
explaining the details of the study, answering questions to the subject's satisfaction, giving
the subject sufficient time for consideration, and obtaining written consent from the subject or
his/her legal representative. All signed ICF must be retained in the investigator's documents or
the subject's folder.
The investigator is responsible for explaining the contents of the ICF and obtaining the ICF
signed and dated by the subject or his/her legal representative prior to starting the study. The
investigator should provide the subject with a copy of the signed ICF. The investigator must
document the informed consent process in the source document of the trial.
10.4 Protection of Subject Data
Information about data protection and privacy protection will be included in the ICF (or in some
cases, in a separate document).
Study personnel must ensure that the privacy of clinical trial subjects are protected. In all
documents submitted to the sponsor, the clinical trial subjects must only be identified with
subject number and not with the full name.
Additional precautions should be taken to ensure the confidentiality of the documents and
to prevent the identification of subjects based on genetic data. However, under special
circumstances, some personnel may be permitted to see the genetic data and personal
identification number of a subject. For example, in the event of a medical emergency, the
sponsor, designated physician, or investigator will have access to the subject identification code
and the subject's genetic data. In addition, regulatory agencies may request access to relevant
documents.


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11 STUDY MANAGEMENT
11.1 Organizational Structure
Refer to Table 3 for relevant collaborating parties.
Table 3. Organizational structure
Sponsor
Innovent Biologics (Suzhou) Co., Ltd.
No. 168 Dongping Street, Suzhou Industrial Park, Jiangsu, China
Telephone: (+86) 0512-69566088
Contract research
organization
WuXi Clinical Development Services (Shanghai) Co., Ltd.
19F, Building A, SOHO Fuxing Plaza, 388 Madang Road, Shanghai
Tel: (+86) 21-23158000
Data management and
biostatistics
WuXi Clinical Development Services (Shanghai) Co., Ltd.
19F, Building A, SOHO Fuxing Plaza, 388 Madang Road, Shanghai
Tel: (+86) 21-23158000
11.1.1 Independent review committee
Central imaging evaluation will be performed by Parexel China Co., Ltd. The CT/MRI images of
each subject will be evaluated using RECIST v1.1.
11.2 Archiving of Study Documents
Clinical trial documents (protocol and amendments, completed eCRFs, signed ICFs, etc.) must
be retained and managed as per GCP requirements. The study site must retain these documents
for 5 years after the completion of the study. The sponsor should retain clinical trial data for
5 years after the investigational drug is approved for marketing.
Study documents should be retained properly for future access or data traceability. Safety and
environmental risks should be considered when retaining documents.
The documents associated with the study may only be destroyed with the written consent of the
sponsor and the investigator. Study documents may be transferred to other parties that comply
with or other locations that meet retention requirements only after the sponsor is notified and
written consent thereof is obtained.


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11.3 Access to Source Data/Documents
Source data refers to source records of subject data obtained from a clinical study. These source
records are source documents, which include but are not limited to medical records (hospital
records, nursing records, pharmacy dispensing records, etc.), electronic data, screening logs,
laboratory test results, as well as medical device test results (ECG, CT/MRI, etc.). All source
documents associated with the trial are retained by the study site and the investigator. The
original ICFs will be retained according to standard practices developed by the clinical trial
institution.
The investigator will prepare sufficient and accurate source documents for each randomized
subject in order to document all examination results and other relevant data, and retain these
documents properly.
During the study, the CRA will conduct on-site visits to verify protocol compliance, EDC data
entry, documentation of subjects' medical history, drug inventory, and whether the study is
carried out in accordance with applicable regulations. In addition, regulatory authorities, IRB,
IEC, and/or the quality assurance department of the sponsor will verify source data and/or
conduct on-site audits or inspections. The investigator should allow direct access to documents
associated with the study, including medical records of subjects.
11.4 Protocol Revisions
The sponsor and the investigator must both agree on any appropriate protocol revisions during
the course of the study. The sponsor shall ensure that the protocol revision is submitted to the
regulatory authority in a timely manner.
All protocol revisions must be submitted to the IEC, and if needed, to regulatory authorities for
approval. Revisions may only be implemented after approval from the IEC and regulatory
authorities (if needed) is obtained (except for changes to eliminate immediate risks to subjects).
11.5 Investigator's Responsibilities
The investigator will conduct this study in accordance with the protocol, ethical principles of the
Declaration of Helsinki, Chinese GCP, and applicable regulations. Details of the investigator's
responsibilities are list in Chapter 5 (Investigator's Responsibilities) of the Chinese GCP (NMPA
order No. 3).


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11.6 Study Termination
The study may be terminated after a discussion between relevant parties if the investigator or the
sponsor becomes aware of circumstances or events that could jeopardize the subjects if the study
is continued. The sponsor may also decide to terminate the study even without such findings.
Reasons for study termination include but are not limited to:

Unexpected, serious, or unacceptable risks to enrolled subjects

Slow recruitment

The sponsor decides to suspend or discontinue the development of the drug
11.7 Publishing Policies
All the data generated in this study is the confidential information owned by the sponsor. The
sponsor has the right to publish study results. The investigator shall not publish any data relevant
to this study (posters, abstracts, papers, etc.) without prior communication with the sponsor.
Information on the publishing policies of the sponsor and investigator will be described in the
clinical trial agreement.
11.8 Finance and Insurance
The sponsor will purchase insurance for subjects participating in the study in accordance with
local regulations, and bear the cost of treatment and corresponding financial compensation for
the subjects who suffer injury during the study due to the investigational drug or the study
process. Insurance related terms shall be saved in the study folder.


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12 REFERENCES
1.
GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. Apr.
11, 2016: http://globocan.iarc.fr/Default.aspx
2.
陈万青，郑荣寿，曾红梅，等. 2011 年中国恶性肿瘤发病和死亡分析. 中国肿瘤.
2015;24(1):1-10.
3.
GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. Apr.
11, 2016: http://www.cancer.org/acs/groups/cid/documents/webcontent/003115-pdf.pdf
4.
支修益，石远凯，于今明. 中国原发性肺癌诊疗规范（2015 年版）. 中华肿瘤杂志.
2015;37(1):67-78.
5.
Pisters KMW and Chevalier TL. Adjuvant Chemotherapy in Completely Resected Non–
Small-Cell Lung Cancer. J Clin Oncol. 2005;23:3270-3278.
6.
石远凯，孙燕，于今明，等. 中国晚期原发性肺癌诊治专家共识（2016 年版）. 中国
肺癌杂志. 2016;19(1):1-15.
7.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN
Guidelines®) Non-Small Cell Lung Cancer (Version 4. 2016). Apr. 11, 2016:
http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
8.
郝希山，魏于全. 肿瘤学（第二版）. 北京: 人民卫生出版社. 108; 2010.
9.
Package insert of bevacizumab (Nov. 25, 2015). Apr. 11, 2016:
http://www.roche.com.cn/content/dam/roche_china/zh_CN/pdf/product/Avastin_20151125_
IM %20PI%20CDS32.0-33.0.pdf
10. Sandler A., Gray R., Perry MC., et al. Paclitaxel-carboplatin alone or with bevacizumab for
non-small-cell lung cancer. N Engl J Med. 2006;355:2542-2550.
11. Reck M., von Pawel J., Zatloukal P., et al. Overall survival with cisplatin-gemcitabine and
bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer:
results from a randomized phase III trial (AVAiL). Annals of Ocology. 2010;21:1804-1809.
12. Zhou CC., Wu YL., C GY., et al. BEYOND: A randomized, double-blind, placebo-
controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab
or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung
cancer. J Clin Oncol. 2015;33:2197-2204.
13. IBI305 研究者手册. 信达生物制药（苏州）有限公司. 2016 年5 月11 日.
14. Technical Guidelines for Development and Evaluation of Biosimilars by NMPA (Trial). Apr. 21,
2016: http://www.sda.gov.cn/WS01/CL1616/115104.html


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13 APPENDIX
13.1 Appendix I
Eastern Cooperative Oncology Group (ECOG) Performance Status Score
Score
Performance Status
0
Fully active, and able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activities but able to move around easily and carry out work of
a light or sedentary nature, e.g. light house work or office work
2
Capable of moving around easily and self-care but unable to carry out any work activities; up and
about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or wheelchair more than 50% of waking hours
4
Bedridden and incapable of self-care
5
Death
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative
Oncology Group. Am J Clin Oncol. 1982;5:649-655.


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13.2 Appendix II
Calculation of body surface area
Body surface are (m2) = 0.00616 height (cm) + 0.01286 weight (kg) - 0.1529
Creatinine Clearance (Cockroft-Gault Equation)
Ccr (mL/min) = [(140 - age) x weight (kg)]/[72 x Scr (mg/dL)]
Female subjects: results × 0.85
1 mg/dL = 88.41 µmol/L
Carboplatin Dose (Calvert Equation)
Carboplatin dose (mg) = target AUC (mg/mL/min) × [creatinine clearance rate (mL/min) + 25]
Note: During the study, if the carboplatin dose calculated using the Calvert equation excessively
exceeds the usual clinical dose, choose one of the following two methods to ensure the patient


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safety:
1. Retest the serum creatinine and re-calculate the dose (preferred option).
2. Based on clinical experience, the investigator may choose the highest dose tolerated by the
subject. The dose should remain unchanged for the subsequent cycles.


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13.3 APPENDIX 3
RECIST v1.1
1
MEASURABILITY OF TUMOR AT BASELINE
1.1
Definitions
At baseline, tumor lesions/lymph nodes will be categorized as measurable or not measurable as
follows:
1.1.1
Measurable
Tumor lesions: must be accurately measured in at least one dimension (longest diameter in the
plane of measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm)

10 mm caliper measurement by clinical exam (lesions which cannot be accurately
measured with calipers should be documented as not measurable).

20 mm by chest X-ray.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will
be measured and followed.
1.1.2
Not measurable
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes
with a short axis ≥10 and <15 mm) as well as truly not measurable lesions. Lesions considered
truly not measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion,
inflammatory breast disease, lymphangitis involving the skin or lungs, abdominal masses/
abdominal organomegaly identified by physical exam but not measurable by reproducible
imaging techniques.
1.1.3
Special considerations regarding measurable bone lesions, cystic lesions, and lesions
with prior locoregional treatment:
Bone lesions:

Bone scan, PET scan or plain films are not considered adequate imaging
techniques to measure bone lesions. However, these techniques can be used to
confirm the presence or disappearance of bone lesions.


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
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue
components, that can be evaluated by cross sectional imaging techniques (such as
CT or MRI) can be considered as measurable lesions if the soft tissue
components meet the definition of measurability described above.

Blastic bone lesions are not measurable.
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not
be considered as malignant lesions (neither measurable nor not measurable) since
they are, by definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as
measurable lesions, if they meet the definition of measurability described above.
However, if noncystic lesions are present in the same patient, these noncystic
lesions are preferred for selection as target lesions.
Lesions with prior locoregional treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to
other locoregional therapy are usually not considered measurable, unless there
has been demonstrated progression in the lesion. The study protocol should detail
the conditions under which such lesions would be considered measurable.
1.2
Specifications by Methods of Measurements
1.2.1
Measurement of lesions
All measurements should be documented with metric symbols. Calipers should be used if clinical
assessments are required. All baseline evaluations should be performed as close as possible to
the beginning of the treatment but never more than 4 weeks before the beginning of the treatment.
1.2.2
Method of assessment
The same method of assessment and the same technique should be used to characterize each
identified and reported lesion at baseline and during follow-up. Imaging evaluation should
always be done rather than clinical examination unless the lesion(s) being followed cannot be
imaged but are assessable by clinical examination.
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial
and its diameter is ≥10 mm as assessed using calipers (e.g. skin nodules). For skin lesions,
documentation by color photography including a plotting scale to estimate the size of the lesion
is recommended. As noted above, when lesions can be evaluated by both clinical examination
and imaging evaluation, the latter should be undertaken since it is more objective and may also


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be reviewed at the end of the study.
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.
However, lesions on chest X-ray may be considered measurable if they have clear boundaries
and are surrounded by aerated lung tissues.
CT and MRI: CT is the best currently available and reproducible method to measure lesions
selected for response assessment. This guideline has defined measurability of lesions on CT scan
based on the assumption that CT slice thickness is 5 mm or less. When CT scans have a slice
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice
thickness. MRI is also acceptable in certain situations (e.g. for body scans).
Ultrasound: Ultrasound should not be used for measuring lesion size and should not be used as
a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for
independent review at a later date and, because they are operator dependent, it cannot be
guaranteed that the same technique and measurements will be taken from one assessment to the
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT
or MRI is recommended. If there is concern about radiation exposure at CT, MRI may be used
instead of CT in selected instances.
Endoscopy and laparoscopy: The utilization of these techniques is not recommended for
objective tumor evaluation. However, they can be used to confirm complete pathological
response when biopsies are obtained or to determine relapse in trials where recurrence following
complete response or surgical resection is an endpoint.
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If
markers are initially above the upper limit of normal, however, they must normalize for a patient
to be considered in complete response. Because tumor markers are disease specific, instructions
for their measurement should be incorporated into the protocol on a disease specific basis.
Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response
(in recurrent prostate cancer) have been published. In addition, the Gynecologic Cancer
Intergroup has developed CA125 progression criteria which are to be integrated with objective
tumor assessment for use in first-line trials in ovarian cancer.
Cytology and histology: These techniques can be used to differentiate between PR and CR in rare
cases if required by the protocol (for example, residual lesions in tumor types such as seminoma,
where known residual benign tumors can remain). When effusions are known to be a potential
adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors),
cytological confirmation of the neoplastic origin of any effusion that appears or worsens during


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treatment can be considered if the measurable tumor has met criteria for response or stable
disease in order to differentiate between response (or stable disease) and progressive disease.
2.
TUMOR RESPONSE EVALUATION
2.1
Assessment of Overall Tumor Burden and Measurable Disease
To assess objective response or future progression, it is necessary to estimate the overall tumor
burden at baseline and use this as a comparator for subsequent measurements. Only patients with
measurable disease at baseline should be included in regimens where objective tumor response is
the primary endpoint. Measurable disease is defined by the presence of at least one measurable
lesion. In studies where the primary endpoint is tumor progression (either time to progression or
proportion with progression at a fixed date), the protocol must specify if entry is restricted to
those with measurable disease or whether patients having non-measurable disease only are also
eligible.
2.2
Baseline Documentation of "Target" and "Non-Target" Lesions
When more than one measurable lesion is present at baseline, all lesions (five lesions at most,
and two lesions per organ at most) representative of all involved organs should be identified as
target lesions and will be recorded and measured at baseline (This means in instances where
patients have only one or two organ sites involved, a maximum of two and four lesions
respectively will be recorded).
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be
representative of all involved organs, and should be those with reproducible repeated
measurements. It may be the case that, the largest lesion does not have reproducible
measurements, in which circumstance the next largest lesion with reproducible measurements
should be selected.
Lymph nodes merit special mention since their normal anatomical structures may be visible by
imaging even if not involved by tumor. Pathological nodes which are defined as measurable and
may be identified as target lesions must have a short axis of ≥15 mm by CT scan. Only the short
axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter
normally used by radiologists to judge if a node is invaded by solid tumor. Nodal size is
normally reported as two dimensions in the plane in which the image is obtained (for CT scan
this is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal or
coronal). The smaller of these measures is the short axis. For example, an abdominal node which
is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies as a malignant
measurable node. In this example, 20 mm should be reported as the node measurement. All other
pathological nodes (those with a short axis ≥10 mm but < 15 mm) should be considered non-


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target lesions. Lymph nodes that have a short axis < 10 mm are considered non-pathological and
should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions; short axis for nodal lesions) for all target
lesions will be calculated and reported as the baseline sum of diameters. If lymph nodes are to be
included in the sum, then as noted above, only the short axis is added into the sum. The baseline
sum of diameters will be used as reference to further characterize any objective tumor regression
in the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as
non-target lesions and should also be recorded at baseline. Measurements are not required and
these lesions should be recorded as "present", "absent", or in rare cases "unequivocal
progression". In addition, it is possible to record multiple target lesions involving the same organ
as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple
liver metastases’).
2.3
Response Criteria
2.3.1
Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes
(whether target or non-target) must have a reduced short axis of <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions vs. the
baseline sum of diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions vs.
the smallest sum during the study (this includes the baseline sum if that is the smallest). In
addition to the relative increase of 20%, the sum must also have an absolute increase of at least
5 mm. (Note: The appearance of one or more new lesions is also considered progression).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to
qualify for PD, using the smallest sum of diameters during the study as reference.
2.3.2
Special notes on the assessment of lymph nodes which are target lesions
Lymph nodes identified as target lesions should always have the actual short axis measurement
recorded (measured in the same anatomical plane as during the baseline examination), even if the
nodes regress to below 10 mm at the time of the study. This means that when lymph nodes are
included as target lesions, the "sum" of lesions may not be zero even if complete response
criteria are met, since a normal lymph node is defined as having a short axis of <10 mm. Case
report forms or other data collection methods may therefore be designed to have target nodal
lesions recorded in a separate section where, in order to qualify for CR, each node must have a


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short axis of <10 mm. For PR, SD, and PD, the actual short axis measurement of the nodes is to
be included in the sum of target lesions.
Target lesions that are "too small to measure". During the study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent
evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or lymph nodes
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist
may not feel comfortable assigning an exact measurement and may report them as being "too
small to measure". When this occurs it is important that a value be recorded on the case report
form. If it is the opinion of the radiologist that the lesion has probably disappeared, the
measurement should be recorded as 0 mm. If the lesion is believed to be present and is faintly
seen but too small to measure, a default value of 5 mm should be assigned (Note: It is less likely
that this rule will be used for lymph nodes since they usually have a definable size when normal
and are frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is
believed to be present and is faintly seen but too small to measure, a default value of 5 mm
should be assigned in this circumstance as well). This default value is derived from the 5 mm CT
slice thickness (but should not be changed with varying CT slice thickness). The measurements
of these lesions are potentially non-reproducible, therefore providing this default value will
prevent false responses or progressions caused by measurement errors. To reiterate, however, if
the radiologist is able to provide an actual measurement, that value should be recorded, even if it
is below 5 mm.
Lesions that split or coalesced at the time of treatment. When non-nodal lesions fragment, the
longest diameters of the fragmented portions should be added together to calculate the target lesion sum.
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such that
they are no longer separable, the vector of the longest diameter in this instance should be the maximal
longest diameter for the "coalesced lesion".
2.3.3
Evaluation of non-target lesions
This section provides the definitions of the criteria used to determine the tumor response for the
group of non-target lesions. While some non-target lesions may actually be measurable, they do
not need to be measured and instead should be assessed only qualitatively at the time points
specified in the protocol.
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor
marker level. All lymph nodes must be non-pathological in size (short axis <10 mm).
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor
marker level above the normal limits.


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Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: The
appearance of one or more new lesions is also considered progression).
2.3.4
Special notes on the assessment of progression of non-target lesions
The concept of progression of non-target disease requires additional explanation as follows: When
the patient also has measurable lesions. In this setting, to achieve ‘unequivocal progression’ on the
basis of the non-target lesion, there must be an overall level of substantial worsening in non-target
disease such that, even in the presence of SD or PR of the target disease, the overall tumor burden
has increased sufficiently to merit discontinuation of therapy. A minimal increase in the size of one
or more non-target lesions is usually not sufficient to quality for unequivocal progression status.
The designation of overall progression solely on the basis of change in non-target lesions in the
face of SD or PR of target disease will therefore be extremely rare.
When the patient has only lesions that are not measurable. This circumstance arises in some
phase III trials when the presence of measurable lesions is not a criterion for study enrollment.
The same general concepts apply here as well. However, in this instance there are no measurable
lesions to factor into the interpretation of an increase in non-measurable lesion burden. Because
worsening in non-target lesion cannot be easily quantified (by definition: if all lesions are truly
not measurable), a useful test that can be applied when assessing patients for unequivocal
progression is to consider if the increase in overall lesion burden based on the change in non-
measurable disease is comparable in magnitude to the increase that would be required to declare
PD for measurable disease: i.e. an increase in tumor burden representing an additional 73%
increase in volume (which is equivalent to a 20% increase of diameter in a measurable lesion).
Examples include an increase in pleural effusion from "trace" to "large amount", an increase in
lymphangitic lesion from localized to widespread, or a description in the protocol such as
"sufficient to require a change in therapy". If ‘unequivocal progression’ is seen, the patient
should be considered to have had overall PD at that point. While it would be ideal to have
objective criteria to apply to diseases that are not measurable, the very nature of these diseases
makes it impossible to do so, therefore the increase must be substantial.
2.3.5
New lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on the detection of new lesions are important. There are no specific criteria for the
identification of new radiographic lesions; however, the finding of a new lesion should be
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging
modality or findings thought to represent something other than tumors (for example, some new
bone lesions which may be simply healed or flare of pre-existing lesions). This is particularly


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important when the patient’s baseline lesions show partial or complete response. For example,
necrosis of a liver lesion may be reported by a CT scan as a "new" cystic lesion, while it is
actually not.
A lesion identified during a follow-up in an anatomical location that is not discovered during the
baseline scan is considered a new lesion and will indicate disease progression. For example, a
patient with a visceral disease at baseline has a brain CT or MRI which reveals metastases. The
patient's brain metastases are considered evidence of PD even if he/she does not have brain
imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents a truly new lesion. If repeat scans confirm there is
definitely a new lesion, then progression should be declared using the date of the initial scan.
While FDG-PET response assessments need additional studies, it is sometimes reasonable to
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of
progression (particularly possible "new" lesions). New lesions on the basis of FDG-PET imaging
can be identified as follows:
a.
A negative FDG-PET at baseline and a positive FDG-PET at follow-up is a sign of PD
based on a new lesion.
b.
No FDG-PET at baseline and a positive FDG-PET at follow-up:
If the positive FDG-PET at follow-up corresponds to a new lesion site confirmed by
CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new lesion
site on CT, additional follow-up CT scans are needed to determine if there is truly
progression at that site (if so, the date of PD will be the date of the initial abnormal
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing
lesion site on CT that is not progressing according to the anatomic images, this is not PD.
2.4
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until
the end of treatment, taking into account any requirement for confirmation. On occasion a
response may not be documented until after the end of therapy, so the study protocol should
clearly state if post-treatment assessments are to be considered when determining best overall
response. The study protocol must specify how any new therapy introduced before progression
will affect best response designation. Assignment of best overall response for the patient will
depend on the findings of both target and non-target lesions and will also take into consideration
the appearance of new lesions. Furthermore, depending on the nature of the study and the


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protocol requirements, confirmatory measurement may also be required. Specifically, in non-
randomized trials where response is the primary endpoint, confirmation of PR or CR is needed to
determine which one is the "best overall response".
2.4.1
Time point response
It is assumed that at each time point specified by the study protocol, a response assessment
occurs. Table 1 on the next page provides a summary of the overall response status calculation at
each time point for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used.
2.4.2
Missing assessments and non-evaluable targets
When no imaging/measurement is done at a particular time point, the patient is not evaluable
(NE) at that time point. If only a subset of lesion measurements is made at an assessment, usually
the case is also considered NE at that time point, unless a convincing argument can be made that
the missing lesion(s) would not change the response at the assigned time point. This would be
most likely to happen in the case of PD. For example, if a patient has a baseline sum of 50 mm
with three measured lesions and at follow-up only two lesions are assessed and with a sum of 80
mm, the patient will have achieved PD status, regardless of the contribution of the missing lesion.
2.4.3
Best overall response: all time points
The best response is determined once all the data for the patient is obtained.
Best response determination in trials where confirmation of complete or partial response is not
required: Best response in these trials is defined as the best response across all time points (for
example, the best overall response of a patient who has SD at the first assessment, PR at the
second, and PD at the last is PR). When SD is believed to be best response, it must also meet the
minimum time from baseline specified by the protocol. If the minimum time is not met,
otherwise SD is the best time point response, the patient’s best response depends on subsequent
assessments. For example, if a patient has SD at the first assessment, PD at the second and does
not meet the minimum duration for SD, his/her best response is PD. The same patient lost to
follow-up after the first SD assessment would be considered not evaluable.
Best response determination in trials where confirmation of complete or partial response is
required: Complete or partial responses may be claimed only if the criteria for each are met at a
subsequent time point specified in the protocol (generally 4 weeks later). In this circumstance,
the best overall response can be interpreted as in Table 3.


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2.4.4
Special notes on response assessment
When nodal lesions are included in the sum of target lesions and the nodes decrease to "normal"
size (<10 mm), they may still have a measurement reported on scans. This measurement should
be recorded even if the nodes are normal in size in order not to overstate progression should it be
based on the increase in size of the nodes. As noted earlier, this means that patients with CR may
not have a total sum of "zero" on the case report form (CRF).
In trials where confirmation of response is required, repeated "NE" time point assessments may
complicate best response determination. The analysis plan for the trial must explain how missing
data/assessments will be addressed in the determination of response and progression. For
example, in most trials it is reasonable to consider a patient with time point responses of PR-NE-
PR as a confirmed response.
Patients with a global deterioration of health status requiring discontinuation of treatment without
objective evidence of disease progression at that time should be reported as "symptomatic
deterioration". Every effort should be made to document objective progression even after
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective
response. Instead, it is a reason for stopping the study treatment. The objective response status of
this type of patients is to be determined by evaluation of target and non-target lesions as shown
in Table 1–3.
Conditions that define "early progression, early death, and non-evaluability" are study specific
and should be clearly described in each study protocol (depending on treatment duration and
treatment periodicity).
In some circumstances it may be difficult to distinguish a residual lesion from normal tissues.
When the evaluation of complete response depends upon this determination, it is recommended
that the residual lesion be investigated (by fine needle aspirate/biopsy) before assigning a status
of complete response.
Like a biopsy, FDG-PET may also be used to upgrade a response to a CR in cases where a
residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-
PET in this circumstance should be pre-defined in the protocol and supported by disease specific
medical literature for the indication. However, it must be acknowledged that both approaches
may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.


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Table 1. Time point response: patients with target (+/– non-target) disease.
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or
No
PR
Not all were evaluated
SD
Non-PD or
No
SD
Not all were evaluated
Not all were
evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not evaluable
Table 2. Time point response: patients with non-target disease only.
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PDa
Not all were evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease, and NE = not evaluable.
a "Non-CR/non-PD" is preferred over "stable disease" for non-target disease, since SD is increasingly used as an
endpoint for assessment of efficacy in some trials, thus assigning this category in the absence of measurable
lesions is not advised.
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at
the next scheduled assessment, progression is confirmed, the date of progression should be the
earlier date when progression is suspected.


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Table 3. Best overall response when confirmation of CR and PR required.
Overall response
First time point
Overall response
Subsequent time
point
Best overall response
CR
CR
CR
CR
PR
SD, PD, or PRa
CR
SD
SD provided that the minimum duration for SD is met, otherwise PD
CR
PD
SD provided that the minimum duration for SD is met, otherwise PD
CR
NE
SD provided that the minimum duration for SD is met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided that the minimum duration for SD is met, otherwise PD
PR
NE
SD provided that the minimum duration for SD is met, otherwise NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not
evaluable.
a If CR is truly achieved at the first time point, then any lesions seen at a subsequent time point, even those meeting
PR criteria relative to baseline, make the disease PD at that time point (since lesions must have reappeared after
CR). Best response would depend on whether the minimum duration for SD is met. However, sometimes CR may
be claimed and subsequent scans suggest small lesions are likely still present, while in fact the patient have PR
instead of CR at the first time point. Under these circumstances, CR should be changed to PR and the best response
is PR.
2.5 Frequency of Tumor Re-Evaluation
Frequency of tumor re-evaluation during treatment should be protocol specific and adapted to the
type and schedule of treatment. However, for phase II studies where the beneficial effect of the
treatment is not known, follow-up every 6–8 weeks (timed to coincide with the end of a cycle) is
reasonable. Smaller or greater time intervals may be justified for certain regimens or circumstances.
The study protocol should specify which organ sites are to be evaluated at baseline (usually those
most likely to be involved with metastatic disease for the tumor type under study) and how
often evaluations are repeated. Normally, all target and non-target sites are evaluated at each
assessment. Under certain circumstances, some non-target organs may be evaluated less frequently.
For example, bone scans may need to be repeated only when complete response is identified in
the target lesion or when progression is suspected.


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After the end of the treatment, the need for repeated tumor evaluations depends on whether the
trial has a goal such as a certain response rate or a certain time to an event (progression/death).
If ‘time to an event’ (e.g. time to progression, disease-free survival, progression-free survival) is
the main endpoint of the study, then routine scheduled re-evaluation of lesion sites specified by
the protocol must be carried out. In randomized comparative trials in particular, the scheduled
assessments should be performed on time (for example: every 6–8 weeks during the treatment or
every 3–4 months after the treatment) and should not be affected by treatment delays, holidays or
any other events that might lead to imbalance in the timing of disease assessment between
treatment arms.
2.6 Confirmation of Measurements/Duration of Response
2.6.1 Confirmation
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is
required to ensure responses identified are not the result of measurement errors. This will also
permit appropriate interpretation of results in the context of historical data. Response
confirmation has been traditionally required in such trials. However, in all other circumstances,
i.e. in randomized trials (phase II or III) or studies where stable disease or progression are the
primary endpoints, confirmation of response is not required since it will not add value to the
interpretation of trial results. However, elimination of the requirement for response confirmation
may increase the importance of central review to protect against bias, in particular in studies
which are not blinded.
In the case of SD, measurements after study entry must have met the minimum interval for SD
(generally not shorter than 6–8 weeks) defined in the study protocol at least once.
2.6.2 Duration of overall response
The duration of overall response is measured from the time CR/PR measurement criteria are first
met CR/PR (whichever is first documented) until the date when recurrent or progressive disease
is objectively documented for the first time (using the shortest time to progressive disease
documented during the study as reference).
The duration of overall complete response is measured from the time CR measurement criteria
are first met until the date when recurrent disease is objectively documented for the first time.
2.6.3 Duration of stable disease
Stable disease is measured from the start of the treatment (in randomized trials, from the date
of randomization) until the criteria for progression are met, using the smallest sum during the
study as reference (if the baseline sum is the smallest, then it is used as the reference for the
calculation of PD).


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The clinical relevance of the duration of stable disease varies with different studies and diseases.
If the proportion of patients achieving stable disease for a minimum period of time is an endpoint
of importance in a particular trial, the protocol should specify the minimal time interval required
between two measurements for the determination of stable disease.
Note: The duration of response and stable disease as well as the progression-free survival are
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of the
guidelines to define a standard follow-up frequency. The frequency should take into account
many parameters including disease types and stages, treatment periodicity, and standard practice.
However, limitations of the precision of the measured endpoint should be taken into account if
comparisons between trials are to be made.


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14 INVESTIGATOR SIGNATURE PAGE
Protocol Title: A randomized, double-blind, multi-center phase III study comparing the efficacy
and safety of IBI305 plus paclitaxel/carboplatin vs. bevacizumab plus paclitaxel/carboplatin in
treatment-naive patients with advanced or relapsed non-squamous NSCLC.
Protocol No.: CIBI305A301
This protocol is a trade secret owned by Innovent Biologics (Suzhou) Co., Ltd. I have read and
fully understood this protocol, and agree to conduct this study in accordance with the
requirements found in this protocol and the Good Clinical Practice, and in compliance with
relevant laws and regulations and the Declaration of Helsinki. At the same time, I promise not to
disclose any confidential information associated with this study to any third party without the
written consent of Innovent Biologics (Suzhou) Co., Ltd.
Instructions for the Investigator: Please sign and date this signature page, type the investigator's name and job
title, as well as the name of the study site, and return this document to Innovent Biologics (Suzhou) Co., Ltd.
I have read the entire contents of this study protocol and shall perform the study as required:
Investigator's signature:
Date:
Name (in Print):
Job Title:
Name and Address of Study Site:


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Amendment History for the Study Protocol of a Randomized, Double-Blinded,
Multi-Center Phase III Study Comparing the Efficacy and Safety of IBI305 in
Combination with Paclitaxel/Carboplatin vs. Bevacizumab in Combination
with Paclitaxel/Carboplatin in Treatment-Naive Subjects with Advanced or
Relapsed Non-Squamous Non-Small Cell Lung Cancer
Protocol no.: CIBI305A301
Document Amendment History
Old Version/Date:
Version 3.1/Aug. 27, 2018
New Version/Date:
Version 3.2/Nov. 5, 2018
1
Subject
Version No. and Version Date
Section/Page
Cover/Page 1; Footer/Pages 1–79
Old text
Aug. 27, 2018/Version 3.1
New text
Nov. 5, 2018/Version 3.2
Reason for change
Version Revision.
2
Subject
Definition of efficacy endpoint
Section/Page
Section 7.1.1/Page 50
Old text
It is defined as the proportion of subjects with tumor size reduction of a predefined
amount
New text
It is defined as the proportion of subjects with tumor size reduction of a predefined
amount and for a minimum time period
Reason for change
Consistent with the content in version 3.0.
3
Subject
Primary efficacy analysis
Section/Page
Section 8.5.4.1/Page 58
Old text
ORR is defined as the incidence of complete response (CR) or partial response (PR),
and a radiological method is used to evaluate target and non-target lesions according
to RECIST v1.1.
New text
ORR is defined as the incidence of confirmed complete response (CR) or partial
response (PR), using a validated imaging method to evaluate target lesions and non-
target lesions according to RECIST v1.1.
Reason for change
Consistent with the content in version 3.0.
4
Subject
Secondary efficacy analysis
Section/Page
Section 8.5.4.2/Page 58
Old text
DCR is defined as the incidence of complete response (CR), partial response (PR) and
stable disease (SD), and a radiological method is used to evaluate target and non-
target lesions according to RECIST v1.1.


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New text
DCR is defined as the incidence of patients with confirmed complete response (CR),
partial response (PR), and stable disease (SD), when a validated imaging method and
RECIST v1.1 are used to evaluate target and non-target lesions.
Reason for change
Consistent with the content in version 3.0.


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CLINICAL STUDY PROTOCOL
Study Title:
A randomized, double-blinded, multi-center phase III study
comparing the efficacy and safety of IBI305 plus paclitaxel/carboplatin
versus bevacizumab plus paclitaxel/carboplatin in treatment-naive
subjects with advanced or relapsed non-squamous non-small cell
lung cancer
Protocol No.:
CIBI305A301
Version and Date:
Aug. 27, 2018/Version 3.1
Product Name:
Recombinant anti-VEGF humanized monoclonal antibody
injection (IBI305)
Study Phase:
Phase III
Sponsor:
Innovent Biologics (Suzhou) Co., Ltd.
No. 168 Dongping Street, Suzhou Industrial Park, Jiangsu, China
Sponsor Contact:
Zhou Hui (Senior Medical Director)
Tel: (+86) 21-31652896
E-mail: hui.zhou@innoventbio.com
Confidentiality Statement
This document is the confidential information of Innovent Biologics (Suzhou) Co., Ltd.
The content of this document shall not be disclosed to any person other than the investigators, research consultants
or related personnel, and Institutional Review Board/Independent Ethics Committee.
The information contained in this document must not be used for any purpose, except for the evaluation or
conduction of this study, without the written consent of the sponsor.


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SIGNATURE PAGE
Protocol Title: A randomized, double-blinded, multi-center phase III study comparing the efficacy
and safety of IBI305 plus paclitaxel/carboplatin versus bevacizumab plus paclitaxel/carboplatin in
treatment-naive subjects with advanced or relapsed non-squamous non-small cell lung cancer
Protocol No.: CIBI305A301
Title
Name
Signature
Date
Senior Medical
Director
Zhou Hui
Senior Director of
Biostatistics
Zhang Nan


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PROTOCOL SYNOPSIS
Sponsor/Company:
Innovent Biologics (Suzhou) Co., Ltd.
Investigational drug:
IBI305
Active Ingredient:
Recombinant anti-VEGF humanized monoclonal antibody
Study Title:
A randomized, double-blinded, multi-center phase III study comparing the efficacy
and safety of IBI305 plus paclitaxel/carboplatin versus bevacizumab plus
paclitaxel/carboplatin in treatment-naive subjects with advanced or relapsed non-
squamous non-small cell lung cancer
Protocol No.:
CIBI305A301
Coordinating Investigator:
Zhang Li
Coordinating Center:
Sun Yat-Sen University Cancer Center
Expected study duration: Each subject will receive treatment every 3-week
until progressive disease (PD), unacceptable toxicity, withdrawal of informed
consent, lost to follow-up or death (whichever comes first).
The end of the study is defined as the 18th month after the randomization of
the last subject.
Phase: III
Study Objectives:
Primary Objective:

To compare the objective response rate (ORR) of IBI305 plus paclitaxel/carboplatin versus bevacizumab
plus paclitaxel/carboplatin for the treatment of advanced or relapsed non-squamous non-small cell lung
cancer (NSCLC)
Secondary Objectives:

To compare the duration of response (DOR), progression-free survival (PFS), disease control rate (DCR),
and overall survival (OS) of IBI305 plus paclitaxel/carboplatin versus bevacizumab plus
paclitaxel/carboplatin for the treatment of advanced or relapsed non-squamous NSCLC

To compare the safety and immunogenicity of IBI305 plus paclitaxel/carboplatin versus bevacizumab
plus paclitaxel/carboplatin for the treatment of advanced or relapsed non-squamous NSCLC
Exploratory objectives:

To compare the population pharmacokinetics (PPK) of IBI305 and bevacizumab in subjects with


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advanced or recurrent non-squamous NSCLC

To compare the PD of IBI305 and bevacizumab in subjects with advanced or recurrent non-squamous
NSCLC
Study design:
This is a randomized, double-blinded, multi-center phase III study. The study planned to enroll and randomize 436
subjects with non-squamous NSCLC in a 1:1 ratio to IBI305 plus paclitaxel/carboplatin group or bevacizumab plus
paclitaxel/carboplatin group. Stratifying factors include age (< 60 vs. ≥60 years old) and EGFR status (wild type vs.
unknown type).
Each treatment cycle is 3 weeks for both groups. 15 mg/kg IBI305 or bevacizumab is administered on D1 of each
cycle along with paclitaxel/carboplatin. Subjects will receive up to 6 treatment cycles of combination therapy until
PD, unacceptable toxicity, withdrawal of informed consent, loss to follow-up, or death (whichever comes first).
Then subjects receive maintenance monotherapy, that is, discontinuing paclitaxel/carboplatin while continuing
therapy with IBI305 or bevacizumab. The maintenance monotherapy continues every 3 weeks. On D1 of each
treatment cycle, subjects will be administered 7.5 mg/kg of either IBI305 or bevacizumab until PD, unacceptable
toxicity, withdrawal of informed consent, loss to follow-up, death, or end of study (whichever comes first).
During the study, a CT or an MRI will be performed every 6 weeks (± 7 days) and be determined whether the study
treatment will be continued by investigators at each site through tumor assessments until PD, withdrawal of informed
consent, lost to follow-up, death, start of other anti-tumor therapies, or end of study. If subjects discontinue the study
treatment for reasons other than PD, tumor assessments will be continued until PD, withdrawal of informed consent, loss
of follow-up, death, start of other anti-tumor therapies, or end of study. If subjects discontinue the study treatment for PD,
the investigators will make telephone follow-up every 12 weeks (± 7 days) to collect information of subsequent anti-tumor
therapies and survival until withdrawal of informed consent, lost to follow-up, death, or end of study.
Number of Subjects:
436
Diagnosis and main inclusion
criteria:
Inclusion Criteria:
Subjects must meet all of the following inclusion criteria to be enrolled in the study:
1)
Sign the formed consent form
2)
Male or female ≥18 and ≤75 years old
3)
Histologically or cytologically confirmed unresectable locoregionally
advanced (stage IIIB), metastatic (stage IV), or relapsed non-squamous
NSCLC; mixed tumors should be categorized according to the main cell
types
4)
Histologically or cytologically confirmed EGFR wild type or non-
sensitive mutation type
5)
Must have at least one measurable target lesion (as per RECIST 1.1)
6)
Eastern Cooperative Oncology Group Performance Status (ECOG PS)


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score of 0–1
7)
Expected survival ≥6 months
8)
Laboratory results during screening:
a)
Routine blood test: WBC ≥3.0 × 109/L, ANC ≥1.5 × 109/L, platelets ≥
100 × 109/L, and hemoglobin ≥90 g/L
b)
Hepatic function: TBIL < 1.5 × ULN; ALT and AST < 2.5 × ULN for
subjects without liver metastasis, or ALT and AST < 5 × ULN for subjects with
liver metastasis
c)
Renal function: SCr ≤1.5 × ULN or CrCl ≥50 mL/min, and urine
protein < 2+ in routine urinalysis. Subjects with urine protein ≥2+ from
urinalysis dipstick at baseline, a 24-h urine should be collected with total protein
content < 1 g
d)
INR ≤1.5 and PTT or aPTT ≤1.5 × ULN within 7 days prior to the
study treatment
9)
Able to comply with study protocol
10)
Female and male subjects of childbearing age, and partners of these male
subjects must agree to use effective contraceptive measures (such as
abstinence, sterilization, oral contraceptives, medroxyprogesterone
injections or contraceptive implants) during the study and for 6 months
after the infusion of the study drug
Exclusion Criteria:
Subjects meeting any of the followings will not enrolled in the study:
1)
Prior systemic chemotherapy or targeted therapy (such as monoclonal
antibody or tyrosine kinase inhibitor) for the treatment of the current
stage of disease (Stage IIIB not suitable for multidisciplinary treatment,
stage IV or relapsed disease). Prior surgery and radiotherapy are
permitted, provided that the criteria outlined in the study protocol are met.
Subjects who received prior adjuvant therapy and relapsed within 6 months
are not eligible
2)
Mixed non-small cell and small cell carcinoma, or mixed adenosquamous
carcinoma predominantly containing squamous cell carcinoma component
3)
Histologically or cytologically confirmed EGFR-sensitive mutation type
(including exon 18-point mutation (G719X), exon 19 deletion, and exon
21-point mutations (L858R and L861Q)). Subjects with unknown EGFR
status for various reasons might enroll.
4)
History of hemoptysis within 3 months prior to screening, with a volume
of blood greater than 2.5 mL each time


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5)
Radiographic evidence of tumor invasion in great vessels. The
investigator or the radiologist must exclude subjects with tumors that are
fully contiguous with, surrounding, or extending into the lumen of a great
vessel (such as pulmonary artery or superior vena cava)
6)
Symptomatic CNS metastasis; subjects with asymptomatic brain
metastasis or subjects who are symptomatically stable after treatment for
brain metastasis might enroll if the following criteria are met: measurable
lesions outside the CNS; no midbrain, pons, cerebellum, medulla or
spinal cord metastasis; no history of intracranial hemorrhage;
7)
Subjects who received radical thoracic radiotherapy within 28 days prior
to enrollment; subjects who received palliative radiation for non-thoracic
bone lesions within 2 weeks prior to the first dose of the study drug
8)
Subjects with severe skin ulcers or fracture, or having major surgery
within 28 days prior to randomization or expecting to have major surgery
during the study
9)
Subjects who received minor surgery within 48 hours prior to the first
dose of the study treatment (Outpatient/inpatient surgery requiring
locoregional anesthetics, including central line insertion)
10)
Currently or recently (within 10 days prior to the first dose of the study
treatment) used aspirin (> 325 mg/day) or other known NSAIDs to
inhibit platelet function for 10 consecutive days
11)
Currently or recently (within 10 days prior to the first dose of the study
treatment) received treatment with full dose oral or parenteral
anticoagulant or thrombolytic agents for 10 consecutive days. However,
anticoagulants for prophylaxis are accepted
12)
Subjects with inherited hemorrhagic tendency or coagulopathy, or history
of thrombosis
13)
Uncontrolled hypertension after treatment (systolic greater than 140
mmHg and/or diastolic greater than 90 mmHg), history of hypertensive
crisis or hypertensive encephalopathy
14)
Any unstable systemic disease including but not limited to: active
infection, unstable angina, cerebrovascular accident or transient cerebral
ischemia (within 6 months prior to screening), myocardial infarction
(within 6 months prior to screening), cardiac failure congestive (NYHA
Class ≥II), severe arrhythmia requiring medication, and liver, kidney or
metabolic disease
15)
History of the following diseases within 6 months prior to screening:
gastrointestinal ulcers, gastrointestinal perforation, corrosive esophagitis
or gastritis, inflammatory bowel disease or diverticulitis, abdominal


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fistula, or intra-abdominal abscess
16)
Subjects with tracheoesophageal fistula
17)
Clinically significant third spacing (such as ascites or pleural effusion
that are uncontrollable by drainage or other treatments)
18)
Subjects with current interstitial lung disease or CT showing active
pneumonia during screening
19)
History of malignant tumors other than NSCLC within 5 years prior to
randomization, except for adequately treated cervical carcinoma in situ,
basal or squamous cell skin cancer, locoregional prostate cancer after
radical surgery, ductal carcinoma in situ after radical surgery, or papillary
thyroid carcinoma
20)
Subjects with active autoimmune disease
21)
Subjects who were HBsAg-positive, and peripheral blood HBV DNA
titer ≥1 × 103 copies/L or ≥200 IU/mL; subjects who were HBsAg-
positive and peripheral blood HBV DNA titer < 1 × 103 copies/L or <
200 IU/mL might be eligible if the investigator determines that the
subject's chronic hepatitis B infection is stable and participation in the
study would add no further risks to the subject
22)
Subjects who are tested positive for HCV antibody, HIV antibody or
syphilis
23)
Subjects with known history of allergic diseases or allergic physique
24)
Received treatment with other investigational drugs or participated in
another interventional study within 30 days prior to screening
25)
History of alcohol or drug abuse
26)
Female subjects who are pregnant or breastfeeding, or expected to be
pregnant or breastfeeding during the study
27)
Known allergies to bevacizumab or any of its excipients, or any
chemotherapeutic agents
28)
Other conditions unsuitable for the inclusion as determined by the investigator
Investigational Drug, Dosage,
and Route of Administration:
IBI305: 15 mg/kg in combination chemotherapy and 7.5 mg/kg maintenance
monotherapy, administered via intravenous infusion on D1 of every 3-week
treatment cycle until PD, unacceptable toxicity, withdrawal of informed consent,
lost to follow-up, death, or end of study (whichever comes first)
Control Drug, Dosage, and
Route of Administration:
Bevacizumab: 15 mg/kg in combination chemotherapy and 7.5 mg/kg
maintenance monotherapy, administered via intravenous infusion on D1 of
every 3-week treatment cycle until PD, unacceptable toxicity, withdrawal of


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informed consent, lost to follow-up, death, or end of study (whichever comes
first)
Chemotherapy:
Paclitaxel: 175 mg/m² administered via intravenous infusion on D1 of every
3-week treatment cycle for up to 6 cycles until PD, unacceptable toxicity,
withdrawal of informed consent, loss of follow-up, or death.
Carboplatin: Areas under the concentration-time curve (AUC) = 6.0 administered
via intravenous infusion on D1 of every 3-week treatment cycle for up to 6 cycles
until PD, unacceptable toxicity, withdrawal of informed consent, loss of follow-up,
or death.
Evaluation criteria:
Efficacy endpoints:
Primary efficacy endpoint:

Objective response rate (ORR)
Secondary efficacy endpoints:

Duration of response (DOR)

Progression-free survival (PFS)

Disease control rate (DCR)

Overall survival (OS)
Safety endpoints:

Vital signs

Physical examination

Laboratory tests (routine blood test, blood chemistry, and urinalysis)

12-Lead ECG

Adverse event (AE, including treatment-emergent AE (TEAE)), AE of special interest (AESI)
(hypertension, proteinuria, gastrointestinal perforation, hemorrhage [cerebral hemorrhage, hematuria and
upper gastrointestinal hemorrhage], cardiotoxicity, and thrombosis), and serious adverse event (SAE)

Immunogenicity: Positive rates of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs)
PK/PD Endpoints:

Population PK parameters, including steady-state trough concentrations after repeated doses

Changes of serum VEGF at different time points


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Statistical methods:
Sample size calculation:
A number of 218 subjects for each group (436 subjects in total) can provide 80% test power to confirm the clinical
equivalence between the treatments of IBI305 in combination with paclitaxel/carboplatin and bevacizumab in
combination with paclitaxel/carboplatin. Estimation parameters for sample size: The significance level of the two-
sided test is 0.05, the ORR of subjects in the IBI305 and bevacizumab groups is about 50.0%, and the equivalence
margin for the ratio of ORR is taken as (0.75, 1/0.75). Based on the above hypothesis, each group requires 218
subjects (436 subjects in total).
Efficacy analysis:
Clinical equivalence will be determined by whether the 90% confidence interval (CI) of the ratio of ORR between
the IBI305 and bevacizumab arms falls within the preset margin of (0.75, 1/0.75). The ORR and 95% CI of two
groups, ORR difference and 90% CI, and ORR ratio and 90% CI will be estimated using the generalized linear
model (GLM, including groups and stratification factors).
Median survival (OS) and survival curves will be estimated using the Kaplan-Meier method. The hazard ratio (HR)
and 95% CI of two groups will be estimated using the Cox model. DORs and PFSs will be analyzed by the same
method as the median survivals. DCR will be analyzed using the same method for primary efficacy endpoints, but
an equivalence test will not be conducted.
Safety analysis:
All adverse events (AE) will be coded using MedDRA and graded according to CTCAE v4.03. All treatment-
emergent adverse events (TEAEs), Grade 3 or greater TEAEs, serious adverse events (SAEs), investigational drug-
related TEAEs, investigational drug-related SAEs, TEAEs leading to treatment discontinuation, TEAEs leading
to study termination, and adverse events of special interest (AESIs) will be listed based on system organ class,
preferred terms, and groups and the numbers of corresponding subjects and percentages will be summarized.
In addition, the severity of TEAEs and the correlation with the study drug will also be summarized by system
organ class, preferred terms, and treatment groups.
Measured values and changes from baseline for vital signs, physical examination, laboratory tests and 12-lead ECG
will be analyzed using descriptive statistics. Baseline results and worst results during the study will be presented in
cross tabulation.
The number and percentage of subjects who developed anti-drug antibodies and neutralizing antibodies during the
study will be summarized by treatment group.
PK/PD exploratory analysis:
Mainly based on description, and inter-group comparison will be carried out if necessary


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Table 1. Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
AEs
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
a.
After completing the on-site end-of-treatment visit 28 days after the last dose, subjects who discontinue the
investigational drug treatment due to reasons other than PD should continue to undergo tumor assessments once
every 6 weeks (±7 days) until PD (and begin post-PD follow-up thereafter), withdrawal of consent, start of another
antineoplastic treatment, loss to follow-up, death, or study completion.
b.
For subjects with PD, collect survival information once every 12 weeks (84 days, ±7 days) by phone until death,
loss to follow-up, withdrawal of informed consent, or study completion. Subsequent antineoplastic treatments
should be documented in the eCRF.
c.
Only measure weight.
d.
Clinical laboratory tests are carried out at the laboratory of each hospital. If screening laboratory tests (routine
blood test, blood chemistry, and urinalysis) are performed within 7 days prior to the first dose, the screening
results may be used as baseline data. For subsequent visits, all laboratory tests have to be completed within 3
days prior to the dose administration.
e.
A urinalysis is required before each IBI305/bevacizumab infusion to test urine protein.
f.
Women of childbearing age should undergo a serum/urine pregnancy test.
g.
Immunogenicity tests will be performed in all subjects at 3 blood sampling time points: Within 1 hour prior to
the first dose of the study treatment (IBI305/bevacizumab) in C1, within 1 hour prior to the administration of
the study treatment in C4, and during the end-of-treatment visit. Blood specimens that are positive for anti-drug
antibodies (ADA) after dosing will be further tested for neutralizing antibodies (NAb). Samples will be tested
at the designated central laboratory.
h.
Image assessments (CT or MRI) of the brain, chest, abdomen, and pelvis should be completed at baseline. If
these tests are performed within 28 days prior to the first dose of the study drug, they do not need to be repeated
unless the investigator believes that there have been changes in the subject's tumor burden. After the start of
treatment, imaging tests are performed once every 6 weeks (±7 days) and have to be completed within 7 days
prior to the scheduled visits, until progressive disease, start of other treatment, withdrawal of informed consent,
loss to follow-up, death, or study completion. The same method of imaging test is used at baseline and during
follow-up. Imaging evaluations of the chest, abdomen, and pelvis are required.
i.
All subjects should undergo tumor tissue EGFR testing.


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j.
Each treatment cycle of the investigational product contains 3 weeks. The dose of IBI305 or bevacizumab is 15
mg/kg when used in combination with chemotherapeutic drugs and 7.5 mg/kg in the maintenance monotherapy,
given on D1 of every treatment cycle until progressive disease (PD), unacceptable toxic reactions, withdrawal
of informed consent, loss to follow-up, death, or end of study, whichever occurs first. After all assessments
were completed, the study drug was administered followed by chemotherapy. The first dose of study drug was
completed within 24 h after randomization.
k.
Each treatment cycle is 3 weeks long. Chemotherapy (paclitaxel + carboplatin) is administered on D1 of each
cycle for up to 6 cycles, or until disease progression (PD), unacceptable toxicity, withdrawal of informed
consent, loss to follow-up, or death. Paclitaxel is administered after the infusion of study drug is completed,
followed by carboplatin.


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TABLE OF CONTENTS
SIGNATURE PAGE..................................................................................................................... 2
PROTOCOL SYNOPSIS..............................................................................................................3
TABLE OF CONTENTS............................................................................................................ 13
LIST OF ABBREVIATIONS AND DEFINITIONS................................................................18
1
INTRODUCTION............................................................................................................... 20
1.1 Study Background........................................................................................................... 20
1.1.1 Disease background............................................................................................... 20
1.1.2 Investigational drug................................................................................................22
1.1.2.1 Description of investigational drug..............................................................22
1.1.2.2 Preclinical studies........................................................................................ 23
1.2 Study Principles and Risk/Benefit Assessment...............................................................25
1.2.1 Study principles and dose selection....................................................................... 25
1.2.2 Risk/benefit assessment......................................................................................... 26
2
STUDY OBJECTIVES....................................................................................................... 27
2.1 Primary Objective............................................................................................................27
2.2 Secondary Objectives......................................................................................................27
2.3 Exploratory Objectives....................................................................................................27
3
STUDY PLAN......................................................................................................................28
3.1 Overview of Study Design.............................................................................................. 28
3.2 Study Design Discussion.................................................................................................29
4
STUDY POPULATION...................................................................................................... 30
4.1 Inclusion Criteria.............................................................................................................30
4.2 Exclusion Criteria............................................................................................................31
4.3 Screening Failure.............................................................................................................33
4.4 Subject Restrictions.........................................................................................................33
4.5 Subject Withdrawal and Replacement............................................................................ 33
5
STUDY TREATMENT.......................................................................................................35
5.1 Therapies by Study Drugs............................................................................................... 35
5.2 Chemotherapy................................................................................................................. 35
5.3 Dose Adjustment of Each Study Drug............................................................................ 35


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5.3.1 General principles.................................................................................................. 35
5.3.2 Dose adjustments of study drugs........................................................................... 38
5.3.3 Dose adjustments of chemotherapy....................................................................... 43
5.4 Study Drug Properties..................................................................................................... 46
5.6 Packaging, Labeling, and Storage................................................................................... 47
5.7 Subjects Allocation..........................................................................................................47
5.8 Blinding...........................................................................................................................49
5.9 Concomitant Medications and Treatments......................................................................49
5.9.1 Prohibited treatment...............................................................................................49
5.9.2 Permitted treatment................................................................................................49
5.9.3 Treatment after study treatment............................................................................. 50
5.10 Treatment Compliance.................................................................................................. 50
5.11 Drug Return and Destruction........................................................................................ 50
5.12 Study Drug-Related Records.........................................................................................50
6
STUDY PROCEDURE....................................................................................................... 51
6.1 Screening Visits (D -28 to D -1)..................................................................................... 52
6.2 Baseline Visits (D1 of cycle 1)........................................................................................53
6.3 Cycle 2 (week 4 ± 3 days)...............................................................................................54
6.4 Cycle 3 (week 7 ± 3 days)...............................................................................................54
6.5 Cycle 4 (week 10 ± 3 days).............................................................................................55
6.6 Cycle 5 (week 13 ± 3 days).............................................................................................55
6.7 Cycle 6 (week 16 ± 3 days).............................................................................................56
6.8 Cycle 7 and Subsequent Treatment Cycles (±3 Days)....................................................56
6.9 End-Of-Treatment Visit.................................................................................................... 2
6.10 Disease Progression Visit................................................................................................3
6.11 Survival Follow-Up.......................................................................................................13
6.12 Study Completion..........................................................................................................18
6.13 Tumor Assessment........................................................................................................ 20
6.14 Clinical Laboratory Evaluations....................................................................................20
6.15 Vital Signs, Physical Examinations, and Other Safety Assessments............................20
6.15.1 Vital signs............................................................................................................ 22


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6.15.2 Height and weight................................................................................................ 22
6.1.5.3 Physical examinations.........................................................................................23
6.15.4 12-Lead ECG....................................................................................................... 25
6.15.5 Immunogenicity assessment.................................................................................25
6.15.6. Pharmacokinetics/pharmacodynamics................................................................ 26
6.15.6.1 Pharmacokinetics.............................................................................................. 27
6.15.6.2 Pharmacodynamics........................................................................................... 27
6.15.7 EGFR testing........................................................................................................27
7
STUDY ASSESSMENTS.................................................................................................... 27
7.1 Efficacy Assessment........................................................................................................28
7.1.1 Primary efficacy endpoint......................................................................................28
7.1.2 Secondary efficacy endpoints................................................................................ 29
7.2 Safety Assessments......................................................................................................... 30
7.2.1 Adverse events....................................................................................................... 30
7.2.1.5 Management and follow-up of adverse events............................................ 31
7.2.1.6 Adverse event of special interest and expedited reporting.......................... 33
7.2.1.7 Pregnancy.....................................................................................................33
7.2.1.8 Time limits of documenting and reporting AEs.......................................... 33
8
STATISTICS........................................................................................................................36
8.1 Sample Size Determination.............................................................................................36
8.2 Statistical Population.......................................................................................................36
8.3 General Principles for Statistical Analyses..................................................................... 36
8.4 Statistical Methods.......................................................................................................... 36
8.4.1 Adjustments for covariates.....................................................................................39
8.4.2 Managing dropouts and missing data.....................................................................44
8.4.3 Multi-center study..................................................................................................47
8.4.4 Multiple comparisons and adjustments to multiplicity..........................................48
8.5 Statistical Analyses..........................................................................................................48
8.5.1 Subject distribution................................................................................................ 50
8.5.2 Demographics and other baseline characteristics.................................................. 50
8.5.3 Compliance and drug exposure..............................................................................50


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8.5.4 Efficacy.................................................................................................................. 50
8.5.4.1 Primary efficacy endpoint............................................................................51
8.5.4.2 Secondary efficacy endpoints...................................................................... 51
8.5.4.3 Sensitivity analysis...................................................................................... 51
8.5.4.4 Antibody and efficacy analysis....................................................................51
8.5.5 Exploratory analysis...............................................................................................52
8.5.6 Interim analysis......................................................................................................53
8.5.7 Stratified analysis...................................................................................................54
8.5.8 Safety analysis........................................................................................................55
8.5.8.2 Laboratory tests............................................................................................55
8.5.8.3 ECG examinations.......................................................................................56
8.5.8.4 Vital signs, physical examinations, and other safety examinations.............56
8.5.8.5 Concomitant medications............................................................................ 57
9
QUALITY ASSURANCE AND QUALITY CONTROL.................................................57
9.1 Clinical Monitoring......................................................................................................... 58
9.2 Data Management/Coding...............................................................................................58
9.3 Audits and Inspections.................................................................................................... 59
10
ETHICS................................................................................................................................ 59
10.1 Independent Ethics Committee..................................................................................... 60
10.2 Implementation of Ethical Principles............................................................................60
10.3 Subject Information and Informed Consent.................................................................. 62
10.4 Protection of Subject Data.............................................................................................62
11
STUDY MANAGEMENT...................................................................................................64
11.1 Organizational Structure................................................................................................64
11.1.1 Independent review committee............................................................................ 65
11.2 Archiving of Study Documents.....................................................................................66
11.3 Access to Source Data/Documents................................................................................66
11.4 Protocol Revisions.........................................................................................................66
11.5 Investigator's Responsibilities.......................................................................................66
11.6 Study Termination.........................................................................................................66
11.7 Publishing Policies........................................................................................................ 68


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11.8 Finance and Insurance...................................................................................................68
12
REFERENCES.................................................................................................................... 68
13
APPENDIX...........................................................................................................................68
13.1 Appendix I.....................................................................................................................69
13.2 Appendix II....................................................................................................................69
13.3 APPENDIX 3................................................................................................................ 72
14
INVESTIGATOR SIGNATURE PAGE........................................................................... 72
LIST OF TABLES
Table 1. Schedule of follow-up visits............................................................................................78
Table 2. Hypertension severity grades and interventions in CTCAE v4.03..................................79
Table 3. Dose adjustments of paclitaxel and carboplatin (febrile neutropenia and
thrombocytopenia)...........................................................................................................79
Table 4. Dose adjustment of paclitaxel (hepatotoxicity)............................................................... 79
Table 5. Dose adjustment of paclitaxel (neurotoxicity).................................................................80
Table 6. Study drugs......................................................................................................................80
Table 7. Correlation between AEs and investigational drugs............................................................. 80
Table 8. Reporting and follow-up of adverse events.....................................................................80
Table 9. Organizational structure...................................................................................................80
LIST OF FIGURE
Figure 1. Study design schematic.................................................................................................. 78


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LIST OF ABBREVIATIONS AND DEFINITIONS
Abbreviations
Definitions
AE
Adverse event
AESI
Adverse event of special interest
ADA
Anti-drug antibody
ALT
Alanine aminotransferase
AUC
Area under the curve
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
CFDA
China Food and Drug Administration (now National Medical
Products Administration)
CQA
Clinical quality assurance
CR
Complete response
CRA
Clinical research associate
CRO
Contract research organization
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DCR
Disease control rate
DOR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data collection
EGFR
Epithelial growth factor receptor
FAS
Full analysis set
GCP
Good Clinical Practice
HBsAg
Hepatitis B surface antigen
HBV-DNA
Hepatitis B virus deoxyribonucleic acid
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Hazard ratio
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
INR
International normalized ratio
ITT
Intention-to-treat


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NCCN
National Comprehensive Cancer Network
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PK
Pharmacokinetics
PP
Per-protocol
PR
Partial response
PRES
Posterior Reversible Encephalopathy Syndrome
PTT
Partial thromboplastin time
SAE
Serious adverse event
SD
Stable disease
SOP
Standard operating procedure
SS
Safety set
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
VEGF
Vascular endothelial growth factor


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1 INTRODUCTION
1.1 Study Background
1.1.1 Disease background
Lung cancer has the highest incidence and mortality globally among all cancers. According to
the 2012 Global Cancer Statistics (GLOBOCAN 2012) published by International Agency for
Research on Cancer, there were approximately 1.8 million new lung cancer cases worldwide,
which accounted for 13% of the global newly-diagnosed cancers, and 58% of these cases
occurred in underdeveloped areas1. According to the data released by the National Central
Cancer Registry of China in 2015, lung cancer was the most prevalent malignancy in China in
2011, with about 650,000 new cases every year. Lung cancer was also the leading cause of death,
with about 520,000 deaths per year2. The limited clinical treatment of lung cancer is the main
reason for its poor prognosis. There is a huge demand for new types of lung cancer treatment
drugs.
Approximately 85–90% of lung cancers are non-small cell lung cancer (NSCLC) and patients
with NSCLC are usually in the advanced stages when diagnosed3. According to the Chinese
guidelines for the diagnosis and treatment of primary lung cancer, anatomic pulmonary resection
is the mainstay of treatment for early stage lung cancers4. However, despite surgery, some
patients develop distance metastases that eventually lead to death5. Surgery is not possible for
most patients with clearly diagnosed stage IIIB and IV as well as some patients with stage IIIA
NSCLC4. Comprehensive treatment based on systemic therapy is used to maximize patient
survival, control progressive disease, and improve the quality of life6.
In recent years, anti-tumor therapies have entered a new era with the emergency of targeted
drugs. Some of these targeted drugs have demonstrated satisfactory efficacy in the treatment of
advanced NSCLC. These targeted drugs include monoclonal antibodies and tyrosine kinase
inhibitors (TKIs), mostly targeting epidermal growth factor receptors (EGFRs) and vascular
endothelial growth factor (VEGF), such as bevacizumab, cetuximab, gefitinib, erlotinib, and
icotinib. Monoclonal antibodies have become the drugs of choice in various treatment guidelines
due to the good targeting ability, low drug resistance, and good patient tolerability. Bevacizumab
combination chemotherapy is a first-line therapy of NSCLC recommended by the National
Comprehensive Cancer Network (NCCN)7. Additionally, bevacizumab in combination with
paclitaxel/carboplatin has also been approved as the first-line therapy of unresectable advanced,
metastatic, or relapsed non-squamous NSCLC by China Food and Drug Administration (CFDA)
on Jul. 9, 20156.


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Compared with traditional chemotherapy that directly inhibit or kill tumor cells, anti-angiogenic
drugs have the following unique advantages8:

The targets are genetically stable vascular endothelial cells (VECs) rather than highly
heterogeneous tumor cells, thus leading to lower drug resistance;

The number of tumor-induced VECs is far less than that of tumor cells, and the efficacy
is preferable targeting on VECs and their cytokines;

Normal VECs are quiescent, whereas tumor VECs are active in proliferation. Anti-
angiogenic therapy targets activated cells and avoids damage to normal VECs, thus
leading to better targeting ability;

Anti-angiogenic therapy can normalize the tumor vessels and thereby reduce the
pressure in tumor tissues. This enhances the delivery of chemotherapeutic agents into
tumor tissues, thus increasing the efficacy of chemotherapy.
Angiogenesis is a basic biological characteristic of tumors. The growth of both solid and
hematologic tumors are depended on angiogenesis regardless of the nature of tumor cells.
Therefore, anti-angiogenic therapy is broad-spectrum and applicable to various tumors.
Bevacizumab is a recombinant humanized monoclonal antibody that selectively binds to human
VEGF and blocks its biological activity. Bevacizumab consists of a framework region of a
human antibody and a humanized murine antigen binding region that can inhibit the binding of
VEGF to its receptors on epithelial cells, Flt-1 and KDR. By blocking the activity of VEGF and
reducing tumor angiogenesis, tumor growth is inhibited9.
In a study conducted by the Estern Cooperative Oncology Group (ECOG), compared with
chemotherapy alone (paclitaxel/ carboplatin), bevacizumab in combination with paclitaxel/carboplatin
significantly increased the overall survival (OS) (median: 12.3 vs. 10.3 months), progression-free
survival (PFS) (median: 6.2 vs. 4.5 months), and overall response rate (ORR) (35% vs. 15%) in
patients with advanced, metastatic, or relapsed non-squamous NSCLC10. In another foreign
AVAiL study, different doses of bevacizumab (7 and 15 mg/kg) in combination with
chemotherapy (cisplatin and gemcitabine) and placebo combine with chemotherapy were
compared for the treatment of non-squamous NSCLC. The study found that the two
bevacizumab groups had significantly increased the PFS (median: 6.7 months (7.5 mg/kg
combination chemotherapy group) vs. 6.5 months (15 mg/kg combination chemotherapy group)
vs. 6.1 months (placebo combination chemotherapy group)) and the ORR (37.8% (7.5 mg/kg
combination chemotherapy group) vs. 34.6% (15 mg/kg combination chemotherapy group) vs.
21.6% (placebo combination chemotherapy group)) in patients with locally advanced, metastatic,
or relapsed non-squamous NSCLC11. In a BEYOND study conducted in China, compared with


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placebo in combination with paclitaxel/carboplatin, bevacizumab in combination with
paclitaxel/carboplatin significantly increase the PFS (median: 9.2 vs. 6.5 months), OS (median:
24.3 vs. 17.7 months), and the ORR (54% vs. 26%) in patients with advanced or relapsed non-
squamous NSCLC12.
In China, the antibodies and fusion proteins targeting VEGF are research hotspots. However,
since 2006, the clinical efficacies of various drugs have not been verified and no products have
been marketed. Considering the complexity of macromolecular drugs and the limitations of drug
development capability in China, advanced technologies in antibody development, production,
and quality control is required to develop high-quality VEGF inhibitors that are safe and
effective. IBI305 has showed high similarity to bevacizumab in various pharmaceutical and
nonclinical studies (refer to Investigator's Brochure [IB]). Besides, the efficacy and safety of
bevacizumab for treatment of locally advanced, metastatic or relapsed lung cancer have been
verified. The relevant domestic and external pivotal clinical studies are referable for the protocol
design of IBI305 clinical study. In summary, the clinical study of IBI305 for treatment of
NSCLC has a solid foundation and relatively low risks. The successful development of IBI305
indicates an additional first-line targeted drug for lung cancer in China, providing doctors and
patients with more therapeutic options.
1.1.2 Investigational drug
1.1.2.1 Description of investigational drug
IBI305 is a recombinant humanized anti-VEGF monoclonal antibody injection developed by
Innovent Biologics (Suzhou) Co., Ltd. (hereafter as sponsor) that specifically binds human
VEGF. The molecular weight of IBI305 is 149 KDa. IBI305 specifically binds to VEGF-A,
inhibits the binding of VEGF-A to VEGF-R1 and VEGF-R2, blocks the signaling pathways such
as PI3K/Akt/PKB and Ras-Raf-MEK-ERK. IBI305 also inhibits the growth, proliferation, and
migration of VECs and angiogenesis, decreases the vascular permeability, blocks blood supply to
tumor tissues, inhibits the proliferation and metastasis of tumor cells, and induces the apoptosis
of tumor cells, thereby generates anti-tumor effects. The main active ingredient is recombinant
humanized anti-VEGF monoclonal antibody and excipients include sodium acetate, sorbitol, and
polysorbate 8013. Refer to the Investigator's Brochure for the detailed structure and
physicochemical properties of IBI305.


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1.1.2.2 Preclinical studies
Pharmaceutical studies
The pharmaceutical studies showed that stability, primary structure, higher-order structure,
oligosaccharide distribution, charge variant, and product-related impurities of IBI305 are highly
similar to those of bevacizumab, and the process-related impurities meet the proposed
specification. Therefore, IBI305 is considered to have highly similar protein properties and
product quality to bevacizumab13.
Pharmacodynamic studies
In vitro and in vivo pharmacodynamic (PD) studies of IBI305 showed the following findings:
1)
Target: IBI305 displayed specifically high-affinity binding to recombinant human
VEGF-A with an affinity constant same as that of bevacizumab, indicating that IBI305,
the same as bevacizumab, is a specific human VEGF blocker with a clear target.
2)
Specificity: IBI305 displayed specifically high-affinity binding to recombinant human
VEGF-A, medium-affinity binding to canine VEGF-A, but low-affinity binding to
human VEGF-B, VEGF-C, VEGF-D, PlGF, suggesting that IBI305 recognizes specific
targets and has low off-target toxicity risk; no obvious affinity to mouse VEGF-A164
and rat VEGF-A164, suggesting that IBI305 has high species specificity.
3)
Mechanism of action: IBI305 specifically binds to VEGF-A and inhibits the activation
of VEGFR-2 and ERK1/2, blocks the proliferation and migration of HUVEC, and
inhibits the sprouting from rat aortic ring, suggesting that IBI305 antagonizes VEGF-
A-induced signaling pathway to block the proliferation and migration of VECs and
inhibit angiogenesis, which leads to the reduction of nutritional supply and metastasis
of tumor.
4)
Anti-tumor effects: IBI305 significantly inhibits the growth of human colon cancer
Ls174t and lung cancer NCI-H460 cells in xenografts in nude mice, indicating that
IBI305 has significant anti-tumor effects.
Results from in vitro and in vivo studies of IBI305 showed highly similarity with that of
bevacizumab designed simultaneously, demonstrating that the target, mechanism of action,
and anti-tumor effects of IBI305 are highly similar to bevacizumab13.


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Pharmacokinetic studies
In vitro and in vivo pharmacokinetic (PK) studies of IBI305 showed the following findings:
1)
IBI305 showed no significant cross-reactivity with normal human tissues and
cynomolgus monkey tissues, and only cross-reacted with the positive-control. i.e.
human angiosarcoma tissue, suggesting that IBI305 is highly specific to cancer tissues
rather than normal human tissues and has very low on-target toxicity.
2)
Linearity: With single dose or repeated doses of IBI305 (2-50 mg/kg) vis intravenous
injection in cynomolgus monkeys, the test showed significant PK, thus reducing the
suddenly rising toxicity risks with increased clinical doses.
3)
Immunogenicity: With single dose or repeated doses of IBI305 or bevacizumab via
intravenous injection in cynomolgus monkeys, the test showed abnormal changes of
drug concentration-time curves in several animals. The anti-drug antibody (ADA) test
results showed that IBI305 has a medium immunogenicity.
4)
Accumulation: With repeated doses of IBI305 or bevacizumab via intravenous
injection in cynomolgus monkeys, the test showed that drug exposure of the last
dose was significantly higher than that of the first dose, and the steady-state drug
concentration after repeated doses was higher than that after a single dose, suggesting
that the drug may be accumulated in body.
The results of tissue cross-reactivity and PK/toxicokinetic studies in cynomolgus monkeys
indicated that IBI305 and bevacizumab have similar characteristics in tissue cross-reactivity and
PK/toxicokinetics13.
Toxicological studies
Toxicological studies of IBI305 showed the following findings:
1)
Single dose: With single dose of IBI305 (up to 300 mg/kg) via intravenous injection in
cynomolgus monkeys, the test showed good tolerability without any abnormal clinical
symptoms and toxicity. The dose was about 48 times the proposed clinical dose for
human based on body surface area. In the safety pharmacology test, with single dose of
IBI305 (50 mg/kg) via intravenous injection in cynomolgus monkeys, the test showed
no significant effects on the central nervous system, respiratory system, and
cardiovascular system, suggesting that the single dose of IBI305 via intravenous
injection has a high safety.


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2)
Repeated doses: With repeated doses of IBI305 (up to 50 mg/kg) via intravenous
injection twice weekly for 9 consecutive doses in cynomolgus monkeys, equivalent to
20 times the proposed clinical dose for humans (based on the weight), the test showed
extremely mild to mild linear growth arrest of metaphyseal lines at knee joint and
disordered chondrocyte proliferation, extremely mild increases in macrophage count
in white pulp of spleen, pulmonary (including bronchial) hemorrhage, and deposits of
hemosiderin in lymphoid tissue of bronchial mucosa, indicating that the target organ
toxicities are mainly in the bone, spleen, and lungs.
3)
Immunotoxicity and immunogenicity: With repeated doses of IBI305 via intravenous
injection twice weekly for 9 consecutive doses in cynomolgus monkeys, the test
showed medium immunotoxicity to the spleen. Different doses of IBI305 may result in
the production of ADAs, a portion of which are neutralizing antibodies (NAbs),
indicating that IBI305 has medium immunotoxicity and immunogenicity.
4)
Local irritation test: With repeated dose of IBI305 via intravenous injection in
cynomolgus monkeys, the test showed no irritation at the injection site, suggesting that
administration of IBI305 via intravenous injection is safe and feasible.
5)
In vitro hemolysis assay: With maximum proposed clinical concentration of IBI305
(9 mg/mL), the assay showed no hemolysis, suggesting that IBI305 is suitable for
intravenous injection.
IBI305 has high similarity with bevacizumab in safety pharmacology, long-term toxicity,
immunotoxicity, immunogenicity, local irritation, and hemolysis13.
1.2 Study Principles and Risk/Benefit Assessment
1.2.1 Study principles and dose selection
A biosimilar drug refers to a therapeutic biological product that is similar in quality, safety and
efficacy with an approved reference drug14. IBI305, developed and sold in the market by the
sponsor, is a bevacizumab biosimilar, and has the same administration method and indications
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This study is conducted in accordance with the "Guidelines on Development and Evaluation of
Bosimilars (for Trial Version)" issued by the NMPA (formerly CFDA)14. The doses of IBI305
selected in this study are based on the preclinical studies that showed highly similarity between
IBI305 and bevacizumab in pharmacology, PD, PK and toxicology (refer to the Investigator's
Brochure for details). Besides, the efficacy and safety of bevacizumab for treatment of advanced,
metastatic or relapsed non-squamous NSCLC have been verified, and the indications have also
been approved in China. Therefore, the dose and administration of IBI305 is similar to
bevacizumab in this study, that is, 15 mg/kg intravenously on D1 of every 3-week cycle
when used in combination with chemotherapy (paclitaxel and carboplatin). In the subsequent
maintenance monotherapy therapy, IBI305 will be given intravenously at a dose of 7.5 mg/kg on
the first day of every 3-week cycle. This design of this study is to further demonstrate that
IBI305 is similar to bevacizumab in clinical efficacy, safety, and immunogenicity in subjects
with advanced, metastatic or relapsed non-squamous NSCLC.
1.2.2 Risk/benefit assessment
IBI305 is a bevacizumab biosimilar developed by the sponsor. Based on the clinical pharmacology
and toxicology characteristics of IBI305, the risks and benefits of IBI305 are expected to be similar
to bevacizumab.
The treatment-related risks of bevacizumab are detailed in its prescribing information. This study
is the first human study of IBI305 so that unexpected adverse reactions will be possible. The
design of this study ensures the minimized subject risks by close monitoring of the adverse
events (AEs) before, during, and after the infusion of the investigational drugs. Once an adverse
reaction occurs, the investigator will immediately take appropriate action for the subject safety.
The platinum-based therapy is the standard first-line regimen of advanced NSCLC4. This study
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2 STUDY OBJECTIVES
2.1 Primary Objective
The primary objective of this study is to compare the objective response rate (ORR) of IBI305
plus paclitaxel/carboplatin versus bevacizumab plus paclitaxel/carboplatin for the treatment of
advanced or relapsed non-squamous NSCLC.
2.2 Secondary Objectives
Secondary objectives include:

To compare the duration of response (DOR), progression-free survival (PFS), disease
control rate (DCR), and overall survival (OS) in subjects with advanced or relapsed
non-squamous NSCLC treated by IBI305 plus paclitaxel/carboplatin versus
bevacizumab plus paclitaxel/carboplatin

To compare the safety and immunogenicity of IBI305 plus paclitaxel/carboplatin
versus bevacizumab plus paclitaxel/carboplatin for the treatment of advanced or
relapsed non-squamous NSCLC
2.3 Exploratory Objectives

To compare the population pharmacokinetics (PPK) characteristics of IBI305 and
bevacizumab in subjects with advanced or relapsed non-squamous NSCLC

To compare the pharmacodynamics (PD) characteristics of IBI305 and bevacizumab in
subjects with advanced or relapsed non-squamous NSCLC


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3 STUDY PLAN
3.1 Overview of Study Design
This is a randomized, double-blind, active-controlled, and multi-center phase III study. A total of
436 subjects across 35 study sites with non-squamous NSCLC will be planned, randomized in a
1:1 ratio into the IBI305 plus paclitaxel/carboplatin group or bevacizumab plus paclitaxel/carboplatin
group, and stratified according to age (< 60 vs. ≥60 years old) and epidermal growth factor
receptor (EGFR) status (wild type vs. unknown type). Each treatment cycle is 3 weeks for both
groups. 15 mg/kg IBI305 or bevacizumab is administered on D1 of each cycle along with
paclitaxel/carboplatin. Subjects will receive up to 6 treatment cycles of combination therapy until
PD, unacceptable toxicity, withdrawal of informed consent, loss of follow-up, or death
(whichever comes first). Then subjects received maintenance monotherapy, that is, discontinuing
paclitaxel/carboplatin while continuing maintenance therapy with IBI305 or bevacizumab. The
maintenance monotherapy continues every 3 weeks. On D1 of each treatment cycle, subjects will
be administered 7.5 mg/kg of either IBI305 or bevacizumab until PD, unacceptable toxicity,
withdrawal of informed consent, lost to follow-up, death, or end of study (whichever comes first).
After discontinuing the study drug, subjects will return to the study site 28 days (± 7 days) after
the last dose for an end-of-treatment visit. If the subjects discontinue the study treatment for
reasons other than PD, subsequent follow-up will be continued until PD, withdrawal of informed
consent, start of other anti-tumor therapies, loss of follow-up, death, or end of study. If the
subjects discontinue the study treatment for PD, the investigator will make telephone follow-up
every 12 weeks (± 7 days) to collect information of subsequent anti-tumor therapies and survival.
A CT or an MRI will be performed every 6 weeks (± 7 days) until PD, withdrawal of informed
consent, start of other anti-tumor therapies, loss of follow-up, death, or end of study. The method
for subsequent imaging examination should be consistent with that at baseline, and the chest,
abdomen and pelvis of the subject must be scanned. Each assessment must be completed within
7 days from the most recent visit. The investigators then perform the evaluation based on the
RECIST v1.1 criteria to determine whether the subject can continue receiving the next cycle of
treatment. Furthermore, the independent tumor evaluation committee (Section 11.1.1) will also
evaluate tumor response according to the RECIST v1.1. If the subjects discontinue the study
treatment for reasons other than PD, subsequent tumor evaluation should be continued according
to the study procedures until PD, withdrawal of informed consent, start of other anti-tumor
therapies, loss of follow-up, death or, end of study.
The study design is shown in Figure 1.


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Figure 1. Study design schematic
3.2 Study Design Discussion
This is a randomized, double-blind study, and bias in treatment groups is avoided. Furthermore,
the CT/MRI images of each subject will be evaluated by an independent tumor evaluation committee
according to the RECIST v1.1 to ensure consistency in evaluation.
Screening
period
Combination therapy (once every 3 weeks)
IBI305 or bevacizumab plus
Paclitaxel + carboplatin
Follow-
up
Monotherapy
(once every 3 weeks) IBI305 or
Bevacizumab
End-of-treatment visit
(28 days (±7 days) after
last dose)
Cycle n
D-28
to
D-1
Cycle 1
randomiz
ation
(D1)
Cycle 2
Cycle 3
Cycle 6
Cycle 7
Post-treatment follow-up


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4 STUDY POPULATION
4.1 Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be enrolled in the study:
1)
Sign the informed consent form
2)
Male or female ≥18 and ≤75 years old
3)
Histologically or cytologically confirmed unresectable locoregionally advanced (stage
IIIB), metastatic (stage IV), or relapsed non-squamous NSCLC; mixed tumors should
be categorized according to the main cell types
4)
Histologically or cytologically confirmed EGFR wild type or non-sensitive mutation
type
5)
Must have at least one measurable target lesion (as per RECIST 1.1)
6)
Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0–1
7)
Expected survival ≥6 months
8)
Laboratory results during screening:
a)
Routine blood test: WBC ≥3.0 × 109/L, ANC ≥1.5 × 109/L, platelets ≥100 × 109/L,
and hemoglobin ≥90 g/L
b)
Hepatic function: TBIL < 1.5 × ULN; ALT and AST < 2.5 × ULN for subjects
without liver metastasis, or ALT and AST < 5 × ULN for subjects with liver
metastasis
c)
Renal function: SCr ≤1.5 × ULN or CrCl ≥50 mL/min, and urine protein < 2+ in
routine urinalysis. Subjects with urine protein ≥2+ at baseline urinalysis must
have undergone 24 h urine collection with total protein content < 1 g
d)
INR ≤1.5 and PTT or aPTT ≤1.5 × ULN within 7 days prior to the study treatment
9)
Able to comply with study protocol
10) Female and male subjects of childbearing age, and partners of these male subjects must
agree to use effective contraceptive measures (such as abstinence, sterilization, oral
contraceptives, medroxyprogesterone injections or contraceptive implants) during the
study and for 6 months after the infusion of the study drug


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4.2 Exclusion Criteria
Subjects meeting any of the followings are not enrolled in the study:
1)
Prior systemic chemotherapy or targeted therapy (such as monoclonal antibody or
tyrosine kinase inhibitor) for the treatment of the current stage of disease (Stage IIIB
not suitable for multidisciplinary treatment, stage IV or relapsed disease). Prior surgery
and radiotherapy are permitted, provided that the criteria outlined in the study protocol
are met. Subjects who received prior adjuvant therapy and relapsed within 6 months are
not eligible
2)
Mixed non-small cell and small cell carcinoma, or mixed adenosquamous carcinoma
predominantly containing squamous cell carcinoma component
3)
Histologically or cytologically confirmed EGFR-sensitive mutation type (including
exon 18 point mutation (G719X), exon 19 deletion, and exon 21 point mutations
(L858R and L861Q)). Subjects with unknown EGFR status for various reasons might
enroll.
4)
History of hemoptysis within 3 months prior to screening, with a volume of blood
greater than 2.5 mL each time
5)
Radiographic evidence of tumor invasion in great vessels. The investigator or the
radiologist must exclude subjects with tumors that are fully contiguous with,
surrounding, or extending into the lumen of a great vessel (such as pulmonary artery or
superior vena cava)
6)
Symptomatic CNS metastasis; subjects with asymptomatic brain metastasis or subjects
who are symptomatically stable after treatment for brain metastasis might enroll if the
following criteria are met: measurable lesions outside the CNS; no midbrain, pons,
cerebellum, medulla or spinal cord metastasis; no history of intracranial hemorrhage;
7)
Subjects who received radical thoracic radiation therapy within 28 days prior to
enrollment; subjects who received palliative radiation for non-thoracic bone lesions
within 2 weeks prior to the first dose of the study drug
8)
Subjects with severe skin ulcers or fracture, or having major surgery within 28 days
prior to randomization or expecting to have major surgery during the study
9)
Subjects who received minor surgery within 48 hours prior to the first dose of the study
treatment (Outpatient/inpatient surgery requiring locoregional anesthetics, including
central line insertion)


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10) Currently or recently (within 10 days prior to the first dose of the study treatment) used
aspirin (> 325 mg/day) or other known NSAIDs to inhibit platelet function for 10
consecutive days
11) Currently or recently (within 10 days prior to the first dose of the study treatment)
received treatment with full dose oral or parenteral anticoagulant or thrombolytic
agents for 10 consecutive days. However, anticoagulants for prophylaxis are accepted
12) Subjects with inherited hemorrhagic tendency or coagulopathy, or history of thrombosis
13) Uncontrolled hypertension (systolic greater than 140 mmHg and/or diastolic greater
than 90 mmHg), history of hypertensive crisis or hypertensive encephalopathy
14) Any unstable systemic disease including but not limited to: active infection, unstable
angina, cerebrovascular accident or transient cerebral ischemia (within 6 months prior
to screening), myocardial infarction (within 6 months prior to screening), cardiac
failure congestive (NYHA Class ≥II), severe arrhythmia requiring medication, and
liver, kidney or metabolic disease
15) History of the following diseases within 6 months prior to screening: gastrointestinal
ulcers, gastrointestinal perforation, corrosive esophagitis or gastritis, inflammatory
bowel disease or diverticulitis, abdominal fistula, or intra-abdominal abscess
16) Subjects with tracheoesophageal fistula
17) Clinically significant third spacing (such as ascites or pleural effusion that are
uncontrollable by drainage or other treatments)
18) Subjects with current interstitial lung disease or CT showing active pneumonia during
screening;
19) History of malignant tumors other than NSCLC within 5 years prior to randomization,
except for adequately treated cervical carcinoma in situ, basal or squamous cell skin
cancer, locoregional prostate cancer after radical surgery, ductal carcinoma in situ after
radical surgery, or papillary thyroid carcinoma
20) Subjects with active autoimmune disease
21) Subjects who were HBsAg-positive, and peripheral blood HBV DNA titer ≥1 × 103
copies/L or ≥200 IU/mL; subjects who were HBsAg-positive and peripheral blood
HBV DNA titer < 1 × 103 copies/L or < 200 IU/mL might be eligible if the investigator
determined that the subject's chronic hepatitis B infection was stable and participation
in the study would add no further risks to the subject


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22) Subjects who are tested positive for HCV antibody, HIV antibody or syphilis
23) Subjects with known history of allergic diseases or allergic physique
24) Received treatment with other investigational drugs or participated in another
interventional study within 30 days prior to screening
25) History of alcohol or drug abuse
26) Female subjects who are pregnant or breastfeeding, or expected to be pregnant or
breastfeeding during the study
27) Known allergies to bevacizumab or any of its excipients, or any chemotherapeutic
agents
28) Other conditions unsuitable for the inclusion as determined by the investigator
4.3 Screening Failure
Screening failure is that the subject who has signed the informed consent form fails to meet the
inclusion criteria. Subjects with screening failure will not get a randomization number. The
reasons of screening failure will be documented in the electronic case report forms (eCRFs).
4.4 Subject Restrictions
Female subjects of childbearing age must take effective contraceptive measures during the study
and 6 months after the last dose.
Male subjects must take effective contraceptive measures during the study and 6 months after the
last dose to avoid the pregnancy of their partners.
Restrictions on the use of medication during the study are shown in Section 5.9.
4.5 Subject Withdrawal and Replacement
All subjects may withdraw from this study at any time, with or without a reason. Subjects who
withdraw from the study will not be subjected to discrimination or retaliation, and their medical
treatment will not be affected.
Subjects may discontinue the study treatment or withdraw from the study under the following
circumstances:

Unacceptable toxicity

Progressive disease


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
Investigator believes that the subject should withdraw from the study. If an unacceptable
adverse event (AE) occurs and the investigator believes that the subject should
withdraw from the study, the study treatment should be discontinued and appropriate
measures should be taken. In addition, the sponsor or personnel designated by the
sponsor should be notified.

Withdrawal of informed consent form by the subject

Serious protocol deviation determined by the investigator and/or sponsor

Poor protocol compliance

Study termination by the investigator or sponsor for any reason

Enrollment error* (enrollment of subjects who have violated the inclusion/exclusion
criteria)

Use of prohibited concomitant medications or other medications that the investigator
believes that it may result in toxicities or may affect study results

Subject lost to follow-up

Death of subject
* If the subject is determined by the investigator and the sponsor's doctor to be medically suitable
to continue with the study drugs without any risk or inconvenience, the mistakenly enrolled or
randomized subject will continue with the study treatment and assessments.
In any cases, reasons for withdrawal must be documented in the eCRFs. If the subject withdraws
from the study prematurely for any reason, the investigator should make every effort to persuade
the subject to receive the corresponding assessment, and continue the follow-up of all unresolved
AEs based on the AE reports and follow-up requirements (Table 2):

If the subject withdraws during the study, the series of assessments listed under the End
of Treatment Visit (Section 6.9) should be performed

If the subject withdraws after the end of the treatment visit and has not experienced PD,
the series of assessments listed under the Follow-Up for PD (Section 6.10) should be
performed (tumor assessment is not required to be repeated if it has been performed
within 6 weeks prior to this follow-up)

If the subject withdraws during the follow-up for survival, the information of subsequent
anti-tumor therapies and survival should be collected by telephone follow-up only
Subjects who withdraw their informed consent are not to be contacted again unless they clearly
indicate the willingness to be contacted. The sponsor may use the clinical study data obtained
before the withdrawal of informed consent.


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Subjects who have been randomized will not be replaced.
5 STUDY TREATMENT
5.1 Therapies by Study Drugs
The study drugs of this study are IBI305 and bevacizumab.
In this study, the dose of IBI305 or bevacizumab during combination therapy with chemotherapy
is 15 mg/kg, while the dose during maintenance monotherapy is 7.5 mg/kg. The study drugs are
administered intravenously on D1 of each 3-week cycle until PD, unacceptable toxicity,
withdrawal of informed consent, loss to follow-up, death, or end of study (whichever comes first).
The duration of the first dose of IBI305 or bevacizumab should be 90 min (± 15 min). If the
first infusion is well-tolerated by the subject, then the duration of the second infusion can be
shortened to 60 min (± 15 min). If the 60 min infusion is also well-tolerated by the subject, then
the subsequent infusions can be completed within 30 min (± 15 min).
5.2 Chemotherapy
Paclitaxel will be administered after the IBI305 or bevacizumab infusion is completed, then
followed by carboplatin:
Paclitaxel: 175 mg/m² administered via intravenous infusion for 3 h (may be adjusted according
to clinical practice of each study site) on D1 of every 3-week cycle for up to 6 cycles until PD,
unacceptable toxicity, withdrawal of informed consent, loss of follow-up, or death.
Carboplatin: AUC 6.0, the infusion time is based on the standard practice of each study site,
administered on D1 of every 3-week cycle for up to 6 cycles until PD, unacceptable toxicity,
withdrawal of informed consent, loss of follow-up, or death.
The chemotherapeutic agents are supplied by the sponsor.
Formulas for calculating surface area, creatinine clearance and carboplatin dose are shown in
Section 13.2.
5.3 Dose Adjustment of Each Study Drug
5.3.1 General principles
The reasons for dose adjustments or delayed administration, measures taken, and
results should be documented in the medical records and eCRFs


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If the concomitant symptoms exist at baseline, the investigator will determine whether
the dose should be adjusted according to the change in severity of toxicity. For example,
if the subject has Grade 1 "weakness" at baseline and Grade 2 "weakness" during the
study treatment, the dose should be adjusted based on Grade 1 toxicity since the
severity has increased by one grade
If several toxic reactions of different grades or severity occur simultaneously, the dose
will be adjusted according to the highest observed grade/severity
If a dose adjustment is required solely due to abnormal lab test results, then the dose
should be adjusted based on the measured values obtained prior to the start of the
treatment cycle
If the investigator determines that the toxicity is unlikely to further develop into a
serious or life-threatening event, the current dose will be continued without any
adjustments or treatment interruptions. In addition, dose adjustments or treatment
interruptions will not be performed for non-hemolytic anemia as the symptoms can be
alleviated through blood transfusions.
If the investigator determines that a toxicity is caused by a specific therapeutic drug,
then the dose adjustments of other drugs are not required
Discontinuation of one or two therapeutic drugs before PD will not affect the continued
treatment with other drugs
Dose reductions or adjustments of IBI305 or bevacizumab are not permitted.
Subsequent therapeutic dose will not be adjusted according to weight change, unless
the subject weight has changed by ≥10% from baseline
Once the dose of any chemotherapeutic agents is reduced, the original dose should no
longer be adopted
If any but not all of the therapeutic drug (IBI305, bevacizumab or chemotherapeutic
agents) treatments is interrupted due to toxicity, then this treatment will be considered
as a treatment cycle
If the administration of any one of the chemotherapeutic agents is delayed for more
than 3 weeks, the subject should permanently discontinue that chemotherapeutic agent


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If IBI305/bevacizumab is continued/infused after a delay for more than 3 weeks, the
investigator must discuss with the sponsor


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5.3.2 Dose adjustments of study drugs
Dose adjustments of IBI305 or bevacizumab are not permitted except for the adjustments
(adjusted to 7.5 mg/kg for maintenance monotherapy) specified in the study protocol. The dose
of IBI305 or bevacizumab is calculated according to the subject weight at baseline (prior to the
first dose), and remains unchanged throughout the study, unless the subject weight has changed
by ≥10% from baseline.
If an infusion reaction occurs during a 60-minute infusion, the infusion time should be extended
to 90 minutes for all subsequent infusions. Likewise, if an infusion reaction occurs during a 30-
minute infusion, the infusion time should be extended to 60 minutes for all subsequent infusions.
IBI305 or bevacizumab in combination with paclitaxel/carboplatin will be administered every
3-week treatment cycle for 6 cycles. If PD is not observed in subject during treatment, then the
subject will continue to receive IBI305 or bevacizumab as maintenance monotherapy every 3-
week treatment cycle until PD, unacceptable toxicity, withdrawal of informed consent, loss of
follow-up, death, or end of study (whichever comes first).
If IBI305 or bevacizumab is permanently discontinued due to unacceptable toxicity or subject
refusal to continue the study drugs during the combination therapy, then the subject will continue
to receive the chemotherapy (paclitaxel/carboplatin) until 6 treatment cycles are completed as
determined by the investigator. If any one of the chemotherapeutic agents (paclitaxel or carboplatin)
is prematurely discontinued due to unacceptable toxicity, the subject can continue to receive
IBI305 or bevacizumab treatment until PD, unacceptable toxicity, withdrawal of informed
consent, loss of follow-up, or death (whichever comes first).
When a Grade 3 or 4 IBI305- or bevacizumab-related toxicity is observed, the investigators
should determine whether to continue or terminate IBI305 or bevacizumab treatment according
to the followings:
First occurrence:
IBI305 or bevacizumab administration should be interrupted until toxicity symptoms return to
baseline level or are at least reduced to the Common Terminology Criteria for Adverse Events
(CTCAE) Grade 1 or lower (except for the special circumstances listed below)
Note that when Grade 4 febrile neutropenia and/or thrombocytopenia occur(s), IBI305
or bevacizumab administration should be interrupted until the symptoms return to
baseline levels or at least reduced to CTCAE Grade 1 or lower, since these events
increase the risk of hemorrhage.


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Re-occurrence in re-administration:
If Grade 3 IBI305- or bevacizumab-related toxicity occurs again, the investigator
should assess the risk/benefit of study drug continuation for the subject. If such toxicity
re-occurs again after re-administration, IBI305 or bevacizumab should be permanently
discontinued
If Grade 4 IBI305- or bevacizumab-related toxicity occurs again, IBI305 or
bevacizumab should be permanently discontinued
Measures should be taken in the following special circumstances (classified based on CTCAE
version 4.03):
Hemorrhage
Subjects with Grade 3 or 4 hemorrhages should be treated accordingly and permanently
discontinue the study treatment
Thrombosis/embolism

Subjects with arterial thrombosis of any severity grades should permanently
discontinue the study treatment

Subjects with Grade 4 venous thrombosis should permanently discontinue the
study treatment

Subjects with Grade 3 venous thrombosis should interrupt the study treatment. If
the anticoagulant therapy at the planned therapeutic dose is < 2 weeks, the study
treatment should be interrupted until the anticoagulant therapy is completed. If
the anticoagulant therapy at the planned therapeutic dose is > 2 weeks, IBI305
or bevacizumab administration should be interrupted for 2 weeks, and the study
treatment can be restarted during the anticoagulant therapy if the following criteria
are met:
- INR is within the target range (usually 2-3) prior to restarting of study treatment
- Subjects must not have experienced Grade 3 or 4 hemorrhage since enrollment
- No signs of great vessel invasion or adjacency to great vessels from previous
tumor assessments
Note: Therapeutic dose of anticoagulant therapy is defined as the escalating dose of
warfarin or other anticogulants until INR is maintained at no less than 1.5 (usually


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2-3). The warfarin dose should be documented in the eCRFs, and the INR of
subjects receiving anticoagulant therapy should be monitored during the treatment.
Hypertension
BP should be measured frequently to monitor the occurrence and exacerbation of hypertension.
Subjects should remain at resting position for at least 5 min before BP measurement.
Definition of hypertension: pathologically increased BP with repeated measurements persistently
over 140/90 mmHg
Table 2. Hypertension severity grades and interventions in CTCAE v4.03
CTCAE
Interventions
Grade 1
Pre-hypertension (systolic blood pressure of
120–139 mmHg, diastolic blood pressure of 80–
89 mmHg)
Intervention not indicated
Grade 2
First-stage hypertension (systolic blood pressure
of 140–159 mmHg, diastolic blood pressure of
90–99
mmHg;
repeated
or
persistent
hypertension of ≥24 h), a symptomatic increase
of > 20 mmHg in systolic blood pressure, or an
increase of > 140/90 mmHg from the previous
normal range
Antihypertensive
monotherapy.
drug interruption. The treatment
with the investigational product can
be
continued
once
the
blood
pressure
is
lower
than
140/90
mmHg.
Grade 3
Second-stage
hypertension
(systolic
blood
pressure of ≥160 mmHg, diastolic blood
pressure of ≥100 mmHg)
Multiple-agent
antihypertensive
therapy. Study treatment should be
interrupted in case of persistent or
symptomatic
hypertension;
study
treatment should be permanently
discontinued
for
uncontrollable
hypertension.
Grade 4
Life-threatening consequences (e.g. malignant
hypertension, transient or permanent
neurological deficit, and hypertensive crisis)
Urgent intervention and permanent
study
treatment
discontinuation
indicated
The dose of antihypertensive agents used should be documented during each visit. If the subject
remains hypertensive despite treatment discontinuation, BP and antihypertensive agents used
should be monitored every 3 months until BP returns to normal or end of study.


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Posterior reversible encephalopathy syndrome (PRES)
There have been a few reports of subjects with signs and symptoms consistent with PRES after
study treatment. This is a rare neurological disease and its signs and symptoms include epilepsy,
headache, altered mental status, visual impairment, or cortical blindness, with or without
hypertension. Subjects with PRES should permanently discontinue the study treatment.
Proteinuria
Urinalysis should be performed prior to each dose of IBI305/bevacizumab unless a 24-hour
urinary protein test has already been done.
First occurrence of proteinuria:
After carrying out the urinalysis, if:
Urine protein is < 2+, continue study treatment as scheduled, no additional tests are
required.
≥2+ (urinalysis): perform 24-hour urinary protein test within 3 days prior to
administration:
•
24-hour urinary protein ≤2 g: continue study treatment as scheduled. and perform
urinalysis dipstick test before each scheduled dose.
•
24-hour urinary protein > 2 g: delay study treatment until 24-hour urinary protein ≤2 g.
and a 24-h urine protein test prior to each subsequent dose is performed until urine protein is
reduced to ≤1 g/24 h. Interrupt study treatment only when 24 h urine protein is > 2 g.
Second and subsequent occurrence of proteinuria:
< 3+ (urinalysis): continue study treatment as scheduled, no additional tests indicated.
≥3+ (urinalysis): perform 24-hour urinary protein test within 3 days prior to
administration:
• 24-hour urinary protein ≤2 g: continue study treatment as scheduled.
• 24-hour urinary protein > 2 g: delay study treatment until 24-hour urinary protein ≤2 g.
and a 24-h urine protein test prior to each subsequent dose is performed until urine protein is
reduced to ≤1 g/24 h. Interrupt study treatment only when 24 h urine protein is > 2 g.
Nephrotic syndrome (Grade 4): Study treatment is permanently discontinued


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Gastrointestinal perforation
If gastrointestinal perforation occurs, appropriate measures should be taken and the study
treatment should be permanently discontinued.
Wound healing complications
The study treatment should not begin within 28 d after a major surgery, or before the surgical
wound is fully healed. If a complication of wound healing occurs during study treatment, the
study treatment should be interrupted until the wound is fully healed. If an elective surgery is
required, the study treatment should be interrupted.
Abdominal abscess or fistula
If abdominal abscess or fistula occurs, the study treatment should be discontinued. However, the
investigator will determine whether study treatment will be continued if the above AE is resolved.
Infusion-related and allergic reactions:
Infusion-related reactions after first dose of the study drug is uncommon (< 3%), and the incidence
of a severe reaction is only 0.2%.
If a mild (grade 1 or 2) reaction (such as fever, chills, headache, and nausea) occurs, pretreatment
prior to subsequent administration should be performed and infusion time should not be reduced.
If the subject is well-tolerated during infusion after pretreatment, the infusion time can be
reduced by 30 minutes (+10 minutes) for subsequent administration with pretreatment. If an
infusion-related AE occurs during a 60-minute infusion, the subsequent infusion should be
completed within 90 minutes (+15 minutes) with pretreatment. Likewise, if an infusion-related
AE occurs during a 30-minute infusion, the subsequent infusion should be completed in 60 minutes
(+10 minutes) with pretreatment. If a subject has a grade 3 infusion-related reaction, the study
treatment should be interrupted and not be restarted on the same day. However, since there lacks
the dose adjustment method for grade 3 infusion-related reactions, the investigators may decide
to either discontinue the study drug or perform pretreatment, and complete the infusion within
90 minutes (+15 minutes). If an adverse reaction still occurs during a 90-minute infusion, the
infusion should be continued at a slower rate and then gradually returned to a 90-minute infusion.
If the investigator is uncertain about the handling, the study treatment should be discontinued.
When the study treatment is restarted, the subject should be closely monitored based on routine
clinical practice until the possible time of adverse reaction has passed. If a subject has a grade 4
infusion-related reaction, the study treatment should be discontinued.
An allergic reaction is defined as the vascular collapse or shock (systolic BP < 90 mmHg,
unresponsive to rehydration) that occurs within 30 minutes of a study drug infusion caused by


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an allergy, with or without respiratory distress. Skin reactions include pruritus, urticaria, and
angioedema. Subjects with allergic reactions should discontinue the study treatment.
5.3.3 Dose adjustments of chemotherapy
Paclitaxel and carboplatin should be administered according to the study site guidelines and local
prescribing information. For the specific information for use, preparation, and storage of
paclitaxel and carboplatin, refer to the prescribing information and local dosing information.
Carboplatin-based chemotherapies have a relatively high incidence of emesis. Therefore,
antiemetics for prophylaxis can be used.
Hematological toxicity:
Absolute neutrophil count (ANC; dose can only be reduced when febrile neutropenia occurs.
ANC must be ≥1.5 × 109/L and platelet count must be ≥100 × 109/L on D1 of each treatment
cycle). Once the chemotherapeutic dose is reduced due to febrile neutropenia or
thrombocytopenia (platelet count < 25 × 109/L or 50 × 109/L with hemorrhage or blood
transfusion required), the original dose should no longer be adopted. If the dose reduction is
required for the third time, the chemotherapy should be immediately discontinued.
Table 3. Dose adjustments of paclitaxel and carboplatin (febrile neutropenia and
thrombocytopenia)
Dose Adjustments of Paclitaxel/Carboplatin
First Occurrence Re-Occurrence After
Dose Adjustment
Re-occurrence After Two Dose
Adjustments
Febrile neutropenia
(regardless of duration)
Paclitaxel = 150 mg/m2
Carboplatin = AUC 4.5
Paclitaxel = 100 mg/m2
Carboplatin = AUC 3
Chemotherapy discontinuation
Lowest Level After
Last Dose
<25 × 109/L or
<50 × 109/L with
hemorrhage or requires
blood transfusion
Paclitaxel = 150 mg/m2
Carboplatin = AUC 4.5
Paclitaxel = 100 mg/m2
Carboplatin = AUC 3
Chemotherapy discontinuation
If the dose adjustment is required when ANC and thrombocytopenia occur concurrently, the low-
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Chemotherapy may be delayed for up to 3 weeks. If after the chemotherapy has been delayed for
3 weeks, ANC does not reach ≥1.5 × 109/L and platelet count does not reach ≥100 × 109/L on
D1 of the scheduled chemotherapy, the chemotherapy should be permanently discontinued. If the
above values have been reached, the next course of chemotherapy should be continued.
The investigator should monitor the subject closely for toxicity with particular attention to early
and evident signs of myelosuppression, infection, or febrile neutropenia to timely and
appropriately treat the complications.
Subjects should be informed to pay attention to these signs and receive treatment as soon as possible.
If the chemotherapy must be interrupted due to hematological toxicity, the complete blood count
should be performed regularly (including WBC differentials) until all the counts reach the
minimum requirements for treatment continuation. Thereafter the scheduled treatment plan will
be performed.
Dose adjustments are not required for anemia. However, treatment based on guidelines of each
clinic should be performed.
Gastrointestinal toxicity
Antiemetics will be used to control nausea and/or emesis. If grade 3 or 4 nausea and/or emesis
occur(s) despite of antiemetics, the chemotherapeutic dose should be reduced by 20% for the next
treatment cycle. The dose should be returned to the initial level as possible if the subject is tolerated.
If the subject experiences stomatitis on D1 of any treatment cycle, the chemotherapy should be
interrupted until the symptoms resolve. If the stomatitis has not resolved after 3 weeks, the
chemotherapy should be permanently discontinued (refer to CTCAE version 4.03). If an acute
Grade 3 stomatitis occurs, the chemotherapeutic dose should be reduced to 75% of the proposed
dose when symptoms resolve.
Hepatotoxicity (Paclitaxel)
The paclitaxel dose should be determined based on the lab values measured on D1 of each
treatment cycle.
Table 4. Dose adjustment of paclitaxel (hepatotoxicity)
AST
Total bilirubin
Paclitaxel Dose
≤5 x UNL
and
WNL
175 mg/m2
> 5 x UNL
or
> UNL ~ 1.5 x UN
150 mg/m
> 1.5 x UN
0


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If paclitaxel is interrupted due to hepatotoxicity, carboplatin should also be interrupted until
paclitaxel is restarted. Paclitaxel will be interrupted for up to 3 weeks. If the subject's hepatic
function does not return to the acceptable ranges in 3 weeks, paclitaxel should be permanently
discontinued. The carboplatin dose will not be adjusted when hepatotoxicity occurs.
The investigators should avoid PD due to abnormal hepatic enzyme levels as possible. If PD
occurs, all the study drugs should be permanently discontinued, including chemotherapy.
Cardiovascular toxicity (paclitaxel)
The arrhythmia in subjects was infrequent in previous clinical studies. However, most subjects
were asymptomatic and electrocardiographic monitoring was not required. Asymptomatic
transient bradycardia was observed in 29% of subjects, but significant atrioventricular block was
rare. Cardiac events should be treated as follows:
Asymptomatic bradycardia: no intervention indicated
Symptomatic arrhythmia during infusion: Discontinue paclitaxel infusion and perform
routine treatment of arrhythmia. Discontinue subsequent paclitaxel treatment.
Document this AE in the AE Report Form of eCRF.
Chest pain and/or symptomatic hypotension (< 90/60 mmHg or rehydration therapy
required): discontinue the paclitaxel infusion. Perform electrocardiography (ECG). If
hypersensitivity reaction is suspected, administer diphenhydramine and dexamethasone
via intravenous infusion. If the chest pain is not considered as cardiogenic, epinephrine
or bronchodilators will be administered. Document this AE in the AE Report Form of
eCRF. Discontinue subsequent paclitaxel treatment and provide symptomatic treatment.
Consult a cardiologist if needed.
Neurotoxicity (paclitaxel)
The dose of paclitaxel should be adjusted according to Table when neuropathy occurs. The dose
adjustment of carboplatin is not needed when neurotoxicity occurs.
Table 5. Dose adjustment of paclitaxel (neurotoxicity)
Toxicity Grade (CTCAE version 4.03)
Paclitaxel dose adjustment
Grade 1 or below
175 mg/m2
2
Interrupt treatment until return to grade 1, then reduce dose to 140 mg/m2
(20% of reduction) and restart infusion


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Grade 3 or above
Interrupt treatment until return to grade 1, then reduce dose to 125 mg/m2
(30% of reduction) and restart infusion.
Once the dose is reduced due to neurotoxicity, the original dose should no longer be adopted.
If the neurotoxicity does not return to grade 1 after paclitaxel interruption for 3 weeks, paclitaxel
should be permanently discontinued.
Allergic reactions/hypersensitivity reactions (paclitaxel)
Note: Prophylaxis for hypersensitivity reactions (see below) and close monitoring of vital signs
are recommended for subjects with history of mild to moderate hypersensitivity reactions when
hypersensitivity reactions reoccur.
Mild symptoms: complete paclitaxel infusion. Close monitoring; no treatment indicated.
Moderate symptoms: Interrupt paclitaxel infusion, administer diphenhydramine 25–
50 mg and dexamethasone 10 mg via intravenous infusion. Once symptoms have
resolved, resume paclitaxel infusion at a slower rate (20 mL/hour for 15 minutes, then
at 40 mL/hour for 15 minutes, and if no further symptoms develop, continue at original
rate until infusion is complete). Document this AE in the AE Report Form of eCRF. If
symptoms reoccur, interrupt the paclitaxel infusion and permanently discontinue
subsequent paclitaxel infusion.
Severe and life-threatening symptoms: Interrupt paclitaxel infusion, administer
diphenhydramine and dexamethasone via intravenous infusion (as above). Use
epinephrine or bronchodilators if indicated. Document this AE in the AE Report Form
of eCRF. Subsequent courses of paclitaxel infusion should be permanently
discontinued.
Moderate or severe hypersensitivity reactions should be documented as AEs.
Other toxicities
If other unmentioned grade 3–4 toxicities occur, the chemotherapy should be interrupted until
symptoms resolve or return to grade 1. Thereafter restart the infusion at 50% of the original dose
(which should no longer be adopted). If the toxicity does not return to grade 1 after an
interruption for 3 weeks, the chemotherapy should be permanently discontinued. Dose
adjustments are not recommended for grade 1 and 2 toxicities.
5.4 Study Drug Properties


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IBI305 is a bevacizumab biosimilar. The active ingredient of both drugs is recombinant humanized
anti-VEGF monoclonal antibody; Bevacizumab is the standard commercially available drug, provided
by the sponsor.
Detailed information on the study drugs is shown in Table .
Table 6. Study drugs
Study Drugs
Dosage Form and
Strength
Excipient
Appearance
Manufacturer
IBI305
4 mL: 100 mg
Sodium acetate,
sorbitol, and
polysorbate 80
Sterile solution for
intravenous injection
pH 5.2
Clear, colorless liquid, no
foreign matters, no floc
or precipitation
Innovent Biologics (Suzhou)
Co., Ltd.
Bevacizumab 4 mL: 100 mg
α,α-trehalose
dihydrate, sodium
dihydrogen phosphate
monohydrate,
disodium hydrogen
phosphate,
polysorbate 20, and
sterile water for
injection
Sterile solution for
intravenous injection
pH 5.9–6.3
Clear to slight
opalescent, colorless to
light brown
Roche Pharma (Schweiz)
Ltd.
5.5 Preparation and Distribution
IBI305 or bevacizumab is diluted in 0.9% sodium chloride solution by the pharmacist or research
nurse before infusion. Check the particles and discoloration prior to administration.
The investigator should ensure that the pharmacist or research nurse administers the study drugs
according to study protocol.
5.6 Packaging, Labeling, and Storage
The sponsor should package and label the study drugs according to appropriate local regulations.
All study drugs (IBI305 and bevacizumab) must be stored at 2–8 °C away from light. The study
drugs should be stored in a safe zone only accessible by authorized staff prior to dispensation to
the subjects.
5.7 Subjects Allocation
After confirming that the subject meets all of the inclusion and exclusion criteria, the study site
will log in the Interactive Web Response System (IWRS) and enter the subject information into
the IWRS. The IWRS will allocate a random number to the subject and provide a medication


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number. Stratified randomization is used in this study. Stratifying factors include age (< 60 vs.
≥60 years old) and EGFR status (wild vs. unknown type).


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5.8 Blinding
This is a randomized, double-blind, and active-controlled study, and only relevant study
personnel had access to the randomization numbers. A non-blinded pharmacist or research nurse
will prepare the medications since IBI305 and bevacizumab do not have an identical appearance.
The pharmacist or research nurse who is responsible for preparing the study drugs is not allowed
to disclose any information regarding treatment allocation to the subject, the subject's family
members, or other personnel including the physician and the relevant study staff.
Unblinding: Subject unblinding should only be performed after database locking.
Emergency unblinding: In case of an emergency where the investigator must know the
medication given to a particular subject, the investigator will unblind the subject via the IWRS
and immediately inform the sponsor and CRO. The reasons for unblinding, date, and outcomes
should be documented in the source document and eCRF of the subject.
5.9 Concomitant Medications and Treatments
All medications except for the study drugs, including other chemotherapies not specified in the
study, Chinese herbal medicines, and other non-traditional therapies, are considered concomitant
medications. All concomitant medications used within 30 days prior to screening should be
documented in the eCRFs, including the information of generic name, route of administration,
start date, end date, and indication.
5.9.1 Prohibited treatment
No other anti-tumor therapies or medications with anti-tumor indications, including Chinese
herbal medicine, radiotherapy, or other investigational drugs, are allowed during this study other
than IBI305, bevacizumab, paclitaxel, and carboplatin.
Severe myelosuppression is possible after chemotherapy. Granulocyte colony-stimulating factor
or granulocyte-macrophage colony-stimulating factor are not allowed to be used prophylactically
in the first treatment cycle.
5.9.2 Permitted treatment
Prophylactic use of anti-emetics, glucocorticoids, or other treatments targeting toxicities is permitted
during the study. Unconventional treatments (such as acupuncture) and vitamins/microelements are
permitted if their use does not affect the study endpoints as determined by the investigators.


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Starting from the 2nd chemotherapy cycle, granulocyte colony-stimulating factor or granulocyte-
macrophage colony-stimulating factor are allowed to be used prophylactically to prevent severe
myelosuppression.
Anti-viral therapy was permitted whenever necessary.
Stable doses of anti-epileptic drugs were permitted.
Radiotherapy for bone metastasis was permitted provided that the radiotherapy field did not
include the target lesion
5.9.3 Treatment after study treatment
Subsequent therapy after the end of study treatment should be determined by the subject's
attending doctor.
5.10 Treatment Compliance
Subjects should receive treatment at the study site. The dose and time of administration of
IBI305 or bevacizumab and paclitaxel/carboplatin should be documented in the source records
and eCRFs during each treatment cycle. Reasons for dose adjustments, therapy delay, and
therapy discontinuation should be documented. Treatment compliance is monitored by
medication dispensing and return records, medical records, and eCRFs.
5.11 Drug Return and Destruction
The containers, vials, infusion bags, and syringes of used and partially used drugs can be
destroyed on-site according to the appropriate guidelines and operating procedures established
by study sites and local agencies.
Unless the contents have significant safety issues requiring immediate destruction in accordance
with local regulations, all the unused drugs should be returned and destroyed based on the
requirements of sponsor.
5.12 Study Drug-Related Records
The designated personnel of the study sites should make timely records of receiving, dispensing,
using, storing, returning, and destroying the study drugs in accordance with the relevant
regulations and guidelines.


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6 STUDY PROCEDURE
The detailed procedures of this study are shown in Table 1. Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
.
6.1 Screening Visits (D -28 to D -1)
Complete the screening visits within 28 days prior to study treatment commencement. The
following procedures must be completed during screening to ensure that subject meets the
requirements for participating in this study:

Sign the ICF

Record the demographics, including age, ethnicity, and gender

Record the past medical history, including smoking history

Record the history of anti-tumor therapies

Record the concomitant medications (within 30 days prior to screening)

Record the vital signs

Measure the height and weight (including BMI)

ECOG score

Physical examination

12-Lead ECG

Hepatitis B panel, anti-HCV, anti-HIV, and syphilis tests

Clinical laboratory tests (routine blood test, coagulation test, blood chemistry, and
urinalysis)


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
Blood/urine pregnancy test (for female subjects of childbearing age only)

Imaging examinations (CT or MRI: Head, chest, abdomen, and pelvis cavity)*

EGFR test#

Review the inclusion/exclusion criteria

Record the AEs and concomitant medications
* Retests are not required if the tests have been performed within 28 days prior to the first dose,
unless the investigators suspect changes in tumor burden. Imaging results during screening will
be used as the baseline data. The same method of imaging test is used at baseline and during
follow-up. Imaging evaluations of the chest, abdomen, and pelvis are required.
# If the subject has been tested for EGFR of tumor sample at the study site with documentation,
the subject will not be required for retest.
6.2 Baseline Visits (D1 of cycle 1)
D1 refers to the day of receiving the first dose of the study drugs. Eligible subjects meeting the
inclusion criteria will return to the study site and complete the following procedures:

Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests * (routine blood test, blood chemistry, and urinalysis)

Confirm the inclusion/exclusion criteria
* If clinical laboratory screening tests (routine blood test, blood chemistry, urinalysis) are
performed within 7 days prior to the first dose, then the results of the screening test can be
used as baseline.
If the subject meets the inclusion criteria, the following procedures should be complete:

Randomization and grouping

Immunogenicity test (within 1 h prior to the study drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Pharmacokinetic (PK) blood sampling (within 1 h prior to the study drug infusion,


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immediately after the study drug infusion [+5 min])

VEGF blood sampling (within 1 h prior to the study drug infusion)

Record the AEs and concomitant medications
6.3 Cycle 2 (week 4 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study drug infusion)

VEGF blood sampling (within 1 h prior to the study drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
6.4 Cycle 3 (week 7 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)


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
Record the AEs and concomitant medications
Imaging tests (CT or MRI) should be done every 6 weeks (±7 days), and tumor assessment
should be completed within 7 days prior to this visit to determine whether the study treatment
should be continued.
6.5 Cycle 4 (week 10 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study drug infusion)

Immunogenicity test (within 1 h prior to the study drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
6.6 Cycle 5 (week 13 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study drug infusion)


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
Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
Imaging tests (CT or MRI) should be done every 6 weeks (±7 days), and tumor assessment
should be completed within 7 days prior to this visit to determine whether the study treatment
should be continued.
6.7 Cycle 6 (week 16 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study drug infusion)

VEGF blood sampling (within 1 h prior to the study drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
6.8 Cycle 7 and Subsequent Treatment Cycles (±3 Days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Maintenance monotherapy will start from week 7 and the dose of study drug will be adjusted to
7.5 mg/kg. Subjects should complete the following procedures during each visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG


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
Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Study drug infusion (IBI305 or bevacizumab)

Record the AEs and concomitant medications
Imaging tests (CT or MRI) should be done every 6 weeks (±7 days), and tumor assessment
should be completed within 7 days prior to this visit to determine whether the study treatment
should be continued.
6.9 End-Of-Treatment Visit
The end of treatment visit in study sites will be conducted in 28 days (±7 days) after the last dose
of study drug. Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Immunogenicity test

PD blood sampling

Blood/urine pregnancy test (for female subjects of childbearing age only)

Tumor assessment (CT or MRI, completed within 7 days prior to this visit; not required
to be repeated if it has been performed within 6 weeks prior to this visit)

Subsequent anti-tumor therapy

Record the AEs and concomitant medications
If the subject has not experienced PD, the subsequent follow-up for PD will be performed
(Section 6.10). If the subject has experienced PD, the subsequent follow-up for survival will be
performed (Section 6.11).
6.10 Disease Progression Visit
If the study drugs are discontinued for reasons other than PD, the end of treatment visit in study
sites will be conducted in 28 days after the last dose of study drug, and tumor assessments should
be conducted every 6 weeks (±7 days) until PD if possible (after which, follow-up for survival
will be conducted [Section 6.11]), withdraw of informed consent, loss to follow-up, death,


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start of other anti-tumor therapies, or end of study. During the visit, vital signs and weight
measurements will be performed, and any subsequent anti-tumor therapies will be documented.
6.11 Survival Follow-Up
The investigator will make telephone follow-up every 12 weeks (±7 days) to collect the
information of subsequent anti-tumor therapies and survival until withdrawal of informed
consent, loss to follow-up, death, or end of study.
6.12 Study Completion
The end of this study will be the18th month after randomization of the last subject. If the subjects
continue to receive the study drug treatment before this cut-off time, the treatment should be
discontinued and the end of treatment visit should be completed (Section 6.9).


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6.13 Tumor Assessment
Imaging tests (CT or MRI) of the brain, chest, abdomen, and pelvis are required at baseline. If
these tests are performed within 28 days prior to the first dose of the study drug, they do not need
to be repeated unless the investigator believes that there have been changes in the subject's tumor
burden. After the start of treatment, imaging tests are performed once every 6 weeks (±7 days)
and have to be completed within 7 days prior to the scheduled visits, until progressive disease,
start of other treatment, withdrawal of informed consent, loss to follow-up, death, or study
completion. The same method of imaging test was used at baseline and during follow-up.
Imaging evaluations of the chest, abdomen, and pelvis are required.
The investigator should perform a tumor assessment based on RECIST v1.1 (Section 13.3) prior
to each dose to determine whether the subject should continue with the next round of treatment.
An independent review committee will also assess the tumor response (Section 11.1.1). Imaging
tests will not be rescheduled if the study drugs or chemotherapeutic agents are interrupted due to
toxicities. Every effort should be made to continue the schedule for imaging tests even for
subjects who discontinue one or two study treatment(s) due to drug-related toxicities.
If subject experience PD according to the RECIST v1.1 criteria, the attending doctor should
discuss with the subject regarding subsequent routine cancer therapies.
6.14 Clinical Laboratory Evaluations
Clinical laboratory tests will be conducted at the laboratories of each study site. Sample collection
and analysis should be performed according to the requirements of each laboratory.
The following laboratory tests should be conducted according to the study procedures (Table 1.
Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
):
Routine blood test: hemoglobin, hematocrit, WBC and differentials (including


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absolute neutrophil and lymphocyte counts), platelets, and RBC
Routine coagulation test (baseline test): INR, aPTT, or PTT
➢
Blood chemistry: Creatinine, blood urea, total protein, albumin, total bilirubin,
alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase
(ALT), fasting blood glucose, sodium, potassium, chloride, calcium, phosphorus, and
magnesium
➢
Urinalysis: Specific gravity, pH, glucose, protein, occult blood, and leukocytes
➢
Pregnancy test: Serum/urine pregnancy tests are performed on women of
childbearing age during screening and the end-of-treatment visit.
These tests are carried out at the laboratory of each trial site.
For subsequent visits, all laboratory tests need to be completed within 3 days prior to the
administration. During the study, the frequency of these laboratory tests will be increased if
safety is a concern. The investigator should review the laboratory test results throughout the
study to determine whether the results are clinically significant. The investigator should assess
the changes in laboratory test results. If the investigator considers a laboratory test result to be
abnormal and of clinical significance, it is considered as an AE.
6.15 Vital Signs, Physical Examinations, and Other Safety Assessments
6.15.1 Vital signs
Vital signs include pulse, BP, temperature, and respiratory rate. The subject must rest for at least
5 minutes prior to each vital sign assessment.
Vital signs will be assessed according to the Schedule of Activities (Table 1. Schedule of follow-
up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
). During the study, the investigator may increase the frequency of vital sign measurement if


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safety is a concern.
6.15.2 Height and weight
Height is only measured during screening. Weight is measure during each visit.
6.1.5.3 Physical examinations
The following organs/systems will be examined according to the Schedule of Activities (Table 1.
Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
x
x
x
x
x
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
(IBI305 or
bevacizumab) j
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
): general condition, head (eyes, ears, nose, and throat), neck and thyroid, respiratory system,
cardiovascular system, abdomen, nervous system, skeletal muscles and limbs, as well as
lymphatic system and skin.
6.15.4 12-Lead ECG
12-lead ECG will be performed during screening. During the study, each medication visit
requires an ECG examination. The following ECG parameters should be documented: HR, PR-
interval, QRS-complex, QT-interval, and QTc-interval. The subject must be in the supine
position for at least 5 minutes prior to undergoing the 12-lead ECG. All ECG are evaluated by
qualified physicians. All clinically significant abnormal findings should be reported as AEs.
6.15.5 Immunogenicity assessment
Immunogenicity tests will be performed in all subjects at 3 blood sampling time points: Within
1 hour prior to the first dose of the study treatment (IBI305/bevacizumab) in C1, within 1 hour
prior to the administration of the study treatment in C4, and during the end-of-treatment visit.
Blood specimens that are positive for anti-drug antibodies (ADA) after dosing will be further
tested for neutralizing antibodies (NAb). Samples were tested at the designated central laboratory.
6.15.6. Pharmacokinetics/pharmacodynamics


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6.15.6.1 Pharmacokinetics
Study sites that are implementing version 3.1 of the study protocol should collect PK samples
until 140 subjects in this study meet the requirements for PPK assessment (based on the written
notice of the sponsor). There are 6 PK sampling time points: Within 1 h prior to the first dose of
the study treatment (IBI305/bevacizumab) in C1, immediately after the first infusion (within 5
minutes), within 1 h prior to the dose in C2, within 1 hour prior to the dose in C4, within 1 h
prior to the dose in C5, and within 1 h prior to the dose in C6. Serum will be separated from the
samples at the study site and the serum samples will be analyzed at the designated central
laboratory.
6.15.6.2 Pharmacodynamics
Study sites that are implementing version 2.0 and subsequent versions of the study protocol
should collect PD samples until 140 subjects in this study meet the requirements for VEGF
testing (based on the written notice of the sponsor). There are 4 VEGF sampling time points:
within 1 h prior to the first dose of the study treatment (IBI305/bevacizumab) in C1, within 1 h
prior to the dose in C2, within 1 h prior to the dose in C6, and during the end-of-treatment visit.
Samples were tested at the designated central laboratory.
6.15.7 EGFR testing
EGFR mutation testing histologically or cytologically will be performed in all subjects (if the
subject has been tested for EGFR at the study site histologically or cytologically with
documentation, the subject will not be required to be retested). The testing will be conducted at
the laboratory of each study site or a qualified third-party laboratory.


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7 STUDY ASSESSMENTS
7.1 Efficacy Assessment
7.1.1 Primary efficacy endpoint

Objective response rate (ORR)
ORR will be assessed using RECIST v1.1. ORR is defined as the proportion of subjects whose
tumor volume has reduced to a predetermined value, including patients who achieved complete
response (CR) and partial response (PR). The cut-off date for data included in the primary
efficacy evaluation is the 18th week after the last subject is randomized.
7.1.2 Secondary efficacy endpoints

Duration of response (DOR)

Progression-free survival (PFS)

Disease control rate (DCR)

Overall survival (OS)
Each endpoint will be assessed using RECIST v1.1.
DOR is defined as the time from initial tumor response (CR or PR) to PD or death before PD;
Subjects with CR or PR who do not progress or die will be censored on the date of the last tumor
assessment.
PFS is defined as the time from the date of randomization to the date of PD or death; Subjects
who do not progress or die will be censored on the date of the last tumor assessment.
DCR is defined as the proportion of patients whose tumor volume has reduced to a
predetermined value for a minimum time limit, including patients who achieved CR, PR, and SD.
OS is defined as the time from the date of randomization to the date of death of any cause. For
subjects that are alive on the date of study completion or are lost to follow-up, their survival time
will be censored at the date of last contact.


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7.2 Safety Assessments
7.2.1 Adverse events
7.2.1.1 Definition
Adverse event
An AE refers to any untoward medical occurrence in a subject after signing the informed consent
form, and does not necessarily have a causal relationship with the treatment. Thus, an AE can be
any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or
disease, whether considered drug related.
Abnormalities resulting from PD are not considered as AEs.
Serious adverse event
A SAE refers to an AE meeting at least one of the followings:
(1) Lead to death, except for deaths caused by PD.
(2) Life-threatening (a "life-threatening event" is defined as an AE when the subject is at
immediate risk of death at the time, but does not include the case that may lead to death
only when the event worsens).
(3) Requires hospitalization or prolonged hospitalization, excluding an emergency or
outpatient visit. Subjects with existing diseases or conditions prior to the enrollment
that do not worsen during the study, and having hospitalization and/or surgery that was
scheduled before the study or during the study do not meet the SAE criterion.
Hospitalizations resulting from PD are not considered as SAEs.
(4) Results in permanent or severe disability/incapacity.
(5) Results in congenital anomalies/birth defects.
(6) Other important medical events: The event that does not result in death, is not life-
threatening or does not require hospitalization, but may jeopardize the health of
subjects and require medical intervention to prevent the SAEs above, is considered as
an SAE
7.2.1.2 Severity of adverse events
The severity of AEs is evaluated using the 5-level criteria of NCI CTCAE v4.03.
For AEs not included in CTCAE v4.03, use the following CTCAE general guidelines:


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
Grade 1: Mild; asymptomatic or mild signs; clinical or diagnostic observations only;
medical intervention not indicated.

Grade 2: Moderate; minimal/local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily life (such as cooking, shopping, using the
phone, financial management, etc.).

Grade 3: Severe or clinically significant but not immediately life-threatening;
hospitalization or prolonged hospitalization indicated; disability; limited ability of self-
care (such as bathing, dressing, undressing, eating, using the toilet, taking medication),
but not bedridden.

Grade 4: Life-threatening consequences; urgent intervention indicated.

Grade 5: Death related to AE
7.2.1.3 Relationship between adverse events and the investigational drug
The relationship between the study drugs and AEs can be determined using the followings:
Table 4. Correlation between AEs and investigational drugs
Correlation
CRITERIA
Related

The occurrence of the AE is reasonably related to the time sequence of
dosing;

The investigational drug can more reasonably explain the AE than the
other causes (such as the pre-existing disease of the subject, environment,
toxicity, or other treatment received);

The AE resolves or is alleviated after treatment interruption or dose
reduction;

The AE is consistent with the known type of AEs of the suspicious drug
or similar drugs;

The AE occurs again after the drug administration is resumed.
Possibly related

The occurrence of the AE is reasonably related to the time sequence of
dosing;

The investigational drug can be used to explain the AE with the same
level of rationality as other reasons (such as the pre-existing disease of the
subject, environmental or toxic factors, or other treatments received by
the subject);

The AE resolves or is alleviated after treatment interruption or dose
reduction (if applicable).
Possibly not related

Other reasons can more reasonably explain the AE than the
investigational drug (such as the pre-existing disease of the subject,
environmental or toxic factors, or other treatments received by the
subject);

The AE does not resolve or be alleviated after treatment interruption or
dose reduction (if applicable), or the situation is unclear;

The AE does not occur again or the situation of the AE is unknown after


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the drug administration is resumed.
Unrelated

The occurrence of the AE is not reasonably related to the time sequence
of dosing, or

The AE has other obvious causes (such as the pre-existing disease of the
subject, environmental or toxic factors, or other treatments received by
the subject).
Cannot be determined

The above information is unclear and cannot be determined based on the
available information. Further follow-up information is not accessible to
the investigator.
7.2.1.4 Serious adverse event reporting
SAEs that occur from the signing of informed consent form until 90 days (inclusive) after the last
dose should be reported. The investigator must fill out the "CFDA SAE Report Form", regardless
of whether it is the initial report or a follow-up report, and sign and date the form. The
investigator must report the SAE to the sponsor, CFDA, and ethics committee within 24 hours of
noticing the event. The contact information for reporting is shown in the table below.
For SAEs occurring outside of the above-mentioned period, those considered related to the
investigational drug shall also be reported to the sponsor.
The investigator must submit the completed SAE report form to the sponsor within 24 hours of
noticing the event. The investigator shall urgently perform visit on missing information and
provide a complete SAE report for events that result in death or are life-threatening.
The investigator should also report the event to the CFDA, health administration departments,
and ethics committees in accordance with the regulations.
When submitting the SAE report by email, it is recommended for the investigator to encrypt the
report file and send the report file and password in separate emails.
Table. SAE report contacts
Unit
Contact
Fax/Telephone/Address
Hospital Name
Ethics committee
Hospital Fax/Telephone
Innovent Biologics (Suzhou) Co.,
Ltd.
Clinical Study Department PV
Fax: 021-31652800
Email:
drugsafety@innoventbio.com


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Office of Drug Research and
Supervision, Department of Drug
and Cosmetics Registration,
China Food and Drug
Administration
Address: Building 2, No. 26,
Xuanwumen
West
Street,
Xicheng District, Beijing
Post Code: 100053
Tel: 010-88330732
Fax: 010-88363228
Medical Administrative
Department, Health
Administration
Address: No. 38, Lishi Road,
Xicheng District, Beijing
Tel: 010- 68792001
Fax: 010-68792734
Province, Autonomous Region,
Municipality Food and Drug
Administration
Based on the requirements of the food and drug administration
department of each province, autonomous region or municipality
7.2.1.5 Management and follow-up of adverse events
The investigator is responsible for providing appropriate medical treatment for all AEs (Indicate
the actions taken, such as suspension/termination of the investigational drug, dose modification,
drug therapy, etc.). When an AE occurs, the investigator should actively take appropriate
measures to ensure the safety of the subject. All AEs observed from the signing of the ICF
to the time specified in the protocol (Table 2) must be followed.
The investigator should report any SAE that occurs after the time specified in the protocol (Table 2)
and is suspected of being related to the investigational drug to the sponsor.
7.2.1.6 Adverse event of special interest and expedited reporting
The AESI for this study include:

Gastrointestinal perforation

Procedural and wound healing complications

Hemorrhage

Fistula

Hypertension

Thrombotic event

Posterior reversible encephalopathy syndrome (PRES)


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
Proteinuria

Infusion-related reaction

Ovarian failure

Cardiac failure congestive
If the criteria for SAE is met, the SAE report should be submitted to the sponsor within the
specified time limit (see 7.2.1.4 for details)
7.2.1.7 Pregnancy
Bevacizumab may be harmful to the fetus. Subjects or female partners of male subjects must use
an effective form of contraception during the 6 months after the last dose.
During the study, if a female subject exposed to the study drug becomes pregnant, she must
discontinue study treatment. The investigator must report to the sponsor within 24 hours of
noticing the event and submit the "Innovent clinical Study Pregnancy Report/Follow-Up Form".
During the study, if a female partner of a male subject exposed to the study drugs becomes
pregnant, the subject will continue in the study. The investigator must report to the sponsor
within 24 hours of noticing the event and submit the "Innovent Clinical Study Pregnancy
Report/Follow-Up Form".
The investigator must continuously monitor and visit on the outcome of the pregnancy until 8
weeks after the subject gives birth. The outcome should be reported to the sponsor.
If the outcome of the pregnancy is stillbirth, spontaneous abortion, fetal malformation (any
congenital anomaly/birth defect), or medical abortion, it should be considered as an SAE and the
event is required to be reported in accordance with SAE procedures and time limits.
If the subject also experiences a SAE during the pregnancy, the CFDA SAE Report Form should
also be filled out and reported according to SAE's procedures.
7.2.1.8 Time limits of documenting and reporting AEs
All AEs occurring from the time the subject signs the informed consent form to the time
specified in the protocol (Table 2) (including SAEs and non-SAEs), regardless of their severity,
must be collected and recorded on the AE page of the eCRF.
The investigator must fill out all the required information, including the description of the AE,
start date, end date, severity, measures taken, outcome, seriousness, and causality with the
investigational drug. Each AE should be documented separately.


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Table 5. Reporting and follow-up of adverse events
Reporting time limit
Visit time limit
AEs
From signing the informed consent form to 90 days
after the last dose (if the subject begins other anti-
tumor therapies, only AEs related to the study drugs
should be collected)
Until resolved or explainable stable
determined by the investigator
Pregnancy
From the first dose until 6 months after the last dose
of the study treatment
Until the outcome of the event is
available, and the health conditions of
the newborn should be followed up
for at least 2 months according to the
protocol
7.2.1.9 Precautions for AE documentation
Diagnosis, signs, and symptoms
If a diagnosis is already made, the eCRF should record the diagnosis instead of individual
symptoms and signs (such as hepatic failure rather than jaundice, transaminase increased, and
asterixis). However, if the signs and symptoms cannot be attributed to a definitive diagnosis, each
independent event should be documented in the eCRFs as an AE or SAE. Update the report with
visit information if a diagnosis is confirmed later.
AEs secondary to other events
Generally, AEs secondary to other events (such as result of another event or clinical sequelae)
should be documented as the primary event, unless the event is severe or an SAE. However,
clinically significant secondary events should be recorded as independent adverse events in the
eCRFs if they occur at different times than the primary event. If the relationship between events is
unclear, document them as separate events in the eCRFs.
Ongoing or recurrent AEs
An ongoing AE refers to an event that does not resolve and is ongoing between two assessment
time points. These AEs should only be documented once in the eCRFs. The initial severity should
be documented, and the information should be updated if the event exacerbates.
Recurring AEs refer to AE that have resolved between the two time points of assessment but
subsequently occur. These events should be independently documented in the eCRFs.


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Abnormalities in laboratory tests/vital signs
All clinically significant laboratory test abnormalities should be reported as AEs. It is the
responsibility of the investigator to review all abnormal laboratory test results, and to make
medical judgments as whether each abnormal laboratory test result should be reported as an AE.
Death
During the entire course of the study, all the deaths that occurred within 90 days after the last dose
were documented in the Death Report Form in the eCRFs, regardless of the causality with the
investigational drug.
When recording a death event, if the cause of death is clear, the cause of death is recorded as an
adverse event with the result of the adverse event being death, and the event is reported as an SAE;
if the cause of the death is unknown at the time of reporting , "Death with Unknown Cause" should
be recorded on the Adverse Event Form of the eCRF and the "Death with Unknown Cause" should
be reported as an SAE first before further investigation is carried out to find the exact cause of
death.
Pre-existing medical conditions
Symptoms/signs presenting during the screening period will be recorded and reported as AEs only
if their severity, frequency, or property becomes aggravated (except for worsening of the studied
disease). The relative change should be documented, such as "increased frequency of headaches".
Hospitalization and prolonged hospitalization, or surgery
Any AE that results in hospitalization or prolonged hospitalization should be documented and
reported as an SAE, except for the following situations:

Hospitalization or prolonged hospitalization as required by study protocol (such as for dose
administration, efficacy evaluation, etc.)

Hospitalization due to a pre-existing medical condition that remains stable, e.g. elective
surgery/therapy scheduled prior to the study.
However, elective surgery/therapy required because of the exacerbated condition during the study
(e.g. surgery/therapy required earlier than scheduled) should be considered as an AE.
The investigator should fill in all required information, including AE terms
(diagnostic terms, or the record of symptoms and signs including laboratory test abnormalities if
there is no diagnosis), start date, end date, severity level, whether it is an AESI, measures taken for
the investigational product, treatment given for the AE, outcome, seriousness, and relationship with
the investigational product. If the signs and symptoms cannot be attributed to a definitive diagnosis,
each AE should be documented independently.


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Progressive disease
A progressive disease is defined as the worsening of subject condition caused by the primary tumor
that the investigational drug is targeting, the appearance of new lesions, or the progression of the
primary lesion. Expected progressive disease should not be reported as an AE. Any deaths, life-
threatening events, hospitalization or prolonged hospitalization, permanent or significant
disability/incapacity, congenital anomaly/birth defects, or other important medical events caused
by progressive disease should not be reported as an SAE
8 STATISTICS
8.1 Sample Size Determination
A number of 218 subjects for each group (436 subjects in total) can provide 80% test power to
confirm the clinical equivalence between the treatments of IBI305 in combination with
paclitaxel/carboplatin and bevacizumab in combination with paclitaxel/carboplatin.
The sample size is estimated based on the following assumptions:

The ORRs between IBI305 and bevacizumab group are equivalent

The ORR of subjects in the bevacizumab groups is set to 50.0%

The equivalence margin for the ratio of ORR is taken as (0.75, 1/0.75))

The significance level of the two one-side test is 0.05

1:1 randomization
Based on the above hypotheses, a number of 218 subjects for each group is required (436
subjects in total). The sample size was estimated using PASS 2013.
8.2 Statistical Population
Intention-to-Treat (ITT): All randomized subjects.
Full Analysis Set (FAS): All randomized and evaluable subjects who received at least one dose
of the study treatment. This dataset is used as the primary analysis set for efficacy assessment.
Per-Protocol (PP): Based on the FAS, subjects with the predetermined minimum drug exposure
and without any predetermined major protocol deviations. This dataset is used as the secondary
analysis set for efficacy assessment.
Safety set (SS): Includes all randomized subjects who received at least one dose of the study
treatment and have safety evaluation data. This data set is used for the safety evaluation of this study.


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PK analysis set (PKAS): Includes subjects in the FAS with at least one PPK measured value.
Pharmacodynamic analysis set (PDAS): Includes all subjects in the FAS set with at least one PD
measured value.
8.3 General Principles for Statistical Analyses
For continuous variables, descriptive statistics should include the count, mean, standard
deviation, median, maximum, and minimum. For categorical variables, descriptive statistics will
include the number and percentage of each category. Statistical analyses will be carried out using
SAS 9.4.
8.4 Statistical Methods
8.4.1 Adjustments for covariates
The stratification factors of randomization in this study include age and EGFR status, and the
stratification factors will be considered in the model analysis (GLM or Cox) of primary and
secondary efficacy parameters
8.4.2 Managing dropouts and missing data
The handling of dropout and missing data will be detailed in the statistical analysis plan
8.4.3 Multi-center study
Since this is a multicenter study, the primary endpoint (ORR) will be listed according to study
sites and treatment groups. However, individual equivalence analysis will not be conducted.
Trial sites with fewer than 5 ITT subjects per treatment group will need to be combined for
analysis. Details will be discussed in the data review meeting.
8.4.4 Multiple comparisons and adjustments to multiplicity
The α adjustment for multiple comparisons is not considered.
8.5 Statistical Analyses
8.5.1 Subject distribution
Refer to Figure 1: Study design schematic for the schedule of activities. The number and percentage
of patients who have completed or dropped out of the study (including the reason for dropouts such
as loss to follow-up, AEs, and poor compliance) are summarized based on treatment groups.


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The number and percentage of subjects in each analysis set are calculated based on treatment groups.
The number and percentage of protocol deviations are calculated based on treatment groups.
8.5.2 Demographics and other baseline characteristics
Demographic information such as age, height, sex, and weight, and other baseline characteristics
such as disease history (including NSCLC diagnosis, staging, previous cancer treatment, and
target and nontarget lesions) are summarized using descriptive statistics.
8.5.3 Compliance and drug exposure
The required dose and the actual dose must be documented in the eCRF. Subject compliance is
calculated based on the ratio of the actual dose (number of doses) to the required dose (number
of doses). Subject compliance is classified into the following categories: < 80%, 80–120%, and >
120%. The number and percentage of subjects in each category will be summarized.
8.5.4 Efficacy
The efficacy analysis will be based on the FAS. Results of the PP set will also be presented.
8.5.4.1 Primary efficacy endpoint
The primary objective of this study is to determine the clinical equivalence between IBI305 +
paclitaxel/carboplatin and bevacizumab + paclitaxel/carboplatin for the treatment of advanced or relapsed
non-squamous non-small cell lung cancer (NSCLC). The primary endpoint is objective response rate
(ORR). ORR is defined as the incidence of complete response (CR) or partial response (PR), and
a radiological method is used to evaluate target and non-target lesions according to RECIST v1.1.
Subjects without tumor assessments after baseline will be considered as not assessable. Subjects
qualified for the evaluation of CR or PR must have at least one measurable lesion according to RECIST
v1.1. The evaluation of clinical equivalence will be based on the ORR provided by the independent
review committee (IRC). Results provided by the investigator will be used for sensitivity analysis.
Clinical equivalence will be determined by whether the 90% CIs of ORR ratio for subjects in
both IBI305 and bevacizumab groups falls within the equivalence margins of (0.75, 1/0.75).
The ORR and corresponding 95% confidence interval of the two treatment groups, the ORR
difference and the 90% confidence interval, as well as the ORR ratio between the two groups and
the 90% confidence interval will be estimated using the generalized linear model (GLM, which
includes treatment groups and stratification factors).
8.5.4.2 Secondary efficacy endpoints
The secondary endpoints for this study include DOR, DCR, progress-free survival (PFS), and
overall survival (OS).


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DCR is defined as the incidence of complete response (CR), partial response (PR) and stable
disease (SD), and a radiological method is used to evaluate target and non-target lesions
according to RECIST v1.1.
DOR is defined as the time from initial tumor response (CR or PR) to PD or death; Subjects with
CR or PR who do not progress or die will be censored on the date of the last tumor assessment.
OS refers to the time from the date of randomization to the date of death (of any cause). For
subjects who are still alive at the time of the analysis, their survival time is censored on the last
known alive date. PFS refers to the time from the date of randomization to the date of first
documented PD or death, whichever occurs first. Subjects who do not progress or die will be
censored on the date of the last tumor assessment. Subjects without tumor assessments after
baseline are censored on their date of randomization.
Median OS and its 95% CI will be estimated using the Kaplan-Meier method. The survival curve
will be plotted. The hazard ratio (HR) between the two groups and its 95% CI will be estimated
using a Cox model. The Cox model includes treatment groups and stratification factors. DOR
and PFS will be analyzed using the same method as for OS. DCR will be analyzed using the
same method for primary efficacy endpoints, but an equivalence test will not be conducted.
8.5.4.3 Sensitivity analysis
The center effect (fixed or random) will be considered in the primary and secondary endpoints
analysis models (GLM or Cox).
8.5.4.4 Antibody and efficacy analysis
Subjects who produce antibodies during the study will be listed. The difference in efficacy
between subjects with and without antibodies will be compared if necessary.
Changes in PK parameters and steady-state trough concentrations of subjects with positive ADA
are analyzed.
8.5.5 Exploratory analysis
Pharmacodynamic parameters: The changes in the serum VEGF level at different time points are
described, and inter-group comparisons are carried out when necessary (based on the PD dataset)
Steady-state trough concentrations of the drug: The level of trough concentration is described
and inter-group comparisons are carried out when necessary (based on the PPK dataset)
8.5.6 Interim analysis
No interim analysis is planned for this study.


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8.5.7 Stratified analysis
Efficacy analysis of different levels of subjects is conducted based on the random stratification
factors
8.5.8 Safety analysis
The safety analysis is based on the safety analysis set.
8.5.8.1 Adverse events
All adverse events (AE) will be coded using MedDRA and graded using CTCAE v4.03. All
TEAEs, TEAEs ≥grade 3, SAEs, drug-related TEAEs, drug-related SAEs, TEAEs resulting in
the termination of study drugs, TEAEs resulting in the termination of study, and AESIs will be
listed based on system organ class, preferred terms, and groups and the corresponding numbers
and percentages of subjects will be summarized. In addition, the severity of TEAEs and
relevance to the study drugs will also be summarized system organ class, preferred terms, and
treatment groups.
8.5.8.2 Laboratory tests
All laboratory test results and changes relative to baseline will be summarized by scheduled time
point and treatment group using descriptive statistics. Laboratory abnormalities will be listed.
8.5.8.3 ECG examinations
Results of ECG and changes relative to baseline will be summarized using descriptive statistics.
8.5.8.4 Vital signs, physical examinations, and other safety examinations
Descriptive statistics of vital signs and relative changes from baseline are shown.
Results of physical examinations are listed by treatment groups.
8.5.8.5 Concomitant medications
Concomitant medications are non-study medications that meet one of the followings:
(1)
Any drug therapy started during or after the first dose of the study treatment;
(2)
Any drug therapy started before the first dose of the study treatment and continued after
the first dose of the study treatment. Concomitant medications are listed by treatment
groups.


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9 QUALITY ASSURANCE AND QUALITY CONTROL
According to GCP principles, the sponsor is responsible for implementing and maintaining
quality assurance and quality control systems based on standard operating procedures (SOP),
to ensure that the implementation of the clinical trial and the collection, documentation, and
reporting of trial data is in accordance with the protocol, GCP, and applicable regulatory
requirements.
To ensure that the data is reliable and processed correctly, there should be quality control for
every step during the data processing.
In addition, the Clinical Quality Assurance (CQA) Department of the sponsor and/or CRO may
conduct regular audits of the study process, including but not limited to auditing the study site,
on-site visits, central laboratory, suppliers, clinical database, and the final clinical study report.
Regulatory authorities may also conduct inspections during the trial or at any time after the trial
is completed. The investigator and the research institution must allow the sponsor's representative
and regulatory authorities to review source data.
9.1 Clinical Monitoring
The sponsor has authorized Wuxi Clinical Co., Ltd. to conduct clinical monitoring for this study.
The clinical research associate (CRA) should follow the SOPs of Wuxi Clinical Co., Ltd. when
carrying out monitoring, and has the same rights and responsibilities as the sponsor's monitor.
The CRA should maintain regular communication with the investigator and the sponsor.
Before the start of the study, the associate monitor assess the qualifications of each study site,
and report issues related to facilities, technical equipment, or medical staff to the sponsor. During
the study, the CRA will be responsible for confirming whether written informed consent is
obtained from all subjects, and whether data documentation is accurate and complete. At the
same time, the CRA will compare data entered in to the eCRF with source data, and notify the
investigator of any errors or omissions. The CRA will also verify protocol compliance of the
study site, as well as the dispensing and storage of investigational drugs to ensure protocol
requirements are met.
The monitoring visit will be conducted in accordance with applicable statutes and regulations.
Each site receives regular monitoring visits from the time the subjects are enrolled. The CRA
should submit a written report to the sponsor after each monitoring visit to the study site.


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9.2 Data Management/Coding
The Data Management and Biostatistics Department of Wuxi Clinical Co., Ltd will process data
generated from this study in accordance with relevant SOPs.
This study will use an electronic data capture (EDC) system. Trial data will be entered into the
eCRF by the investigator or authorized study personnel. Prior to launching of the study site or
data entry, the investigator and authorized study personnel will receive appropriate training, and
appropriate safety measures will be taken.
All data are input in Chinese. The eCRF should be completed during or soon after each visit, and
should be constantly updated to ensure that it reflects the latest status of the subject. To avoid
discrepancies in outcome assessments between different evaluators, ensure that baseline and all
subsequent efficacy and safety assessments for the same subject are performed by the same
person. The investigator must review trial data to ensure the accuracy and correctness of all data
entered into the eCRF. During the study, the investigator should document any evaluations that
are not conducted, or any information that is not available, applicable, or known. The
investigator needs to sign all verified data electronically.
The CRA will review the eCRF, and evaluate its completeness and consistency. The CRA will
also compare the eCRF with the source documents to ensure the consistency of critical data. Data
entry, corrections, or modifications are completed by the investigator or designated staff. The
CRA do not have access to data entry. The data in eCRF is submitted to the data server, and any
changes to the data will be documented in the audit trail, including the reason for the change, the
name of the operator, as well as the time and date of the change. The roles and permissions of
study personnel responsible for data entry will be predetermined. The CRA or data manager will
submit data queries in the EDC system, and study personnel shall respond to the queries. The
EDC system will record the audit trail of each query, including the name of the investigator, as
well as the time and date.
Unless otherwise specified, the eCRF should be considered simply as a form for data collection
and not a source document. A source file is used by the investigator or hospital, relevant to the
subject, and can prove the existence of the subject, inclusion criteria, and all records of
participation in the study, including laboratory records, ECG results, memorandum, pharmacy
dispensing records, and subject folders.


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The investigators are required to maintain all source documents and to offer the documents to the
CRA for review during each visit. In addition, the investigator must submit a complete eCRF for
each subject, regardless of the duration of the subject's participation in the study. The study
number and subject number in all supporting documents (such as laboratory records or hospital
records) submitted along with the eCRF should be carefully verified. All personal privacy
information (including the name of the subject) should be deleted or be made indecipherable in
order to protect subject privacy.
The investigator could be automatically added to the eCRF with his/her user ID. The investigators
verify that the record have been reviewed and that the data are accurate with an electronic
signature. The electronic signature is completed with the investigator's user ID and password.
The system automatically attaches the date and time of the signature. The investigator could not
share the user ID and password with other personnel. If data in the eCRF need to be modified,
the procedures defined by the EDC system have to be followed. All modifications and reasons
for the changes are recorded in the audit trail.
Training on the EDC system will be provided to study personnel at the study site.
Adverse events, and concurrent diseases/medical history will be coded. The medical dictionary
used for coding will be described in the Clinical Study Report (CSR).
9.3 Audits and Inspections
The sponsor or its representative (WuXi Clinical Co., Ltd) may conduct quality assurance audits
on the study site, database, and relevant study-related documents. Also, regulatory authorities
may also decide to inspect the study site, database, and relevant study-related documents at its
own discretion. The aim of audits and inspections is to systematically and independently check
all study-related procedures and documents to ensure that the clinical study is being carried out
in accordance with requirements of the trial protocol, GCP, Declaration of Helsinki, and
applicable regulations. The investigator must inform the sponsor immediately when an
inspection notice is received from the regulatory authorities.


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10 ETHICS
10.1 Independent Ethics Committee
The sponsor and its designated personnel will prepare all documents to be submitted to the
independent ethics committee (IEC) of each study site. The trial protocol, informed consent form
(ICF), investigators brochure, subject recruitment material or advertisements (if applicable), as
well as other documents required by regulations must be submitted to the IEC for approval. Prior
to the start of the study, written approval from the IEC must be obtained and provided to the
sponsor. The IEC approval must clearly state the title, number, and version of the study protocol
as well as the version of other documents (e.g. ICF) and the date of approval. The investigator
must notify the sponsor of the IEC's written comments concerning delays, suspension and re-
approval.
The study site must follow the requirements of the IEC. IEC requirements may include
submitting the revised protocol, ICF, or subject recruitment material to the IEC for approval,
local regulatory requirements for safety reports, and regular reports, updates, and submitting the
final report as per IEC requirements. The above documents as well as the IEC approval must be
provided to the sponsor or its designated personnel.
10.2 Implementation of Ethical Principles
The study process and the acquisition of informed consent should comply with the Declaration of
Helsinki, relevant GCP requirements (CPMP/ICH/135/95), and applicable statutes and
regulations related to drugs and data protection in the country in which the study is conducted.
The GCP is an international ethical and scientific quality standard for designing, conducting,
recording and reporting clinical trials that involve the participation of human subjects. To protect
the rights, safety, and healthy of subjects, this study will be carried out in accordance with GCP
and applicable national regulations, as well as ethical principles outlined in the Declaration of
Helsinki.
The investigator is required to follow the procedures specified in this protocol and must not
change the procedures without the permission from the sponsor. Protocol deviations will be
reported in accordance with the requirements of each ethics committee.


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10.3 Subject Information and Informed Consent
Prior to undergoing any study procedure, the ICF should be used to explain to potential participants
the potential risks and benefits of this study. The informed consent form should be in a language
that is simple and be easy to understand. The ICF should state that informed consent is voluntary,
emphasize the potential risks and benefits of participating in this study, and that the subject may
withdraw from the study at any time. The investigator may only enroll a subject after fully
explaining the details of the study, answering questions to the subject's satisfaction, giving
the subject sufficient time for consideration, and obtaining written consent from the subject or
his/her legal representative. All signed ICF must be retained in the investigator's documents or
the subject's folder.
The investigator is responsible for explaining the contents of the ICF and obtaining the ICF
signed and dated by the subject or his/her legal representative prior to starting the study. The
investigator should provide the subject with a copy of the signed ICF. The investigator must
document the informed consent process in the source document of the trial.
10.4 Protection of Subject Data
Information about data protection and privacy protection will be included in the ICF (or in some
cases, in a separate document).
Study personnel must ensure that the privacy of clinical trial subjects are protected. In all
documents submitted to the sponsor, the clinical trial subjects must only be identified with
subject number and not with the full name.
Additional precautions should be taken to ensure the confidentiality of the documents and
to prevent the identification of subjects based on genetic data. However, under special
circumstances, some personnel may be permitted to see the genetic data and personal
identification number of a subject. For example, in the event of a medical emergency, the
sponsor, designated physician, or investigator will have access to the subject identification code
and the subject's genetic data. In addition, regulatory agencies may request access to relevant
documents.


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11 STUDY MANAGEMENT
11.1 Organizational Structure
Refer to Table 3 for relevant collaborating parties.
Table 6. Organizational structure
Sponsor
Innovent Biologics (Suzhou) Co., Ltd.
No. 168 Dongping Street, Suzhou Industrial Park, Jiangsu, China
Telephone: (+86) 0512-69566088
Contract research
organization
WuXi Clinical Development Services (Shanghai) Co., Ltd.
19F, Building A, SOHO Fuxing Plaza, 388 Madang Road, Shanghai
Tel: (+86) 21-23158000
Data management and
biostatistics
WuXi Clinical Development Services (Shanghai) Co., Ltd.
19F, Building A, SOHO Fuxing Plaza, 388 Madang Road, Shanghai
Tel: (+86) 21-23158000
11.1.1 Independent review committee
Central imaging evaluation will be performed by Parexel China Co., Ltd. The CT/MRI images of
each subject will be evaluated using RECIST v1.1.
11.2 Archiving of Study Documents
Clinical trial documents (protocol and amendments, completed eCRFs, signed ICFs, etc.) must
be retained and managed as per GCP requirements. The study site must retain these documents
for 5 years after the completion of the study. The sponsor should retain clinical trial data for
5 years after the investigational drug is approved for marketing.
Study documents should be retained properly for future access or data traceability. Safety and
environmental risks should be considered when retaining documents.
The documents associated with the study may only be destroyed with the written consent of the
sponsor and the investigator. Study documents may be transferred to other parties that comply
with or other locations that meet retention requirements only after the sponsor is notified and
written consent thereof is obtained.


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11.3 Access to Source Data/Documents
Source data refers to source records of subject data obtained from a clinical study. These source
records are source documents, which include but are not limited to medical records (hospital
records, nursing records, pharmacy dispensing records, etc.), electronic data, screening logs,
laboratory test results, as well as medical device test results (ECG, CT/MRI, etc.). All source
documents associated with the trial are retained by the study site and the investigator. The
original ICFs will be retained according to standard practices developed by the clinical trial
institution.
The investigator will prepare sufficient and accurate source documents for each randomized
subject in order to document all examination results and other relevant data, and retain these
documents properly.
During the study, the CRA will conduct on-site visits to verify protocol compliance, EDC data
entry, documentation of subjects' medical history, drug inventory, and whether the study is
carried out in accordance with applicable regulations. In addition, regulatory authorities, IRB,
IEC, and/or the quality assurance department of the sponsor will verify source data and/or
conduct on-site audits or inspections. The investigator should allow direct access to documents
associated with the study, including medical records of subjects.
11.4 Protocol Revisions
The sponsor and the investigator must both agree on any appropriate protocol revisions during
the course of the study. The sponsor shall ensure that the protocol revision is submitted to the
regulatory authority in a timely manner.
All protocol revisions must be submitted to the IEC, and if needed, to regulatory authorities for
approval. Revisions may only be implemented after approval from the IEC and regulatory
authorities (if needed) is obtained (except for changes to eliminate immediate risks to subjects).
11.5 Investigator's Responsibilities
The investigator will conduct this study in accordance with the protocol, ethical principles of the
Declaration of Helsinki, Chinese GCP, and applicable regulations. Details of the investigator's
responsibilities are list in Chapter 5 (Investigator's Responsibilities) of the Chinese GCP (NMPA
order No. 3).


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11.6 Study Termination
The study may be terminated after a discussion between relevant parties if the investigator or the
sponsor becomes aware of circumstances or events that could jeopardize the subjects if the study
is continued. The sponsor may also decide to terminate the study even without such findings.
Reasons for study termination include but are not limited to:

Unexpected, serious, or unacceptable risks to enrolled subjects

Slow recruitment

The sponsor decides to suspend or discontinue the development of the drug
11.7 Publishing Policies
All the data generated in this study is the confidential information owned by the sponsor. The
sponsor has the right to publish study results. The investigator shall not publish any data relevant
to this study (posters, abstracts, papers, etc.) without prior communication with the sponsor.
Information on the publishing policies of the sponsor and investigator will be described in the
clinical trial agreement.
11.8 Finance and Insurance
The sponsor will purchase insurance for subjects participating in the study in accordance with
local regulations, and bear the cost of treatment and corresponding financial compensation for
the subjects who suffer injury during the study due to the investigational drug or the study
process. Insurance related terms shall be saved in the study folder.


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12 REFERENCES
1.
GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. Apr.
11, 2016: http://globocan.iarc.fr/Default.aspx
2.
陈万青，郑荣寿，曾红梅，等. 2011 年中国恶性肿瘤发病和死亡分析. 中国肿瘤.
2015;24(1):1-10.
3.
GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. Apr.
11, 2016: http://www.cancer.org/acs/groups/cid/documents/webcontent/003115-pdf.pdf
4.
支修益，石远凯，于今明. 中国原发性肺癌诊疗规范（2015 年版）. 中华肿瘤杂志.
2015;37(1):67-78.
5.
Pisters KMW and Chevalier TL. Adjuvant Chemotherapy in Completely Resected Non–
Small-Cell Lung Cancer. J Clin Oncol. 2005;23:3270-3278.
6.
石远凯，孙燕，于今明，等. 中国晚期原发性肺癌诊治专家共识（2016 年版）. 中国
肺癌杂志. 2016;19(1):1-15.
7.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN
Guidelines®) Non-Small Cell Lung Cancer (Version 4. 2016). Apr. 11, 2016:
http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
8.
郝希山，魏于全. 肿瘤学（第二版）. 北京: 人民卫生出版社. 108; 2010.
9.
Package insert of bevacizumab (Nov. 25, 2015). Apr. 11, 2016:
http://www.roche.com.cn/content/dam/roche_china/zh_CN/pdf/product/Avastin_20151125_
IM %20PI%20CDS32.0-33.0.pdf
10. Sandler A., Gray R., Perry MC., et al. Paclitaxel-carboplatin alone or with bevacizumab for
non-small-cell lung cancer. N Engl J Med. 2006;355:2542-2550.
11. Reck M., von Pawel J., Zatloukal P., et al. Overall survival with cisplatin-gemcitabine and
bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer:
results from a randomized phase III trial (AVAiL). Annals of Ocology. 2010;21:1804-1809.
12. Zhou CC., Wu YL., C GY., et al. BEYOND: A randomized, double-blind, placebo-
controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab
or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung
cancer. J Clin Oncol. 2015;33:2197-2204.
13. IBI305 研究者手册. 信达生物制药（苏州）有限公司. 2016 年5 月11 日.
14. Technical Guidelines for Development and Evaluation of Biosimilars by NMPA (Trial). Apr. 21,
2016: http://www.sda.gov.cn/WS01/CL1616/115104.html


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13 APPENDIX
13.1 Appendix I
Eastern Cooperative Oncology Group (ECOG) Performance Status Score
Score
Performance Status
0
Fully active, and able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activities but able to move around easily and carry out work of
a light or sedentary nature, e.g. light house work or office work
2
Capable of moving around easily and self-care but unable to carry out any work activities; up and
about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or wheelchair more than 50% of waking hours
4
Bedridden and incapable of self-care
5
Death
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative
Oncology Group. Am J Clin Oncol. 1982;5:649-655.


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13.2 Appendix II
Calculation of body surface area
Body surface are (m2) = 0.00616 height (cm) + 0.01286 weight (kg) - 0.1529
Creatinine Clearance (Cockroft-Gault Equation)
Ccr (mL/min) = [(140 - age) x weight (kg)]/[72 x Scr (mg/dL)]
Female subjects: results × 0.85
1 mg/dL = 88.41 µmol/L
Carboplatin Dose (Calvert Equation)
Carboplatin dose (mg) = target AUC (mg/mL/min) × [creatinine clearance rate (mL/min) + 25]
Note: During the study, if the carboplatin dose calculated using the Calvert equation excessively
exceeds the usual clinical dose, choose one of the following two methods to ensure the patient safety:


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1. Retest the serum creatinine and re-calculate the dose (preferred option).
2. Based on clinical experience, the investigator may choose the highest dose tolerated by the
subject. The dose should remain unchanged for the subsequent cycles.


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13.3 APPENDIX 3
RECIST v1.1
1
MEASURABILITY OF TUMOR AT BASELINE
1.1
Definitions
At baseline, tumor lesions/lymph nodes will be categorized as measurable or not measurable as
follows:
1.1.1
Measurable
Tumor lesions: must be accurately measured in at least one dimension (longest diameter in the
plane of measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm)

10 mm caliper measurement by clinical exam (lesions which cannot be accurately
measured with calipers should be documented as not measurable).

20 mm by chest X-ray.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will
be measured and followed.
1.1.2
Not measurable
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes
with a short axis ≥10 and <15 mm) as well as truly not measurable lesions. Lesions considered
truly not measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion,
inflammatory breast disease, lymphangitis involving the skin or lungs, abdominal masses/
abdominal organomegaly identified by physical exam but not measurable by reproducible
imaging techniques.
1.1.3
Special considerations regarding measurable bone lesions, cystic lesions, and lesions
with prior locoregional treatment:
Bone lesions:

Bone scan, PET scan or plain films are not considered adequate imaging
techniques to measure bone lesions. However, these techniques can be used to
confirm the presence or disappearance of bone lesions.


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
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue
components, that can be evaluated by cross sectional imaging techniques (such as
CT or MRI) can be considered as measurable lesions if the soft tissue
components meet the definition of measurability described above.

Blastic bone lesions are not measurable.
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not
be considered as malignant lesions (neither measurable nor not measurable) since
they are, by definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as
measurable lesions, if they meet the definition of measurability described above.
However, if noncystic lesions are present in the same patient, these noncystic
lesions are preferred for selection as target lesions.
Lesions with prior locoregional treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to
other locoregional therapy are usually not considered measurable, unless there
has been demonstrated progression in the lesion. The study protocol should detail
the conditions under which such lesions would be considered measurable.
1.2
Specifications by Methods of Measurements
1.2.1
Measurement of lesions
All measurements should be documented with metric symbols. Calipers should be used if clinical
assessments are required. All baseline evaluations should be performed as close as possible to
the beginning of the treatment but never more than 4 weeks before the beginning of the treatment.
1.2.2
Method of assessment
The same method of assessment and the same technique should be used to characterize each
identified and reported lesion at baseline and during follow-up. Imaging evaluation should
always be done rather than clinical examination unless the lesion(s) being followed cannot be
imaged but are assessable by clinical examination.
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial
and its diameter is ≥10 mm as assessed using calipers (e.g. skin nodules). For skin lesions,
documentation by color photography including a plotting scale to estimate the size of the lesion
is recommended. As noted above, when lesions can be evaluated by both clinical examination
and imaging evaluation, the latter should be undertaken since it is more objective and may also


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be reviewed at the end of the study.
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.
However, lesions on chest X-ray may be considered measurable if they have clear boundaries
and are surrounded by aerated lung tissues.
CT and MRI: CT is the best currently available and reproducible method to measure lesions
selected for response assessment. This guideline has defined measurability of lesions on CT scan
based on the assumption that CT slice thickness is 5 mm or less. When CT scans have a slice
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice
thickness. MRI is also acceptable in certain situations (e.g. for body scans).
Ultrasound: Ultrasound should not be used for measuring lesion size and should not be used as
a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for
independent review at a later date and, because they are operator dependent, it cannot be
guaranteed that the same technique and measurements will be taken from one assessment to the
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT
or MRI is recommended. If there is concern about radiation exposure at CT, MRI may be used
instead of CT in selected instances.
Endoscopy and laparoscopy: The utilization of these techniques is not recommended for
objective tumor evaluation. However, they can be used to confirm complete pathological
response when biopsies are obtained or to determine relapse in trials where recurrence following
complete response or surgical resection is an endpoint.
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If
markers are initially above the upper limit of normal, however, they must normalize for a patient
to be considered in complete response. Because tumor markers are disease specific, instructions
for their measurement should be incorporated into the protocol on a disease specific basis.
Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response
(in recurrent prostate cancer) have been published. In addition, the Gynecologic Cancer
Intergroup has developed CA125 progression criteria which are to be integrated with objective
tumor assessment for use in first-line trials in ovarian cancer.
Cytology and histology: These techniques can be used to differentiate between PR and CR in rare
cases if required by the protocol (for example, residual lesions in tumor types such as seminoma,
where known residual benign tumors can remain). When effusions are known to be a potential
adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors),
cytological confirmation of the neoplastic origin of any effusion that appears or worsens during


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treatment can be considered if the measurable tumor has met criteria for response or stable
disease in order to differentiate between response (or stable disease) and progressive disease.
2.
TUMOR RESPONSE EVALUATION
2.1
Assessment of Overall Tumor Burden and Measurable Disease
To assess objective response or future progression, it is necessary to estimate the overall tumor
burden at baseline and use this as a comparator for subsequent measurements. Only patients with
measurable disease at baseline should be included in regimens where objective tumor response is
the primary endpoint. Measurable disease is defined by the presence of at least one measurable
lesion. In studies where the primary endpoint is tumor progression (either time to progression or
proportion with progression at a fixed date), the protocol must specify if entry is restricted to
those with measurable disease or whether patients having non-measurable disease only are also
eligible.
2.2
Baseline Documentation of "Target" and "Non-Target" Lesions
When more than one measurable lesion is present at baseline, all lesions (five lesions at most,
and two lesions per organ at most) representative of all involved organs should be identified as
target lesions and will be recorded and measured at baseline (This means in instances where
patients have only one or two organ sites involved, a maximum of two and four lesions
respectively will be recorded).
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be
representative of all involved organs, and should be those with reproducible repeated
measurements. It may be the case that, the largest lesion does not have reproducible
measurements, in which circumstance the next largest lesion with reproducible measurements
should be selected.
Lymph nodes merit special mention since their normal anatomical structures may be visible by
imaging even if not involved by tumor. Pathological nodes which are defined as measurable and
may be identified as target lesions must have a short axis of ≥15 mm by CT scan. Only the short
axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter
normally used by radiologists to judge if a node is invaded by solid tumor. Nodal size is
normally reported as two dimensions in the plane in which the image is obtained (for CT scan
this is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal or
coronal). The smaller of these measures is the short axis. For example, an abdominal node which
is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies as a malignant
measurable node. In this example, 20 mm should be reported as the node measurement. All other
pathological nodes (those with a short axis ≥10 mm but < 15 mm) should be considered non-


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target lesions. Lymph nodes that have a short axis < 10 mm are considered non-pathological and
should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions; short axis for nodal lesions) for all target
lesions will be calculated and reported as the baseline sum of diameters. If lymph nodes are to be
included in the sum, then as noted above, only the short axis is added into the sum. The baseline
sum of diameters will be used as reference to further characterize any objective tumor regression
in the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as
non-target lesions and should also be recorded at baseline. Measurements are not required and
these lesions should be recorded as "present", "absent", or in rare cases "unequivocal
progression". In addition, it is possible to record multiple target lesions involving the same organ
as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple
liver metastases’).
2.3
Response Criteria
2.3.1
Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes
(whether target or non-target) must have a reduced short axis of <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions vs. the
baseline sum of diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions vs.
the smallest sum during the study (this includes the baseline sum if that is the smallest). In
addition to the relative increase of 20%, the sum must also have an absolute increase of at least
5 mm. (Note: The appearance of one or more new lesions is also considered progression).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to
qualify for PD, using the smallest sum of diameters during the study as reference.
2.3.2
Special notes on the assessment of lymph nodes which are target lesions
Lymph nodes identified as target lesions should always have the actual short axis measurement
recorded (measured in the same anatomical plane as during the baseline examination), even if the
nodes regress to below 10 mm at the time of the study. This means that when lymph nodes are
included as target lesions, the "sum" of lesions may not be zero even if complete response
criteria are met, since a normal lymph node is defined as having a short axis of <10 mm. Case
report forms or other data collection methods may therefore be designed to have target nodal
lesions recorded in a separate section where, in order to qualify for CR, each node must have a


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short axis of <10 mm. For PR, SD, and PD, the actual short axis measurement of the nodes is to
be included in the sum of target lesions.
Target lesions that are "too small to measure". During the study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent
evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or lymph nodes
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist
may not feel comfortable assigning an exact measurement and may report them as being "too
small to measure". When this occurs it is important that a value be recorded on the case report
form. If it is the opinion of the radiologist that the lesion has probably disappeared, the
measurement should be recorded as 0 mm. If the lesion is believed to be present and is faintly
seen but too small to measure, a default value of 5 mm should be assigned (Note: It is less likely
that this rule will be used for lymph nodes since they usually have a definable size when normal
and are frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is
believed to be present and is faintly seen but too small to measure, a default value of 5 mm
should be assigned in this circumstance as well). This default value is derived from the 5 mm CT
slice thickness (but should not be changed with varying CT slice thickness). The measurements
of these lesions are potentially non-reproducible, therefore providing this default value will
prevent false responses or progressions caused by measurement errors. To reiterate, however, if
the radiologist is able to provide an actual measurement, that value should be recorded, even if it
is below 5 mm.
Lesions that split or coalesced at the time of treatment. When non-nodal lesions fragment, the
longest diameters of the fragmented portions should be added together to calculate the target lesion sum.
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such that
they are no longer separable, the vector of the longest diameter in this instance should be the maximal
longest diameter for the "coalesced lesion".
2.3.3
Evaluation of non-target lesions
This section provides the definitions of the criteria used to determine the tumor response for the
group of non-target lesions. While some non-target lesions may actually be measurable, they do
not need to be measured and instead should be assessed only qualitatively at the time points
specified in the protocol.
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor
marker level. All lymph nodes must be non-pathological in size (short axis <10 mm).
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor
marker level above the normal limits.


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Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: The
appearance of one or more new lesions is also considered progression).
2.3.4
Special notes on the assessment of progression of non-target lesions
The concept of progression of non-target disease requires additional explanation as follows: When
the patient also has measurable lesions. In this setting, to achieve ‘unequivocal progression’ on the
basis of the non-target lesion, there must be an overall level of substantial worsening in non-target
disease such that, even in the presence of SD or PR of the target disease, the overall tumor burden
has increased sufficiently to merit discontinuation of therapy. A minimal increase in the size of one
or more non-target lesions is usually not sufficient to quality for unequivocal progression status.
The designation of overall progression solely on the basis of change in non-target lesions in the
face of SD or PR of target disease will therefore be extremely rare.
When the patient has only lesions that are not measurable. This circumstance arises in some
phase III trials when the presence of measurable lesions is not a criterion for study enrollment.
The same general concepts apply here as well. However, in this instance there are no measurable
lesions to factor into the interpretation of an increase in non-measurable lesion burden. Because
worsening in non-target lesion cannot be easily quantified (by definition: if all lesions are truly
not measurable), a useful test that can be applied when assessing patients for unequivocal
progression is to consider if the increase in overall lesion burden based on the change in non-
measurable disease is comparable in magnitude to the increase that would be required to declare
PD for measurable disease: i.e. an increase in tumor burden representing an additional 73%
increase in volume (which is equivalent to a 20% increase of diameter in a measurable lesion).
Examples include an increase in pleural effusion from "trace" to "large amount", an increase in
lymphangitic lesion from localized to widespread, or a description in the protocol such as
"sufficient to require a change in therapy". If ‘unequivocal progression’ is seen, the patient
should be considered to have had overall PD at that point. While it would be ideal to have
objective criteria to apply to diseases that are not measurable, the very nature of these diseases
makes it impossible to do so, therefore the increase must be substantial.
2.3.5
New lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on the detection of new lesions are important. There are no specific criteria for the
identification of new radiographic lesions; however, the finding of a new lesion should be
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging
modality or findings thought to represent something other than tumors (for example, some new
bone lesions which may be simply healed or flare of pre-existing lesions). This is particularly


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important when the patient’s baseline lesions show partial or complete response. For example,
necrosis of a liver lesion may be reported by a CT scan as a "new" cystic lesion, while it is
actually not.
A lesion identified during a follow-up in an anatomical location that is not discovered during the
baseline scan is considered a new lesion and will indicate disease progression. For example, a
patient with a visceral disease at baseline has a brain CT or MRI which reveals metastases. The
patient's brain metastases are considered evidence of PD even if he/she does not have brain
imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents a truly new lesion. If repeat scans confirm there is
definitely a new lesion, then progression should be declared using the date of the initial scan.
While FDG-PET response assessments need additional studies, it is sometimes reasonable to
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of
progression (particularly possible "new" lesions). New lesions on the basis of FDG-PET imaging
can be identified as follows:
a.
A negative FDG-PET at baseline and a positive FDG-PET at follow-up is a sign of PD
based on a new lesion.
b.
No FDG-PET at baseline and a positive FDG-PET at follow-up:
If the positive FDG-PET at follow-up corresponds to a new lesion site confirmed by
CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new lesion
site on CT, additional follow-up CT scans are needed to determine if there is truly
progression at that site (if so, the date of PD will be the date of the initial abnormal
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing
lesion site on CT that is not progressing according to the anatomic images, this is not PD.
2.4
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until
the end of treatment, taking into account any requirement for confirmation. On occasion a
response may not be documented until after the end of therapy, so the study protocol should
clearly state if post-treatment assessments are to be considered when determining best overall
response. The study protocol must specify how any new therapy introduced before progression
will affect best response designation. Assignment of best overall response for the patient will
depend on the findings of both target and non-target lesions and will also take into consideration
the appearance of new lesions. Furthermore, depending on the nature of the study and the


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protocol requirements, confirmatory measurement may also be required. Specifically, in non-
randomized trials where response is the primary endpoint, confirmation of PR or CR is needed to
determine which one is the "best overall response".
2.4.1
Time point response
It is assumed that at each time point specified by the study protocol, a response assessment
occurs. Table 1 on the next page provides a summary of the overall response status calculation at
each time point for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used.
2.4.2
Missing assessments and non-evaluable targets
When no imaging/measurement is done at a particular time point, the patient is not evaluable
(NE) at that time point. If only a subset of lesion measurements is made at an assessment, usually
the case is also considered NE at that time point, unless a convincing argument can be made that
the missing lesion(s) would not change the response at the assigned time point. This would be
most likely to happen in the case of PD. For example, if a patient has a baseline sum of 50 mm
with three measured lesions and at follow-up only two lesions are assessed and with a sum of 80
mm, the patient will have achieved PD status, regardless of the contribution of the missing lesion.
2.4.3
Best overall response: all time points
The best response is determined once all the data for the patient is obtained.
Best response determination in trials where confirmation of complete or partial response is not
required: Best response in these trials is defined as the best response across all time points (for
example, the best overall response of a patient who has SD at the first assessment, PR at the
second, and PD at the last is PR). When SD is believed to be best response, it must also meet the
minimum time from baseline specified by the protocol. If the minimum time is not met,
otherwise SD is the best time point response, the patient’s best response depends on subsequent
assessments. For example, if a patient has SD at the first assessment, PD at the second and does
not meet the minimum duration for SD, his/her best response is PD. The same patient lost to
follow-up after the first SD assessment would be considered not evaluable.
Best response determination in trials where confirmation of complete or partial response is
required: Complete or partial responses may be claimed only if the criteria for each are met at a
subsequent time point specified in the protocol (generally 4 weeks later). In this circumstance,
the best overall response can be interpreted as in Table 3.


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2.4.4
Special notes on response assessment
When nodal lesions are included in the sum of target lesions and the nodes decrease to "normal"
size (<10 mm), they may still have a measurement reported on scans. This measurement should
be recorded even if the nodes are normal in size in order not to overstate progression should it be
based on the increase in size of the nodes. As noted earlier, this means that patients with CR may
not have a total sum of "zero" on the case report form (CRF).
In trials where confirmation of response is required, repeated "NE" time point assessments may
complicate best response determination. The analysis plan for the trial must explain how missing
data/assessments will be addressed in the determination of response and progression. For
example, in most trials it is reasonable to consider a patient with time point responses of PR-NE-
PR as a confirmed response.
Patients with a global deterioration of health status requiring discontinuation of treatment without
objective evidence of disease progression at that time should be reported as "symptomatic
deterioration". Every effort should be made to document objective progression even after
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective
response. Instead, it is a reason for stopping the study treatment. The objective response status of
this type of patients is to be determined by evaluation of target and non-target lesions as shown
in Table 1–3.
Conditions that define "early progression, early death, and non-evaluability" are study specific
and should be clearly described in each study protocol (depending on treatment duration and
treatment periodicity).
In some circumstances it may be difficult to distinguish a residual lesion from normal tissues.
When the evaluation of complete response depends upon this determination, it is recommended
that the residual lesion be investigated (by fine needle aspirate/biopsy) before assigning a status
of complete response.
Like a biopsy, FDG-PET may also be used to upgrade a response to a CR in cases where a
residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-
PET in this circumstance should be pre-defined in the protocol and supported by disease specific
medical literature for the indication. However, it must be acknowledged that both approaches
may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.


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Table 1. Time point response: patients with target (+/– non-target) disease.
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or
No
PR
Not all were evaluated
SD
Non-PD or
No
SD
Not all were evaluated
Not all were
evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not evaluable
Table 2. Time point response: patients with non-target disease only.
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PDa
Not all were evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease, and NE = not evaluable.
a "Non-CR/non-PD" is preferred over "stable disease" for non-target disease, since SD is increasingly used as an
endpoint for assessment of efficacy in some trials, thus assigning this category in the absence of measurable
lesions is not advised.
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at
the next scheduled assessment, progression is confirmed, the date of progression should be the
earlier date when progression is suspected.


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Table 3. Best overall response when confirmation of CR and PR required.
Overall response
First time point
Overall response
Subsequent time
point
Best overall response
CR
CR
CR
CR
PR
SD, PD, or PRa
CR
SD
SD provided that the minimum duration for SD is met, otherwise PD
CR
PD
SD provided that the minimum duration for SD is met, otherwise PD
CR
NE
SD provided that the minimum duration for SD is met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided that the minimum duration for SD is met, otherwise PD
PR
NE
SD provided that the minimum duration for SD is met, otherwise NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not
evaluable.
a If CR is truly achieved at the first time point, then any lesions seen at a subsequent time point, even those meeting
PR criteria relative to baseline, make the disease PD at that time point (since lesions must have reappeared after
CR). Best response would depend on whether the minimum duration for SD is met. However, sometimes CR may
be claimed and subsequent scans suggest small lesions are likely still present, while in fact the patient have PR
instead of CR at the first time point. Under these circumstances, CR should be changed to PR and the best response
is PR.
2.5 Frequency of Tumor Re-Evaluation
Frequency of tumor re-evaluation during treatment should be protocol specific and adapted to the
type and schedule of treatment. However, for phase II studies where the beneficial effect of the
treatment is not known, follow-up every 6–8 weeks (timed to coincide with the end of a cycle) is
reasonable. Smaller or greater time intervals may be justified for certain regimens or circumstances.
The study protocol should specify which organ sites are to be evaluated at baseline (usually those
most likely to be involved with metastatic disease for the tumor type under study) and how
often evaluations are repeated. Normally, all target and non-target sites are evaluated at each
assessment. Under certain circumstances, some non-target organs may be evaluated less frequently.
For example, bone scans may need to be repeated only when complete response is identified in
the target lesion or when progression is suspected.


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After the end of the treatment, the need for repeated tumor evaluations depends on whether the
trial has a goal such as a certain response rate or a certain time to an event (progression/death).
If ‘time to an event’ (e.g. time to progression, disease-free survival, progression-free survival) is
the main endpoint of the study, then routine scheduled re-evaluation of lesion sites specified by
the protocol must be carried out. In randomized comparative trials in particular, the scheduled
assessments should be performed on time (for example: every 6–8 weeks during the treatment or
every 3–4 months after the treatment) and should not be affected by treatment delays, holidays or
any other events that might lead to imbalance in the timing of disease assessment between
treatment arms.
2.6 Confirmation of Measurements/Duration of Response
2.6.1 Confirmation
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is
required to ensure responses identified are not the result of measurement errors. This will also
permit appropriate interpretation of results in the context of historical data. Response
confirmation has been traditionally required in such trials. However, in all other circumstances,
i.e. in randomized trials (phase II or III) or studies where stable disease or progression are the
primary endpoints, confirmation of response is not required since it will not add value to the
interpretation of trial results. However, elimination of the requirement for response confirmation
may increase the importance of central review to protect against bias, in particular in studies
which are not blinded.
In the case of SD, measurements after study entry must have met the minimum interval for SD
(generally not shorter than 6–8 weeks) defined in the study protocol at least once.
2.6.2 Duration of overall response
The duration of overall response is measured from the time CR/PR measurement criteria are first
met CR/PR (whichever is first documented) until the date when recurrent or progressive disease
is objectively documented for the first time (using the shortest time to progressive disease
documented during the study as reference).
The duration of overall complete response is measured from the time CR measurement criteria
are first met until the date when recurrent disease is objectively documented for the first time.
2.6.3 Duration of stable disease
Stable disease is measured from the start of the treatment (in randomized trials, from the date
of randomization) until the criteria for progression are met, using the smallest sum during the
study as reference (if the baseline sum is the smallest, then it is used as the reference for the
calculation of PD).


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The clinical relevance of the duration of stable disease varies with different studies and diseases.
If the proportion of patients achieving stable disease for a minimum period of time is an endpoint
of importance in a particular trial, the protocol should specify the minimal time interval required
between two measurements for the determination of stable disease.
Note: The duration of response and stable disease as well as the progression-free survival are
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of the
guidelines to define a standard follow-up frequency. The frequency should take into account
many parameters including disease types and stages, treatment periodicity, and standard practice.
However, limitations of the precision of the measured endpoint should be taken into account if
comparisons between trials are to be made.


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14 INVESTIGATOR SIGNATURE PAGE
Protocol Title: A randomized, double-blind, multi-center phase III study comparing the efficacy
and safety of IBI305 plus paclitaxel/carboplatin vs. bevacizumab plus paclitaxel/carboplatin in
treatment-naive patients with advanced or relapsed non-squamous NSCLC.
Protocol No.: CIBI305A301
This protocol is a trade secret owned by Innovent Biologics (Suzhou) Co., Ltd. I have read and
fully understood this protocol, and agree to conduct this study in accordance with the
requirements found in this protocol and the Good Clinical Practice, and in compliance with
relevant laws and regulations and the Declaration of Helsinki. At the same time, I promise not to
disclose any confidential information associated with this study to any third party without the
written consent of Innovent Biologics (Suzhou) Co., Ltd.
Instructions for the Investigator: Please sign and date this signature page, type the investigator's name and job
title, as well as the name of the study site, and return this document to Innovent Biologics (Suzhou) Co., Ltd.
I have read the entire contents of this study protocol and shall perform the study as required:
Investigator's signature:
Date:
Name (in Print):
Job Title:
Name and Address of Study Site:


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A randomized, double-blinded, multi-center phase III study comparing the efficacy and
safety of IBI305 plus paclitaxel/carboplatin versus bevacizumab plus paclitaxel/carboplatin
in treatment-naive subjects with advanced or relapsed non-squamous non-small cell lung
cancer
Protocol no.: CIBI305A301
Document Amendment History
Old Version/Date: V3.0/Sep. 25, 2017
New Version/Date: V3.1/Aug. 27, 2018
1
Subject
Version No. and Version Date
Section/Page
Cover/Page 1; Footer/Pages 1–79
Old text
Sep. 25, 2017/Version 3.0
New text
Aug. 27, 2018/Version 3.1
Reason for change
Version Revision.
2
Subject
Contact
Section/Page
Cover/Page 1
Old text
Tel: (+86) 021-31652896
New text
Tel: (+86) 21-31652896
Reason for change
Clerical errors are corrected.
3
Subject
Statistician
Section/Page
Signature Page/Page 2
Old text
Wei Zhaohui, Director of Biostatistics
New text
Zhang Nan, Senior Director of Biostatistics
Reason for change
Statistician is updated
4
Subject
The criteria for the equivalence evaluation are changed from the difference of ORR
between the equivalence margin of (-12.5%, 16.7%) to the ratio of ORR between the
equivalence margin of (0.75, 1/0.75)
Section/Page
Protocol Synopsis/Page 8; Section 8.1/Page 56
Old text
The equivalence margin is taken as (-12.5%, 16.7%)
New text
The equivalence margin for the ratio of ORR is taken as (0.75, 1/0.75)
Reason for change
In the "Considerations for the design and review of clinical studies on biosimilars of
bevacizumab injection" published by the CDE in Nov. 2017, the use of ratio (RR) is
recommended to calculate the equivalence margin.
5
Subject
Version number is updated
Section/Page
Section 6.15.6/Pages 48 and 49
Study centers that officially implement the 2.0 version of the protocol


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Old text
New text
Study centers that officially implement the 2.0 and subsequent versions of the protocol
Reason for change
Version Revision.
6
Subject
Definition of efficacy endpoint
Section/Page
Section 7.1.1/Page 50
Old text
It is defined as the proportion of subjects with tumor size reduction of a predefined
amount and for a minimum time period
New text
It is defined as the proportion of subjects with tumor size reduction of a predefined
amount
Reason for change
According to RECIST 1.1, the efficacy evaluation in randomized double-blind
controlled studies does not require to verify the response
7
Subject
Definition of efficacy endpoint
Section/Page
Section 7.1.1/Page 50
Old text
The cut-off date for the analysis of primary efficacy endpoint in this study is 18 weeks
after subject randomization.
New text
The cut-off date for data included in the primary efficacy evaluation is the 18th week
after the last subject is randomized.
Reason for change
This point is clarified here
8
Subject
Statistical Population
Section/Page
Section 8.2/Page 56
Old text
Full Analysis Set (FAS): All randomized subjects who received at least one dose of
the study treatment.
New text
Full analysis set (FAS): includes all randomized and evaluable subjects who have
received at least one dose of the study drugs.
Reason for change
The sensitivity in detecting the equivalence at the endpoint can be improved by
rejecting subjects from the analysis set who cannot be evaluated
due to the lack of measurable lesions at baseline
9
Subject
Descriptive statistics of categorical variables
Section/Page
Section 8.3/Page 57
Old text
For categorical variables, descriptive statistics will include frequency as well as the
absolute or relative percentage
New text
For categorical variables, descriptive statistics will include the number and percentage
of each category
Reason for change
In general, the statistical description of categorical variables uses the number of cases
and percentage rather than the absolute or relative rate
10
Subject
Covariate adjustment
Section/Page
Section 8.4.1/Page 57
Old text
Not applicable
New text
The stratification factors of randomization in this study include age and EGFR status,
and the stratification factors will be considered in the model analysis (GLM or Cox) of


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primary and secondary efficacy parameters
Reason for change
In the protocol description of the generalized linear model (GLM) and Cox model, the
following stratification factors are also included in addition to the group: Age (< 60
years vs. ≥60 years) and EGFR status (wild type vs. unknown type), so corresponding
changes are made here.
11
Subject
Handling of dropouts or missing data
Section/Page
Section 8.4.2/Page 57
Old text
The analyses of primary and secondary endpoints will include data from dropouts.
The handling of missing data will be detailed in the statistical analysis plan
New text
The handling of dropout and missing data will be detailed in the statistical analysis
plan
Reason for change
A detailed description of the methods used for handling dropout and missing data will
be provided in the statistical analysis plan (SAP), including which methods are used
for the primary analysis and which method is used for the sensitive analysis
12
Subject
Primary efficacy analysis
Section/Page
Section 8.5.4.1/Page 58
Old text
ORR is defined as the incidence of confirmed complete response (CR) or partial
response (PR), using a validated imaging method to evaluate target lesions and non-
target lesions according to RECIST v1.1.
New text
ORR is defined as the incidence of complete response (CR) or partial response (PR),
and a radiological method is used to evaluate target and non-target lesions according
to RECIST v1.1.
Reason for change
According to RECIST 1.1, the efficacy evaluation in randomized double-blind
controlled studies does not require to verify the response.
13
Subject
The criteria for the equivalence evaluation are changed from the difference of ORR
between the equivalence margin of (-12.5%, 16.7%) to the ratio of ORR between the
equivalence margin of (0.75, 1/0.75)
Section/Page
Section 8.5.4.1/Page 58
Old text
Clinical equivalence will be determined by whether the 90% confidence interval (CI)
of the difference in ORR between the IBI305 and bevacizumab arms falls within the
preset margin of (12.5% to 16.7%).
New text
Clinical equivalence will be determined by whether the 90% CIs of ORR ratio for
subjects in both IBI305 and bevacizumab groups falls within the equivalence margins
of (0.75, 1/0.75).
Reason for change
In the "Considerations for the design and review of clinical studies on biosimilars of
bevacizumab injection" published by the CDE in Nov. 2017, the use of ratio (RR) is
recommended to calculate the equivalence margin.
14
Subject
Handling of the missing data
Section/Page
Section 8.5.4.1/Page 58
Old text
Subjects without tumor assessments beyond baseline will be considered unresponsive
to treatment
New text
Subjects without tumor assessments after baseline will be considered as not assessable
Reason for change
A detailed description of the treatment methods will be provided in the SAP, including


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which methods are used for the primary analysis and which method is used for the
sensitive analysis, rather than directly defining these subjects here as no response.
15
Subject
Secondary efficacy analysis
Section/Page
Section 8.5.4.2/Page 58
Old text
DCR is defined as the incidence of patients with confirmed complete response (CR),
partial response (PR), and stable disease (SD), when a validated imaging method and
RECIST v1.1 are used to evaluate target and non-target lesions.
New text
DCR is defined as the incidence of complete response (CR), partial response (PR) and
stable disease (SD), and a radiological method is used to evaluate target and non-
target lesions according to RECIST v1.1
Reason for change
According to RECIST 1.1, the efficacy evaluation in randomized double-blind
controlled studies does not require to verify the response.
16
Subject
Secondary efficacy analysis
Section/Page
Section 8.5.4.2/Page 58
Old text
PFS refers to the time from the date of randomization to the date of first documented
PD or death, whichever occurs first. The investigator will assess PD using RECIST
v1.1
New text
PFS refers to the time from the date of randomization to the date of first documented
PD or death, whichever occurs first.
Reason for change
Both analyses will be performed
17
Subject
Antibody and efficacy analysis
Section/Page
Section 8.5.4.4/Page 59
Old text
Subjects who develop antibodies during the clinical study will be summarized in detail
New text
Subjects who produce antibodies during the study will be listed.
Reason for change
It is clarified that the method used in case-by-case description is through a list.


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CLINICAL STUDY PROTOCOL
Study Title:
A randomized, double-blinded, multi-center phase III study
comparing the efficacy and safety of IBI305 plus paclitaxel/carboplatin
versus bevacizumab plus paclitaxel/carboplatin in treatment-naive
subjects with advanced or relapsed non-squamous non-small cell
lung cancer
Protocol No.:
CIBI305A301
Version and Date:
Sep. 25, 2017/Version 3.0
Product Name:
Recombinant anti-VEGF humanized monoclonal antibody
injection (IBI305)
Study Phase:
Phase III
Sponsor:
Innovent Biologics (Suzhou) Co., Ltd.
No. 168 Dongping Street, Suzhou Industrial Park, Jiangsu, China
Sponsor Contact:
Zhou Hui (Senior Medical Director)
Tel: (+86) 021-31652896
E-mail: hui.zhou@innoventbio.com
Confidentiality Statement
This document is the confidential information of Innovent Biologics (Suzhou) Co., Ltd.
The content of this document shall not be disclosed to any person other than the investigators, research consultants
or related personnel, and Institutional Review Board/Independent Ethics Committee.
The information contained in this document must not be used for any purpose, except for the evaluation or
conduction of this study, without the written consent of the sponsor.


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SIGNATURE PAGE
Protocol Title: A randomized, double-blinded, multi-center phase III study comparing the efficacy
and safety of IBI305 plus paclitaxel/carboplatin versus bevacizumab plus paclitaxel/carboplatin in
treatment-naive subjects with advanced or relapsed non-squamous non-small cell lung cancer
Protocol No.: CIBI305A301
Title
Name
Signature
Date
Senior Medical
Director
Zhou Hui
Director of
Biostatistics
Wei Zhaohui


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PROTOCOL SYNOPSIS
Sponsor/Company:
Innovent Biologics (Suzhou) Co., Ltd.
Investigational drug:
IBI305
Active Ingredient:
Recombinant anti-VEGF humanized monoclonal antibody
Study Title:
A randomized, double-blinded, multi-center phase III study comparing the efficacy
and safety of IBI305 plus paclitaxel/carboplatin versus bevacizumab plus
paclitaxel/carboplatin in treatment-naive subjects with advanced or relapsed non-
squamous non-small cell lung cancer
Protocol No.:
CIBI305A301
Coordinating Investigator:
Zhang Li
Coordinating Center:
Sun Yat-Sen University Cancer Center
Expected study duration: Each subject will receive treatment every 3-week
until progressive disease (PD), unacceptable toxicity, withdrawal of informed
consent, lost to follow-up or death (whichever comes first).
The end of the study is defined as the 18th month after the randomization of
the last subject.
Phase: III
Study Objectives:
Primary Objective:

To compare the objective response rate (ORR) of IBI305 plus paclitaxel/carboplatin versus bevacizumab
plus paclitaxel/carboplatin for the treatment of advanced or relapsed non-squamous non-small cell lung
cancer (NSCLC)
Secondary Objectives:

To compare the duration of response (DOR), progression-free survival (PFS), disease control rate (DCR),
and overall survival (OS) of IBI305 plus paclitaxel/carboplatin versus bevacizumab plus
paclitaxel/carboplatin for the treatment of advanced or relapsed non-squamous NSCLC

To compare the safety and immunogenicity of IBI305 plus paclitaxel/carboplatin versus bevacizumab
plus paclitaxel/carboplatin for the treatment of advanced or relapsed non-squamous NSCLC
Exploratory objectives:

To compare the population pharmacokinetics (PPK) of IBI305 and bevacizumab in subjects with


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advanced or recurrent non-squamous NSCLC

To compare the PD of IBI305 and bevacizumab in subjects with advanced or recurrent non-squamous
NSCLC
Study design:
This is a randomized, double-blinded, multi-center phase III study. The study planned to enroll and randomize 436
subjects with non-squamous NSCLC in a 1:1 ratio to IBI305 plus paclitaxel/carboplatin group or bevacizumab plus
paclitaxel/carboplatin group. Stratifying factors include age (< 60 vs. ≥60 years old) and EGFR status (wild type vs.
unknown type).
Each treatment cycle is 3 weeks for both groups. 15 mg/kg IBI305 or bevacizumab is administered on D1 of each
cycle along with paclitaxel/carboplatin. Subjects will receive up to 6 treatment cycles of combination therapy until
PD, unacceptable toxicity, withdrawal of informed consent, loss to follow-up, or death (whichever comes first).
Then subjects receive maintenance monotherapy, that is, discontinuing paclitaxel/carboplatin while continuing
therapy with IBI305 or bevacizumab. The maintenance monotherapy continues every 3 weeks. On D1 of each
treatment cycle, subjects will be administered 7.5 mg/kg of either IBI305 or bevacizumab until PD, unacceptable
toxicity, withdrawal of informed consent, loss to follow-up, death, or end of study (whichever comes first).
During the study, a CT or an MRI will be performed every 6 weeks (± 7 days) and be determined whether the study
treatment will be continued by investigators at each site through tumor assessments until PD, withdrawal of informed
consent, lost to follow-up, death, start of other anti-tumor therapies, or end of study. If subjects discontinue the study
treatment for reasons other than PD, tumor assessments will be continued until PD, withdrawal of informed consent, loss
of follow-up, death, start of other anti-tumor therapies, or end of study. If subjects discontinue the study treatment for PD,
the investigators will make telephone follow-up every 12 weeks (± 7 days) to collect information of subsequent anti-tumor
therapies and survival until withdrawal of informed consent, lost to follow-up, death, or end of study.
Number of Subjects:
436
Diagnosis and main inclusion
criteria:
Inclusion Criteria:
Subjects must meet all of the following inclusion criteria to be enrolled in the study:
1)
Sign the formed consent form
2)
Male or female ≥18 and ≤75 years old
3)
Histologically or cytologically confirmed unresectable locoregionally
advanced (stage IIIB), metastatic (stage IV), or relapsed non-squamous
NSCLC; mixed tumors should be categorized according to the main cell
types
4)
Histologically or cytologically confirmed EGFR wild type or non-
sensitive mutation type
5)
Must have at least one measurable target lesion (as per RECIST 1.1)
6)
Eastern Cooperative Oncology Group Performance Status (ECOG PS)


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score of 0–1
7)
Expected survival ≥6 months
8)
Laboratory results during screening:
a)
Routine blood test: WBC ≥3.0 × 109/L, ANC ≥1.5 × 109/L, platelets ≥
100 × 109/L, and hemoglobin ≥90 g/L
b)
Hepatic function: TBIL < 1.5 × ULN; ALT and AST < 2.5 × ULN for
subjects without liver metastasis, or ALT and AST < 5 × ULN for subjects with
liver metastasis
c)
Renal function: SCr ≤1.5 × ULN or CrCl ≥50 mL/min, and urine
protein < 2+ in routine urinalysis. Subjects with urine protein ≥2+ from
urinalysis dipstick at baseline, a 24-h urine should be collected with total protein
content < 1 g
d)
INR ≤1.5 and PTT or aPTT ≤1.5 × ULN within 7 days prior to the
study treatment
9)
Able to comply with study protocol
10)
Female and male subjects of childbearing age, and partners of these male
subjects must agree to use effective contraceptive measures (such as
abstinence, sterilization, oral contraceptives, medroxyprogesterone
injections or contraceptive implants) during the study and for 6 months
after the infusion of the study drug
Exclusion Criteria:
Subjects meeting any of the followings will not enrolled in the study:
1)
Prior systemic chemotherapy or targeted therapy (such as monoclonal
antibody or tyrosine kinase inhibitor) for the treatment of the current
stage of disease (Stage IIIB not suitable for multidisciplinary treatment,
stage IV or relapsed disease). Prior surgery and radiotherapy are
permitted, provided that the criteria outlined in the study protocol are met.
Subjects who received prior adjuvant therapy and relapsed within 6 months
are not eligible
2)
Mixed non-small cell and small cell carcinoma, or mixed adenosquamous
carcinoma predominantly containing squamous cell carcinoma component
3)
Histologically or cytologically confirmed EGFR-sensitive mutation type
(including exon 18-point mutation (G719X), exon 19 deletion, and exon
21-point mutations (L858R and L861Q)). Subjects with unknown EGFR
status for various reasons might enroll.
4)
History of hemoptysis within 3 months prior to screening, with a volume
of blood greater than 2.5 mL each time


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5)
Radiographic evidence of tumor invasion in great vessels. The
investigator or the radiologist must exclude subjects with tumors that are
fully contiguous with, surrounding, or extending into the lumen of a great
vessel (such as pulmonary artery or superior vena cava)
6)
Symptomatic CNS metastasis; subjects with asymptomatic brain
metastasis or subjects who are symptomatically stable after treatment for
brain metastasis might enroll if the following criteria are met: measurable
lesions outside the CNS; no midbrain, pons, cerebellum, medulla or
spinal cord metastasis; no history of intracranial hemorrhage;
7)
Subjects who received radical thoracic radiotherapy within 28 days prior
to enrollment; subjects who received palliative radiation for non-thoracic
bone lesions within 2 weeks prior to the first dose of the study drug
8)
Subjects with severe skin ulcers or fracture, or having major surgery
within 28 days prior to randomization or expecting to have major surgery
during the study
9)
Subjects who received minor surgery within 48 hours prior to the first
dose of the study treatment (Outpatient/inpatient surgery requiring
locoregional anesthetics, including central line insertion)
10)
Currently or recently (within 10 days prior to the first dose of the study
treatment) used aspirin (> 325 mg/day) or other known NSAIDs to
inhibit platelet function for 10 consecutive days
11)
Currently or recently (within 10 days prior to the first dose of the study
treatment) received treatment with full dose oral or parenteral
anticoagulant or thrombolytic agents for 10 consecutive days. However,
anticoagulants for prophylaxis are accepted
12)
Subjects with inherited hemorrhagic tendency or coagulopathy, or history
of thrombosis
13)
Uncontrolled hypertension after treatment (systolic greater than 140
mmHg and/or diastolic greater than 90 mmHg), history of hypertensive
crisis or hypertensive encephalopathy
14)
Any unstable systemic disease including but not limited to: active
infection, unstable angina, cerebrovascular accident or transient cerebral
ischemia (within 6 months prior to screening), myocardial infarction
(within 6 months prior to screening), cardiac failure congestive (NYHA
Class ≥II), severe arrhythmia requiring medication, and liver, kidney or
metabolic disease
15)
History of the following diseases within 6 months prior to screening:
gastrointestinal ulcers, gastrointestinal perforation, corrosive esophagitis
or gastritis, inflammatory bowel disease or diverticulitis, abdominal


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fistula, or intra-abdominal abscess
16)
Subjects with tracheoesophageal fistula
17)
Clinically significant third spacing (such as ascites or pleural effusion
that are uncontrollable by drainage or other treatments)
18)
Subjects with current interstitial lung disease or CT showing active
pneumonia during screening
19)
History of malignant tumors other than NSCLC within 5 years prior to
randomization, except for adequately treated cervical carcinoma in situ,
basal or squamous cell skin cancer, locoregional prostate cancer after
radical surgery, ductal carcinoma in situ after radical surgery, or papillary
thyroid carcinoma
20)
Subjects with active autoimmune disease
21)
Subjects who were HBsAg-positive, and peripheral blood HBV DNA
titer ≥1 × 103 copies/L or ≥200 IU/mL; subjects who were HBsAg-
positive and peripheral blood HBV DNA titer < 1 × 103 copies/L or <
200 IU/mL might be eligible if the investigator determines that the
subject's chronic hepatitis B infection is stable and participation in the
study would add no further risks to the subject
22)
Subjects who are tested positive for HCV antibody, HIV antibody or
syphilis
23)
Subjects with known history of allergic diseases or allergic physique
24)
Received treatment with other investigational drugs or participated in
another interventional study within 30 days prior to screening
25)
History of alcohol or drug abuse
26)
Female subjects who are pregnant or breastfeeding, or expected to be
pregnant or breastfeeding during the study
27)
Known allergies to bevacizumab or any of its excipients, or any
chemotherapeutic agents
28)
Other conditions unsuitable for the inclusion as determined by the investigator
Investigational Drug, Dosage,
and Route of Administration:
IBI305: 15 mg/kg in combination chemotherapy and 7.5 mg/kg maintenance
monotherapy, administered via intravenous infusion on D1 of every 3-week
treatment cycle until PD, unacceptable toxicity, withdrawal of informed consent,
lost to follow-up, death, or end of study (whichever comes first)
Control Drug, Dosage, and
Route of Administration:
Bevacizumab: 15 mg/kg in combination chemotherapy and 7.5 mg/kg
maintenance monotherapy, administered via intravenous infusion on D1 of every
3-week treatment cycle until PD, unacceptable toxicity, withdrawal of informed


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consent, lost to follow-up, death, or end of study (whichever comes first)
Chemotherapy:
Paclitaxel: 175 mg/m² administered via intravenous infusion on D1 of every
3-week treatment cycle for up to 6 cycles until PD, unacceptable toxicity,
withdrawal of informed consent, loss of follow-up, or death.
Carboplatin: Areas under the concentration-time curve (AUC) = 6.0 administered
via intravenous infusion on D1 of every 3-week treatment cycle for up to 6 cycles
until PD, unacceptable toxicity, withdrawal of informed consent, loss of follow-up,
or death.
Evaluation criteria:
Efficacy endpoints:
Primary efficacy endpoint:

Objective response rate (ORR)
Secondary efficacy endpoints:

Duration of response (DOR)

Progression-free survival (PFS)

Disease control rate (DCR)

Overall survival (OS)
Safety endpoints:

Vital signs

Physical examination

Laboratory tests (routine blood test, blood chemistry, and urinalysis)

12-Lead ECG

Adverse event (AE, including treatment-emergent AE (TEAE)), AE of special interest (AESI)
(hypertension, proteinuria, gastrointestinal perforation, hemorrhage [cerebral hemorrhage, hematuria and
upper gastrointestinal hemorrhage], cardiotoxicity, and thrombosis), and serious adverse event (SAE)

Immunogenicity: Positive rates of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs)
PK/PD Endpoints:

Population PK parameters, including steady-state trough concentrations after repeated doses

Changes of serum VEGF at different time points


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Statistical methods:
Sample size calculation:
A number of 218 subjects for each group (436 subjects in total) can provide 80% test power to confirm the clinical
equivalence between the treatments of IBI305 in combination with paclitaxel/carboplatin and bevacizumab in
combination with paclitaxel/carboplatin. Estimation parameters for sample size: The significance level of the two-
sided test is 0.05, the ORR of subjects in the IBI305 and bevacizumab groups is about 50.0%, and the equivalence
margin is taken as (-12.5%, 16.7%). Based on the above hypothesis, each group requires 218 subjects (436 subjects
in total).
Efficacy analysis:
Clinical equivalence will be determined by whether the 90% confidence interval (CI) of the difference in ORR
between the IBI305 and bevacizumab arms falls within the preset margin of (-12.5%, 16.7%). The ORR and 95% CI
of two groups, ORR difference and 90% CI, and ORR ratio and 90% CI will be estimated using the generalized
linear model (GLM, including groups and stratification factors).
Median survival (OS) and survival curves will be estimated using the Kaplan-Meier method. The hazard ratio (HR)
and 95% CI of two groups will be estimated using the Cox model. DORs and PFSs will be analyzed by the same
method as the median survivals. DCR will be analyzed using the same method for primary efficacy endpoints, but
an equivalence test will not be conducted.
Safety analysis:
All adverse events (AE) will be coded using MedDRA and graded according to CTCAE v4.03. All treatment-
emergent adverse events (TEAEs), Grade 3 or greater TEAEs, serious adverse events (SAEs), investigational drug-
related TEAEs, investigational drug-related SAEs, TEAEs leading to treatment discontinuation, TEAEs leading
to study termination, and adverse events of special interest (AESIs) will be listed based on system organ class,
preferred terms, and groups and the numbers of corresponding subjects and percentages will be summarized.
In addition, the severity of TEAEs and the correlation with the study drug will also be summarized by system
organ class, preferred terms, and treatment groups.
Measured values and changes from baseline for vital signs, physical examination, laboratory tests and 12-lead ECG
will be analyzed using descriptive statistics. Baseline results and worst results during the study will be presented in
cross tabulation.
The number and percentage of subjects who developed anti-drug antibodies and neutralizing antibodies during the
study will be summarized by treatment group.
PK/PD exploratory analysis:
Mainly based on description, and inter-group comparison will be carried out if necessary


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Table 1. Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
AEs
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
a.
After completing the on-site end-of-treatment visit 28 days after the last dose, subjects who discontinue the
investigational drug treatment due to reasons other than PD should continue to undergo tumor assessments once
every 6 weeks (±7 days) until PD (and begin post-PD follow-up thereafter), withdrawal of consent, start of
another antineoplastic treatment, loss to follow-up, death, or study completion.
b.
For subjects with PD, collect survival information once every 12 weeks (84 days, ±7 days) by phone until death,
loss to follow-up, withdrawal of informed consent, or study completion. Subsequent antineoplastic treatments
should be documented in the eCRF.
c.
Only measure weight.
d.
Clinical laboratory tests are carried out at the laboratory of each hospital. If screening laboratory tests (routine
blood test, blood chemistry, and urinalysis) are performed within 7 days prior to the first dose, the screening
results may be used as baseline data. For subsequent visits, all laboratory tests have to be completed within 3
days prior to the dose administration.
e.
A urinalysis is required before each IBI305/bevacizumab infusion to test urine protein.
f.
Women of childbearing age should undergo a serum/urine pregnancy test.
g.
Immunogenicity tests will be performed in all subjects at 3 blood sampling time points: Within 1 hour prior to
the first dose of the study treatment (IBI305/bevacizumab) in C1, within 1 hour prior to the administration of
the study treatment in C4, and during the end-of-treatment visit. Blood specimens that are positive for anti-drug
antibodies (ADA) after dosing will be further tested for neutralizing antibodies (NAb). Samples will be tested
at the designated central laboratory.
h.
Image assessments (CT or MRI) of the brain, chest, abdomen, and pelvis should be completed at baseline. If
these tests are performed within 28 days prior to the first dose of the study drug, they do not need to be repeated
unless the investigator believes that there have been changes in the subject's tumor burden. After the start of
treatment, imaging tests are performed once every 6 weeks (±7 days) and have to be completed within 7 days
prior to the scheduled visits, until progressive disease, start of other treatment, withdrawal of informed consent,
loss to follow-up, death, or study completion. The same method of imaging test is used at baseline and during
follow-up. Imaging evaluations of the chest, abdomen, and pelvis are required.
i.
All subjects should undergo tumor tissue EGFR testing.


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j.
Each treatment cycle of the investigational product contains 3 weeks. The dose of IBI305 or bevacizumab is 15
mg/kg when used in combination with chemotherapeutic drugs and 7.5 mg/kg in the maintenance monotherapy,
given on D1 of every treatment cycle until progressive disease (PD), unacceptable toxic reactions, withdrawal
of informed consent, loss to follow-up, death, or end of study, whichever occurs first. After all assessments
were completed, the study drug was administered followed by chemotherapy. The first dose of study drug was
completed within 24 h after randomization.
k.
Each treatment cycle is 3 weeks long. Chemotherapy (paclitaxel + carboplatin) is administered on D1 of each
cycle for up to 6 cycles, or until disease progression (PD), unacceptable toxicity, withdrawal of informed
consent, loss to follow-up, or death. Paclitaxel is administered after the infusion of study drug is completed,
followed by carboplatin.


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TABLE OF CONTENTS
SIGNATURE PAGE..................................................................................................................... 2
PROTOCOL SYNOPSIS..............................................................................................................3
TABLE OF CONTENTS............................................................................................................ 13
LIST OF ABBREVIATIONS AND DEFINITIONS................................................................18
1
INTRODUCTION............................................................................................................... 20
1.1 Study Background........................................................................................................... 20
1.1.1 Disease background............................................................................................... 20
1.1.2 Investigational drug................................................................................................22
1.1.2.1 Description of investigational drug..............................................................22
1.1.2.2 Preclinical studies........................................................................................ 23
1.2 Study Principles and Risk/Benefit Assessment...............................................................25
1.2.1 Study principles and dose selection....................................................................... 25
1.2.2 Risk/benefit assessment......................................................................................... 26
2
STUDY OBJECTIVES....................................................................................................... 27
2.1 Primary Objective............................................................................................................27
2.2 Secondary Objectives......................................................................................................27
2.3 Exploratory Objectives....................................................................................................27
3
STUDY PLAN......................................................................................................................28
3.1 Overview of Study Design.............................................................................................. 28
3.2 Study Design Discussion.................................................................................................29
4
STUDY POPULATION...................................................................................................... 30
4.1 Inclusion Criteria.............................................................................................................30
4.2 Exclusion Criteria............................................................................................................31
4.3 Screening Failure.............................................................................................................33
4.4 Subject Restrictions.........................................................................................................33
4.5 Subject Withdrawal and Replacement............................................................................ 33
5
STUDY TREATMENT.......................................................................................................35
5.1 Therapies by Study Drugs............................................................................................... 35
5.2 Chemotherapy................................................................................................................. 35
5.3 Dose Adjustment of Each Study Drug............................................................................ 35


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5.3.1 General principles.................................................................................................. 35
5.3.2 Dose adjustments of study drugs........................................................................... 38
5.3.3 Dose adjustments of chemotherapy....................................................................... 43
5.4 Study Drug Properties..................................................................................................... 46
5.6 Packaging, Labeling, and Storage................................................................................... 47
5.7 Subjects Allocation..........................................................................................................47
5.8 Blinding...........................................................................................................................49
5.9 Concomitant Medications and Treatments......................................................................49
5.9.1 Prohibited treatment...............................................................................................49
5.9.2 Permitted treatment................................................................................................49
5.9.3 Treatment after study treatment............................................................................. 50
5.10 Treatment Compliance.................................................................................................. 50
5.11 Drug Return and Destruction........................................................................................ 50
5.12 Study Drug-Related Records.........................................................................................50
6
STUDY PROCEDURE....................................................................................................... 51
6.1 Screening Visits (D -28 to D -1)..................................................................................... 52
6.2 Baseline Visits (D1 of cycle 1)........................................................................................53
6.3 Cycle 2 (week 4 ± 3 days)...............................................................................................54
6.4 Cycle 3 (week 7 ± 3 days)...............................................................................................54
6.5 Cycle 4 (week 10 ± 3 days).............................................................................................55
6.6 Cycle 5 (week 13 ± 3 days).............................................................................................55
6.7 Cycle 6 (week 16 ± 3 days).............................................................................................56
6.8 Cycle 7 and Subsequent Treatment Cycles (±3 Days)....................................................56
6.9 End-Of-Treatment Visit.................................................................................................. 57
6.10 Disease Progression Visit..............................................................................................57
6.11 Survival Follow-Up.......................................................................................................58
6.12 Study Completion..........................................................................................................58
6.13 Tumor Assessment........................................................................................................ 59
6.14 Clinical Laboratory Evaluations....................................................................................59
6.15 Vital Signs, Physical Examinations, and Other Safety Assessments............................61
6.15.1 Vital signs............................................................................................................ 61


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6.15.2 Height and weight................................................................................................ 63
6.1.5.3 Physical examinations.........................................................................................63
6.15.4 12-Lead ECG....................................................................................................... 64
6.15.5 Immunogenicity assessment.................................................................................65
6.15.6. Pharmacokinetics/pharmacodynamics................................................................ 65
6.15.6.1 Pharmacokinetics.............................................................................................. 65
6.15.6.2 Pharmacodynamics........................................................................................... 65
6.15.7 EGFR testing........................................................................................................65
7
STUDY ASSESSMENTS.................................................................................................... 67
7.1 Efficacy Assessment........................................................................................................67
7.1.1 Primary efficacy endpoint......................................................................................67
7.1.2 Secondary efficacy endpoints................................................................................ 67
7.2 Safety Assessments......................................................................................................... 68
7.2.1 Adverse events....................................................................................................... 68
7.2.1.5 Management and follow-up of adverse events............................................ 71
7.2.1.6 Adverse event of special interest and expedited reporting.......................... 71
7.2.1.7 Pregnancy.....................................................................................................72
7.2.1.8 Time limits of documenting and reporting AEs.......................................... 72
8
STATISTICS........................................................................................................................75
8.1 Sample Size Determination.............................................................................................75
8.2 Statistical Population.......................................................................................................75
8.3 General Principles for Statistical Analyses..................................................................... 76
8.4 Statistical Methods.......................................................................................................... 76
8.4.1 Adjustments for covariates.....................................................................................76
8.4.2 Managing dropouts and missing data.....................................................................76
8.4.3 Multi-center study..................................................................................................76
8.4.4 Multiple comparisons and adjustments to multiplicity..........................................76
8.5 Statistical Analyses..........................................................................................................76
8.5.1 Subject distribution................................................................................................ 76
8.5.2 Demographics and other baseline characteristics.................................................. 77
8.5.3 Compliance and drug exposure..............................................................................77


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8.5.4 Efficacy.................................................................................................................. 77
8.5.4.1 Primary efficacy endpoint............................................................................77
8.5.4.2 Secondary efficacy endpoints...................................................................... 78
8.5.4.3 Sensitivity analysis...................................................................................... 78
8.5.4.4 Antibody and efficacy analysis....................................................................78
8.5.5 Exploratory analysis...............................................................................................78
8.5.6 Interim analysis......................................................................................................79
8.5.7 Stratified analysis...................................................................................................79
8.5.8 Safety analysis........................................................................................................79
8.5.8.2 Laboratory tests............................................................................................79
8.5.8.3 ECG examinations.......................................................................................79
8.5.8.4 Vital signs, physical examinations, and other safety examinations.............79
8.5.8.5 Concomitant medications............................................................................ 79
9
QUALITY ASSURANCE AND QUALITY CONTROL.................................................80
9.1 Clinical Monitoring......................................................................................................... 80
9.2 Data Management/Coding...............................................................................................81
9.3 Audits and Inspections.................................................................................................... 82
10
ETHICS................................................................................................................................ 83
10.1 Independent Ethics Committee..................................................................................... 83
10.2 Implementation of Ethical Principles............................................................................83
10.3 Subject Information and Informed Consent.................................................................. 84
10.4 Protection of Subject Data.............................................................................................84
11
STUDY MANAGEMENT...................................................................................................85
11.1 Organizational Structure................................................................................................85
11.1.1 Independent review committee............................................................................ 85
11.2 Archiving of Study Documents.....................................................................................85
11.3 Access to Source Data/Documents................................................................................86
11.4 Protocol Revisions.........................................................................................................86
11.5 Investigator's Responsibilities.......................................................................................86
11.6 Study Termination.........................................................................................................87
11.7 Publishing Policies........................................................................................................ 87


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11.8 Finance and Insurance...................................................................................................87
12
REFERENCES.................................................................................................................... 88
13
APPENDIX...........................................................................................................................89
13.1 Appendix I.....................................................................................................................89
13.2 Appendix II....................................................................................................................90
13.3 APPENDIX 3................................................................................................................ 91
14
INVESTIGATOR SIGNATURE PAGE......................................................................... 105
LIST OF TABLES
Table 1. Schedule of follow-up visits............................................................................................10
Table 2. Hypertension severity grades and interventions in CTCAE v4.03..................................40
Table 3. Dose adjustments of paclitaxel and carboplatin (febrile neutropenia and thrombocytopenia)... 43
Table 4. Dose adjustment of paclitaxel (hepatotoxicity)............................................................... 44
Table 5. Dose adjustment of paclitaxel (neurotoxicity).................................................................45
Table 6. Study drugs......................................................................................................................47
Table 7. Correlation between AEs and investigational drugs........................................................69
Table 8. Reporting and follow-up of adverse events.....................................................................73
Table 9. Organizational structure...................................................................................................85
LIST OF FIGURE
Figure 1. Study design schematic.................................................................................................. 29


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LIST OF ABBREVIATIONS AND DEFINITIONS
Abbreviations
Definitions
AE
Adverse event
AESI
Adverse event of special interest
ADA
Anti-drug antibody
ALT
Alanine aminotransferase
AUC
Area under the curve
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
CFDA
China Food and Drug Administration (now National Medical
Products Administration)
CQA
Clinical quality assurance
CR
Complete response
CRA
Clinical research associate
CRO
Contract research organization
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DCR
Disease control rate
DOR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data collection
EGFR
Epithelial growth factor receptor
FAS
Full analysis set
GCP
Good Clinical Practice
HBsAg
Hepatitis B surface antigen
HBV-DNA
Hepatitis B virus deoxyribonucleic acid
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Hazard ratio
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
INR
International normalized ratio
ITT
Intention-to-treat


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NCCN
National Comprehensive Cancer Network
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PK
Pharmacokinetics
PP
Per-protocol
PR
Partial response
PRES
Posterior Reversible Encephalopathy Syndrome
PTT
Partial thromboplastin time
SAE
Serious adverse event
SD
Stable disease
SOP
Standard operating procedure
SS
Safety set
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
VEGF
Vascular endothelial growth factor


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1 INTRODUCTION
1.1 Study Background
1.1.1 Disease background
Lung cancer has the highest incidence and mortality globally among all cancers. According to
the 2012 Global Cancer Statistics (GLOBOCAN 2012) published by International Agency for
Research on Cancer, there were approximately 1.8 million new lung cancer cases worldwide,
which accounted for 13% of the global newly-diagnosed cancers, and 58% of these cases
occurred in underdeveloped areas1. According to the data released by the National Central
Cancer Registry of China in 2015, lung cancer was the most prevalent malignancy in China in
2011, with about 650,000 new cases every year. Lung cancer was also the leading cause of death,
with about 520,000 deaths per year2. The limited clinical treatment of lung cancer is the main
reason for its poor prognosis. There is a huge demand for new types of lung cancer treatment
drugs.
Approximately 85–90% of lung cancers are non-small cell lung cancer (NSCLC) and patients
with NSCLC are usually in the advanced stages when diagnosed3. According to the Chinese
guidelines for the diagnosis and treatment of primary lung cancer, anatomic pulmonary resection
is the mainstay of treatment for early stage lung cancers4. However, despite surgery, some
patients develop distance metastases that eventually lead to death5. Surgery is not possible for
most patients with clearly diagnosed stage IIIB and IV as well as some patients with stage IIIA
NSCLC4. Comprehensive treatment based on systemic therapy is used to maximize patient
survival, control progressive disease, and improve the quality of life6.
In recent years, anti-tumor therapies have entered a new era with the emergency of targeted
drugs. Some of these targeted drugs have demonstrated satisfactory efficacy in the treatment of
advanced NSCLC. These targeted drugs include monoclonal antibodies and tyrosine kinase
inhibitors (TKIs), mostly targeting epidermal growth factor receptors (EGFRs) and vascular
endothelial growth factor (VEGF), such as bevacizumab, cetuximab, gefitinib, erlotinib, and
icotinib. Monoclonal antibodies have become the drugs of choice in various treatment guidelines
due to the good targeting ability, low drug resistance, and good patient tolerability. Bevacizumab
combination chemotherapy is a first-line therapy of NSCLC recommended by the National
Comprehensive Cancer Network (NCCN)7. Additionally, bevacizumab in combination with
paclitaxel/carboplatin has also been approved as the first-line therapy of unresectable advanced,
metastatic, or relapsed non-squamous NSCLC by China Food and Drug Administration (CFDA)
on Jul. 9, 20156.


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Compared with traditional chemotherapy that directly inhibit or kill tumor cells, anti-angiogenic
drugs have the following unique advantages8:

The targets are genetically stable vascular endothelial cells (VECs) rather than highly
heterogeneous tumor cells, thus leading to lower drug resistance;

The number of tumor-induced VECs is far less than that of tumor cells, and the efficacy
is preferable targeting on VECs and their cytokines;

Normal VECs are quiescent, whereas tumor VECs are active in proliferation. Anti-
angiogenic therapy targets activated cells and avoids damage to normal VECs, thus
leading to better targeting ability;

Anti-angiogenic therapy can normalize the tumor vessels and thereby reduce the
pressure in tumor tissues. This enhances the delivery of chemotherapeutic agents into
tumor tissues, thus increasing the efficacy of chemotherapy.
Angiogenesis is a basic biological characteristic of tumors. The growth of both solid and
hematologic tumors are depended on angiogenesis regardless of the nature of tumor cells.
Therefore, anti-angiogenic therapy is broad-spectrum and applicable to various tumors.
Bevacizumab is a recombinant humanized monoclonal antibody that selectively binds to human
VEGF and blocks its biological activity. Bevacizumab consists of a framework region of a
human antibody and a humanized murine antigen binding region that can inhibit the binding of
VEGF to its receptors on epithelial cells, Flt-1 and KDR. By blocking the activity of VEGF and
reducing tumor angiogenesis, tumor growth is inhibited9.
In a study conducted by the Estern Cooperative Oncology Group (ECOG), compared with
chemotherapy alone (paclitaxel/ carboplatin), bevacizumab in combination with paclitaxel/carboplatin
significantly increased the overall survival (OS) (median: 12.3 vs. 10.3 months), progression-free
survival (PFS) (median: 6.2 vs. 4.5 months), and overall response rate (ORR) (35% vs. 15%) in
patients with advanced, metastatic, or relapsed non-squamous NSCLC10. In another foreign
AVAiL study, different doses of bevacizumab (7 and 15 mg/kg) in combination with
chemotherapy (cisplatin and gemcitabine) and placebo combine with chemotherapy were
compared for the treatment of non-squamous NSCLC. The study found that the two
bevacizumab groups had significantly increased the PFS (median: 6.7 months (7.5 mg/kg
combination chemotherapy group) vs. 6.5 months (15 mg/kg combination chemotherapy group)
vs. 6.1 months (placebo combination chemotherapy group)) and the ORR (37.8% (7.5 mg/kg
combination chemotherapy group) vs. 34.6% (15 mg/kg combination chemotherapy group) vs.
21.6% (placebo combination chemotherapy group)) in patients with locally advanced, metastatic,
or relapsed non-squamous NSCLC11. In a BEYOND study conducted in China, compared with


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placebo in combination with paclitaxel/carboplatin, bevacizumab in combination with
paclitaxel/carboplatin significantly increase the PFS (median: 9.2 vs. 6.5 months), OS (median:
24.3 vs. 17.7 months), and the ORR (54% vs. 26%) in patients with advanced or relapsed non-
squamous NSCLC12.
In China, the antibodies and fusion proteins targeting VEGF are research hotspots. However,
since 2006, the clinical efficacies of various drugs have not been verified and no products have
been marketed. Considering the complexity of macromolecular drugs and the limitations of drug
development capability in China, advanced technologies in antibody development, production,
and quality control is required to develop high-quality VEGF inhibitors that are safe and
effective. IBI305 has showed high similarity to bevacizumab in various pharmaceutical and
nonclinical studies (refer to Investigator's Brochure [IB]). Besides, the efficacy and safety of
bevacizumab for treatment of locally advanced, metastatic or relapsed lung cancer have been
verified. The relevant domestic and external pivotal clinical studies are referable for the protocol
design of IBI305 clinical study. In summary, the clinical study of IBI305 for treatment of
NSCLC has a solid foundation and relatively low risks. The successful development of IBI305
indicates an additional first-line targeted drug for lung cancer in China, providing doctors and
patients with more therapeutic options.
1.1.2 Investigational drug
1.1.2.1 Description of investigational drug
IBI305 is a recombinant humanized anti-VEGF monoclonal antibody injection developed by
Innovent Biologics (Suzhou) Co., Ltd. (hereafter as sponsor) that specifically binds human
VEGF. The molecular weight of IBI305 is 149 KDa. IBI305 specifically binds to VEGF-A,
inhibits the binding of VEGF-A to VEGF-R1 and VEGF-R2, blocks the signaling pathways such
as PI3K/Akt/PKB and Ras-Raf-MEK-ERK. IBI305 also inhibits the growth, proliferation, and
migration of VECs and angiogenesis, decreases the vascular permeability, blocks blood supply to
tumor tissues, inhibits the proliferation and metastasis of tumor cells, and induces the apoptosis
of tumor cells, thereby generates anti-tumor effects. The main active ingredient is recombinant
humanized anti-VEGF monoclonal antibody and excipients include sodium acetate, sorbitol, and
polysorbate 8013. Refer to the Investigator's Brochure for the detailed structure and
physicochemical properties of IBI305.


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1.1.2.2 Preclinical studies
Pharmaceutical studies
The pharmaceutical studies showed that stability, primary structure, higher-order structure,
oligosaccharide distribution, charge variant, and product-related impurities of IBI305 are highly
similar to those of bevacizumab, and the process-related impurities meet the proposed
specification. Therefore, IBI305 is considered to have highly similar protein properties and
product quality to bevacizumab13.
Pharmacodynamic studies
In vitro and in vivo pharmacodynamic (PD) studies of IBI305 showed the following findings:
1)
Target: IBI305 displayed specifically high-affinity binding to recombinant human
VEGF-A with an affinity constant same as that of bevacizumab, indicating that IBI305,
the same as bevacizumab, is a specific human VEGF blocker with a clear target.
2)
Specificity: IBI305 displayed specifically high-affinity binding to recombinant human
VEGF-A, medium-affinity binding to canine VEGF-A, but low-affinity binding to
human VEGF-B, VEGF-C, VEGF-D, PlGF, suggesting that IBI305 recognizes specific
targets and has low off-target toxicity risk; no obvious affinity to mouse VEGF-A164
and rat VEGF-A164, suggesting that IBI305 has high species specificity.
3)
Mechanism of action: IBI305 specifically binds to VEGF-A and inhibits the activation
of VEGFR-2 and ERK1/2, blocks the proliferation and migration of HUVEC, and
inhibits the sprouting from rat aortic ring, suggesting that IBI305 antagonizes VEGF-
A-induced signaling pathway to block the proliferation and migration of VECs and
inhibit angiogenesis, which leads to the reduction of nutritional supply and metastasis
of tumor.
4)
Anti-tumor effects: IBI305 significantly inhibits the growth of human colon cancer
Ls174t and lung cancer NCI-H460 cells in xenografts in nude mice, indicating that
IBI305 has significant anti-tumor effects.
Results from in vitro and in vivo studies of IBI305 showed highly similarity with that of
bevacizumab designed simultaneously, demonstrating that the target, mechanism of action,
and anti-tumor effects of IBI305 are highly similar to bevacizumab13.


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Pharmacokinetic studies
In vitro and in vivo pharmacokinetic (PK) studies of IBI305 showed the following findings:
1)
IBI305 showed no significant cross-reactivity with normal human tissues and
cynomolgus monkey tissues, and only cross-reacted with the positive-control. i.e.
human angiosarcoma tissue, suggesting that IBI305 is highly specific to cancer tissues
rather than normal human tissues and has very low on-target toxicity.
2)
Linearity: With single dose or repeated doses of IBI305 (2-50 mg/kg) vis intravenous
injection in cynomolgus monkeys, the test showed significant PK, thus reducing the
suddenly rising toxicity risks with increased clinical doses.
3)
Immunogenicity: With single dose or repeated doses of IBI305 or bevacizumab via
intravenous injection in cynomolgus monkeys, the test showed abnormal changes of
drug concentration-time curves in several animals. The anti-drug antibody (ADA) test
results showed that IBI305 has a medium immunogenicity.
4)
Accumulation: With repeated doses of IBI305 or bevacizumab via intravenous
injection in cynomolgus monkeys, the test showed that drug exposure of the last
dose was significantly higher than that of the first dose, and the steady-state drug
concentration after repeated doses was higher than that after a single dose, suggesting
that the drug may be accumulated in body.
The results of tissue cross-reactivity and PK/toxicokinetic studies in cynomolgus monkeys
indicated that IBI305 and bevacizumab have similar characteristics in tissue cross-reactivity and
PK/toxicokinetics13.
Toxicological studies
Toxicological studies of IBI305 showed the following findings:
1)
Single dose: With single dose of IBI305 (up to 300 mg/kg) via intravenous injection in
cynomolgus monkeys, the test showed good tolerability without any abnormal clinical
symptoms and toxicity. The dose was about 48 times the proposed clinical dose for
human based on body surface area. In the safety pharmacology test, with single dose of
IBI305 (50 mg/kg) via intravenous injection in cynomolgus monkeys, the test showed
no significant effects on the central nervous system, respiratory system, and
cardiovascular system, suggesting that the single dose of IBI305 via intravenous
injection has a high safety.


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2)
Repeated doses: With repeated doses of IBI305 (up to 50 mg/kg) via intravenous
injection twice weekly for 9 consecutive doses in cynomolgus monkeys, equivalent to
20 times the proposed clinical dose for humans (based on the weight), the test showed
extremely mild to mild linear growth arrest of metaphyseal lines at knee joint and
disordered chondrocyte proliferation, extremely mild increases in macrophage count
in white pulp of spleen, pulmonary (including bronchial) hemorrhage, and deposits of
hemosiderin in lymphoid tissue of bronchial mucosa, indicating that the target organ
toxicities are mainly in the bone, spleen, and lungs.
3)
Immunotoxicity and immunogenicity: With repeated doses of IBI305 via intravenous
injection twice weekly for 9 consecutive doses in cynomolgus monkeys, the test
showed medium immunotoxicity to the spleen. Different doses of IBI305 may result in
the production of ADAs, a portion of which are neutralizing antibodies (NAbs),
indicating that IBI305 has medium immunotoxicity and immunogenicity.
4)
Local irritation test: With repeated dose of IBI305 via intravenous injection in
cynomolgus monkeys, the test showed no irritation at the injection site, suggesting that
administration of IBI305 via intravenous injection is safe and feasible.
5)
In vitro hemolysis assay: With maximum proposed clinical concentration of IBI305
(9 mg/mL), the assay showed no hemolysis, suggesting that IBI305 is suitable for
intravenous injection.
IBI305 has high similarity with bevacizumab in safety pharmacology, long-term toxicity,
immunotoxicity, immunogenicity, local irritation, and hemolysis13.
1.2 Study Principles and Risk/Benefit Assessment
1.2.1 Study principles and dose selection
A biosimilar drug refers to a therapeutic biological product that is similar in quality, safety and
efficacy with an approved reference drug14. IBI305, developed and sold in the market by the
sponsor, is a bevacizumab biosimilar, and has the same administration method and indications
as bevacizumab.


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This study is conducted in accordance with the "Guidelines on Development and Evaluation of
Bosimilars (for Trial Version)" issued by the NMPA (formerly CFDA)14. The doses of IBI305
selected in this study are based on the preclinical studies that showed highly similarity between
IBI305 and bevacizumab in pharmacology, PD, PK and toxicology (refer to the Investigator's
Brochure for details). Besides, the efficacy and safety of bevacizumab for treatment of advanced,
metastatic or relapsed non-squamous NSCLC have been verified, and the indications have also
been approved in China. Therefore, the dose and administration of IBI305 is similar to
bevacizumab in this study, that is, 15 mg/kg intravenously on D1 of every 3-week cycle
when used in combination with chemotherapy (paclitaxel and carboplatin). In the subsequent
maintenance monotherapy therapy, IBI305 will be given intravenously at a dose of 7.5 mg/kg on
the first day of every 3-week cycle. This design of this study is to further demonstrate that
IBI305 is similar to bevacizumab in clinical efficacy, safety, and immunogenicity in subjects
with advanced, metastatic or relapsed non-squamous NSCLC.
1.2.2 Risk/benefit assessment
IBI305 is a bevacizumab biosimilar developed by the sponsor. Based on the clinical pharmacology
and toxicology characteristics of IBI305, the risks and benefits of IBI305 are expected to be similar
to bevacizumab.
The treatment-related risks of bevacizumab are detailed in its prescribing information. This study
is the first human study of IBI305 so that unexpected adverse reactions will be possible. The
design of this study ensures the minimized subject risks by close monitoring of the adverse
events (AEs) before, during, and after the infusion of the investigational drugs. Once an adverse
reaction occurs, the investigator will immediately take appropriate action for the subject safety.
The platinum-based therapy is the standard first-line regimen of advanced NSCLC4. This study
uses the combination of paclitaxel/carboplatin, ensuring the basic anti-tumor therapy for subjects.


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2 STUDY OBJECTIVES
2.1 Primary Objective
The primary objective of this study is to compare the objective response rate (ORR) of IBI305
plus paclitaxel/carboplatin versus bevacizumab plus paclitaxel/carboplatin for the treatment of
advanced or relapsed non-squamous NSCLC.
2.2 Secondary Objectives
Secondary objectives include:

To compare the duration of response (DOR), progression-free survival (PFS), disease
control rate (DCR), and overall survival (OS) in subjects with advanced or relapsed
non-squamous NSCLC treated by IBI305 plus paclitaxel/carboplatin versus
bevacizumab plus paclitaxel/carboplatin

To compare the safety and immunogenicity of IBI305 plus paclitaxel/carboplatin
versus bevacizumab plus paclitaxel/carboplatin for the treatment of advanced or
relapsed non-squamous NSCLC
2.3 Exploratory Objectives

To compare the population pharmacokinetics (PPK) characteristics of IBI305 and
bevacizumab in subjects with advanced or relapsed non-squamous NSCLC

To compare the pharmacodynamics (PD) characteristics of IBI305 and bevacizumab in
subjects with advanced or relapsed non-squamous NSCLC


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3 STUDY PLAN
3.1 Overview of Study Design
This is a randomized, double-blind, active-controlled, and multi-center phase III study. A total of
436 subjects across 35 study sites with non-squamous NSCLC will be planned, randomized in a
1:1 ratio into the IBI305 plus paclitaxel/carboplatin group or bevacizumab plus paclitaxel/carboplatin
group, and stratified according to age (< 60 vs. ≥60 years old) and epidermal growth factor
receptor (EGFR) status (wild type vs. unknown type). Each treatment cycle is 3 weeks for both
groups. 15 mg/kg IBI305 or bevacizumab is administered on D1 of each cycle along with
paclitaxel/carboplatin. Subjects will receive up to 6 treatment cycles of combination therapy until
PD, unacceptable toxicity, withdrawal of informed consent, loss of follow-up, or death
(whichever comes first). Then subjects received maintenance monotherapy, that is, discontinuing
paclitaxel/carboplatin while continuing maintenance therapy with IBI305 or bevacizumab. The
maintenance monotherapy continues every 3 weeks. On D1 of each treatment cycle, subjects will
be administered 7.5 mg/kg of either IBI305 or bevacizumab until PD, unacceptable toxicity,
withdrawal of informed consent, lost to follow-up, death, or end of study (whichever comes first).
After discontinuing the study drug, subjects will return to the study site 28 days (± 7 days) after
the last dose for an end-of-treatment visit. If the subjects discontinue the study treatment for
reasons other than PD, subsequent follow-up will be continued until PD, withdrawal of informed
consent, start of other anti-tumor therapies, loss of follow-up, death, or end of study. If the
subjects discontinue the study treatment for PD, the investigator will make telephone follow-up
every 12 weeks (± 7 days) to collect information of subsequent anti-tumor therapies and survival.
A CT or an MRI will be performed every 6 weeks (± 7 days) until PD, withdrawal of informed
consent, start of other anti-tumor therapies, loss of follow-up, death, or end of study. The method
for subsequent imaging examination should be consistent with that at baseline, and the chest,
abdomen and pelvis of the subject must be scanned. Each assessment must be completed within
7 days from the most recent visit. The investigators then perform the evaluation based on the
RECIST v1.1 criteria to determine whether the subject can continue receiving the next cycle of
treatment. Furthermore, the independent tumor evaluation committee (Section 11.1.1) will also
evaluate tumor response according to the RECIST v1.1. If the subjects discontinue the study
treatment for reasons other than PD, subsequent tumor evaluation should be continued according
to the study procedures until PD, withdrawal of informed consent, start of other anti-tumor
therapies, loss of follow-up, death or, end of study.
The study design is shown in Figure 1.


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Figure 1. Study design schematic
3.2 Study Design Discussion
This is a randomized, double-blind study, and bias in treatment groups is avoided. Furthermore,
the CT/MRI images of each subject will be evaluated by an independent tumor evaluation committee
according to the RECIST v1.1 to ensure consistency in evaluation.
Screening
period
Combination therapy (once every 3 weeks)
IBI305 or bevacizumab plus
Paclitaxel + carboplatin
Follow-
up
Monotherapy
(once every 3 weeks) IBI305 or
Bevacizumab
End-of-treatment visit
(28 days (±7 days) after
last dose)
Cycle n
D-28
to
D-1
Cycle 1
randomiz
ation
(D1)
Cycle 2
Cycle 3
Cycle 6
Cycle 7
Post-treatment follow-up


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4 STUDY POPULATION
4.1 Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be enrolled in the study:
1)
Sign the informed consent form
2)
Male or female ≥18 and ≤75 years old
3)
Histologically or cytologically confirmed unresectable locoregionally advanced (stage
IIIB), metastatic (stage IV), or relapsed non-squamous NSCLC; mixed tumors should
be categorized according to the main cell types
4)
Histologically or cytologically confirmed EGFR wild type or non-sensitive mutation
type
5)
Must have at least one measurable target lesion (as per RECIST 1.1)
6)
Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0–1
7)
Expected survival ≥6 months
8)
Laboratory results during screening:
a)
Routine blood test: WBC ≥3.0 × 109/L, ANC ≥1.5 × 109/L, platelets ≥100 × 109/L,
and hemoglobin ≥90 g/L
b)
Hepatic function: TBIL < 1.5 × ULN; ALT and AST < 2.5 × ULN for subjects
without liver metastasis, or ALT and AST < 5 × ULN for subjects with liver
metastasis
c)
Renal function: SCr ≤1.5 × ULN or CrCl ≥50 mL/min, and urine protein < 2+ in
routine urinalysis. Subjects with urine protein ≥2+ at baseline urinalysis must
have undergone 24 h urine collection with total protein content < 1 g
d)
INR ≤1.5 and PTT or aPTT ≤1.5 × ULN within 7 days prior to the study treatment
9)
Able to comply with study protocol
10) Female and male subjects of childbearing age, and partners of these male subjects must
agree to use effective contraceptive measures (such as abstinence, sterilization, oral
contraceptives, medroxyprogesterone injections or contraceptive implants) during the
study and for 6 months after the infusion of the study drug


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4.2 Exclusion Criteria
Subjects meeting any of the followings are not enrolled in the study:
1)
Prior systemic chemotherapy or targeted therapy (such as monoclonal antibody or
tyrosine kinase inhibitor) for the treatment of the current stage of disease (Stage IIIB
not suitable for multidisciplinary treatment, stage IV or relapsed disease). Prior surgery
and radiotherapy are permitted, provided that the criteria outlined in the study protocol
are met. Subjects who received prior adjuvant therapy and relapsed within 6 months are
not eligible
2)
Mixed non-small cell and small cell carcinoma, or mixed adenosquamous carcinoma
predominantly containing squamous cell carcinoma component
3)
Histologically or cytologically confirmed EGFR-sensitive mutation type (including
exon 18 point mutation (G719X), exon 19 deletion, and exon 21 point mutations
(L858R and L861Q)). Subjects with unknown EGFR status for various reasons might
enroll.
4)
History of hemoptysis within 3 months prior to screening, with a volume of blood
greater than 2.5 mL each time
5)
Radiographic evidence of tumor invasion in great vessels. The investigator or the
radiologist must exclude subjects with tumors that are fully contiguous with,
surrounding, or extending into the lumen of a great vessel (such as pulmonary artery or
superior vena cava)
6)
Symptomatic CNS metastasis; subjects with asymptomatic brain metastasis or subjects
who are symptomatically stable after treatment for brain metastasis might enroll if the
following criteria are met: measurable lesions outside the CNS; no midbrain, pons,
cerebellum, medulla or spinal cord metastasis; no history of intracranial hemorrhage;
7)
Subjects who received radical thoracic radiation therapy within 28 days prior to
enrollment; subjects who received palliative radiation for non-thoracic bone lesions
within 2 weeks prior to the first dose of the study drug
8)
Subjects with severe skin ulcers or fracture, or having major surgery within 28 days
prior to randomization or expecting to have major surgery during the study
9)
Subjects who received minor surgery within 48 hours prior to the first dose of the study
treatment (Outpatient/inpatient surgery requiring locoregional anesthetics, including
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10) Currently or recently (within 10 days prior to the first dose of the study treatment) used
aspirin (> 325 mg/day) or other known NSAIDs to inhibit platelet function for 10
consecutive days
11) Currently or recently (within 10 days prior to the first dose of the study treatment)
received treatment with full dose oral or parenteral anticoagulant or thrombolytic
agents for 10 consecutive days. However, anticoagulants for prophylaxis are accepted
12) Subjects with inherited hemorrhagic tendency or coagulopathy, or history of thrombosis
13) Uncontrolled hypertension (systolic greater than 140 mmHg and/or diastolic greater
than 90 mmHg), history of hypertensive crisis or hypertensive encephalopathy
14) Any unstable systemic disease including but not limited to: active infection, unstable
angina, cerebrovascular accident or transient cerebral ischemia (within 6 months prior
to screening), myocardial infarction (within 6 months prior to screening), cardiac
failure congestive (NYHA Class ≥II), severe arrhythmia requiring medication, and
liver, kidney or metabolic disease
15) History of the following diseases within 6 months prior to screening: gastrointestinal
ulcers, gastrointestinal perforation, corrosive esophagitis or gastritis, inflammatory
bowel disease or diverticulitis, abdominal fistula, or intra-abdominal abscess
16) Subjects with tracheoesophageal fistula
17) Clinically significant third spacing (such as ascites or pleural effusion that are
uncontrollable by drainage or other treatments)
18) Subjects with current interstitial lung disease or CT showing active pneumonia during
screening;
19) History of malignant tumors other than NSCLC within 5 years prior to randomization,
except for adequately treated cervical carcinoma in situ, basal or squamous cell skin
cancer, locoregional prostate cancer after radical surgery, ductal carcinoma in situ after
radical surgery, or papillary thyroid carcinoma
20) Subjects with active autoimmune disease
21) Subjects who were HBsAg-positive, and peripheral blood HBV DNA titer ≥1 × 103
copies/L or ≥200 IU/mL; subjects who were HBsAg-positive and peripheral blood
HBV DNA titer < 1 × 103 copies/L or < 200 IU/mL might be eligible if the investigator
determined that the subject's chronic hepatitis B infection was stable and participation
in the study would add no further risks to the subject


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22) Subjects who are tested positive for HCV antibody, HIV antibody or syphilis
23) Subjects with known history of allergic diseases or allergic physique
24) Received treatment with other investigational drugs or participated in another
interventional study within 30 days prior to screening
25) History of alcohol or drug abuse
26) Female subjects who are pregnant or breastfeeding, or expected to be pregnant or
breastfeeding during the study
27) Known allergies to bevacizumab or any of its excipients, or any chemotherapeutic
agents
28) Other conditions unsuitable for the inclusion as determined by the investigator
4.3 Screening Failure
Screening failure is that the subject who has signed the informed consent form fails to meet the
inclusion criteria. Subjects with screening failure will not get a randomization number. The
reasons of screening failure will be documented in the electronic case report forms (eCRFs).
4.4 Subject Restrictions
Female subjects of childbearing age must take effective contraceptive measures during the study
and 6 months after the last dose.
Male subjects must take effective contraceptive measures during the study and 6 months after the
last dose to avoid the pregnancy of their partners.
Restrictions on the use of medication during the study are shown in Section 5.9.
4.5 Subject Withdrawal and Replacement
All subjects may withdraw from this study at any time, with or without a reason. Subjects who
withdraw from the study will not be subjected to discrimination or retaliation, and their medical
treatment will not be affected.
Subjects may discontinue the study treatment or withdraw from the study under the following
circumstances:

Unacceptable toxicity

Progressive disease


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
Investigator believes that the subject should withdraw from the study. If an unacceptable
adverse event (AE) occurs and the investigator believes that the subject should
withdraw from the study, the study treatment should be discontinued and appropriate
measures should be taken. In addition, the sponsor or personnel designated by the
sponsor should be notified.

Withdrawal of informed consent form by the subject

Serious protocol deviation determined by the investigator and/or sponsor

Poor protocol compliance

Study termination by the investigator or sponsor for any reason

Enrollment error* (enrollment of subjects who have violated the inclusion/exclusion
criteria)

Use of prohibited concomitant medications or other medications that the investigator
believes that it may result in toxicities or may affect study results

Subject lost to follow-up

Death of subject
* If the subject is determined by the investigator and the sponsor's doctor to be medically suitable
to continue with the study drugs without any risk or inconvenience, the mistakenly enrolled or
randomized subject will continue with the study treatment and assessments.
In any cases, reasons for withdrawal must be documented in the eCRFs. If the subject withdraws
from the study prematurely for any reason, the investigator should make every effort to persuade
the subject to receive the corresponding assessment, and continue the follow-up of all unresolved
AEs based on the AE reports and follow-up requirements (Table 2):

If the subject withdraws during the study, the series of assessments listed under the End
of Treatment Visit (Section 6.9) should be performed

If the subject withdraws after the end of the treatment visit and has not experienced PD,
the series of assessments listed under the Follow-Up for PD (Section 6.10) should be
performed (tumor assessment is not required to be repeated if it has been performed
within 6 weeks prior to this follow-up)

If the subject withdraws during the follow-up for survival, the information of subsequent
anti-tumor therapies and survival should be collected by telephone follow-up only
Subjects who withdraw their informed consent are not to be contacted again unless they clearly
indicate the willingness to be contacted. The sponsor may use the clinical study data obtained
before the withdrawal of informed consent.
Subjects who have been randomized will not be replaced.


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5 STUDY TREATMENT
5.1 Therapies by Study Drugs
The study drugs of this study are IBI305 and bevacizumab.
In this study, the dose of IBI305 or bevacizumab during combination therapy with chemotherapy
is 15 mg/kg, while the dose during maintenance monotherapy is 7.5 mg/kg. The study drugs are
administered intravenously on D1 of each 3-week cycle until PD, unacceptable toxicity,
withdrawal of informed consent, loss to follow-up, death, or end of study (whichever comes first).
The duration of the first dose of IBI305 or bevacizumab should be 90 min (± 15 min). If the
first infusion is well-tolerated by the subject, then the duration of the second infusion can be
shortened to 60 min (± 15 min). If the 60 min infusion is also well-tolerated by the subject, then
the subsequent infusions can be completed within 30 min (± 15 min).
5.2 Chemotherapy
Paclitaxel will be administered after the IBI305 or bevacizumab infusion is completed, then
followed by carboplatin:
Paclitaxel: 175 mg/m² administered via intravenous infusion for 3 h (may be adjusted according
to clinical practice of each study site) on D1 of every 3-week cycle for up to 6 cycles until PD,
unacceptable toxicity, withdrawal of informed consent, loss of follow-up, or death.
Carboplatin: AUC 6.0, the infusion time is based on the standard practice of each study site,
administered on D1 of every 3-week cycle for up to 6 cycles until PD, unacceptable toxicity,
withdrawal of informed consent, loss of follow-up, or death.
The chemotherapeutic agents are supplied by the sponsor.
Formulas for calculating surface area, creatinine clearance and carboplatin dose are shown in
Section 13.2.
5.3 Dose Adjustment of Each Study Drug
5.3.1 General principles
The reasons for dose adjustments or delayed administration, measures taken, and
results should be documented in the medical records and eCRFs


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If the concomitant symptoms exist at baseline, the investigator will determine whether
the dose should be adjusted according to the change in severity of toxicity. For example,
if the subject has Grade 1 "weakness" at baseline and Grade 2 "weakness" during the
study treatment, the dose should be adjusted based on Grade 1 toxicity since the
severity has increased by one grade
If several toxic reactions of different grades or severity occur simultaneously, the dose
will be adjusted according to the highest observed grade/severity
If a dose adjustment is required solely due to abnormal lab test results, then the dose
should be adjusted based on the measured values obtained prior to the start of the
treatment cycle
If the investigator determines that the toxicity is unlikely to further develop into a
serious or life-threatening event, the current dose will be continued without any
adjustments or treatment interruptions. In addition, dose adjustments or treatment
interruptions will not be performed for non-hemolytic anemia as the symptoms can be
alleviated through blood transfusions.
If the investigator determines that a toxicity is caused by a specific therapeutic drug,
then the dose adjustments of other drugs are not required
Discontinuation of one or two therapeutic drugs before PD will not affect the continued
treatment with other drugs
Dose reductions or adjustments of IBI305 or bevacizumab are not permitted.
Subsequent therapeutic dose will not be adjusted according to weight change, unless
the subject weight has changed by ≥10% from baseline
Once the dose of any chemotherapeutic agents is reduced, the original dose should no
longer be adopted
If any but not all of the therapeutic drug (IBI305, bevacizumab or chemotherapeutic
agents) treatments is interrupted due to toxicity, then this treatment will be considered
as a treatment cycle
If the administration of any one of the chemotherapeutic agents is delayed for more
than 3 weeks, the subject should permanently discontinue that chemotherapeutic agent


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If IBI305/bevacizumab is continued/infused after a delay for more than 3 weeks, the
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5.3.2 Dose adjustments of study drugs
Dose adjustments of IBI305 or bevacizumab are not permitted except for the adjustments
(adjusted to 7.5 mg/kg for maintenance monotherapy) specified in the study protocol. The dose
of IBI305 or bevacizumab is calculated according to the subject weight at baseline (prior to the
first dose), and remains unchanged throughout the study, unless the subject weight has changed
by ≥10% from baseline.
If an infusion reaction occurs during a 60-minute infusion, the infusion time should be extended
to 90 minutes for all subsequent infusions. Likewise, if an infusion reaction occurs during a 30-
minute infusion, the infusion time should be extended to 60 minutes for all subsequent infusions.
IBI305 or bevacizumab in combination with paclitaxel/carboplatin will be administered every
3-week treatment cycle for 6 cycles. If PD is not observed in subject during treatment, then the
subject will continue to receive IBI305 or bevacizumab as maintenance monotherapy every 3-
week treatment cycle until PD, unacceptable toxicity, withdrawal of informed consent, loss of
follow-up, death, or end of study (whichever comes first).
If IBI305 or bevacizumab is permanently discontinued due to unacceptable toxicity or subject
refusal to continue the study drugs during the combination therapy, then the subject will continue
to receive the chemotherapy (paclitaxel/carboplatin) until 6 treatment cycles are completed as
determined by the investigator. If any one of the chemotherapeutic agents (paclitaxel or carboplatin)
is prematurely discontinued due to unacceptable toxicity, the subject can continue to receive
IBI305 or bevacizumab treatment until PD, unacceptable toxicity, withdrawal of informed
consent, loss of follow-up, or death (whichever comes first).
When a Grade 3 or 4 IBI305- or bevacizumab-related toxicity is observed, the investigators
should determine whether to continue or terminate IBI305 or bevacizumab treatment according
to the followings:
First occurrence:
IBI305 or bevacizumab administration should be interrupted until toxicity symptoms return to
baseline level or are at least reduced to the Common Terminology Criteria for Adverse Events
(CTCAE) Grade 1 or lower (except for the special circumstances listed below)
Note that when Grade 4 febrile neutropenia and/or thrombocytopenia occur(s), IBI305
or bevacizumab administration should be interrupted until the symptoms return to
baseline levels or at least reduced to CTCAE Grade 1 or lower, since these events
increase the risk of hemorrhage.


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Re-occurrence in re-administration:
If Grade 3 IBI305- or bevacizumab-related toxicity occurs again, the investigator
should assess the risk/benefit of study drug continuation for the subject. If such toxicity
re-occurs again after re-administration, IBI305 or bevacizumab should be permanently
discontinued
If Grade 4 IBI305- or bevacizumab-related toxicity occurs again, IBI305 or
bevacizumab should be permanently discontinued
Measures should be taken in the following special circumstances (classified based on CTCAE
version 4.03):
Hemorrhage
Subjects with Grade 3 or 4 hemorrhages should be treated accordingly and permanently
discontinue the study treatment
Thrombosis/embolism

Subjects with arterial thrombosis of any severity grades should permanently
discontinue the study treatment

Subjects with Grade 4 venous thrombosis should permanently discontinue the
study treatment

Subjects with Grade 3 venous thrombosis should interrupt the study treatment. If
the anticoagulant therapy at the planned therapeutic dose is < 2 weeks, the study
treatment should be interrupted until the anticoagulant therapy is completed. If
the anticoagulant therapy at the planned therapeutic dose is > 2 weeks, IBI305
or bevacizumab administration should be interrupted for 2 weeks, and the study
treatment can be restarted during the anticoagulant therapy if the following criteria
are met:
- INR is within the target range (usually 2-3) prior to restarting of study treatment
- Subjects must not have experienced Grade 3 or 4 hemorrhage since enrollment
- No signs of great vessel invasion or adjacency to great vessels from previous
tumor assessments
Note: Therapeutic dose of anticoagulant therapy is defined as the escalating dose of
warfarin or other anticogulants until INR is maintained at no less than 1.5 (usually


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2-3). The warfarin dose should be documented in the eCRFs, and the INR of
subjects receiving anticoagulant therapy should be monitored during the treatment.
Hypertension
BP should be measured frequently to monitor the occurrence and exacerbation of hypertension.
Subjects should remain at resting position for at least 5 min before BP measurement.
Definition of hypertension: pathologically increased BP with repeated measurements persistently
over 140/90 mmHg
Table 2. Hypertension severity grades and interventions in CTCAE v4.03
CTCAE
Interventions
Grade 1
Pre-hypertension (systolic blood pressure of
120–139 mmHg, diastolic blood pressure of 80–
89 mmHg)
Intervention not indicated
Grade 2
First-stage hypertension (systolic blood pressure
of 140–159 mmHg, diastolic blood pressure of
90–99
mmHg;
repeated
or
persistent
hypertension of ≥24 h), a symptomatic increase
of > 20 mmHg in systolic blood pressure, or an
increase of > 140/90 mmHg from the previous
normal range
Antihypertensive
monotherapy.
drug interruption. The treatment
with the investigational product can
be
continued
once
the
blood
pressure
is
lower
than
140/90
mmHg.
Grade 3
Second-stage
hypertension
(systolic
blood
pressure of ≥160 mmHg, diastolic blood
pressure of ≥100 mmHg)
Multiple-agent
antihypertensive
therapy. Study treatment should be
interrupted in case of persistent or
symptomatic
hypertension;
study
treatment should be permanently
discontinued
for
uncontrollable
hypertension.
Grade 4
Life-threatening consequences (e.g. malignant
hypertension, transient or permanent
neurological deficit, and hypertensive crisis)
Urgent intervention and permanent
study
treatment
discontinuation
indicated
The dose of antihypertensive agents used should be documented during each visit. If the subject
remains hypertensive despite treatment discontinuation, BP and antihypertensive agents used
should be monitored every 3 months until BP returns to normal or end of study.


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Posterior reversible encephalopathy syndrome (PRES)
There have been a few reports of subjects with signs and symptoms consistent with PRES after
study treatment. This is a rare neurological disease and its signs and symptoms include epilepsy,
headache, altered mental status, visual impairment, or cortical blindness, with or without
hypertension. Subjects with PRES should permanently discontinue the study treatment.
Proteinuria
Urinalysis should be performed prior to each dose of IBI305/bevacizumab unless a 24-hour
urinary protein test has already been done.
First occurrence of proteinuria:
After carrying out the urinalysis, if:
Urine protein is < 2+, continue study treatment as scheduled, no additional tests are
required.
≥2+ (urinalysis): perform 24-hour urinary protein test within 3 days prior to
administration:
•
24-hour urinary protein ≤2 g: continue study treatment as scheduled. and perform
urinalysis dipstick test before each scheduled dose.
•
24-hour urinary protein > 2 g: delay study treatment until 24-hour urinary protein ≤2 g.
and a 24-h urine protein test prior to each subsequent dose is performed until urine protein is
reduced to ≤1 g/24 h. Interrupt study treatment only when 24 h urine protein is > 2 g.
Second and subsequent occurrence of proteinuria:
< 3+ (urinalysis): continue study treatment as scheduled, no additional tests indicated.
≥3+ (urinalysis): perform 24-hour urinary protein test within 3 days prior to
administration:
• 24-hour urinary protein ≤2 g: continue study treatment as scheduled.
• 24-hour urinary protein > 2 g: delay study treatment until 24-hour urinary protein ≤2 g.
and a 24-h urine protein test prior to each subsequent dose is performed until urine protein is
reduced to ≤1 g/24 h. Interrupt study treatment only when 24 h urine protein is > 2 g.
Nephrotic syndrome (Grade 4): Study treatment is permanently discontinued
Gastrointestinal perforation


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If gastrointestinal perforation occurs, appropriate measures should be taken and the study
treatment should be permanently discontinued.
Wound healing complications
The study treatment should not begin within 28 d after a major surgery, or before the surgical
wound is fully healed. If a complication of wound healing occurs during study treatment, the
study treatment should be interrupted until the wound is fully healed. If an elective surgery is
required, the study treatment should be interrupted.
Abdominal abscess or fistula
If abdominal abscess or fistula occurs, the study treatment should be discontinued. However, the
investigator will determine whether study treatment will be continued if the above AE is resolved.
Infusion-related and allergic reactions:
Infusion-related reactions after first dose of the study drug is uncommon (< 3%), and the incidence
of a severe reaction is only 0.2%.
If a mild (grade 1 or 2) reaction (such as fever, chills, headache, and nausea) occurs, pretreatment
prior to subsequent administration should be performed and infusion time should not be reduced.
If the subject is well-tolerated during infusion after pretreatment, the infusion time can be
reduced by 30 minutes (+10 minutes) for subsequent administration with pretreatment. If an
infusion-related AE occurs during a 60-minute infusion, the subsequent infusion should be
completed within 90 minutes (+15 minutes) with pretreatment. Likewise, if an infusion-related
AE occurs during a 30-minute infusion, the subsequent infusion should be completed in 60 minutes
(+10 minutes) with pretreatment. If a subject has a grade 3 infusion-related reaction, the study
treatment should be interrupted and not be restarted on the same day. However, since there lacks
the dose adjustment method for grade 3 infusion-related reactions, the investigators may decide
to either discontinue the study drug or perform pretreatment, and complete the infusion within
90 minutes (+15 minutes). If an adverse reaction still occurs during a 90-minute infusion, the
infusion should be continued at a slower rate and then gradually returned to a 90-minute infusion.
If the investigator is uncertain about the handling, the study treatment should be discontinued.
When the study treatment is restarted, the subject should be closely monitored based on routine
clinical practice until the possible time of adverse reaction has passed. If a subject has a grade 4
infusion-related reaction, the study treatment should be discontinued.
An allergic reaction is defined as the vascular collapse or shock (systolic BP < 90 mmHg,
unresponsive to rehydration) that occurs within 30 minutes of a study drug infusion caused by
an allergy, with or without respiratory distress. Skin reactions include pruritus, urticaria, and
angioedema. Subjects with allergic reactions should discontinue the study treatment.


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5.3.3 Dose adjustments of chemotherapy
Paclitaxel and carboplatin should be administered according to the study site guidelines and local
prescribing information. For the specific information for use, preparation, and storage of
paclitaxel and carboplatin, refer to the prescribing information and local dosing information.
Carboplatin-based chemotherapies have a relatively high incidence of emesis. Therefore,
antiemetics for prophylaxis can be used.
Hematological toxicity:
Absolute neutrophil count (ANC; dose can only be reduced when febrile neutropenia occurs.
ANC must be ≥1.5 × 109/L and platelet count must be ≥100 × 109/L on D1 of each treatment
cycle). Once the chemotherapeutic dose is reduced due to febrile neutropenia or
thrombocytopenia (platelet count < 25 × 109/L or 50 × 109/L with hemorrhage or blood
transfusion required), the original dose should no longer be adopted. If the dose reduction is
required for the third time, the chemotherapy should be immediately discontinued.
Table 3. Dose adjustments of paclitaxel and carboplatin (febrile neutropenia and
thrombocytopenia)
Dose Adjustments of Paclitaxel/Carboplatin
First Occurrence Re-Occurrence After
Dose Adjustment
Re-occurrence After Two Dose
Adjustments
Febrile neutropenia
(regardless of duration)
Paclitaxel = 150 mg/m2
Carboplatin = AUC 4.5
Paclitaxel = 100 mg/m2
Carboplatin = AUC 3
Chemotherapy discontinuation
Lowest Level After
Last Dose
<25 × 109/L or
<50 × 109/L with
hemorrhage or requires
blood transfusion
Paclitaxel = 150 mg/m2
Carboplatin = AUC 4.5
Paclitaxel = 100 mg/m2
Carboplatin = AUC 3
Chemotherapy discontinuation
If the dose adjustment is required when ANC and thrombocytopenia occur concurrently, the low-
dose chemotherapy should be adopted.
Chemotherapy may be delayed for up to 3 weeks. If after the chemotherapy has been delayed for
3 weeks, ANC does not reach ≥1.5 × 109/L and platelet count does not reach ≥100 × 109/L on
D1 of the scheduled chemotherapy, the chemotherapy should be permanently discontinued. If the
above values have been reached, the next course of chemotherapy should be continued.


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The investigator should monitor the subject closely for toxicity with particular attention to early
and evident signs of myelosuppression, infection, or febrile neutropenia to timely and
appropriately treat the complications.
Subjects should be informed to pay attention to these signs and receive treatment as soon as possible.
If the chemotherapy must be interrupted due to hematological toxicity, the complete blood count
should be performed regularly (including WBC differentials) until all the counts reach the
minimum requirements for treatment continuation. Thereafter the scheduled treatment plan will
be performed.
Dose adjustments are not required for anemia. However, treatment based on guidelines of each
clinic should be performed.
Gastrointestinal toxicity
Antiemetics will be used to control nausea and/or emesis. If grade 3 or 4 nausea and/or emesis
occur(s) despite of antiemetics, the chemotherapeutic dose should be reduced by 20% for the
next treatment cycle. The dose should be returned to the initial level as possible if the subject is
tolerated.
If the subject experiences stomatitis on D1 of any treatment cycle, the chemotherapy should be
interrupted until the symptoms resolve. If the stomatitis has not resolved after 3 weeks, the
chemotherapy should be permanently discontinued (refer to CTCAE version 4.03). If an acute
Grade 3 stomatitis occurs, the chemotherapeutic dose should be reduced to 75% of the proposed
dose when symptoms resolve.
Hepatotoxicity (Paclitaxel)
The paclitaxel dose should be determined based on the lab values measured on D1 of each
treatment cycle.
Table 4. Dose adjustment of paclitaxel (hepatotoxicity)
AST
Total bilirubin
Paclitaxel Dose
≤5 x UNL
and
WNL
175 mg/m2
> 5 x UNL
or
> UNL ~ 1.5 x UN
150 mg/m
> 1.5 x UN
0


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If paclitaxel is interrupted due to hepatotoxicity, carboplatin should also be interrupted until
paclitaxel is restarted. Paclitaxel will be interrupted for up to 3 weeks. If the subject's hepatic
function does not return to the acceptable ranges in 3 weeks, paclitaxel should be permanently
discontinued. The carboplatin dose will not be adjusted when hepatotoxicity occurs.
The investigators should avoid PD due to abnormal hepatic enzyme levels as possible. If PD
occurs, all the study drugs should be permanently discontinued, including chemotherapy.
Cardiovascular toxicity (paclitaxel)
The arrhythmia in subjects was infrequent in previous clinical studies. However, most subjects
were asymptomatic and electrocardiographic monitoring was not required. Asymptomatic
transient bradycardia was observed in 29% of subjects, but significant atrioventricular block was
rare. Cardiac events should be treated as follows:
Asymptomatic bradycardia: no intervention indicated
Symptomatic arrhythmia during infusion: Discontinue paclitaxel infusion and perform
routine treatment of arrhythmia. Discontinue subsequent paclitaxel treatment.
Document this AE in the AE Report Form of eCRF.
Chest pain and/or symptomatic hypotension (< 90/60 mmHg or rehydration therapy
required): discontinue the paclitaxel infusion. Perform electrocardiography (ECG). If
hypersensitivity reaction is suspected, administer diphenhydramine and dexamethasone
via intravenous infusion. If the chest pain is not considered as cardiogenic, epinephrine
or bronchodilators will be administered. Document this AE in the AE Report Form of
eCRF. Discontinue subsequent paclitaxel treatment and provide symptomatic treatment.
Consult a cardiologist if needed.
Neurotoxicity (paclitaxel)
The dose of paclitaxel should be adjusted according to Table when neuropathy occurs. The dose
adjustment of carboplatin is not needed when neurotoxicity occurs.
Table 5. Dose adjustment of paclitaxel (neurotoxicity)
Toxicity Grade (CTCAE version 4.03)
Paclitaxel dose adjustment
Grade 1 or below
175 mg/m2
2
Interrupt treatment until return to grade 1, then reduce dose to 140 mg/m2
(20% of reduction) and restart infusion


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Grade 3 or above
Interrupt treatment until return to grade 1, then reduce dose to 125 mg/m2
(30% of reduction) and restart infusion.
Once the dose is reduced due to neurotoxicity, the original dose should no longer be adopted.
If the neurotoxicity does not return to grade 1 after paclitaxel interruption for 3 weeks, paclitaxel
should be permanently discontinued.
Allergic reactions/hypersensitivity reactions (paclitaxel)
Note: Prophylaxis for hypersensitivity reactions (see below) and close monitoring of vital signs
are recommended for subjects with history of mild to moderate hypersensitivity reactions when
hypersensitivity reactions reoccur.
Mild symptoms: complete paclitaxel infusion. Close monitoring; no treatment indicated.
Moderate symptoms: Interrupt paclitaxel infusion, administer diphenhydramine 25–
50 mg and dexamethasone 10 mg via intravenous infusion. Once symptoms have
resolved, resume paclitaxel infusion at a slower rate (20 mL/hour for 15 minutes, then
at 40 mL/hour for 15 minutes, and if no further symptoms develop, continue at original
rate until infusion is complete). Document this AE in the AE Report Form of eCRF. If
symptoms reoccur, interrupt the paclitaxel infusion and permanently discontinue
subsequent paclitaxel infusion.
Severe and life-threatening symptoms: Interrupt paclitaxel infusion, administer
diphenhydramine and dexamethasone via intravenous infusion (as above). Use
epinephrine or bronchodilators if indicated. Document this AE in the AE Report Form
of eCRF. Subsequent courses of paclitaxel infusion should be permanently
discontinued.
Moderate or severe hypersensitivity reactions should be documented as AEs.
Other toxicities
If other unmentioned grade 3–4 toxicities occur, the chemotherapy should be interrupted until
symptoms resolve or return to grade 1. Thereafter restart the infusion at 50% of the original dose
(which should no longer be adopted). If the toxicity does not return to grade 1 after an
interruption for 3 weeks, the chemotherapy should be permanently discontinued. Dose
adjustments are not recommended for grade 1 and 2 toxicities.
5.4 Study Drug Properties


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IBI305 is a bevacizumab biosimilar. The active ingredient of both drugs is recombinant humanized
anti-VEGF monoclonal antibody; Bevacizumab is the standard commercially available drug, provided
by the sponsor.
Detailed information on the study drugs is shown in Table .
Table 6. Study drugs
Study Drugs
Dosage Form and
Strength
Excipient
Appearance
Manufacturer
IBI305
4 mL: 100 mg
Sodium acetate,
sorbitol, and
polysorbate 80
Sterile solution for
intravenous injection
pH 5.2
Clear, colorless liquid, no
foreign matters, no floc
or precipitation
Innovent Biologics (Suzhou)
Co., Ltd.
Bevacizumab 4 mL: 100 mg
α,α-trehalose
dihydrate, sodium
dihydrogen phosphate
monohydrate,
disodium hydrogen
phosphate,
polysorbate 20, and
sterile water for
injection
Sterile solution for
intravenous injection
pH 5.9–6.3
Clear to slight
opalescent, colorless to
light brown
Roche Pharma (Schweiz)
Ltd.
5.5 Preparation and Distribution
IBI305 or bevacizumab is diluted in 0.9% sodium chloride solution by the pharmacist or research
nurse before infusion. Check the particles and discoloration prior to administration.
The investigator should ensure that the pharmacist or research nurse administers the study drugs
according to study protocol.
5.6 Packaging, Labeling, and Storage
The sponsor should package and label the study drugs according to appropriate local regulations.
All study drugs (IBI305 and bevacizumab) must be stored at 2–8 °C away from light. The study
drugs should be stored in a safe zone only accessible by authorized staff prior to dispensation to
the subjects.
5.7 Subjects Allocation
After confirming that the subject meets all of the inclusion and exclusion criteria, the study site
will log in the Interactive Web Response System (IWRS) and enter the subject information into
the IWRS. The IWRS will allocate a random number to the subject and provide a medication


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number. Stratified randomization is used in this study. Stratifying factors include age (< 60 vs.
≥60 years old) and EGFR status (wild vs. unknown type).


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5.8 Blinding
This is a randomized, double-blind, and active-controlled study, and only relevant study
personnel had access to the randomization numbers. A non-blinded pharmacist or research nurse
will prepare the medications since IBI305 and bevacizumab do not have an identical appearance.
The pharmacist or research nurse who is responsible for preparing the study drugs is not allowed
to disclose any information regarding treatment allocation to the subject, the subject's family
members, or other personnel including the physician and the relevant study staff.
Unblinding: Subject unblinding should only be performed after database locking.
Emergency unblinding: In case of an emergency where the investigator must know the
medication given to a particular subject, the investigator will unblind the subject via the IWRS
and immediately inform the sponsor and CRO. The reasons for unblinding, date, and outcomes
should be documented in the source document and eCRF of the subject.
5.9 Concomitant Medications and Treatments
All medications except for the study drugs, including other chemotherapies not specified in the
study, Chinese herbal medicines, and other non-traditional therapies, are considered concomitant
medications. All concomitant medications used within 30 days prior to screening should be
documented in the eCRFs, including the information of generic name, route of administration,
start date, end date, and indication.
5.9.1 Prohibited treatment
No other anti-tumor therapies or medications with anti-tumor indications, including Chinese
herbal medicine, radiotherapy, or other investigational drugs, are allowed during this study other
than IBI305, bevacizumab, paclitaxel, and carboplatin.
Severe myelosuppression is possible after chemotherapy. Granulocyte colony-stimulating factor
or granulocyte-macrophage colony-stimulating factor are not allowed to be used prophylactically
in the first treatment cycle.
5.9.2 Permitted treatment
Prophylactic use of anti-emetics, glucocorticoids, or other treatments targeting toxicities is permitted
during the study. Unconventional treatments (such as acupuncture) and vitamins/microelements are
permitted if their use does not affect the study endpoints as determined by the investigators.


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Starting from the 2nd chemotherapy cycle, granulocyte colony-stimulating factor or granulocyte-
macrophage colony-stimulating factor are allowed to be used prophylactically to prevent severe
myelosuppression.
Anti-viral therapy was permitted whenever necessary.
Stable doses of anti-epileptic drugs were permitted.
Radiotherapy for bone metastasis was permitted provided that the radiotherapy field did not
include the target lesion
5.9.3 Treatment after study treatment
Subsequent therapy after the end of study treatment should be determined by the subject's
attending doctor.
5.10 Treatment Compliance
Subjects should receive treatment at the study site. The dose and time of administration of
IBI305 or bevacizumab and paclitaxel/carboplatin should be documented in the source records
and eCRFs during each treatment cycle. Reasons for dose adjustments, therapy delay, and
therapy discontinuation should be documented. Treatment compliance is monitored by
medication dispensing and return records, medical records, and eCRFs.
5.11 Drug Return and Destruction
The containers, vials, infusion bags, and syringes of used and partially used drugs can be
destroyed on-site according to the appropriate guidelines and operating procedures established
by study sites and local agencies.
Unless the contents have significant safety issues requiring immediate destruction in accordance
with local regulations, all the unused drugs should be returned and destroyed based on the
requirements of sponsor.
5.12 Study Drug-Related Records
The designated personnel of the study sites should make timely records of receiving, dispensing,
using, storing, returning, and destroying the study drugs in accordance with the relevant
regulations and guidelines.


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6 STUDY PROCEDURE
The detailed procedures of this study are shown in Table 1. Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
.
6.1 Screening Visits (D -28 to D -1)
Complete the screening visits within 28 days prior to study treatment commencement. The
following procedures must be completed during screening to ensure that subject meets the
requirements for participating in this study:

Sign the ICF

Record the demographics, including age, ethnicity, and gender

Record the past medical history, including smoking history

Record the history of anti-tumor therapies

Record the concomitant medications (within 30 days prior to screening)

Record the vital signs

Measure the height and weight (including BMI)

ECOG score

Physical examination

12-Lead ECG

Hepatitis B panel, anti-HCV, anti-HIV, and syphilis tests

Clinical laboratory tests (routine blood test, coagulation test, blood chemistry, and
urinalysis)


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
Blood/urine pregnancy test (for female subjects of childbearing age only)

Imaging examinations (CT or MRI: Head, chest, abdomen, and pelvis cavity)*

EGFR test#

Review the inclusion/exclusion criteria

Record the AEs and concomitant medications
* Retests are not required if the tests have been performed within 28 days prior to the first dose,
unless the investigators suspect changes in tumor burden. Imaging results during screening will
be used as the baseline data. The same method of imaging test is used at baseline and during
follow-up. Imaging evaluations of the chest, abdomen, and pelvis are required.
# If the subject has been tested for EGFR of tumor sample at the study site with documentation,
the subject will not be required for retest.
6.2 Baseline Visits (D1 of cycle 1)
D1 refers to the day of receiving the first dose of the study drugs. Eligible subjects meeting the
inclusion criteria will return to the study site and complete the following procedures:

Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests * (routine blood test, blood chemistry, and urinalysis)

Confirm the inclusion/exclusion criteria
* If clinical laboratory screening tests (routine blood test, blood chemistry, urinalysis) are
performed within 7 days prior to the first dose, then the results of the screening test can be
used as baseline.
If the subject meets the inclusion criteria, the following procedures should be complete:

Randomization and grouping

Immunogenicity test (within 1 h prior to the study drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Pharmacokinetic (PK) blood sampling (within 1 h prior to the study drug infusion,


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immediately after the study drug infusion [+5 min])

VEGF blood sampling (within 1 h prior to the study drug infusion)

Record the AEs and concomitant medications
6.3 Cycle 2 (week 4 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study drug infusion)

VEGF blood sampling (within 1 h prior to the study drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
6.4 Cycle 3 (week 7 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)


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
Record the AEs and concomitant medications
Imaging tests (CT or MRI) should be done every 6 weeks (±7 days), and tumor assessment
should be completed within 7 days prior to this visit to determine whether the study treatment
should be continued.
6.5 Cycle 4 (week 10 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study drug infusion)

Immunogenicity test (within 1 h prior to the study drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
6.6 Cycle 5 (week 13 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study drug infusion)


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
Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
Imaging tests (CT or MRI) should be done every 6 weeks (±7 days), and tumor assessment
should be completed within 7 days prior to this visit to determine whether the study treatment
should be continued.
6.7 Cycle 6 (week 16 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study drug infusion)

VEGF blood sampling (within 1 h prior to the study drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
6.8 Cycle 7 and Subsequent Treatment Cycles (±3 Days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Maintenance monotherapy will start from week 7 and the dose of study drug will be adjusted to
7.5 mg/kg. Subjects should complete the following procedures during each visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG


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
Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Study drug infusion (IBI305 or bevacizumab)

Record the AEs and concomitant medications
Imaging tests (CT or MRI) should be done every 6 weeks (±7 days), and tumor assessment
should be completed within 7 days prior to this visit to determine whether the study treatment
should be continued.
6.9 End-Of-Treatment Visit
The end of treatment visit in study sites will be conducted in 28 days (±7 days) after the last dose
of study drug. Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Immunogenicity test

PD blood sampling

Blood/urine pregnancy test (for female subjects of childbearing age only)

Tumor assessment (CT or MRI, completed within 7 days prior to this visit; not required
to be repeated if it has been performed within 6 weeks prior to this visit)

Subsequent anti-tumor therapy

Record the AEs and concomitant medications
If the subject has not experienced PD, the subsequent follow-up for PD will be performed
(Section 6.10). If the subject has experienced PD, the subsequent follow-up for survival will be
performed (Section 6.11).
6.10 Disease Progression Visit
If the study drugs are discontinued for reasons other than PD, the end of treatment visit in study
sites will be conducted in 28 days after the last dose of study drug, and tumor assessments should
be conducted every 6 weeks (±7 days) until PD if possible (after which, follow-up for survival
will be conducted [Section 6.11]), withdraw of informed consent, loss to follow-up, death,


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start of other anti-tumor therapies, or end of study. During the visit, vital signs and weight
measurements will be performed, and any subsequent anti-tumor therapies will be documented.
6.11 Survival Follow-Up
The investigator will make telephone follow-up every 12 weeks (±7 days) to collect the
information of subsequent anti-tumor therapies and survival until withdrawal of informed
consent, loss to follow-up, death, or end of study.
6.12 Study Completion
The end of this study will be the18th month after randomization of the last subject. If the subjects
continue to receive the study drug treatment before this cut-off time, the treatment should be
discontinued and the end of treatment visit should be completed (Section 6.9).


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6.13 Tumor Assessment
Imaging tests (CT or MRI) of the brain, chest, abdomen, and pelvis are required at baseline. If
these tests are performed within 28 days prior to the first dose of the study drug, they do not need
to be repeated unless the investigator believes that there have been changes in the subject's tumor
burden. After the start of treatment, imaging tests are performed once every 6 weeks (±7 days)
and have to be completed within 7 days prior to the scheduled visits, until progressive disease,
start of other treatment, withdrawal of informed consent, loss to follow-up, death, or study
completion. The same method of imaging test was used at baseline and during follow-up.
Imaging evaluations of the chest, abdomen, and pelvis are required.
The investigator should perform a tumor assessment based on RECIST v1.1 (Section 13.3) prior
to each dose to determine whether the subject should continue with the next round of treatment.
An independent review committee will also assess the tumor response (Section 11.1.1). Imaging
tests will not be rescheduled if the study drugs or chemotherapeutic agents are interrupted due to
toxicities. Every effort should be made to continue the schedule for imaging tests even for
subjects who discontinue one or two study treatment(s) due to drug-related toxicities.
If subject experience PD according to the RECIST v1.1 criteria, the attending doctor should
discuss with the subject regarding subsequent routine cancer therapies.
6.14 Clinical Laboratory Evaluations
Clinical laboratory tests will be conducted at the laboratories of each study site. Sample collection
and analysis should be performed according to the requirements of each laboratory.
The following laboratory tests should be conducted according to the study procedures (Table 1.
Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
):
Routine blood test: hemoglobin, hematocrit, WBC and differentials (including


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absolute neutrophil and lymphocyte counts), platelets, and RBC
Routine coagulation test (baseline test): INR, aPTT, or PTT
➢
Blood chemistry: Creatinine, blood urea, total protein, albumin, total bilirubin,
alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase
(ALT), fasting blood glucose, sodium, potassium, chloride, calcium, phosphorus, and
magnesium
➢
Urinalysis: Specific gravity, pH, glucose, protein, occult blood, and leukocytes
➢
Pregnancy test: Serum/urine pregnancy tests are performed on women of
childbearing age during screening and the end-of-treatment visit.
These tests are carried out at the laboratory of each trial site.
For subsequent visits, all laboratory tests need to be completed within 3 days prior to the
administration. During the study, the frequency of these laboratory tests will be increased if
safety is a concern. The investigator should review the laboratory test results throughout the
study to determine whether the results are clinically significant. The investigator should assess
the changes in laboratory test results. If the investigator considers a laboratory test result to be
abnormal and of clinical significance, it is considered as an AE.
6.15 Vital Signs, Physical Examinations, and Other Safety Assessments
6.15.1 Vital signs
Vital signs include pulse, BP, temperature, and respiratory rate. The subject must rest for at least
5 minutes prior to each vital sign assessment.
Vital signs will be assessed according to the Schedule of Activities (Table 1. Schedule of follow-
up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
). During the study, the investigator may increase the frequency of vital sign measurement if


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safety is a concern.
6.15.2 Height and weight
Height is only measured during screening. Weight is measure during each visit.
6.1.5.3 Physical examinations
The following organs/systems will be examined according to the Schedule of Activities (Table 1.
Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
x
x
x
x
x
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
(IBI305 or
bevacizumab) j
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
): general condition, head (eyes, ears, nose, and throat), neck and thyroid, respiratory system,
cardiovascular system, abdomen, nervous system, skeletal muscles and limbs, as well as
lymphatic system and skin.
6.15.4 12-Lead ECG
12-lead ECG will be performed during screening. During the study, each medication visit
requires an ECG examination. The following ECG parameters should be documented: HR, PR-
interval, QRS-complex, QT-interval, and QTc-interval. The subject must be in the supine
position for at least 5 minutes prior to undergoing the 12-lead ECG. All ECG are evaluated by
qualified physicians. All clinically significant abnormal findings should be reported as AEs.


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6.15.5 Immunogenicity assessment
Immunogenicity tests will be performed in all subjects at 3 blood sampling time points: Within
1 hour prior to the first dose of the study treatment (IBI305/bevacizumab) in C1, within 1 hour
prior to the administration of the study treatment in C4, and during the end-of-treatment visit.
Blood specimens that are positive for anti-drug antibodies (ADA) after dosing will be further
tested for neutralizing antibodies (NAb). Samples were tested at the designated central laboratory.
6.15.6. Pharmacokinetics/pharmacodynamics
6.15.6.1 Pharmacokinetics
Study sites that are implementing version 2.0 of the study protocol should collect PK samples
until 140 subjects in this study meet the requirements for PPK assessment (based on the written
notice of the sponsor). There are 6 PK sampling time points: Within 1 h prior to the first dose of
the study treatment (IBI305/bevacizumab) in C1, immediately after the first infusion (within 5
minutes), within 1 h prior to the dose in C2, within 1 hour prior to the dose in C4, within 1 h
prior to the dose in C5, and within 1 h prior to the dose in C6. Serum will be separated from the
samples at the study site and the serum samples will be analyzed at the designated central
laboratory.
6.15.6.2 Pharmacodynamics
Study sites that are implementing version 2.0 of the study protocol should collect PD samples
until 140 subjects in this study meet the requirements for VEGF testing (based on the written
notice of the sponsor). There are 4 VEGF sampling time points: within 1 h prior to the first dose
of the study treatment (IBI305/bevacizumab) in C1, within 1 h prior to the dose in C2, within 1 h
prior to the dose in C6, and during the end-of-treatment visit. Samples were tested at the
designated central laboratory.
6.15.7 EGFR testing
EGFR mutation testing histologically or cytologically will be performed in all subjects (if the
subject has been tested for EGFR at the study site histologically or cytologically with
documentation, the subject will not be required to be retested). The testing will be conducted at
the laboratory of each study site or a qualified third-party laboratory.


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7 STUDY ASSESSMENTS
7.1 Efficacy Assessment
7.1.1 Primary efficacy endpoint

Objective response rate (ORR)
ORR will be assessed using RECIST v1.1. ORR is defined as the proportion of subjects whose
tumor volume has reduced to a predetermined value for a minimum time limit, including patients
who achieved complete response (CR) and partial response (PR). The cut-off date for the
analysis of primary efficacy endpoint in this study is 18 weeks after subject randomization.
7.1.2 Secondary efficacy endpoints

Duration of response (DOR)

Progression-free survival (PFS)

Disease control rate (DCR)

Overall survival (OS)
Each endpoint will be assessed using RECIST v1.1.
DOR is defined as the time from initial tumor response (CR or PR) to PD or death before PD;
Subjects with CR or PR who do not progress or die will be censored on the date of the last tumor
assessment.
PFS is defined as the time from the date of randomization to the date of PD or death; Subjects
who do not progress or die will be censored on the date of the last tumor assessment.
DCR is defined as the proportion of patients whose tumor volume has reduced to a
predetermined value for a minimum time limit, including patients who achieved CR, PR, and SD.
OS is defined as the time from the date of randomization to the date of death of any cause. For
subjects that are alive on the date of study completion or are lost to follow-up, their survival time
will be censored at the date of last contact.


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7.2 Safety Assessments
7.2.1 Adverse events
7.2.1.1 Definition
Adverse event
An AE refers to any untoward medical occurrence in a subject after signing the informed consent
form, and does not necessarily have a causal relationship with the treatment. Thus, an AE can be
any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or
disease, whether considered drug related.
Abnormalities resulting from PD are not considered as AEs.
Serious adverse event
A SAE refers to an AE meeting at least one of the followings:
(1) Lead to death, except for deaths caused by PD.
(2) Life-threatening (a "life-threatening event" is defined as an AE when the subject is at
immediate risk of death at the time, but does not include the case that may lead to death
only when the event worsens).
(3) Requires hospitalization or prolonged hospitalization, excluding an emergency or
outpatient visit. Subjects with existing diseases or conditions prior to the enrollment
that do not worsen during the study, and having hospitalization and/or surgery that was
scheduled before the study or during the study do not meet the SAE criterion.
Hospitalizations resulting from PD are not considered as SAEs.
(4) Results in permanent or severe disability/incapacity.
(5) Results in congenital anomalies/birth defects.
(6) Other important medical events: The event that does not result in death, is not life-
threatening or does not require hospitalization, but may jeopardize the health of
subjects and require medical intervention to prevent the SAEs above, is considered as
an SAE
7.2.1.2 Severity of adverse events
The severity of AEs is evaluated using the 5-level criteria of NCI CTCAE v4.03.
For AEs not included in CTCAE v4.03, use the following CTCAE general guidelines:


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
Grade 1: Mild; asymptomatic or mild signs; clinical or diagnostic observations only;
medical intervention not indicated.

Grade 2: Moderate; minimal/local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily life (such as cooking, shopping, using the
phone, financial management, etc.).

Grade 3: Severe or clinically significant but not immediately life-threatening;
hospitalization or prolonged hospitalization indicated; disability; limited ability of self-
care (such as bathing, dressing, undressing, eating, using the toilet, taking medication),
but not bedridden.

Grade 4: Life-threatening consequences; urgent intervention indicated.

Grade 5: Death related to AE
7.2.1.3 Relationship between adverse events and the investigational drug
The relationship between the study drugs and AEs can be determined using the followings:
Table 7. Correlation between AEs and investigational drugs
Correlation
CRITERIA
Related

The occurrence of the AE is reasonably related to the time sequence of
dosing;

The investigational drug can more reasonably explain the AE than the
other causes (such as the pre-existing disease of the subject, environment,
toxicity, or other treatment received);

The AE resolves or is alleviated after treatment interruption or dose
reduction;

The AE is consistent with the known type of AEs of the suspicious drug or
similar drugs;

The AE occurs again after the drug administration is resumed.
Possibly related

The occurrence of the AE is reasonably related to the time sequence of
dosing;

The investigational drug can be used to explain the AE with the same level
of rationality as other reasons (such as the pre-existing disease of the
subject, environmental or toxic factors, or other treatments received by the
subject);

The AE resolves or is alleviated after treatment interruption or dose
reduction (if applicable).
Possibly not related

Other reasons can more reasonably explain the AE than the investigational
drug (such as the pre-existing disease of the subject, environmental or
toxic factors, or other treatments received by the subject);

The AE does not resolve or be alleviated after treatment interruption or
dose reduction (if applicable), or the situation is unclear;

The AE does not occur again or the situation of the AE is unknown after
the drug administration is resumed.


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Unrelated

The occurrence of the AE is not reasonably related to the time sequence of
dosing, or

The AE has other obvious causes (such as the pre-existing disease of the
subject, environmental or toxic factors, or other treatments received by the
subject).
Cannot be determined

The above information is unclear and cannot be determined based on the
available information. Further follow-up information is not accessible to
the investigator.
7.2.1.4 Serious adverse event reporting
SAEs that occur from the signing of informed consent form until 90 days (inclusive) after the last
dose should be reported. The investigator must fill out the "CFDA SAE Report Form", regardless
of whether it is the initial report or a follow-up report, and sign and date the form. The
investigator must report the SAE to the sponsor, CFDA, and ethics committee within 24 hours of
noticing the event. The contact information for reporting is shown in the table below.
For SAEs occurring outside of the above-mentioned period, those considered related to the
investigational drug shall also be reported to the sponsor.
The investigator must submit the completed SAE report form to the sponsor within 24 hours of
noticing the event. The investigator shall urgently perform visit on missing information and
provide a complete SAE report for events that result in death or are life-threatening.
The investigator should also report the event to the CFDA, health administration departments,
and ethics committees in accordance with the regulations.
When submitting the SAE report by email, it is recommended for the investigator to encrypt the
report file and send the report file and password in separate emails.
Table. SAE report contacts
Unit
Contact
Fax/Telephone/Address
Hospital Name
Ethics committee
Hospital Fax/Telephone
Innovent Biologics (Suzhou) Co.,
Ltd.
Clinical Study Department PV
Fax: 021-31652800
Email:
drugsafety@innoventbio.com


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Office of Drug Research and
Supervision, Department of Drug
and Cosmetics Registration,
China Food and Drug
Administration
Address: Building 2, No. 26,
Xuanwumen
West
Street,
Xicheng District, Beijing
Post Code: 100053
Tel: 010-88330732
Fax: 010-88363228
Medical Administrative
Department, Health
Administration
Address: No. 38, Lishi Road,
Xicheng District, Beijing
Tel: 010- 68792001
Fax: 010-68792734
Province, Autonomous Region,
Municipality Food and Drug
Administration
Based on the requirements of the food and drug administration
department of each province, autonomous region or municipality
7.2.1.5 Management and follow-up of adverse events
The investigator is responsible for providing appropriate medical treatment for all AEs (Indicate
the actions taken, such as suspension/termination of the investigational drug, dose modification,
drug therapy, etc.). When an AE occurs, the investigator should actively take appropriate
measures to ensure the safety of the subject. All AEs observed from the signing of the ICF
to the time specified in the protocol (Table 2) must be followed.
The investigator should report any SAE that occurs after the time specified in the protocol (Table 2)
and is suspected of being related to the investigational drug to the sponsor.
7.2.1.6 Adverse event of special interest and expedited reporting
The AESI for this study include:

Gastrointestinal perforation

Procedural and wound healing complications

Hemorrhage

Fistula

Hypertension

Thrombotic event

Posterior reversible encephalopathy syndrome (PRES)


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
Proteinuria

Infusion-related reaction

Ovarian failure

Cardiac failure congestive
If the criteria for SAE is met, the SAE report should be submitted to the sponsor within the
specified time limit (see 7.2.1.4 for details)
7.2.1.7 Pregnancy
Bevacizumab may be harmful to the fetus. Subjects or female partners of male subjects must use
an effective form of contraception during the 6 months after the last dose.
During the study, if a female subject exposed to the study drug becomes pregnant, she must
discontinue study treatment. The investigator must report to the sponsor within 24 hours of
noticing the event and submit the "Innovent clinical Study Pregnancy Report/Follow-Up Form".
During the study, if a female partner of a male subject exposed to the study drugs becomes
pregnant, the subject will continue in the study. The investigator must report to the sponsor
within 24 hours of noticing the event and submit the "Innovent Clinical Study Pregnancy
Report/Follow-Up Form".
The investigator must continuously monitor and visit on the outcome of the pregnancy until 8
weeks after the subject gives birth. The outcome should be reported to the sponsor.
If the outcome of the pregnancy is stillbirth, spontaneous abortion, fetal malformation (any
congenital anomaly/birth defect), or medical abortion, it should be considered as an SAE and the
event is required to be reported in accordance with SAE procedures and time limits.
If the subject also experiences a SAE during the pregnancy, the CFDA SAE Report Form should
also be filled out and reported according to SAE's procedures.
7.2.1.8 Time limits of documenting and reporting AEs
All AEs occurring from the time the subject signs the informed consent form to the time
specified in the protocol (Table 2) (including SAEs and non-SAEs), regardless of their severity,
must be collected and recorded on the AE page of the eCRF.
The investigator must fill out all the required information, including the description of the AE,
start date, end date, severity, measures taken, outcome, seriousness, and causality with the
investigational drug. Each AE should be documented separately.


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Table 8. Reporting and follow-up of adverse events
Reporting time limit
Visit time limit
AEs
From signing the informed consent form to 90 days
after the last dose (if the subject begins other anti-
tumor therapies, only AEs related to the study drugs
should be collected)
Until resolved or explainable stable
determined by the investigator
Pregnancy
From the first dose until 6 months after the last dose
of the study treatment
Until the outcome of the event is
available, and the health conditions of
the newborn should be followed up
for at least 2 months according to the
protocol
7.2.1.9 Precautions for AE documentation
Diagnosis, signs, and symptoms
If a diagnosis is already made, the eCRF should record the diagnosis instead of individual
symptoms and signs (such as hepatic failure rather than jaundice, transaminase increased, and
asterixis). However, if the signs and symptoms cannot be attributed to a definitive diagnosis, each
independent event should be documented in the eCRFs as an AE or SAE. Update the report with
visit information if a diagnosis is confirmed later.
AEs secondary to other events
Generally, AEs secondary to other events (such as result of another event or clinical sequelae)
should be documented as the primary event, unless the event is severe or an SAE. However,
clinically significant secondary events should be recorded as independent adverse events in the
eCRFs if they occur at different times than the primary event. If the relationship between events is
unclear, document them as separate events in the eCRFs.
Ongoing or recurrent AEs
An ongoing AE refers to an event that does not resolve and is ongoing between two assessment
time points. These AEs should only be documented once in the eCRFs. The initial severity should
be documented, and the information should be updated if the event exacerbates.
Recurring AEs refer to AE that have resolved between the two time points of assessment but
subsequently occur. These events should be independently documented in the eCRFs.
Abnormalities in laboratory tests/vital signs
All clinically significant laboratory test abnormalities should be reported as AEs. It is the
responsibility of the investigator to review all abnormal laboratory test results, and to make
medical judgments as whether each abnormal laboratory test result should be reported as an AE.


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Death
During the entire course of the study, all the deaths that occurred within 90 days after the last dose
were documented in the Death Report Form in the eCRFs, regardless of the causality with the
investigational drug.
When recording a death event, if the cause of death is clear, the cause of death is recorded as an
adverse event with the result of the adverse event being death, and the event is reported as an SAE;
if the cause of the death is unknown at the time of reporting , "Death with Unknown Cause" should
be recorded on the Adverse Event Form of the eCRF and the "Death with Unknown Cause" should
be reported as an SAE first before further investigation is carried out to find the exact cause of
death.
Pre-existing medical conditions
Symptoms/signs presenting during the screening period will be recorded and reported as AEs only
if their severity, frequency, or property becomes aggravated (except for worsening of the studied
disease). The relative change should be documented, such as "increased frequency of headaches".
Hospitalization and prolonged hospitalization, or surgery
Any AE that results in hospitalization or prolonged hospitalization should be documented and
reported as an SAE, except for the following situations:

Hospitalization or prolonged hospitalization as required by study protocol (such as for dose
administration, efficacy evaluation, etc.)

Hospitalization due to a pre-existing medical condition that remains stable, e.g. elective
surgery/therapy scheduled prior to the study.
However, elective surgery/therapy required because of the exacerbated condition during the study
(e.g. surgery/therapy required earlier than scheduled) should be considered as an AE.
The investigator should fill in all required information, including AE terms
(diagnostic terms, or the record of symptoms and signs including laboratory test abnormalities if
there is no diagnosis), start date, end date, severity level, whether it is an AESI, measures taken for
the investigational product, treatment given for the AE, outcome, seriousness, and relationship with
the investigational product. If the signs and symptoms cannot be attributed to a definitive diagnosis,
each AE should be documented independently.


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Progressive disease
A progressive disease is defined as the worsening of subject condition caused by the primary tumor
that the investigational drug is targeting, the appearance of new lesions, or the progression of the
primary lesion. Expected progressive disease should not be reported as an AE. Any deaths, life-
threatening events, hospitalization or prolonged hospitalization, permanent or significant
disability/incapacity, congenital anomaly/birth defects, or other important medical events caused
by progressive disease should not be reported as an SAE
8 STATISTICS
8.1 Sample Size Determination
A number of 218 subjects for each group (436 subjects in total) can provide 80% test power to
confirm the clinical equivalence between the treatments of IBI305 in combination with
paclitaxel/carboplatin and bevacizumab in combination with paclitaxel/carboplatin.
The sample size is estimated based on the following assumptions:

The ORRs between IBI305 and bevacizumab group are equivalent

The ORR of subjects in the bevacizumab groups is set to 50.0%

The equivalence margin is taken as (-12.5%, 16.7%)

The significance level of the two one-side test is 0.05

1:1 randomization
Based on the above hypotheses, a number of 218 subjects for each group is required (436
subjects in total). The sample size was estimated using PASS 2013.
8.2 Statistical Population
Intention-to-Treat (ITT): All randomized subjects.
Full Analysis Set (FAS): All randomized subjects who received at least one dose of the study
treatment. This dataset is used as the primary analysis set for efficacy assessment.
Per-Protocol (PP): Based on the FAS, subjects with the predetermined minimum drug exposure
and without any predetermined major protocol deviations. This dataset is used as the secondary
analysis set for efficacy assessment.
Safety set (SS): Includes all randomized subjects who received at least one dose of the study
treatment and have safety evaluation data. This data set is used for the safety evaluation of this study.


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PK analysis set (PKAS): Includes subjects in the FAS with at least one PPK measured value.
Pharmacodynamic analysis set (PDAS): Includes all subjects in the FAS set with at least one PD
measured value.
8.3 General Principles for Statistical Analyses
For continuous variables, descriptive statistics should include the count, mean, standard
deviation, median, maximum, and minimum. For categorical variables, descriptive statistics will
include the frequency as well as the absolute or relative percentage. Statistical analyses will be
carried out using SAS 9.4.
8.4 Statistical Methods
8.4.1 Adjustments for covariates
Not applicable.
8.4.2 Managing dropouts and missing data
The analyses of primary and secondary endpoints will include data from dropouts. The management
of missing data is described in the Statistical Analysis Plan.
8.4.3 Multi-center study
Since this is a multicenter study, the primary endpoint (ORR) will be listed according to study
sites and treatment groups. However, individual equivalence analysis will not be conducted.
Trial sites with fewer than 5 ITT subjects per treatment group will need to be combined for
analysis. Details will be discussed in the data review meeting.
8.4.4 Multiple comparisons and adjustments to multiplicity
The α adjustment for multiple comparisons is not considered.
8.5 Statistical Analyses
8.5.1 Subject distribution
Refer to Figure 1: Study design schematic for the schedule of activities. The number and
percentage of patients who have completed or dropped out of the study (including the reason for
dropouts such as loss to follow-up, AEs, and poor compliance) are summarized based on
treatment groups.


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The number and percentage of subjects in each analysis set are calculated based on treatment groups.
The number and percentage of protocol deviations are calculated based on treatment groups.
8.5.2 Demographics and other baseline characteristics
Demographic information such as age, height, sex, and weight, and other baseline characteristics
such as disease history (including NSCLC diagnosis, staging, previous cancer treatment, and
target and nontarget lesions) are summarized using descriptive statistics.
8.5.3 Compliance and drug exposure
The required dose and the actual dose must be documented in the eCRF. Subject compliance is
calculated based on the ratio of the actual dose (number of doses) to the required dose (number
of doses). Subject compliance is classified into the following categories: < 80%, 80–120%, and >
120%. The number and percentage of subjects in each category will be summarized.
8.5.4 Efficacy
The efficacy analysis will be based on the FAS. Results of the PP set will also be presented.
8.5.4.1 Primary efficacy endpoint
The primary objective of this study is to determine the clinical equivalence between IBI305 +
paclitaxel/carboplatin and bevacizumab + paclitaxel/carboplatin for the treatment of advanced or
relapsed non-squamous non-small cell lung cancer (NSCLC). The primary endpoint is objective
response rate (ORR). ORR is defined as the incidence of patients with confirmed complete
response (CR) or partial response (PR), when a validated imaging method and RECIST v1.1
are used to evaluate target and non-target lesions. Subjects without tumor assessments beyond
baseline will be considered unresponsive to treatment. Subjects qualified for the evaluation of
CR or PR must have at least one measurable lesion according to RECIST v1.1. The evaluation
of clinical equivalence will be based on the ORR provided by the independent review committee
(IRC). Results provided by the investigator will be used for sensitivity analysis.
Clinical equivalence will be declared if the 90% confidence interval of the difference in ORR
between IBI305 and bevacizumab groups falls within the preset margin of (-12.5%, 16.7%).
The ORR and corresponding 95% confidence interval of the two treatment groups, the ORR
difference and the 90% confidence interval, as well as the ORR ratio between the two groups and
the 90% confidence interval will be estimated using the generalized linear model (GLM, which
includes treatment groups and stratification factors).


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8.5.4.2 Secondary efficacy endpoints
The secondary endpoints for this study include DOR, DCR, progress-free survival (PFS), and
overall survival (OS).
DCR is defined as the incidence of patients with confirmed complete response (CR), partial
response (PR), and stable disease (SD), when a validated imaging method and RECIST v1.1 are
used to evaluate target and non-target lesions.
DOR is defined as the time from initial tumor response (CR or PR) to PD or death; Subjects with
CR or PR who do not progress or die will be censored on the date of the last tumor assessment.
OS refers to the time from the date of randomization to the date of death (of any cause). For
subjects who are still alive at the time of the analysis, their survival time is censored on the last
known alive date. PFS refers to the time from the date of randomization to the date of first
documented PD or death, whichever occurs first. The investigator will assess PD using RECIST
v1.1. Subjects who do not progress or die will be censored on the date of the last tumor
assessment. Subjects without tumor assessments after baseline are censored on their date of
randomization.
Median OS and its 95% CI will be estimated using the Kaplan-Meier method. The survival curve
will be plotted. The hazard ratio (HR) between the two groups and its 95% CI will be estimated
using a Cox model. The Cox model includes treatment groups and stratification factors. DOR
and PFS will be analyzed using the same method as for OS. DCR will be analyzed using the
same method for primary efficacy endpoints, but an equivalence test will not be conducted.
8.5.4.3 Sensitivity analysis
The center effect (fixed or random) will be considered in the primary and secondary endpoints
analysis models (GLM or Cox).
8.5.4.4 Antibody and efficacy analysis
Subjects who develop antibodies during the clinical study will be summarized in detail. The
difference in efficacy between subjects with and without antibodies will be compared if
necessary.
Changes in PK parameters and steady-state trough concentrations of subjects with positive ADA
are analyzed.
8.5.5 Exploratory analysis
Pharmacodynamic parameters: The changes in the serum VEGF level at different time points are
described, and inter-group comparisons are carried out when necessary (based on the PD dataset)


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Steady-state trough concentrations of the drug: The level of trough concentration is described
and inter-group comparisons are carried out when necessary (based on the PPK dataset)
8.5.6 Interim analysis
No interim analysis is planned for this study.
8.5.7 Stratified analysis
Efficacy analysis of different levels of subjects is conducted based on the random stratification
factors
8.5.8 Safety analysis
The safety analysis is based on the safety analysis set.
8.5.8.1 Adverse events
All adverse events (AE) will be coded using MedDRA and graded using CTCAE v4.03. All
TEAEs, TEAEs ≥grade 3, SAEs, drug-related TEAEs, drug-related SAEs, TEAEs resulting in
the termination of study drugs, TEAEs resulting in the termination of study, and AESIs will be
listed based on system organ class, preferred terms, and groups and the corresponding numbers
and percentages of subjects will be summarized. In addition, the severity of TEAEs and
relevance to the study drugs will also be summarized system organ class, preferred terms, and
treatment groups.
8.5.8.2 Laboratory tests
All laboratory test results and changes relative to baseline will be summarized by scheduled time
point and treatment group using descriptive statistics. Laboratory abnormalities will be listed.
8.5.8.3 ECG examinations
Results of ECG and changes relative to baseline will be summarized using descriptive statistics.
8.5.8.4 Vital signs, physical examinations, and other safety examinations
Descriptive statistics of vital signs and relative changes from baseline are shown.
Results of physical examinations are listed by treatment groups.
8.5.8.5 Concomitant medications
Concomitant medications are non-study medications that meet one of the followings:
(1)
Any drug therapy started during or after the first dose of the study treatment;


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(2)
Any drug therapy started before the first dose of the study treatment and continued after
the first dose of the study treatment. Concomitant medications are listed by treatment
groups.
9 QUALITY ASSURANCE AND QUALITY CONTROL
According to GCP principles, the sponsor is responsible for implementing and maintaining
quality assurance and quality control systems based on standard operating procedures (SOP),
to ensure that the implementation of the clinical trial and the collection, documentation, and
reporting of trial data is in accordance with the protocol, GCP, and applicable regulatory
requirements.
To ensure that the data is reliable and processed correctly, there should be quality control for
every step during the data processing.
In addition, the Clinical Quality Assurance (CQA) Department of the sponsor and/or CRO may
conduct regular audits of the study process, including but not limited to auditing the study site,
on-site visits, central laboratory, suppliers, clinical database, and the final clinical study report.
Regulatory authorities may also conduct inspections during the trial or at any time after the trial
is completed. The investigator and the research institution must allow the sponsor's representative
and regulatory authorities to review source data.
9.1 Clinical Monitoring
The sponsor has authorized Wuxi Clinical Co., Ltd. to conduct clinical monitoring for this study.
The clinical research associate (CRA) should follow the SOPs of Wuxi Clinical Co., Ltd. when
carrying out monitoring, and has the same rights and responsibilities as the sponsor's monitor.
The CRA should maintain regular communication with the investigator and the sponsor.
Before the start of the study, the associate monitor assess the qualifications of each study site,
and report issues related to facilities, technical equipment, or medical staff to the sponsor. During
the study, the CRA will be responsible for confirming whether written informed consent is
obtained from all subjects, and whether data documentation is accurate and complete. At the
same time, the CRA will compare data entered in to the eCRF with source data, and notify the
investigator of any errors or omissions. The CRA will also verify protocol compliance of the
study site, as well as the dispensing and storage of investigational drugs to ensure protocol
requirements are met.
The monitoring visit will be conducted in accordance with applicable statutes and regulations.
Each site receives regular monitoring visits from the time the subjects are enrolled. The CRA
should submit a written report to the sponsor after each monitoring visit to the study site.


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9.2 Data Management/Coding
The Data Management and Biostatistics Department of Wuxi Clinical Co., Ltd will process data
generated from this study in accordance with relevant SOPs.
This study will use an electronic data capture (EDC) system. Trial data will be entered into the
eCRF by the investigator or authorized study personnel. Prior to launching of the study site or
data entry, the investigator and authorized study personnel will receive appropriate training, and
appropriate safety measures will be taken.
All data are input in Chinese. The eCRF should be completed during or soon after each visit, and
should be constantly updated to ensure that it reflects the latest status of the subject. To avoid
discrepancies in outcome assessments between different evaluators, ensure that baseline and all
subsequent efficacy and safety assessments for the same subject are performed by the same
person. The investigator must review trial data to ensure the accuracy and correctness of all data
entered into the eCRF. During the study, the investigator should document any evaluations that
are not conducted, or any information that is not available, applicable, or known. The
investigator needs to sign all verified data electronically.
The CRA will review the eCRF, and evaluate its completeness and consistency. The CRA will
also compare the eCRF with the source documents to ensure the consistency of critical data. Data
entry, corrections, or modifications are completed by the investigator or designated staff. The
CRA do not have access to data entry. The data in eCRF is submitted to the data server, and any
changes to the data will be documented in the audit trail, including the reason for the change, the
name of the operator, as well as the time and date of the change. The roles and permissions of
study personnel responsible for data entry will be predetermined. The CRA or data manager will
submit data queries in the EDC system, and study personnel shall respond to the queries. The
EDC system will record the audit trail of each query, including the name of the investigator, as
well as the time and date.
Unless otherwise specified, the eCRF should be considered simply as a form for data collection
and not a source document. A source file is used by the investigator or hospital, relevant to the
subject, and can prove the existence of the subject, inclusion criteria, and all records of
participation in the study, including laboratory records, ECG results, memorandum, pharmacy
dispensing records, and subject folders.


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The investigators are required to maintain all source documents and to offer the documents to the
CRA for review during each visit. In addition, the investigator must submit a complete eCRF for
each subject, regardless of the duration of the subject's participation in the study. The study
number and subject number in all supporting documents (such as laboratory records or hospital
records) submitted along with the eCRF should be carefully verified. All personal privacy
information (including the name of the subject) should be deleted or be made indecipherable in
order to protect subject privacy.
The investigator could be automatically added to the eCRF with his/her user ID. The investigators
verify that the record have been reviewed and that the data are accurate with an electronic
signature. The electronic signature is completed with the investigator's user ID and password.
The system automatically attaches the date and time of the signature. The investigator could not
share the user ID and password with other personnel. If data in the eCRF need to be modified,
the procedures defined by the EDC system have to be followed. All modifications and reasons
for the changes are recorded in the audit trail.
Training on the EDC system will be provided to study personnel at the study site.
Adverse events, and concurrent diseases/medical history will be coded. The medical dictionary
used for coding will be described in the Clinical Study Report (CSR).
9.3 Audits and Inspections
The sponsor or its representative (WuXi Clinical Co., Ltd) may conduct quality assurance audits
on the study site, database, and relevant study-related documents. Also, regulatory authorities
may also decide to inspect the study site, database, and relevant study-related documents at its
own discretion. The aim of audits and inspections is to systematically and independently check
all study-related procedures and documents to ensure that the clinical study is being carried out
in accordance with requirements of the trial protocol, GCP, Declaration of Helsinki, and
applicable regulations. The investigator must inform the sponsor immediately when an
inspection notice is received from the regulatory authorities.


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10 ETHICS
10.1 Independent Ethics Committee
The sponsor and its designated personnel will prepare all documents to be submitted to the
independent ethics committee (IEC) of each study site. The trial protocol, informed consent form
(ICF), investigators brochure, subject recruitment material or advertisements (if applicable), as
well as other documents required by regulations must be submitted to the IEC for approval. Prior
to the start of the study, written approval from the IEC must be obtained and provided to the
sponsor. The IEC approval must clearly state the title, number, and version of the study protocol
as well as the version of other documents (e.g. ICF) and the date of approval. The investigator
must notify the sponsor of the IEC's written comments concerning delays, suspension and re-
approval.
The study site must follow the requirements of the IEC. IEC requirements may include
submitting the revised protocol, ICF, or subject recruitment material to the IEC for approval,
local regulatory requirements for safety reports, and regular reports, updates, and submitting the
final report as per IEC requirements. The above documents as well as the IEC approval must be
provided to the sponsor or its designated personnel.
10.2 Implementation of Ethical Principles
The study process and the acquisition of informed consent should comply with the Declaration of
Helsinki, relevant GCP requirements (CPMP/ICH/135/95), and applicable statutes and
regulations related to drugs and data protection in the country in which the study is conducted.
The GCP is an international ethical and scientific quality standard for designing, conducting,
recording and reporting clinical trials that involve the participation of human subjects. To protect
the rights, safety, and healthy of subjects, this study will be carried out in accordance with GCP
and applicable national regulations, as well as ethical principles outlined in the Declaration of
Helsinki.
The investigator is required to follow the procedures specified in this protocol and must not
change the procedures without the permission from the sponsor. Protocol deviations will be
reported in accordance with the requirements of each ethics committee.


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10.3 Subject Information and Informed Consent
Prior to undergoing any study procedure, the ICF should be used to explain to potential participants
the potential risks and benefits of this study. The informed consent form should be in a language
that is simple and be easy to understand. The ICF should state that informed consent is voluntary,
emphasize the potential risks and benefits of participating in this study, and that the subject may
withdraw from the study at any time. The investigator may only enroll a subject after fully
explaining the details of the study, answering questions to the subject's satisfaction, giving
the subject sufficient time for consideration, and obtaining written consent from the subject or
his/her legal representative. All signed ICF must be retained in the investigator's documents or
the subject's folder.
The investigator is responsible for explaining the contents of the ICF and obtaining the ICF
signed and dated by the subject or his/her legal representative prior to starting the study. The
investigator should provide the subject with a copy of the signed ICF. The investigator must
document the informed consent process in the source document of the trial.
10.4 Protection of Subject Data
Information about data protection and privacy protection will be included in the ICF (or in some
cases, in a separate document).
Study personnel must ensure that the privacy of clinical trial subjects is protected. In all
documents submitted to the sponsor, the clinical trial subjects must only be identified with
subject number and not with the full name.
Additional precautions should be taken to ensure the confidentiality of the documents and
to prevent the identification of subjects based on genetic data. However, under special
circumstances, some personnel may be permitted to see the genetic data and personal
identification number of a subject. For example, in the event of a medical emergency, the
sponsor, designated physician, or investigator will have access to the subject identification code
and the subject's genetic data. In addition, regulatory agencies may request access to relevant
documents.


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11 STUDY MANAGEMENT
11.1 Organizational Structure
Refer to Table 3 for relevant collaborating parties.
Table 9. Organizational structure
Sponsor
Innovent Biologics (Suzhou) Co., Ltd.
No. 168 Dongping Street, Suzhou Industrial Park, Jiangsu, China
Telephone: (+86) 0512-69566088
Contract research
organization
WuXi Clinical Development Services (Shanghai) Co., Ltd.
19F, Building A, SOHO Fuxing Plaza, 388 Madang Road, Shanghai
Tel: (+86) 21-23158000
Data management and
biostatistics
WuXi Clinical Development Services (Shanghai) Co., Ltd.
19F, Building A, SOHO Fuxing Plaza, 388 Madang Road, Shanghai
Tel: (+86) 21-23158000
11.1.1 Independent review committee
Central imaging evaluation will be performed by Parexel China Co., Ltd. The CT/MRI images of
each subject will be evaluated using RECIST v1.1.
11.2 Archiving of Study Documents
Clinical trial documents (protocol and amendments, completed eCRFs, signed ICFs, etc.) must
be retained and managed as per GCP requirements. The study site must retain these documents
for 5 years after the completion of the study. The sponsor should retain clinical trial data for
5 years after the investigational drug is approved for marketing.
Study documents should be retained properly for future access or data traceability. Safety and
environmental risks should be considered when retaining documents.
The documents associated with the study may only be destroyed with the written consent of the
sponsor and the investigator. Study documents may be transferred to other parties that comply
with or other locations that meet retention requirements only after the sponsor is notified and
written consent thereof is obtained.


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11.3 Access to Source Data/Documents
Source data refers to source records of subject data obtained from a clinical study. These source
records are source documents, which include but are not limited to medical records (hospital
records, nursing records, pharmacy dispensing records, etc.), electronic data, screening logs,
laboratory test results, as well as medical device test results (ECG, CT/MRI, etc.). All source
documents associated with the trial are retained by the study site and the investigator. The
original ICFs will be retained according to standard practices developed by the clinical trial
institution.
The investigator will prepare sufficient and accurate source documents for each randomized
subject in order to document all examination results and other relevant data, and retain these
documents properly.
During the study, the CRA will conduct on-site visits to verify protocol compliance, EDC data
entry, documentation of subjects' medical history, drug inventory, and whether the study is
carried out in accordance with applicable regulations. In addition, regulatory authorities, IRB,
IEC, and/or the quality assurance department of the sponsor will verify source data and/or
conduct on-site audits or inspections. The investigator should allow direct access to documents
associated with the study, including medical records of subjects.
11.4 Protocol Revisions
The sponsor and the investigator must both agree on any appropriate protocol revisions during
the course of the study. The sponsor shall ensure that the protocol revision is submitted to the
regulatory authority in a timely manner.
All protocol revisions must be submitted to the IEC, and if needed, to regulatory authorities for
approval. Revisions may only be implemented after approval from the IEC and regulatory
authorities (if needed) is obtained (except for changes to eliminate immediate risks to subjects).
11.5 Investigator's Responsibilities
The investigator will conduct this study in accordance with the protocol, ethical principles of the
Declaration of Helsinki, Chinese GCP, and applicable regulations. Details of the investigator's
responsibilities are list in Chapter 5 (Investigator's Responsibilities) of the Chinese GCP (NMPA
order No. 3).


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11.6 Study Termination
The study may be terminated after a discussion between relevant parties if the investigator or the
sponsor becomes aware of circumstances or events that could jeopardize the subjects if the study
is continued. The sponsor may also decide to terminate the study even without such findings.
Reasons for study termination include but are not limited to:

Unexpected, serious, or unacceptable risks to enrolled subjects

Slow recruitment

The sponsor decides to suspend or discontinue the development of the drug
11.7 Publishing Policies
All the data generated in this study is the confidential information owned by the sponsor. The
sponsor has the right to publish study results. The investigator shall not publish any data relevant
to this study (posters, abstracts, papers, etc.) without prior communication with the sponsor.
Information on the publishing policies of the sponsor and investigator will be described in the
clinical trial agreement.
11.8 Finance and Insurance
The sponsor will purchase insurance for subjects participating in the study in accordance with
local regulations, and bear the cost of treatment and corresponding financial compensation for
the subjects who suffer injury during the study due to the investigational drug or the study
process. Insurance related terms shall be saved in the study folder.


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12 REFERENCES
1.
GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. Apr.
11, 2016: http://globocan.iarc.fr/Default.aspx
2.
陈万青，郑荣寿，曾红梅，等. 2011 年中国恶性肿瘤发病和死亡分析. 中国肿瘤.
2015;24(1):1-10.
3.
GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. Apr.
11, 2016: http://www.cancer.org/acs/groups/cid/documents/webcontent/003115-pdf.pdf
4.
支修益，石远凯，于今明. 中国原发性肺癌诊疗规范（2015 年版）. 中华肿瘤杂志.
2015;37(1):67-78.
5.
Pisters KMW and Chevalier TL. Adjuvant Chemotherapy in Completely Resected Non–
Small-Cell Lung Cancer. J Clin Oncol. 2005;23:3270-3278.
6.
石远凯，孙燕，于今明，等. 中国晚期原发性肺癌诊治专家共识（2016 年版）. 中国
肺癌杂志. 2016;19(1):1-15.
7.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN
Guidelines®) Non-Small Cell Lung Cancer (Version 4. 2016). Apr. 11, 2016:
http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
8.
郝希山，魏于全. 肿瘤学（第二版）. 北京: 人民卫生出版社. 108; 2010.
9.
Package insert of bevacizumab (Nov. 25, 2015). Apr. 11, 2016:
http://www.roche.com.cn/content/dam/roche_china/zh_CN/pdf/product/Avastin_20151125_
IM %20PI%20CDS32.0-33.0.pdf
10. Sandler A., Gray R., Perry MC., et al. Paclitaxel-carboplatin alone or with bevacizumab for
non-small-cell lung cancer. N Engl J Med. 2006;355:2542-2550.
11. Reck M., von Pawel J., Zatloukal P., et al. Overall survival with cisplatin-gemcitabine and
bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer:
results from a randomized phase III trial (AVAiL). Annals of Ocology. 2010;21:1804-1809.
12. Zhou CC., Wu YL., C GY., et al. BEYOND: A randomized, double-blind, placebo-
controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab
or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung
cancer. J Clin Oncol. 2015;33:2197-2204.
13. IBI305 研究者手册. 信达生物制药（苏州）有限公司. 2016 年5 月11 日.
14. Technical Guidelines for Development and Evaluation of Biosimilars by NMPA (Trial). Apr. 21,
2016: http://www.sda.gov.cn/WS01/CL1616/115104.html


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13 APPENDIX
13.1 Appendix I
Eastern Cooperative Oncology Group (ECOG) Performance Status Score
Score
Performance Status
0
Fully active, and able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activities but able to move around easily and carry out work of
a light or sedentary nature, e.g. light house work or office work
2
Capable of moving around easily and self-care but unable to carry out any work activities; up and
about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or wheelchair more than 50% of waking hours
4
Bedridden and incapable of self-care
5
Death
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative
Oncology Group. Am J Clin Oncol. 1982;5:649-655.


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13.2 Appendix II
Calculation of body surface area
Body surface are (m2) = 0.00616 height (cm) + 0.01286 weight (kg) - 0.1529
Creatinine Clearance (Cockroft-Gault Equation)
Ccr (mL/min) = [(140 - age) x weight (kg)]/[72 x Scr (mg/dL)]
Female subjects: results × 0.85
1 mg/dL = 88.41 µmol/L
Carboplatin Dose (Calvert Equation)
Carboplatin dose (mg) = target AUC (mg/mL/min) × [creatinine clearance rate (mL/min) + 25]
Note: During the study, if the carboplatin dose calculated using the Calvert equation excessively
exceeds the usual clinical dose, choose one of the following two methods to ensure the patient
safety:
1. Retest the serum creatinine and re-calculate the dose (preferred option).
2. Based on clinical experience, the investigator may choose the highest dose tolerated by the
subject. The dose should remain unchanged for the subsequent cycles.


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13.3 APPENDIX 3
RECIST v1.1
1
MEASURABILITY OF TUMOR AT BASELINE
1.1
Definitions
At baseline, tumor lesions/lymph nodes will be categorized as measurable or not measurable as
follows:
1.1.1
Measurable
Tumor lesions: must be accurately measured in at least one dimension (longest diameter in the
plane of measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm)

10 mm caliper measurement by clinical exam (lesions which cannot be accurately
measured with calipers should be documented as not measurable).

20 mm by chest X-ray.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will
be measured and followed.
1.1.2
Not measurable
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes
with a short axis ≥10 and <15 mm) as well as truly not measurable lesions. Lesions considered
truly not measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion,
inflammatory breast disease, lymphangitis involving the skin or lungs, abdominal masses/
abdominal organomegaly identified by physical exam but not measurable by reproducible
imaging techniques.
1.1.3
Special considerations regarding measurable bone lesions, cystic lesions, and lesions
with prior locoregional treatment:
Bone lesions:

Bone scan, PET scan or plain films are not considered adequate imaging
techniques to measure bone lesions. However, these techniques can be used to
confirm the presence or disappearance of bone lesions.


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
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue
components, that can be evaluated by cross sectional imaging techniques (such as
CT or MRI) can be considered as measurable lesions if the soft tissue
components meet the definition of measurability described above.

Blastic bone lesions are not measurable.
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not
be considered as malignant lesions (neither measurable nor not measurable) since
they are, by definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as
measurable lesions, if they meet the definition of measurability described above.
However, if noncystic lesions are present in the same patient, these noncystic
lesions are preferred for selection as target lesions.
Lesions with prior locoregional treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to
other locoregional therapy are usually not considered measurable, unless there
has been demonstrated progression in the lesion. The study protocol should detail
the conditions under which such lesions would be considered measurable.
1.2
Specifications by Methods of Measurements
1.2.1
Measurement of lesions
All measurements should be documented with metric symbols. Calipers should be used if clinical
assessments are required. All baseline evaluations should be performed as close as possible to
the beginning of the treatment but never more than 4 weeks before the beginning of the treatment.
1.2.2
Method of assessment
The same method of assessment and the same technique should be used to characterize each
identified and reported lesion at baseline and during follow-up. Imaging evaluation should
always be done rather than clinical examination unless the lesion(s) being followed cannot be
imaged but are assessable by clinical examination.
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial
and its diameter is ≥10 mm as assessed using calipers (e.g. skin nodules). For skin lesions,
documentation by color photography including a plotting scale to estimate the size of the lesion
is recommended. As noted above, when lesions can be evaluated by both clinical examination
and imaging evaluation, the latter should be undertaken since it is more objective and may also


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be reviewed at the end of the study.
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.
However, lesions on chest X-ray may be considered measurable if they have clear boundaries
and are surrounded by aerated lung tissues.
CT and MRI: CT is the best currently available and reproducible method to measure lesions
selected for response assessment. This guideline has defined measurability of lesions on CT scan
based on the assumption that CT slice thickness is 5 mm or less. When CT scans have a slice
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice
thickness. MRI is also acceptable in certain situations (e.g. for body scans).
Ultrasound: Ultrasound should not be used for measuring lesion size and should not be used as
a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for
independent review at a later date and, because they are operator dependent, it cannot be
guaranteed that the same technique and measurements will be taken from one assessment to the
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT
or MRI is recommended. If there is concern about radiation exposure at CT, MRI may be used
instead of CT in selected instances.
Endoscopy and laparoscopy: The utilization of these techniques is not recommended for
objective tumor evaluation. However, they can be used to confirm complete pathological
response when biopsies are obtained or to determine relapse in trials where recurrence following
complete response or surgical resection is an endpoint.
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If
markers are initially above the upper limit of normal, however, they must normalize for a patient
to be considered in complete response. Because tumor markers are disease specific, instructions
for their measurement should be incorporated into the protocol on a disease specific basis.
Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response
(in recurrent prostate cancer) have been published. In addition, the Gynecologic Cancer
Intergroup has developed CA125 progression criteria which are to be integrated with objective
tumor assessment for use in first-line trials in ovarian cancer.
Cytology and histology: These techniques can be used to differentiate between PR and CR in rare
cases if required by the protocol (for example, residual lesions in tumor types such as seminoma,
where known residual benign tumors can remain). When effusions are known to be a potential
adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors),
cytological confirmation of the neoplastic origin of any effusion that appears or worsens during


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treatment can be considered if the measurable tumor has met criteria for response or stable
disease in order to differentiate between response (or stable disease) and progressive disease.
2.
TUMOR RESPONSE EVALUATION
2.1
Assessment of Overall Tumor Burden and Measurable Disease
To assess objective response or future progression, it is necessary to estimate the overall tumor
burden at baseline and use this as a comparator for subsequent measurements. Only patients with
measurable disease at baseline should be included in regimens where objective tumor response is
the primary endpoint. Measurable disease is defined by the presence of at least one measurable
lesion. In studies where the primary endpoint is tumor progression (either time to progression or
proportion with progression at a fixed date), the protocol must specify if entry is restricted to
those with measurable disease or whether patients having non-measurable disease only are also
eligible.
2.2
Baseline Documentation of "Target" and "Non-Target" Lesions
When more than one measurable lesion is present at baseline, all lesions (five lesions at most,
and two lesions per organ at most) representative of all involved organs should be identified as
target lesions and will be recorded and measured at baseline (This means in instances where
patients have only one or two organ sites involved, a maximum of two and four lesions
respectively will be recorded).
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be
representative of all involved organs, and should be those with reproducible repeated
measurements. It may be the case that, the largest lesion does not have reproducible
measurements, in which circumstance the next largest lesion with reproducible measurements
should be selected.
Lymph nodes merit special mention since their normal anatomical structures may be visible by
imaging even if not involved by tumor. Pathological nodes which are defined as measurable and
may be identified as target lesions must have a short axis of ≥15 mm by CT scan. Only the short
axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter
normally used by radiologists to judge if a node is invaded by solid tumor. Nodal size is
normally reported as two dimensions in the plane in which the image is obtained (for CT scan
this is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal or
coronal). The smaller of these measures is the short axis. For example, an abdominal node which
is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies as a malignant
measurable node. In this example, 20 mm should be reported as the node measurement. All other
pathological nodes (those with a short axis ≥10 mm but < 15 mm) should be considered non-


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target lesions. Lymph nodes that have a short axis < 10 mm are considered non-pathological and
should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions; short axis for nodal lesions) for all target
lesions will be calculated and reported as the baseline sum of diameters. If lymph nodes are to be
included in the sum, then as noted above, only the short axis is added into the sum. The baseline
sum of diameters will be used as reference to further characterize any objective tumor regression
in the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as
non-target lesions and should also be recorded at baseline. Measurements are not required and
these lesions should be recorded as "present", "absent", or in rare cases "unequivocal
progression". In addition, it is possible to record multiple target lesions involving the same organ
as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple
liver metastases’).
2.3
Response Criteria
2.3.1
Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes
(whether target or non-target) must have a reduced short axis of <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions vs. the
baseline sum of diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions vs.
the smallest sum during the study (this includes the baseline sum if that is the smallest). In
addition to the relative increase of 20%, the sum must also have an absolute increase of at least
5 mm. (Note: The appearance of one or more new lesions is also considered progression).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to
qualify for PD, using the smallest sum of diameters during the study as reference.
2.3.2
Special notes on the assessment of lymph nodes which are target lesions
Lymph nodes identified as target lesions should always have the actual short axis measurement
recorded (measured in the same anatomical plane as during the baseline examination), even if the
nodes regress to below 10 mm at the time of the study. This means that when lymph nodes are
included as target lesions, the "sum" of lesions may not be zero even if complete response
criteria are met, since a normal lymph node is defined as having a short axis of <10 mm. Case
report forms or other data collection methods may therefore be designed to have target nodal
lesions recorded in a separate section where, in order to qualify for CR, each node must have a


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short axis of <10 mm. For PR, SD, and PD, the actual short axis measurement of the nodes is to
be included in the sum of target lesions.
Target lesions that are "too small to measure". During the study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent
evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or lymph nodes
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist
may not feel comfortable assigning an exact measurement and may report them as being "too
small to measure". When this occurs it is important that a value be recorded on the case report
form. If it is the opinion of the radiologist that the lesion has probably disappeared, the
measurement should be recorded as 0 mm. If the lesion is believed to be present and is faintly
seen but too small to measure, a default value of 5 mm should be assigned (Note: It is less likely
that this rule will be used for lymph nodes since they usually have a definable size when normal
and are frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is
believed to be present and is faintly seen but too small to measure, a default value of 5 mm
should be assigned in this circumstance as well). This default value is derived from the 5 mm CT
slice thickness (but should not be changed with varying CT slice thickness). The measurements
of these lesions are potentially non-reproducible, therefore providing this default value will
prevent false responses or progressions caused by measurement errors. To reiterate, however, if
the radiologist is able to provide an actual measurement, that value should be recorded, even if it
is below 5 mm.
Lesions that split or coalesced at the time of treatment. When non-nodal lesions fragment, the
longest diameters of the fragmented portions should be added together to calculate the target lesion sum.
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such that
they are no longer separable, the vector of the longest diameter in this instance should be the maximal
longest diameter for the "coalesced lesion".
2.3.3
Evaluation of non-target lesions
This section provides the definitions of the criteria used to determine the tumor response for the
group of non-target lesions. While some non-target lesions may actually be measurable, they do
not need to be measured and instead should be assessed only qualitatively at the time points
specified in the protocol.
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor
marker level. All lymph nodes must be non-pathological in size (short axis <10 mm).
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor
marker level above the normal limits.


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Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: The
appearance of one or more new lesions is also considered progression).
2.3.4
Special notes on the assessment of progression of non-target lesions
The concept of progression of non-target disease requires additional explanation as follows: When
the patient also has measurable lesions. In this setting, to achieve ‘unequivocal progression’ on the
basis of the non-target lesion, there must be an overall level of substantial worsening in non-target
disease such that, even in the presence of SD or PR of the target disease, the overall tumor burden
has increased sufficiently to merit discontinuation of therapy. A minimal increase in the size of one
or more non-target lesions is usually not sufficient to quality for unequivocal progression status.
The designation of overall progression solely on the basis of change in non-target lesions in the
face of SD or PR of target disease will therefore be extremely rare.
When the patient has only lesions that are not measurable. This circumstance arises in some
phase III trials when the presence of measurable lesions is not a criterion for study enrollment.
The same general concepts apply here as well. However, in this instance there are no measurable
lesions to factor into the interpretation of an increase in non-measurable lesion burden. Because
worsening in non-target lesion cannot be easily quantified (by definition: if all lesions are truly
not measurable), a useful test that can be applied when assessing patients for unequivocal
progression is to consider if the increase in overall lesion burden based on the change in non-
measurable disease is comparable in magnitude to the increase that would be required to declare
PD for measurable disease: i.e. an increase in tumor burden representing an additional 73%
increase in volume (which is equivalent to a 20% increase of diameter in a measurable lesion).
Examples include an increase in pleural effusion from "trace" to "large amount", an increase in
lymphangitic lesion from localized to widespread, or a description in the protocol such as
"sufficient to require a change in therapy". If ‘unequivocal progression’ is seen, the patient
should be considered to have had overall PD at that point. While it would be ideal to have
objective criteria to apply to diseases that are not measurable, the very nature of these diseases
makes it impossible to do so, therefore the increase must be substantial.
2.3.5
New lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on the detection of new lesions are important. There are no specific criteria for the
identification of new radiographic lesions; however, the finding of a new lesion should be
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging
modality or findings thought to represent something other than tumors (for example, some new
bone lesions which may be simply healed or flare of pre-existing lesions). This is particularly


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important when the patient’s baseline lesions show partial or complete response. For example,
necrosis of a liver lesion may be reported by a CT scan as a "new" cystic lesion, while it is
actually not.
A lesion identified during a follow-up in an anatomical location that is not discovered during the
baseline scan is considered a new lesion and will indicate disease progression. For example, a
patient with a visceral disease at baseline has a brain CT or MRI which reveals metastases. The
patient's brain metastases are considered evidence of PD even if he/she does not have brain
imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents a truly new lesion. If repeat scans confirm there is
definitely a new lesion, then progression should be declared using the date of the initial scan.
While FDG-PET response assessments need additional studies, it is sometimes reasonable to
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of
progression (particularly possible "new" lesions). New lesions on the basis of FDG-PET imaging
can be identified as follows:
a.
A negative FDG-PET at baseline and a positive FDG-PET at follow-up is a sign of PD
based on a new lesion.
b.
No FDG-PET at baseline and a positive FDG-PET at follow-up:
If the positive FDG-PET at follow-up corresponds to a new lesion site confirmed by
CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new lesion
site on CT, additional follow-up CT scans are needed to determine if there is truly
progression at that site (if so, the date of PD will be the date of the initial abnormal
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing
lesion site on CT that is not progressing according to the anatomic images, this is not PD.
2.4
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until
the end of treatment, taking into account any requirement for confirmation. On occasion a
response may not be documented until after the end of therapy, so the study protocol should
clearly state if post-treatment assessments are to be considered when determining best overall
response. The study protocol must specify how any new therapy introduced before progression
will affect best response designation. Assignment of best overall response for the patient will
depend on the findings of both target and non-target lesions and will also take into consideration
the appearance of new lesions. Furthermore, depending on the nature of the study and the


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protocol requirements, confirmatory measurement may also be required. Specifically, in non-
randomized trials where response is the primary endpoint, confirmation of PR or CR is needed to
determine which one is the "best overall response".
2.4.1
Time point response
It is assumed that at each time point specified by the study protocol, a response assessment
occurs. Table 1 on the next page provides a summary of the overall response status calculation at
each time point for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used.
2.4.2
Missing assessments and non-evaluable targets
When no imaging/measurement is done at a particular time point, the patient is not evaluable
(NE) at that time point. If only a subset of lesion measurements is made at an assessment, usually
the case is also considered NE at that time point, unless a convincing argument can be made that
the missing lesion(s) would not change the response at the assigned time point. This would be
most likely to happen in the case of PD. For example, if a patient has a baseline sum of 50 mm
with three measured lesions and at follow-up only two lesions are assessed and with a sum of 80
mm, the patient will have achieved PD status, regardless of the contribution of the missing lesion.
2.4.3
Best overall response: all time points
The best response is determined once all the data for the patient is obtained.
Best response determination in trials where confirmation of complete or partial response is not
required: Best response in these trials is defined as the best response across all time points (for
example, the best overall response of a patient who has SD at the first assessment, PR at the
second, and PD at the last is PR). When SD is believed to be best response, it must also meet the
minimum time from baseline specified by the protocol. If the minimum time is not met,
otherwise SD is the best time point response, the patient’s best response depends on subsequent
assessments. For example, if a patient has SD at the first assessment, PD at the second and does
not meet the minimum duration for SD, his/her best response is PD. The same patient lost to
follow-up after the first SD assessment would be considered not evaluable.
Best response determination in trials where confirmation of complete or partial response is
required: Complete or partial responses may be claimed only if the criteria for each are met at a
subsequent time point specified in the protocol (generally 4 weeks later). In this circumstance,
the best overall response can be interpreted as in Table 3.


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2.4.4
Special notes on response assessment
When nodal lesions are included in the sum of target lesions and the nodes decrease to "normal"
size (<10 mm), they may still have a measurement reported on scans. This measurement should
be recorded even if the nodes are normal in size in order not to overstate progression should it be
based on the increase in size of the nodes. As noted earlier, this means that patients with CR may
not have a total sum of "zero" on the case report form (CRF).
In trials where confirmation of response is required, repeated "NE" time point assessments may
complicate best response determination. The analysis plan for the trial must explain how missing
data/assessments will be addressed in the determination of response and progression. For
example, in most trials it is reasonable to consider a patient with time point responses of PR-NE-
PR as a confirmed response.
Patients with a global deterioration of health status requiring discontinuation of treatment without
objective evidence of disease progression at that time should be reported as "symptomatic
deterioration". Every effort should be made to document objective progression even after
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective
response. Instead, it is a reason for stopping the study treatment. The objective response status of
this type of patients is to be determined by evaluation of target and non-target lesions as shown
in Table 1–3.
Conditions that define "early progression, early death, and non-evaluability" are study specific
and should be clearly described in each study protocol (depending on treatment duration and
treatment periodicity).
In some circumstances it may be difficult to distinguish a residual lesion from normal tissues.
When the evaluation of complete response depends upon this determination, it is recommended
that the residual lesion be investigated (by fine needle aspirate/biopsy) before assigning a status
of complete response.
Like a biopsy, FDG-PET may also be used to upgrade a response to a CR in cases where a
residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-
PET in this circumstance should be pre-defined in the protocol and supported by disease specific
medical literature for the indication. However, it must be acknowledged that both approaches
may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.


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Table 1. Time point response: patients with target (+/– non-target) disease.
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or
No
PR
Not all were evaluated
SD
Non-PD or
No
SD
Not all were evaluated
Not all were
evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not evaluable
Table 2. Time point response: patients with non-target disease only.
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PDa
Not all were evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease, and NE = not evaluable.
a "Non-CR/non-PD" is preferred over "stable disease" for non-target disease, since SD is increasingly used as an
endpoint for assessment of efficacy in some trials, thus assigning this category in the absence of measurable
lesions is not advised.
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at
the next scheduled assessment, progression is confirmed, the date of progression should be the
earlier date when progression is suspected.


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Table 3. Best overall response when confirmation of CR and PR required.
Overall response
First time point
Overall response
Subsequent time
point
Best overall response
CR
CR
CR
CR
PR
SD, PD, or PRa
CR
SD
SD provided that the minimum duration for SD is met, otherwise PD
CR
PD
SD provided that the minimum duration for SD is met, otherwise PD
CR
NE
SD provided that the minimum duration for SD is met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided that the minimum duration for SD is met, otherwise PD
PR
NE
SD provided that the minimum duration for SD is met, otherwise NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not
evaluable.
a If CR is truly achieved at the first time point, then any lesions seen at a subsequent time point, even those meeting
PR criteria relative to baseline, make the disease PD at that time point (since lesions must have reappeared after
CR). Best response would depend on whether the minimum duration for SD is met. However, sometimes CR may
be claimed and subsequent scans suggest small lesions are likely still present, while in fact the patient have PR
instead of CR at the first time point. Under these circumstances, CR should be changed to PR and the best response
is PR.
2.5 Frequency of Tumor Re-Evaluation
Frequency of tumor re-evaluation during treatment should be protocol specific and adapted to the
type and schedule of treatment. However, for phase II studies where the beneficial effect of the
treatment is not known, follow-up every 6–8 weeks (timed to coincide with the end of a cycle) is
reasonable. Smaller or greater time intervals may be justified for certain regimens or circumstances.
The study protocol should specify which organ sites are to be evaluated at baseline (usually those
most likely to be involved with metastatic disease for the tumor type under study) and how
often evaluations are repeated. Normally, all target and non-target sites are evaluated at each
assessment. Under certain circumstances, some non-target organs may be evaluated less frequently.
For example, bone scans may need to be repeated only when complete response is identified in
the target lesion or when progression is suspected.


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After the end of the treatment, the need for repeated tumor evaluations depends on whether the
trial has a goal such as a certain response rate or a certain time to an event (progression/death).
If ‘time to an event’ (e.g. time to progression, disease-free survival, progression-free survival) is
the main endpoint of the study, then routine scheduled re-evaluation of lesion sites specified by
the protocol must be carried out. In randomized comparative trials in particular, the scheduled
assessments should be performed on time (for example: every 6–8 weeks during the treatment or
every 3–4 months after the treatment) and should not be affected by treatment delays, holidays or
any other events that might lead to imbalance in the timing of disease assessment between
treatment arms.
2.6 Confirmation of Measurements/Duration of Response
2.6.1 Confirmation
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is
required to ensure responses identified are not the result of measurement errors. This will also
permit appropriate interpretation of results in the context of historical data. Response
confirmation has been traditionally required in such trials. However, in all other circumstances,
i.e. in randomized trials (phase II or III) or studies where stable disease or progression are the
primary endpoints, confirmation of response is not required since it will not add value to the
interpretation of trial results. However, elimination of the requirement for response confirmation
may increase the importance of central review to protect against bias, in particular in studies
which are not blinded.
In the case of SD, measurements after study entry must have met the minimum interval for SD
(generally not shorter than 6–8 weeks) defined in the study protocol at least once.
2.6.2 Duration of overall response
The duration of overall response is measured from the time CR/PR measurement criteria are first
met CR/PR (whichever is first documented) until the date when recurrent or progressive disease
is objectively documented for the first time (using the shortest time to progressive disease
documented during the study as reference).
The duration of overall complete response is measured from the time CR measurement criteria
are first met until the date when recurrent disease is objectively documented for the first time.
2.6.3 Duration of stable disease
Stable disease is measured from the start of the treatment (in randomized trials, from the date
of randomization) until the criteria for progression are met, using the smallest sum during the
study as reference (if the baseline sum is the smallest, then it is used as the reference for the
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The clinical relevance of the duration of stable disease varies with different studies and diseases.
If the proportion of patients achieving stable disease for a minimum period of time is an endpoint
of importance in a particular trial, the protocol should specify the minimal time interval required
between two measurements for the determination of stable disease.
Note: The duration of response and stable disease as well as the progression-free survival are
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of the
guidelines to define a standard follow-up frequency. The frequency should take into account
many parameters including disease types and stages, treatment periodicity, and standard practice.
However, limitations of the precision of the measured endpoint should be taken into account if
comparisons between trials are to be made.


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14 INVESTIGATOR SIGNATURE PAGE
Protocol Title: A randomized, double-blind, multi-center phase III study comparing the efficacy
and safety of IBI305 plus paclitaxel/carboplatin vs. bevacizumab plus paclitaxel/carboplatin in
treatment-naive patients with advanced or relapsed non-squamous NSCLC.
Protocol No.: CIBI305A301
This protocol is a trade secret owned by Innovent Biologics (Suzhou) Co., Ltd. I have read and
fully understood this protocol, and agree to conduct this study in accordance with the
requirements found in this protocol and the Good Clinical Practice, and in compliance with
relevant laws and regulations and the Declaration of Helsinki. At the same time, I promise not to
disclose any confidential information associated with this study to any third party without the
written consent of Innovent Biologics (Suzhou) Co., Ltd.
Instructions for the Investigator: Please sign and date this signature page, type the investigator's name and job
title, as well as the name of the study site, and return this document to Innovent Biologics (Suzhou) Co., Ltd.
I have read the entire contents of this study protocol and shall perform the study as required:
Investigator's signature:
Date:
Name (in Print):
Job Title:
Name and Address of Study Site:


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原文
After revision
Reason for amendment
P1: Cover
●
Protocol
version
number
and
version date are
updated
Version and Date:
Sep. 26, 2016/Version 2.0
Version Date/No.:
Sep. 25, 2017/Version 3.0
P1: Cover
●
The
contact
of
sponsor
is
updated
Sponsor Contact:
Sponsor Contact:
Zhou Hui (Medical Director)
Tel: (+86) 021-31652896
E-mail: hui.zhou@innoventbio.com
Zhou Hui, Senior Medical Director
Tel: (+86) 021-31652896
E-mail: hui.zhou@innoventbio.com
P2: SIGNATURE PAGE
Title
Medical Director
Title
Senior Medical Director
●
The
contact
of
sponsor
is
updated
P4: Diagnosis and main inclusion criteria:
Inclusion Criteria:
2)
Male or female ≥18 and ≤70 years old
2) Male or female ≥18 and ≤75 years old
●
The
upper
age
limit is modified


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P4: Diagnosis and main inclusion criteria:
Inclusion Criteria:
●
The medical term
is modified
3)
Histologically or cytologically confirmed unresectable
locoregionally advanced (stage IIIb), metastatic (stage IV),
or relapsed non-squamous NSCLC; mixed tumors should
be categorized according to the main cell types
3)
Histologically
or
cytologically
confirmed
unresectable
locoregionally advanced (stage IIIB), metastatic (stage IV), or
relapsed non-squamous NSCLC; mixed tumors should be
categorized according to the main cell types
P4: Diagnosis and main inclusion criteria:
Inclusion Criteria:
4)
Histologically or cytologically confirmed EGFR wild type
4)
Histologically or cytologically confirmed EGFR wild type or
non-sensitive mutation type
●
The enrollment of
patients
carrying
the
non-sensitive
mutant
type
of
EGFR is added
P4: Diagnosis and main inclusion criteria:
Inclusion Criteria:
8)
Laboratory results during screening:
9)
Routine blood test: WBC ≥3.0 × 109/L, ANC ≥1.5 ×
109/L, platelets ≥100 × 109/L, and hemoglobin ≥90 g/L
8) Laboratory results during screening:
a) Routine blood test: WBC ≥3.0 × 109/L, ANC ≥1.5 × 109/L,
platelets ≥100 × 109/L, and hemoglobin ≥90 g/L
●
The
laboratory
test
results
are
unified,


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10)
Hepatic function: TBIL < 1.5 × ULN; ALT and AST <
2.5 × ULN for subjects without liver metastasis, or ALT and AST
< 5 × ULN for subjects with liver metastasis
11)
Renal function: SCr ≤1.5 × ULN or CrCl ≥50 mL/min,
and urine protein < 2+ in routine urinalysis. Subjects with urine
protein ≥2+ from urinalysis dipstick at baseline, a 24-h urine
should be collected with total protein content < 1 g
12)
INR ≤1.5 and PTT or aPTT ≤1.5 × ULN within 7 days
prior to the study treatment
b) Hepatic function: TBIL < 1.5 × ULN; ALT and AST < 2.5 ×
ULN for patients without liver metastasis, or ALT and AST
< 5 × ULN for patients with liver metastasis
c) Renal function: SCr ≤1.5 × ULN or CrCl ≥50 mL/min, and
urine protein < 2+ in routine urinalysis. Subjects with urine
protein ≥2+ at baseline urinalysis must have undergone 24
h urine collection with total protein content < 1 g
d) INR ≤1.5 and PTT or aPTT ≤1.5 × ULN within 7 days prior
to the study treatment
P4: Diagnosis and main inclusion criteria:
Inclusion Criteria:
13)
Able to comply with study protocol
9) Able to comply with study protocol
●
The
No.
of
inclusion
criteria
is changed
P4: Diagnosis and main inclusion criteria:
Inclusion Criteria:
14)
Female and male subjects of childbearing age, and partners
of these male subjects must agree to use effective
contraceptive measures (such as abstinence, sterilization,
oral contraceptives, medroxyprogesterone injections or
10) Female and male subjects of childbearing age, and partners of
these male subjects must agree to use effective contraceptive
measures (such as abstinence, sterilization, oral contraceptives,
medroxyprogesterone
injections
or
contraceptive
implants)
●
The
No.
of
inclusion
criteria
is changed


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contraceptive implants) during the study and for 6 months
after the infusion of the study drug
during the study and for 6 months after the infusion of the study
drug
P5: Exclusion Criteria:
1)
Prior chemotherapy or targeted therapy (such as
monoclonal antibody or tyrosine kinase inhibitor) for the
treatment of the current stage of disease (Stage IIIb not
suitable for multidisciplinary treatment, stage IV or
relapsed disease). Prior surgery and radiotherapy are
permitted, provided that the criteria outlined in the study
protocol are met. Subjects who received prior adjuvant therapy
and relapsed within 6 months are not eligible
1) Prior systemic chemotherapy or targeted therapy (such as
monoclonal antibody or tyrosine kinase inhibitor) for the
treatment of the current stage of disease (Stage IIIB not suitable
for multidisciplinary treatment, stage IV or relapsed disease).
Prior surgery and radiotherapy are permitted, provided that the
criteria outlined in the study protocol are met. Subjects who
received prior adjuvant therapy and relapsed within 6 months
are not eligible
●
Patients
who
clearly underwent
systemic
chemotherapy
or
targeted
therapy
need
to
be
excluded
P5: Exclusion Criteria:
3)
Histologically or cytologically confirmed EGFR mutation
type. Subjects with unknown EGFR status for various
reasons could be enrolled
3)
Histologically
or
cytologically
confirmed
EGFR-sensitive
mutation type (including exon 18-point mutation (G719X),
exon 19 deletion, and exon 21-point mutations (L858R and
L861Q)). Subjects with unknown EGFR status for various
reasons might enroll.
●
The definition of
EGRF
sensitive
mutations
are
clarified
P5: Exclusion Criteria:
●
The
amount
of
blood coughed up


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4)
History of hemoptysis within 3 months prior to screening,
with a volume of blood greater than 2.5 mL
4) History of hemoptysis within 3 months prior to screening, with a
volume of blood greater than 2.5 mL each time
each
time
is
specified
P5: Exclusion Criteria:
6)
History of brain metastasis, spinal cord compression, or
carcinomatous meningitis, or brain metastasis confirmed by
CT or MRI during screening
6) Symptomatic CNS metastasis; subjects with asymptomatic brain
metastasis or subjects who are symptomatically stable after
treatment for brain metastasis might enroll if the following
criteria are met: measurable lesions outside the CNS; no
midbrain,
pons,
cerebellum,
medulla
or
spinal
cord
metastasis; no history of intracranial hemorrhage;
●
The
description
of
brain
metastasis
is
clarified
P6: Exclusion Criteria:
9)
Subject who received minor surgery (including
catheterization) within 48 h prior to the first dose of the
study drug
9) Subjects who received minor surgery within 48 hours prior to the
first
dose
of
the
study
treatment
(Outpatient/inpatient
surgery requiring locoregional anesthetics, including central
line insertion)
●
The definition of
minor surgery is
clarified
P6: Exclusion Criteria:
10)
Currently or recently (within 10 days prior to the first dose
of study drug) used aspirin (> 325 mg/day) or other
nonsteroidal anti-inflammatory drugs known to inhibit
platelet function
10) Currently or recently (within 10 days prior to the first dose of
the study treatment) used aspirin (> 325 mg/day) or other
known NSAIDs to inhibit platelet function for 10 consecutive
days
●
The unacceptable
number of days of
use is clarified


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P6: Exclusion Criteria:
11)
Currently or recently (within 10 days prior to the first dose
of study drug) received treatment with full dose oral or
parenteral anticoagulants or thrombolytic agents. However,
anticoagulants for prophylaxis are accepted.
11) Currently or recently (within 10 days prior to the first dose of
the study treatment) received treatment with full dose oral or
parenteral
anticoagulant
or
thrombolytic
agents
for
10
consecutive days. However, anticoagulants for prophylaxis are
accepted
●
The unacceptable
number of days of
use is clarified
P6: Exclusion Criteria:
13) Uncontrolled hypertension (systolic greater than 150 mmHg
and/or diastolic greater than 100 mmHg), history of
hypertensive crisis or hypertensive encephalopathy
13) Uncontrolled hypertension after treatment (systolic greater
than 140 mmHg and/or diastolic greater than 90 mmHg),
history of hypertensive crisis or hypertensive encephalopathy
●
Correction
P6: Exclusion Criteria:
18)
Subjects with pulmonary fibrosis history or active
pneumonia shown on CT during screening
18) Subjects with current interstitial lung disease or CT showing
active pneumonia during screening
●
The exclusion of
patients
with
interstitial
lung
disease
is
clarified
P6: Exclusion Criteria:
19)
History of malignant tumors other than NSCLC within 5
years prior to randomization, except for adequately treated
cervical carcinoma in situ, basal or squamous cell skin
cancer, locoregional prostate cancer after radical surgery,
19) History of malignant tumors other than NSCLC within 5 years
prior to randomization, except for adequately treated cervical
carcinoma in situ, basal or squamous cell skin cancer,
locoregional prostate cancer after radical surgery, ductal
●
Thyroid papillary
carcinoma
is
excluded


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ductal carcinoma in situ after radical surgery
carcinoma in situ after radical surgery, or papillary thyroid
carcinoma
P6: Exclusion Criteria:
20)
Subjects with autoimmune disease
20) Subjects with active autoimmune disease
●
The exclusion of
active
autoimmune
diseases
is
clarified
P6: Exclusion Criteria:
21)
Subjects with positive test result of HBsAg, and peripheral
blood HBV DNA titer ≥1 × 103 copies/L; subjects with
positive test result of HBsAg and peripheral blood HBV
DNA titer < 1 × 103 copies/L are eligible if the investigator
determine that the subject's chronic hepatitis B is stable and
participation in the study would add no further risks to the
subject
21) Subjects who were HBsAg-positive, and peripheral blood HBV
DNA titer ≥1 × 103 copies/L or ≥200 IU/mL; subjects who
were HBsAg-positive and peripheral blood HBV DNA titer <
1 × 103 copies/L or < 200 IU/mL might be eligible if the
investigator determines that the subject's chronic hepatitis B
infection is stable and participation in the study would add no
further risks to the subject
●
Correction
P10: Table 1. Schedule of follow-up visits
●
Format
adjustment
Cycle (C) and day (D)
C4D1
Cycle (C) and day (D)
C4D1
Vital signs
X
Vital signs
X


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Physical examination
X
Physical examination
X
12-Lead ECG
X
12-Lead ECG
X
Routine blood test d
X
Routine blood test d
X
Blood chemistry d
X
Blood chemistry d
X
Immunogenicity g
X
Immunogenicity g
X
Study drug (IBI305 or
bevacizumab) j
X
Study drug (IBI305 or
bevacizumab) j
X
Chemotherapy (paclitaxel +
carboplatin) k
X
Chemotherapy (paclitaxel +
carboplatin) k
X
Concomitant medications
X
Concomitant medications
X
AEs
X
AEs
X
Pharmacokinetics (PK)
X
Pharmacokinetics (PK)
X
P11:
●
The
requirement
for
urinalysis
is


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e)
Prior to each IBI305/bevacizumab infusion, test paper should
be used to examine urinary protein.
e) A urinalysis is required before each IBI305/bevacizumab
infusion to test urine protein.
clarified
P11:
f)
Women of childbearing age should undergo serum pregnancy
tests.
f) Women of childbearing age should undergo a serum/urine
pregnancy test.
●
It is clarified that
the
urine
pregnancy
test
can be performed
P12:
i)
All subjects should undergo tumor tissue EGFR testing, but
the test does not need to be repeated if it can be confirmed
with relevant reports that the test has already been completed
at the trial site. EGFR testing will be carried out at the
laboratory of each trial site.
i) All subjects should undergo tumor tissue EGFR testing.
●
Correction
P12:
j)
Each treatment cycle for the investigational drug is 3 weeks
long. IBI305 or bevacizumab is administered on D1 of each
cycle, at 15 mg/kg during combination treatment with
chemotherapy and 7.5 mg/kg during monotherapy, until
disease progression (PD), unacceptable toxicity, withdrawal
of informed consent, loss to follow-up, death, or study
completion, whichever occurs first. After all assessments are
j) Each treatment cycle of the investigational product contains 3
weeks. The dose of IBI305 or bevacizumab is 15 mg/kg when
used in combination with chemotherapeutic drugs and 7.5
mg/kg in the maintenance monotherapy, given on D1 of every
treatment cycle until progressive disease (PD), unacceptable
toxic reactions, withdrawal of informed consent, loss to
follow-up, death, or end of study, whichever occurs first. After
●
The time window
for
the
administration of
the first dose was
clarified


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completed, the study drug is administered followed by
chemotherapy. After all assessments are completed, the study
drug is administered followed by chemotherapy.
all
assessments
were
completed,
the
study
drug
was
administered followed by chemotherapy. The first dose of
study drug was completed within 24 h after randomization.
P12:
l)
Study sites that are implementing version 2.0 of the study
protocol should collect PK samples until 140 subjects in this
study meet the requirements for PPK assessment (based on
the written notice of the sponsor). There are 6 PK sampling
time points: Within 1 h before the first dose of the study drug
(IBI305/bevacizumab) in C1, immediately after the first
infusion (within 5 minutes), within 1 h prior to the dose in
C2, within 1 h prior to the dose in C4, within 1 hour prior to
the dose in C5, and within 1 h prior to the dose in C6. Serum
will be separated from the samples at the study site and the
serum samples will be analyzed at the designated central
laboratory.
Deleted from the original text
●
Deletion
m)
Study sites that are implementing version 2.0 of the study
protocol should collect PD samples until 140 subjects in this
study meet the requirements for VEGF testing (based on the
written notice of the sponsor). There are 4 VEGF sampling
time points: Within 1 h prior to the first dose of the study
Deleted from the original text
●
Deletion


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drug (IBI305/bevacizumab) in C1, within 1 h prior to the
dose in C2, within 1 h prior to the dose in C6, and at the end
of treatment visit. Samples were tested at the designated
central laboratory.
P18: Study Background
●
The medical term
is modified
However,
despite
surgery,
some
patients
develop
distance
metastases that eventually lead to death5. Surgery is not possible
for most patients with clearly diagnosed stage IIIb and IV as well
as some patients with stage IIIa NSCLC4. Comprehensive
treatment based on systemic therapy is used to maximize patient
survival, control progressive disease, and improve the quality of
life6
However, surgical operations cannot be carried out for almost all
stage IV patients with a clear diagnosis, most stage IIIB patients, and
some stage IIIA patients of NSCLC 4. These patients are mostly given
a comprehensive treatment based on systemic therapy to maximize
their survival and control the degree of disease progression while
improving their quality of life 6.
P26: 4.1 Inclusion Criteria
2)
Male or female ≥18 and ≤70 years old
2) Male or female ≥18 and ≤75 years old
●
The
upper
age
limit is modified
P26: 4.1 Inclusion Criteria
3)
Histologically
or
cytologically
confirmed
unresectable
locoregionally advanced (stage IIIb), metastatic (stage IV),
or relapsed non-squamous NSCLC; mixed tumors should be
3)
Histologically
or
cytologically
confirmed
unresectable
locoregionally advanced (stage IIIB), metastatic (stage IV), or
relapsed non-squamous NSCLC; mixed tumors should be
●
The medical term
is modified


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categorized according to the main cell types
categorized according to the main cell types
P26: 4.1 Inclusion Criteria
4)
Histologically or cytologically confirmed EGFR wild type
4)
Histologically or cytologically confirmed EGFR wild type or
non-sensitive mutation type
●
The enrollment of
patients
carrying
the
non-sensitive
mutant
type
of
EGFR is added
P26: 4.1 Inclusion Criteria
8)
Laboratory results during screening:
9)
Routine blood test: WBC ≥3.0 × 109/L, ANC ≥1.5 ×
109/L, platelets ≥100 × 109/L, and hemoglobin ≥90 g/L
10) Hepatic function: TBIL < 1.5 × ULN; ALT and AST < 2.5
× ULN for subjects without liver metastasis, or ALT and
AST < 5 × ULN for subjects with liver metastasis
11) Renal function: SCr ≤1.5 × ULN or CrCl ≥50 mL/min, and
urine protein < 2 + in routine urinalysis. Subjects with urine
protein ≥2+ at baseline must have undergone 24 h urine
collection with total protein content <1 g
12) INR ≤1.5 and PTT or aPTT ≤1.5 × ULN within 7 days
8) Laboratory results during screening:
a) Routine blood test: WBC ≥3.0 × 109/L, ANC ≥1.5 × 109/L,
platelets ≥100 × 109/L, and hemoglobin ≥90 g/L
b) Hepatic function: TBIL < 1.5 × ULN; ALT and AST < 2.5 ×
ULN for patients without liver metastasis, or ALT and AST <
5 × ULN for patients with liver metastasis
c) Renal function: SCr ≤1.5 × ULN or CrCl ≥50 mL/min, and
urine protein < 2+ in routine urinalysis. Subjects with urine
protein ≥2+ at baseline urinalysis must have undergone 24 h
urine collection with total protein content < 1 g
d) INR ≤1.5 and PTT or aPTT ≤1.5 × ULN within 7 days prior
to the study treatment
●
The
laboratory
test
results
are
unified


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P26: 4.2 Exclusion Criteria
1)
Prior chemotherapy or targeted therapy (such as
monoclonal antibody or tyrosine kinase inhibitor) for
the treatment of the current stage of disease (Stage IIIb
not suitable for multidisciplinary treatment, stage IV or
relapsed disease). Prior surgery and radiotherapy are
permitted, provided that the criteria outlined in the
study protocol are met. Subjects who received prior
adjuvant therapy and relapsed within 6 months are not
eligible
1) Prior systemic chemotherapy or targeted therapy (such as
monoclonal antibody or tyrosine kinase inhibitor) for the
treatment of the current stage of disease (Stage IIIB not
suitable for multidisciplinary treatment, stage IV or relapsed
disease).
Prior
surgery
and
radiotherapy
are
permitted,
provided that the criteria outlined in the study protocol are met.
Subjects who received prior adjuvant therapy and relapsed
within 6 months are not eligible
●
Patients
who
clearly underwent
systemic
chemotherapy
or
targeted
therapy
need
to
be
excluded
P27：
3)
Histologically or cytologically confirmed EGFR
mutation type. Subjects with unknown EGFR status for
various reasons could be enrolled.
3)
Histologically
or
cytologically
confirmed
EGFR-sensitive
mutation type (including exon 18 point mutation (G719X),
exon 19 deletion, and exon 21 point mutations (L858R and
L861Q)). Subjects with unknown EGFR status for various
reasons might enroll.
●
The definition of
EGRF
sensitive
mutations
are
clarified
P27:
4)
History of hemoptysis within 3 months prior to
screening, with a volume of blood greater than 2.5 mL
4) History of hemoptysis within 3 months prior to screening, with a
volume of blood greater than 2.5 mL each time
●
The
amount
of
blood coughed up
each
time
is


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each time
specified
P27：
6)
History of brain metastasis, spinal cord compression, or
carcinomatous meningitis, or brain metastasis confirmed by
CT or MRI during screening
6) Symptomatic CNS metastasis; subjects with asymptomatic brain
metastasis or subjects who are symptomatically stable after
treatment for brain metastasis might enroll if the following
criteria are met: measurable lesions outside the CNS; no
midbrain,
pons,
cerebellum,
medulla
or
spinal
cord
metastasis; no history of intracranial hemorrhage;
●
The
description
of
brain
metastasis
is
clarified
P27：
9)
Subject
who
received
minor
surgery
(including
catheterization) within 48 h prior to the first dose of the
study drug
9) Subjects who received minor surgery within 48 hours prior to the
first
dose
of
the
study
treatment
(Outpatient/inpatient
surgery requiring locoregional anesthetics, including central
line insertion)
●
The definition of
minor surgery is
clarified
P27：
10) Currently or recently (within 10 days prior to the first dose
of
study
drug)
used
aspirin
(> 325 mg/day) or other nonsteroidal anti-inflammatory
drugs known to inhibit platelet function
10) Currently or recently (within 10 days prior to the first dose of
the study treatment) used aspirin (> 325 mg/day) or other
known NSAIDs to inhibit platelet function for 10 consecutive
days
●
The unacceptable
number of days of
use is clarified


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P27：
11) Currently or recently (within 10 days prior to the first dose
of study drug) received treatment with full dose oral or
parenteral anticoagulants or thrombolytic agents. However,
anticoagulants for prophylaxis are accepted.
11) Currently or recently (within 10 days prior to the first dose of
the study treatment) received treatment with full dose oral or
parenteral
anticoagulant
or
thrombolytic
agents
for
10
consecutive days. However, anticoagulants for prophylaxis are
accepted
●
The unacceptable
number of days of
use is clarified
P27：
13) Uncontrolled hypertension (systolic greater than 150 mmHg
and/or diastolic greater than 100 mmHg), history of
hypertensive crisis or hypertensive encephalopathy
13) Uncontrolled hypertension (systolic greater than 140 mmHg
and/or
diastolic
greater
than
90
mmHg),
history
of
hypertensive crisis or hypertensive encephalopathy
●
Correction
P27：
18) Subjects with pulmonary fibrosis history or active
pneumonia shown on CT during screening
18) Subjects with current interstitial lung disease or CT showing
active pneumonia during screening;
19) History of malignant tumors other than NSCLC within
5 years prior to randomization, except for adequately
treated cervical carcinoma in situ, basal or squamous
cell skin cancer, locoregional prostate cancer after
19) History of malignant tumors other than NSCLC within 5 years
prior to randomization, except for adequately treated cervical
●
Thyroid papillary
carcinoma
is
excluded


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radical surgery, ductal carcinoma in situ after radical
surgery
carcinoma in situ, basal or squamous cell skin cancer,
locoregional prostate cancer after radical surgery, ductal
carcinoma in situ after radical surgery, or papillary thyroid
carcinoma
P28：
20) Subjects with autoimmune disease
20) Subjects with active autoimmune disease
●
The exclusion of
active
autoimmune
diseases
is
clarified
P28：
21) Subjects with positive test result of HBsAg, and peripheral
blood HBV DNA titer ≥1 × 103 copies/L; subjects with
positive test result of HBsAg and peripheral blood HBV
DNA titer < 1 × 103 copies/L are eligible if the investigator
determined that the subject's chronic hepatitis B is table and
participation in the study would add no further risks to the
subject
21) Subjects who were HBsAg-positive, and peripheral blood HBV
DNA titer ≥1 × 103 copies/L or ≥200 IU/mL; subjects who
were HBsAg-positive and peripheral blood HBV DNA titer < 1
× 103 copies/L or < 200 IU/mL might be eligible if the
investigator determined that the subject's chronic hepatitis B
infection was stable and participation in the study would add no
further risks to the subject
●
Correction
P32：Hypertension
Subjects should remain at resting position for at least 5 min before
BP measurement.
Definition of hypertension: pathologically increased BP with
repeated measurements persistently over 140/90 mmHg
●
The
description
of hypertension is
updated
according to the
definition
in
Table 2. Hypertension severity grades and interventions in


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Grade 1 hypertension: Asymptomatic transient (< 24 h)
increase in BP (> 20 mmHg diastolic blood pressure),
or > 150/100 mmHg in this measurement, but previous
BP was within normal range. No interventions are
required.
Grade 2 hypertension: Repeated or sustained (> 24 h) or
symptomatic BP increase (> 20 mmHg diastolic blood
pressure), or > 150/100 mmHg in this measurement, but
previous BP was within normal range. One
antihypertensive drug can be used. Once BP is lowered
to < 150/100 mmHg, the subject may continue the study
treatment.
Grade 3 hypertension: Requires more than one
antihypertensive drugs or more potent treatment. Study
treatment should be interrupted in case of persistent or
symptomatic hypertension; study treatment should be
permanently discontinued for uncontrollable
hypertension.
Grade 4 hypertension: Life-threatening (i.e.
hypertensive crisis). The study treatment should be
permanently discontinued in case of Grade 4
CTCAE4.03
CTCAE v4.03
CTCAE
Interventions
Grade 1
Pre-hypertension
(systolic blood pressure
of
120–139
mmHg,
diastolic blood pressure
of 80–89 mmHg)
Intervention
not
indicated
Grade 2
First-stage
hypertension
(systolic
blood pressure of 140–
159
mmHg,
diastolic
blood pressure of 90–99
mmHg;
repeated
or
persistent hypertension
of
≥
24
h),
a
symptomatic
increase
of
>
20
mmHg
in
systolic blood pressure,
or
an
increase
of
>
140/90 mmHg from the
previous normal range
Antihypertensive
monotherapy.
drug
interruption.
The
treatment
with
the
investigational product
can be continued once
the blood pressure is
lower
than
140/90
mmHg.


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hypertension. The dose of all antihypertensive agents
used should be documented during each visit.
Grade 3
Second-stage
hypertension
(systolic
blood pressure of ≥160
mmHg, diastolic blood
pressure
of
≥
100
mmHg)
Multiple-agent
antihypertensive
therapy.
Study
treatment
should
be
interrupted in case of
persistent
or
symptomatic
hypertension;
study
treatment
should
be
permanently
discontinued
for
uncontrollable
hypertension.
Grade 4
Life-threatening
consequences
(e.g.
malignant
hypertension, transient
or
permanent
neurological deficit, and
hypertensive crisis)
Urgent
intervention
and
permanent
study
treatment
discontinuation
indicated
P33：Proteinuria
Urinalysis dipstick test should be performed prior to each IBI305
Urinalysis should be performed prior to each dose of
●
The
requirement
for
urinalysis
is


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or bevacizumab infusion unless 24-h proteinuria test has already
been performed.
First occurrence of proteinuria:
The urinalysis dipstick test should be performed if:
Urine protein is < 2+, continue study treatment as
scheduled, no additional tests are required.
Urine protein is ≥2+ (strip test), continue study
treatment as scheduled, and a 24-h urine protein test
should be performed within 3 days prior to the next
treatment cycle:

If 24-h urine protein is < 2 g, continue study
treatment as scheduled, and perform urinalysis
dipstick test before each scheduled dose.

If 24-h urine protein is > 2 g, the current study
treatment is interrupted, and a 24-h urine protein
test should be performed within 3 days prior to the
next planned dose. Study treatment is delayed until
24-h urine protein is ≤2 g, and a 24-h urine protein
test prior to each subsequent dose is performed
until urine protein is reduced to ≤1 g/24 h.
Interrupt study treatment only when 24-h urine
IBI305/bevacizumab unless a 24-hour urinary protein test has already
been done.
First occurrence of proteinuria:
After carrying out the urinalysis, if:
Urine protein is < 2+, continue study treatment as scheduled,
no additional tests are required.
≥2+ (urinalysis): perform 24-hour urinary protein test within
3 days prior to administration:
•
24-hour urinary protein ≤2 g: continue study treatment
as scheduled. and perform urinalysis dipstick test
before each scheduled dose.
•
24-hour urinary protein > 2 g: delay study treatment
until 24-hour urinary protein ≤2 g. and a 24-h urine
protein test prior to each subsequent dose is performed
until urine protein is reduced to ≤1 g/24 h. Interrupt
study treatment only when 24 h urine protein is > 2 g.
Second and subsequent occurrence of proteinuria:
< 3+ (urinalysis): continue study treatment as scheduled, no
additional tests indicated.
clarified


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protein is > 2 g.
Second and subsequent occurrence of proteinuria:
< 3+ (strip test): continue study treatment as scheduled,
no additional tests are required.
Urine protein is ≥3+ (strip test), continue study
treatment as scheduled, and a 24-h urine protein test
should be performed within 3 days prior to the next
treatment cycle:

If 24-h urine protein ≤2 g, continue study
treatment as scheduled.

If 24-h urine protein is > 2 g, the current study
treatment is interrupted, and a 24-h urine protein
test should be performed within 3 days prior to the
next planned dose. Study treatment is delayed
until 24-h urine protein is ≤2 g, and a 24-h urine
protein test prior to each subsequent dose is
performed until urine protein is reduced to ≤
1 g/24 h. Interrupt study treatment only when 24-h
urine protein is > 2 g.
Nephrotic syndrome (Grade 4): Study treatment is
permanently discontinued
≥3+ (urinalysis): perform 24-hour urinary protein test within
3 days prior to administration:
•
24-hour urinary protein ≤2 g: continue study treatment
as scheduled.
•
24-hour urinary protein > 2 g: delay study treatment
until 24-hour urinary protein ≤2 g. and a 24-h urine
protein test prior to each subsequent dose is performed
until urine protein is reduced to ≤1 g/24 h. Interrupt
study treatment only when 24 h urine protein is > 2 g.
Nephrotic
syndrome
(Grade
4):
Study
treatment
is
permanently discontinued


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P35：Absolute neutrophil count (ANC; dose can only be reduced
when febrile neutropenia occurs. ANC must be ≥1.5 × 109/L and
platelet count ≥100 × 109/L on D1 of each treatment cycle)
Table 2. Dose adjustments of paclitaxel and carboplatin
(febrile neutropenia)
Dose Adjustments of
Paclitaxel/Carboplatin
ANC (D1 of ea h treatment
cycle)
< 1.5 x
109/L
≥1.5 x 109/L
Febrile neutropenia
(regardless of
duration)
0
Paclitaxel = 150
mg/m2
Carboplatin = AUC
4.5
Platelet count:
Table 3. Dose adjustments of paclitaxel and carboplatin
(thrombocytopenia)
Dose Adjustments of
Absolute neutrophil count (ANC; dose can only be reduced when
febrile neutropenia occurs. ANC must be ≥1.5 × 109/L and platelet
count must be ≥100 × 109/L on D1 of each treatment cycle). Once
the chemotherapeutic dose is reduced due to febrile neutropenia
or thrombocytopenia (platelet count < 25 × 109/L or 50 × 109/L
with hemorrhage or blood transfusion required), the original
dose should no longer be adopted. If the dose reduction is
required for the third time, the chemotherapy should be
immediately discontinued.
Table 3. Dose adjustments of paclitaxel and carboplatin (febrile
neutropenia and thrombocytopenia)
●
The principles of
dose
adjustment
due
to
hematological
toxicity
are
clarified
Dose Adjustments of Paclitaxel/Carboplatin
First Occurrence Re-
Occurrence
After Dose
Adjustment
Re-occurrence
After Two Dose
Adjustments
Febrile
neutropenia
Paclitaxel =
150 mg/m2
Paclitaxel =
100 mg/m2
Chemotherapy
discontinuation


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Lowest Level After
L st Dose
Paclitaxel/Carboplatin
Platelet count (D1 of each
treatment cycle)
< 100 x
109/L
≥100 x 109/L
< 25 × 109/L or
< 50 × 109/L with
hemorrhage or
requires blood
transfusion
0
Paclitaxel = 150
mg/m2
Carboplatin = AUC
4.5
Once the chemotherapeutic dose is reduced due to febrile
neutropenia or thrombocytopenia (platelet count < 25 × 109/L or <
50 × 109/L with hemorrhage or blood transfusion required), the
original dose should no longer be adopted. If dose reduction is
required due to another incident of febrile neutropenia or
thrombocytopenia, the dose of paclitaxel and carboplatin will be
reduced to 100 mg/m2 and AUC 3.0, respectively. If the dose
reduction is required for the third time, the chemotherapy should
be immediately discontinued.
(regardless of
duration)
Carboplatin
= AUC 4.5
Carboplatin =
AUC 3
Lowest Level
After Last
Dose
<25 × 109/L
or
<50 × 109/L
with
hemorrhage
or requires
blood
transfusion
Paclitaxel =
150 mg/m2
Carboplatin
= AUC 4.5
Paclitaxel =
100 mg/m2
Carboplatin
= AUC 3
Chemotherapy
discontinuation
P39：Concomitant Medications and Treatments
5.9.1
Prohibited treatment
●
Correction


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5.9.1
Prohibited medications
5.9.2
Medications allowed
5.9.2
Permitted treatment
P39：Medications allowed
None
Anti-viral therapy was permitted whenever necessary.
Stable doses of anti-epileptic drugs were permitted.
Radiotherapy for bone metastasis was permitted provided that
the radiotherapy field did not include the target lesion.
●
Addition
P40：Screening Visits (D -28 to D -1)
• Blood pregnancy test (for female subjects of childbearing age
only)
•
Blood/urine pregnancy test (for women of childbearing age only) ●
Urine
pregnancy
test is added
P44：End-Of-Treatment Visit
• Blood pregnancy test (for female subjects of childbearing age
only)
•
Blood/urine pregnancy test (for women of childbearing age only) ●
Urine
pregnancy
test is added


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P45：Clinical Laboratory Evaluations
Blood chemistry: blood urea nitrogen
Blood chemistry: Blood urea
●
The name of urea
test
item
is
clarified
P45：Clinical Laboratory Evaluations
➢
Pregnancy test: Serum pregnancy tests are
performed on women of childbearing age during
screening and the end-of-treatment visit.
Pregnancy test:Blood/urine pregnancy test will be carried out for
all women of childbearing age during the screening period and
in the end-of-treatment visit
●
Urine
pregnancy
test is added
P48：Primary efficacy endpoint
The cutoff date for the primary efficacy endpoint analysis of this
study is 6 months after subject randomization.
The cut-off date for the analysis of primary efficacy endpoint in this
study is 18 weeks after subject randomization.
●
The evaluation of
primary
efficacy
endpoint
is
adjusted to after
the completion of
the
combined
treatment
P50: Serious adverse event reporting
The investigator should immediately take appropriate medical
measures to treat any SAE that occurs during the trial. And the
SAE should be recorded in the tables of adverse events and
serious adverse events in the eCRF and source documents;
SAEs that occur from the signing of informed consent form until 90
days (inclusive) after the last dose should be reported. The
investigator must fill out the "CFDA SAE Report Form", regardless
of whether it is the initial report or a follow-up report, and sign and
date the form. The investigator must report the SAE to the sponsor,
CFDA, and ethics committee within 24 hours of noticing the event.
●
The
contact
information
for
serious
adverse
events is added


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regardless of whether the SAE is related to the treatment, the
investigator must submit the completed SAE report form to the
sponsor within 24 hours of noticing the event. The investigator
shall urgently perform visit on missing information and provide a
complete SAE report for events that result in death or are life-
threatening.
Contact information for the reporting of SAE/pregnancy to the
sponsor:
Fax: 021-31652800
SAE reporting email: drugsafety@innoventbio.com
When submitting the SAE report by email, it is recommended for
the investigator to encrypt the report file and send the report file
and password in separate emails.
At the same time, the investigator should follow the SAE
reporting procedures issued by relevant regulatory authorities or
the independent ethics committee.
The investigator should follow up the SAE until it disappears or
recovers to a result that the investigator believes it can be
explained without further follow-ups, such as clinical stability or
improvement. The time limit for the follow-up report and the
report of answered queries is the same as that for the initial report.
The contact information for reporting is shown in the table below.
For SAEs occurring outside of the above-mentioned period, those
considered related to the investigational drug shall also be
reported to the sponsor.
The investigator must submit the completed SAE report form to the
sponsor within 24 hours of noticing the event. The investigator shall
urgently perform visit on missing information and provide a
complete SAE report for events that result in death or are life-
threatening.
The investigator should also report the event to the CFDA, health
administration departments, and ethics committees in accordance
with the regulations.
When submitting the SAE report by email, it is recommended for
the investigator to encrypt the report file and send the report file
and password in separate emails.
Table. SAE report contacts
Unit
Contact
Fax/Telephone/Ad
dress
Hospital Name
Ethics committee
Hospital


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Fax/Telephone
Innovent Biologics
(Suzhou) Co., Ltd.
Clinical
Study
Department PV
Fax:
021-
31652800
Email:
drugsafety@innov
entbio.com
Office
of
Drug
Research
and
Supervision,
Department
of
Drug
and
Cosmetics
Registration,
China
Food
and
Drug
Administration
Address: Building
2,
No.
26,
Xuanwumen West
Street,
Xicheng
District, Beijing
Post Code: 100053
Tel: 010-88330732
Fax:
010-
88363228
Medical
Administrative
Department,
Health
Administration
Address: No. 38,
Lishi
Road,
Xicheng
District,
Beijing
Tel:
010-


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68792001
Fax:
010-
68792734
Province,
Autonomous
Region,
Municipality Food
and Drug
Administration
Based on the requirements of the food
and drug administration department
of each province, autonomous region
or municipality
P51：
Among them, Grade 2 gastrointestinal perforation, procedural and
wound healing complications, hemorrhage, fistula, arterial
thrombotic events and proteinuria, and all above adverse events of
special interest (AESIs) of Grade 3 and above should be reported as
AESIs to the sponsor in accordance with the SAE reporting time
limit and procedures (see 7.2.1.4 for details) even if they do not
meet the SAE definition.
If the criteria for SAE is met, the SAE report should be submitted to
the sponsor within the specified time limit (see 7.2.1.4 for details).
●
It is clarified that
all events meeting
the SAE criteria
should
be
reported
P51：pregnancy
Bevacizumab may be harmful to the fetus. Subjects or female
Bevacizumab may be harmful to the fetus. Subjects or female
●
The management
of
pregnancy


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partners of male subjects must use an effective form of
contraception during the 6 months after the last dose. If any female
subject or the female partner of any male subject becomes pregnant
during the study, the drug should be discontinued immediately and
the investigator should be notified. The investigator should report
the pregnancy to the sponsor within 24 h of knowing the event by
filling out the pregnancy form. The Investigator should also discuss
with the subject (and the female partner of the male subject)
regarding the risk of continuing pregnancy and its possible impact
on the fetus. The investigator should follow up the pregnancy to
determine its outcome (including abortion) and the status of the
mother and the baby for not less than 8 weeks after delivery, and
report the follow-up results as the pregnancy follow-up report to the
sponsor according to the procedure and time limit the same as those
for the first report. Complications and termination of pregnancy due
to medical reasons should be reported as AE or SAE. A
spontaneous abortion should be reported as an SAE. For any
congenital abnormalities/birth defects or SAEs of the mother and
child during the perinatal period, they should be recorded and
reported in accordance with the procedure and time limit for
reporting SAEs.
partners of male subjects must use an effective form of contraception
during the 6 months after the last dose.
During the study, if a female subject exposed to the study drug
becomes pregnant, she must discontinue study treatment. The
investigator must report to the sponsor within 24 hours of
noticing the event and submit the "Innovent clinical Study
Pregnancy Report/Follow-Up Form".
During the study, if a female partner of a male subject exposed to
the study drugs becomes pregnant, the subject will continue in
the study. The investigator must report to the sponsor within 24
hours of noticing the event and submit the "Innovent Clinical
Study Pregnancy Report/Follow-Up Form".
The investigator must continuously monitor and visit on the
outcome of the pregnancy until 8 weeks after the subject gives
birth. The outcome should be reported to the sponsor.
If the outcome of the pregnancy is stillbirth, spontaneous
abortion, fetal malformation (any congenital anomaly/birth
defect), or medical abortion, it should be considered as an SAE
and the event is required to be reported in accordance with SAE
procedures and time limits.
If the subject also experiences a SAE during the pregnancy, the
CFDA SAE Report Form should also be filled out and reported
according to SAE's procedures.
events is clarified


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P51：
Table 10. Reporting and follow-up of adverse events
Reporting time limit
Visit time limit
AEs
From signing of the informed
consent form to 3 months
after the last dose of the
study treatment
Until resolved or
explainable stable
determined by the
investigator
Adverse
events of
special
interest
(AESIs)
From signing of the informed
consent form to 3 months
after the last dose of the
study treatment
Until resolved or
explainable stable
determined by the
investigator
Serious
adverse
event
From signing of the informed
consent form to 3 months
after the last dose of the
study treatment
Until resolved or
explainable stable
determined by the
investigator
Pregnancy
From the first dose until 6
months after the last dose of
the study treatment
Until the outcome of
the event is
available, and the
health conditions of
the newborn should
Table 8. Report and follow-up of adverse events
●
The time limit for
the reporting and
follow-up
of
adverse events is
modified
Reporting Time
Limit
Visit Time Limit
AEs
From
signing
the
informed
consent
form
to
90
days
after the last dose (if
the subject begins
other
anti-tumor
therapies,
only
AEs related to the
study drugs should
be collected)
Until resolved or stable
determined
by
the
investigator
Pregnancy
From the first dose
until 6 months after
the last dose of the
study treatment
Until
the
end
of
the
pregnancy,
and
visit
according to the protocol
on the health status of
the newborn for at least
2 months


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Version Date: Sep. 25, 2017
Note:
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The italicized part is revised content
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be followed up for at
least 2 months
according to the
protocol
P52：Abnormalities in laboratory tests/vital signs
Not all abnormalities in laboratory tests/vital signs should be
reported as AEs. Only the abnormalities in laboratory tests/vital
signs that meet the following criteria are reported as AEs:

Accompanied with clinical symptoms

Lead to changes in the dose of the study treatment (such as
dose adjustment, dose interruption, or permanent drug withdrawal)

Require medical intervention or changes in concomitant
therapy

Judged by the investigator as clinically significant
It is the responsibility of the investigator to review all abnormal
laboratory test results and vital signs, and to determine whether each
abnormal laboratory test result or vital signs should be reported as
AEs.
If clinically significant laboratory abnormalities or abnormal vital
signs are characteristic of a disease or syndrome (such as increased
levels of alkaline phosphatase and total bilirubin caused by
cholecystitis that are higher than 5 times the upper limit of normal),
All clinically significant laboratory test abnormalities should be
reported as AEs. It is the responsibility of the investigator to review
all abnormal laboratory test results, and to make medical judgments
as whether each abnormal laboratory test result should be reported
as an AE.
●
The
recording
criteria
of
AEs
are clarified


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only the diagnosis is recorded on the AE report of the eCRF (i.e.,
cholecystitis). Conversely, the laboratory abnormalities or abnormal
vital signs are recorded on the AE report of the eCRF, and it should
be indicated that whether the test value is above or below the
normal range (for example, it should be recorded as "blood
potassium increased" instead of "blood potassium abnormal"). If
there is a standard clinical term corresponding to the laboratory
abnormalities or abnormal vital signs, the clinical term should be
recorded on the eCRF (such as "anemia", instead of "hemoglobin
decreased"). The same clinically significant laboratory
abnormalities or abnormal vital signs found during multiple follow-
ups should not be repeatedly recorded as AEs or SAEs in the eCRF
unless there is a change in its severity or etiology.
P53：Death
During the entire course of the study, all the deaths that occurred
within 90 days after the last dose were documented in the Death
Report Form in the eCRFs and reported to the sponsor timely,
regardless of the causality with the investigational drug.
When recording a death event, if there is an AE leading to the death,
a single medical concept should be used on the AE report of the
eCRF to record the event leading to the death, and the event should
be reported as an SAE in an expedited manner; if the cause of the
death is unknown at the time of reporting , "Death with Unknown
During the entire course of the study, all the deaths that occurred
within 90 days after the last dose were documented in the Death
Report Form in the eCRFs, regardless of the causality with the
investigational drug.
When recording a death event, if the cause of death is clear, the
cause of death is recorded as an adverse event with the result of the
adverse event being death, and the event is reported as an SAE; if the
cause of the death is unknown at the time of reporting , "Death with
Unknown Cause" should be recorded on the Adverse Event Form of
●
The
treatment
procedure
of
death
events
is
clarified


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Cause" should be recorded on the AE report of the eCRF. The
"Death with Unknown Cause" should be reported as an SAE in an
expedited manner before further investigation is carried out to find
the exact cause of death.
If the cause of death is confirmed to be PD, then the event should
not be documented and reported as an AE/SAE. However, the event
should be documented in the Mortality Report Form of the eCRF
and reported to the sponsor timely.
the eCRF and the "Death with Unknown Cause" should be reported
as an SAE first before further investigation is carried out to find the
exact cause of death.
P54：
Progressive disease
For any event, if it can be clearly determined that the event is
caused by progressive disease, the event is not reported as an AE.
Hospitalization or death caused by progressive disease does not
need to be reported in an expedited fashion.
Progressive disease
A progressive disease is defined as the worsening of subject
condition caused by the primary tumor that the investigational drug
is targeting, the appearance of new lesions, or the progression of the
primary lesion. Expected progressive disease should not be reported
as an AE. Any deaths, life-threatening events, hospitalization or
prolonged
hospitalization,
permanent
or
significant
disability/incapacity, congenital anomaly/birth defects, or other
important medical events caused by progressive disease should not
be reported as an SAE.
●
The definition of
progressive
disease
is
clarified
P54：
Lack of efficacy
When the disease treated by the study treatment deteriorates, it may
Deleted from the original text
●
Deletion


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not be possible to determine whether it is due to the lack of efficacy
or the occurrence of an adverse event. In this case, unless the
investigator believes that the deterioration of the condition is related
to the study treatment, such changes are all regarded as the lack of
efficacy rather than adverse events.
P54: Overdose
When there is an accompanying AE, the AE should be recorded;
when there is not accompanying AE, the overdose should be
recorded on the eCRF.
Deleted from the original text
●
Deletion
P67: Appendix II
Carboplatin Dose (Calvert Equation)
Carboplatin dose (mg) = target AUC (mg/mL/min) × [creatinine
clearance rate (mL/min) + 25]
Carboplatin Dose (Calvert Equation)
Carboplatin dose (mg) = target AUC (mg/mL/min) × [creatinine
clearance rate (mL/min) + 25]
Note: During the study, if the carboplatin dose calculated using
the Calvert equation excessively exceeds the usual clinical dose,
choose one of the following two methods to ensure the patient safety:
1. Retest the serum creatinine and re-calculate the dose (preferred
option).
2.
Based on clinical experience, the investigator may choose the
highest dose tolerated by the subject. The dose should remain
●
The
calculation
method
for
the
dose
of
carboplatin when
it
exceeds
the
clinical
dose
is
added


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unchanged for the subsequent cycles.


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CLINICAL STUDY PROTOCOL
Study Title:
A randomized, double-blinded, multi-center phase III study
comparing the efficacy and safety of IBI305 plus paclitaxel/carboplatin
versus bevacizumab plus paclitaxel/carboplatin in treatment-naive
subjects with advanced or relapsed non-squamous non-small cell
lung cancer
Protocol No.:
CIBI305A301
Version and Date:
Sep. 26, 2016/Version 2.0
Jun. 02, 2016/Version 1.0
Product Name:
Recombinant anti-VEGF humanized monoclonal antibody
injection (IBI305)
Study Phase:
Phase III
Sponsor:
Innovent Biologics (Suzhou) Co., Ltd.
No. 168 Dongping Street, Suzhou Industrial Park, Jiangsu, China
Sponsor Contact:
Zhou Hui (Medical Director)
Tel: (+86) 021-31652896
E-mail: hui.zhou@innoventbio.com
Confidentiality Statement
This document is the confidential information of Innovent Biologics (Suzhou) Co., Ltd.
The content of this document shall not be disclosed to any person other than the investigators, research consultants
or related personnel, and Institutional Review Board/Independent Ethics Committee.
The information contained in this document must not be used for any purpose, except for the evaluation or
conduction of this study, without the written consent of the sponsor.


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SIGNATURE PAGE
Protocol Title: A randomized, double-blinded, multi-center phase III study comparing the efficacy
and safety of IBI305 plus paclitaxel/carboplatin versus bevacizumab plus paclitaxel/carboplatin in
treatment-naive subjects with advanced or relapsed non-squamous non-small cell lung cancer
Protocol No.: CIBI305A301
Title
Name
Signature
Date
Medical Director
Zhou Hui
Director of
Biostatistics
Wei Zhaohui


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PROTOCOL SYNOPSIS
Sponsor/Company:
Innovent Biologics (Suzhou) Co., Ltd.
Investigational drug:
IBI305
Active Ingredient:
Recombinant anti-VEGF humanized monoclonal antibody
Study Title:
A randomized, double-blinded, multi-center phase III study comparing the efficacy
and safety of IBI305 plus paclitaxel/carboplatin versus bevacizumab plus
paclitaxel/carboplatin in treatment-naive subjects with advanced or relapsed non-
squamous non-small cell lung cancer
Protocol No.:
CIBI305A301
Coordinating Investigator:
Zhang Li
Coordinating Center:
Sun Yat-Sen University Cancer Center
Expected study duration: Each subject will receive treatment every 3-week
until progressive disease (PD), unacceptable toxicity, withdrawal of informed
consent, lost to follow-up or death (whichever comes first).
The end of the study is defined as the 18th month after the randomization of
the last subject.
Phase: III
Study Objectives:
Primary Objective:

To compare the objective response rate (ORR) of IBI305 plus paclitaxel/carboplatin versus bevacizumab
plus paclitaxel/carboplatin for the treatment of advanced or relapsed non-squamous non-small cell lung
cancer (NSCLC)
Secondary Objectives:

To compare the duration of response (DOR), progression-free survival (PFS), disease control rate (DCR),
and overall survival (OS) of IBI305 plus paclitaxel/carboplatin versus bevacizumab plus
paclitaxel/carboplatin for the treatment of advanced or relapsed non-squamous NSCLC

To compare the safety and immunogenicity of IBI305 plus paclitaxel/carboplatin versus bevacizumab
plus paclitaxel/carboplatin for the treatment of advanced or relapsed non-squamous NSCLC
Exploratory objectives:

To compare the population pharmacokinetics (PPK) of IBI305 and bevacizumab in subjects with


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advanced or recurrent non-squamous NSCLC

To compare the PD of IBI305 and bevacizumab in subjects with advanced or recurrent non-squamous
NSCLC
Study design:
This is a randomized, double-blinded, multi-center phase III study. The study planned to enroll and randomize 436
subjects with non-squamous NSCLC in a 1:1 ratio to IBI305 plus paclitaxel/carboplatin group or bevacizumab plus
paclitaxel/carboplatin group. Stratifying factors include age (< 60 vs. ≥60 years old) and EGFR status (wild type vs.
unknown type).
Each treatment cycle is 3 weeks for both groups. 15 mg/kg IBI305 or bevacizumab is administered on D1 of each
cycle along with paclitaxel/carboplatin. Subjects will receive up to 6 treatment cycles of combination therapy until
PD, unacceptable toxicity, withdrawal of informed consent, loss to follow-up, or death (whichever comes first).
Then subjects receive maintenance monotherapy, that is, discontinuing paclitaxel/carboplatin while continuing
therapy with IBI305 or bevacizumab. The maintenance monotherapy continues every 3 weeks. On D1 of each
treatment cycle, subjects will be administered 7.5 mg/kg of either IBI305 or bevacizumab until PD, unacceptable
toxicity, withdrawal of informed consent, loss to follow-up, death, or end of study (whichever comes first).
During the study, a CT or an MRI will be performed every 6 weeks (± 7 days) and be determined whether the study
treatment will be continued by investigators at each site through tumor assessments until PD, withdrawal of
informed consent, lost to follow-up, death, start of other anti-tumor therapies, or end of study. If subjects discontinue
the study treatment for reasons other than PD, tumor assessments will be continued until PD, withdrawal of
informed consent, loss of follow-up, death, start of other anti-tumor therapies, or end of study. If subjects discontinue
the study treatment for PD, the investigators will make telephone follow-up every 12 weeks (± 7 days) to collect
information of subsequent anti-tumor therapies and survival until withdrawal of informed consent, lost to follow-up,
death, or end of study.
Number of Subjects:
436
Diagnosis and main inclusion
criteria:
Inclusion Criteria:
Subjects must meet all of the following inclusion criteria to be enrolled in the study:
1)
Sign the formed consent form
2)
Male or female ≥18 and ≤70 years old
3)
Histologically or cytologically confirmed unresectable locoregionally
advanced (stage IIIb), metastatic (stage IV), or relapsed non-squamous
NSCLC; mixed tumors should be categorized according to the main cell
types
4)
Histologically or cytologically confirmed EGFR wild type
5)
Must have at least one measurable target lesion (as per RECIST 1.1)
6)
Eastern Cooperative Oncology Group Performance Status (ECOG PS)


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score of 0–1
7)
Expected survival ≥6 months
8)
Laboratory results during screening:
9)
Routine blood test: WBC ≥3.0 × 109/L, ANC ≥1.5 × 109/L, platelets ≥
100 × 109/L, and hemoglobin ≥90 g/L
10)
Hepatic function: TBIL < 1.5 × ULN; ALT and AST < 2.5 × ULN for
subjects without liver metastasis, or ALT and AST < 5 × ULN for
subjects with liver metastasis
11)
Renal function: SCr ≤1.5 × ULN or CrCl ≥50 mL/min, and urine protein
< 2+ in routine urinalysis. Subjects with urine protein ≥2+ from
urinalysis dipstick at baseline, a 24-h urine should be collected with total
protein content < 1 g
12)
INR ≤1.5 and PTT or aPTT ≤1.5 × ULN within 7 days prior to the study
treatment
13)
Able to comply with study protocol
14)
Female and male subjects of childbearing age, and partners of these male
subjects must agree to use effective contraceptive measures (such as
abstinence, sterilization, oral contraceptives, medroxyprogesterone
injections or contraceptive implants) during the study and for 6 months
after the infusion of the study drug
Exclusion Criteria:
Subjects meeting any of the followings will not enrolled in the study:
1)
Prior chemotherapy or targeted therapy (such as monoclonal antibody or
tyrosine kinase inhibitor) for the treatment of the current stage of disease
(Stage IIIb not suitable for multidisciplinary treatment, stage IV or
relapsed disease). Prior surgery and radiotherapy are permitted, provided
that the criteria outlined in the study protocol are met. Subjects who received
prior adjuvant therapy and relapsed within 6 months are not eligible
2)
Mixed non-small cell and small cell carcinoma, or mixed adenosquamous
carcinoma predominantly containing squamous cell carcinoma component
3)
Histologically or cytologically confirmed EGFR mutation type. Subjects
with unknown EGFR status for various reasons could be enrolled
4)
History of hemoptysis within 3 months prior to screening, with a volume
of blood greater than 2.5 mL
5)
Radiographic evidence of tumor invasion in great vessels. The
investigator or the radiologist must exclude subjects with tumors that are
fully contiguous with, surrounding, or extending into the lumen of a great


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vessel (such as pulmonary artery or superior vena cava)
6)
History of brain metastasis, spinal cord compression, or carcinomatous
meningitis, or brain metastasis confirmed by CT or MRI during screening
7)
Subjects who received radical thoracic radiotherapy within 28 days prior
to enrollment; subjects who received palliative radiation for non-thoracic
bone lesions within 2 weeks prior to the first dose of the study drug
8)
Subjects with severe skin ulcers or fracture, or having major surgery
within 28 days prior to randomization or expecting to have major surgery
during the study
9)
Subject who received minor surgery (including catheterization) within
48 h prior to the first dose of the study drug
10)
Currently or recently (within 10 days prior to the first dose of study drug)
used aspirin (> 325 mg/day) or other nonsteroidal anti-inflammatory
drugs known to inhibit platelet function
11)
Currently or recently (within 10 days prior to the first dose of study drug)
received treatment with full dose oral or parenteral anticoagulants or
thrombolytic agents. However, anticoagulants for prophylaxis are accepted.
12)
Subjects with inherited hemorrhagic tendency or coagulopathy, or history
of thrombosis
13)
Uncontrolled hypertension (systolic greater than 150 mmHg and/or
diastolic greater than 100 mmHg), history of hypertensive crisis or
hypertensive encephalopathy
14)
Any unstable systemic disease including but not limited to: active
infection, unstable angina, cerebrovascular accident or transient cerebral
ischemia (within 6 months prior to screening), myocardial infarction
(within 6 months prior to screening), cardiac failure congestive (NYHA
Class ≥II), severe arrhythmia requiring medication, and liver, kidney or
metabolic disease
15)
History of the following diseases within 6 months prior to screening:
gastrointestinal ulcers, gastrointestinal perforation, corrosive esophagitis
or gastritis, inflammatory bowel disease or diverticulitis, abdominal
fistula, or intra-abdominal abscess
16)
Subjects with tracheoesophageal fistula
17)
Clinically significant third spacing (such as ascites or pleural effusion
that are uncontrollable by drainage or other treatments)
18)
Subjects with pulmonary fibrosis history or active pneumonia shown on
CT during screening


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19)
History of malignant tumors other than NSCLC within 5 years prior to
randomization, except for adequately treated cervical carcinoma in situ,
basal or squamous cell skin cancer, locoregional prostate cancer after
radical surgery, ductal carcinoma in situ after radical surgery
20)
Subjects with autoimmune disease
21)
Subjects with positive test result of HBsAg, and peripheral blood HBV
DNA titer ≥1 × 103 copies/L; subjects with positive test result of HBsAg
and peripheral blood HBV DNA titer < 1 × 103 copies/L are eligible if
the investigator determine that the subject's chronic hepatitis B is stable
and participation in the study would add no further risks to the subject
22)
Subjects who are tested positive for HCV antibody, HIV antibody or
syphilis
23)
Subjects with known history of allergic diseases or allergic physique
24)
Received treatment with other investigational drugs or participated in
another interventional study within 30 days prior to screening
25)
History of alcohol or drug abuse
26)
Female subjects who are pregnant or breastfeeding, or expected to be
pregnant or breastfeeding during the study
27)
Known allergies to bevacizumab or any of its excipients, or any
chemotherapeutic agents
28)
Other conditions unsuitable for the inclusion as determined by the investigator
Investigational Drug, Dosage,
and Route of Administration:
IBI305: 15 mg/kg in combination chemotherapy and 7.5 mg/kg maintenance
monotherapy, administered via intravenous infusion on D1 of every 3-week
treatment cycle until PD, unacceptable toxicity, withdrawal of informed consent,
lost to follow-up, death, or end of study (whichever comes first)
Control Drug, Dosage, and
Route of Administration:
Bevacizumab: 15 mg/kg in combination chemotherapy and 7.5 mg/kg maintenance
monotherapy, administered via intravenous infusion on D1 of every 3-week
treatment cycle until PD, unacceptable toxicity, withdrawal of informed consent,
lost to follow-up, death, or end of study (whichever comes first)
Chemotherapy:
Paclitaxel: 175 mg/m² administered via intravenous infusion on D1 of every
3-week treatment cycle for up to 6 cycles until PD, unacceptable toxicity,
withdrawal of informed consent, loss of follow-up, or death.
Carboplatin: Areas under the concentration-time curve (AUC) = 6.0 administered
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until PD, unacceptable toxicity, withdrawal of informed consent, loss of follow-up,
or death.


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Evaluation criteria:
Efficacy endpoints:
Primary efficacy endpoint:

Objective response rate (ORR)
Secondary efficacy endpoints:

Duration of response (DOR)

Progression-free survival (PFS)

Disease control rate (DCR)

Overall survival (OS)
Safety endpoints:

Vital signs

Physical examination

Laboratory tests (routine blood test, blood chemistry, and urinalysis)

12-Lead ECG

Adverse event (AE, including treatment-emergent AE (TEAE)), AE of special interest (AESI)
(hypertension, proteinuria, gastrointestinal perforation, hemorrhage [cerebral hemorrhage, hematuria and
upper gastrointestinal hemorrhage], cardiotoxicity, and thrombosis), and serious adverse event (SAE)

Immunogenicity: Positive rates of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs)
PK/PD Endpoints:

Population PK parameters, including steady-state trough concentrations after repeated doses

Changes of serum VEGF at different time points
Statistical methods:
Sample size calculation:
A number of 218 subjects for each group (436 subjects in total) can provide 80% test power to confirm the clinical
equivalence between the treatments of IBI305 in combination with paclitaxel/carboplatin and bevacizumab in combination
with paclitaxel/carboplatin. Estimation parameters for sample size: The significance level of the two-sided test is 0.05, the
ORR of subjects in the IBI305 and bevacizumab groups is about 50.0%, and the equivalence margin is taken as (-12.5%,
16.7%). Based on the above hypothesis, each group requires 218 subjects (436 subjects in total).
Efficacy analysis:
Clinical equivalence will be determined by whether the 90% confidence interval (CI) of the difference in ORR
between the IBI305 and bevacizumab arms falls within the preset margin of (-12.5%, 16.7%). The ORR and 95% CI
of two groups, ORR difference and 90% CI, and ORR ratio and 90% CI will be estimated using the generalized


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linear model (GLM, including groups and stratification factors).
Median survival (OS) and survival curves will be estimated using the Kaplan-Meier method. The hazard ratio (HR)
and 95% CI of two groups will be estimated using the Cox model. DORs and PFSs will be analyzed by the same
method as the median survivals. DCR will be analyzed using the same method for primary efficacy endpoints, but
an equivalence test will not be conducted.
Safety analysis:
All adverse events (AE) will be coded using MedDRA and graded according to CTCAE v4.03. All treatment-
emergent adverse events (TEAEs), Grade 3 or greater TEAEs, serious adverse events (SAEs), investigational drug-
related TEAEs, investigational drug-related SAEs, TEAEs leading to treatment discontinuation, TEAEs leading
to study termination, and adverse events of special interest (AESIs) will be listed based on system organ class,
preferred terms, and groups and the numbers of corresponding subjects and percentages will be summarized.
In addition, the severity of TEAEs and the correlation with the study drug will also be summarized by system
organ class, preferred terms, and treatment groups.
Measured values and changes from baseline for vital signs, physical examination, laboratory tests and 12-lead ECG
will be analyzed using descriptive statistics. Baseline results and worst results during the study will be presented in
cross tabulation.
The number and percentage of subjects who developed anti-drug antibodies and neutralizing antibodies during the
study will be summarized by treatment group.
PK/PD exploratory analysis:
Mainly based on description, and inter-group comparison will be carried out if necessary


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Table 1. Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Survival follow-up
x
x
x
Pharmacokinetic
(PK) l
x
x
x
x
x
VEGF testingm
x
x
x
x
a.
After completing the on-site end-of-treatment visit 28 days after the last dose, subjects who discontinue the
investigational drug treatment due to reasons other than PD should continue to undergo tumor assessments once
every 6 weeks (±7 days) until PD (and begin post-PD follow-up thereafter), withdrawal of consent, start of another
antineoplastic treatment, loss to follow-up, death, or study completion.
b.
For subjects with PD, collect survival information once every 12 weeks (84 days, ±7 days) by phone until death,
loss to follow-up, withdrawal of informed consent, or study completion. Subsequent antineoplastic treatments
should be documented in the eCRF.
c.
Only measure weight.
d.
Clinical laboratory tests are carried out at the laboratory of each hospital. If screening laboratory tests (routine
blood test, blood chemistry, and urinalysis) are performed within 7 days prior to the first dose, the screening
results may be used as baseline data. For subsequent visits, all laboratory tests have to be completed within 3
days prior to the dose administration.
e.
Prior to each IBI305/bevacizumab infusion, test paper should be used to examine urinary protein.
f.
Women of childbearing age should undergo serum pregnancy tests.
g.
Immunogenicity tests will be performed in all subjects at 3 blood sampling time points: Within 1 hour prior to
the first dose of the study treatment (IBI305/bevacizumab) in C1, within 1 hour prior to the administration of
the study treatment in C4, and during the end-of-treatment visit. Blood specimens that are positive for anti-drug
antibodies (ADA) after dosing will be further tested for neutralizing antibodies (NAb). Samples will be tested
at the designated central laboratory.
h.
Image assessments (CT or MRI) of the brain, chest, abdomen, and pelvis should be completed at baseline. If
these tests are performed within 28 days prior to the first dose of the study drug, they do not need to be repeated
unless the investigator believes that there have been changes in the subject's tumor burden. After the start of
treatment, imaging tests are performed once every 6 weeks (±7 days) and have to be completed within 7 days
prior to the scheduled visits, until progressive disease, start of other treatment, withdrawal of informed consent,
loss to follow-up, death, or study completion. The same method of imaging test is used at baseline and during
follow-up. Imaging evaluations of the chest, abdomen, and pelvis are required.
i.
All subjects should undergo tumor tissue EGFR testing, but the test does not need to be repeated if it can be
confirmed with relevant reports that the test has already been completed at the trial site. EGFR testing will be
carried out at the laboratory of each trial site.


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j.
Each treatment cycle for the investigational drug is 3 weeks long. IBI305 or bevacizumab is administered on
D1 of each cycle, at 15 mg/kg during combination treatment with chemotherapy and 7.5 mg/kg during
monotherapy, until disease progression (PD), unacceptable toxicity, withdrawal of informed consent, loss to
follow-up, death, or study completion, whichever occurs first. After all assessments are completed, the study
drug is administered followed by chemotherapy. After all assessments are completed, the study drug is
administered followed by chemotherapy.
k.
Each treatment cycle is 3 weeks long. Chemotherapy (paclitaxel + carboplatin) is administered on D1 of each
cycle for up to 6 cycles, or until disease progression (PD), unacceptable toxicity, withdrawal of informed
consent, loss to follow-up, or death. Paclitaxel is administered after the infusion of study drug is completed,
followed by carboplatin.
l.
Study sites that are implementing version 2.0 of the study protocol should collect PK samples until 140 subjects
in this study meet the requirements for PPK assessment (based on the written notice of the sponsor). There are
6 PK sampling time points: Within 1 h before the first dose of the study drug (IBI305/bevacizumab) in C1,
immediately after the first infusion (within 5 minutes), within 1 h prior to the dose in C2, within 1 h prior to the
dose in C4, within 1 hour prior to the dose in C5, and within 1 h prior to the dose in C6. Serum will be
separated from the samples at the study site and the serum samples will be analyzed at the designated central
laboratory.
m.
Study sites that are implementing version 2.0 of the study protocol should collect PD samples until 140 subjects
in this study meet the requirements for VEGF testing (based on the written notice of the sponsor). There are 4
VEGF sampling time points: Within 1 h prior to the first dose of the study drug (IBI305/bevacizumab) in C1,
within 1 h prior to the dose in C2, within 1 h prior to the dose in C6, and at the end of treatment visit. Samples
were tested at the designated central laboratory.


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TABLE OF CONTENTS
SIGNATURE PAGE..................................................................................................................... 2
PROTOCOL SYNOPSIS..............................................................................................................3
TABLE OF CONTENTS............................................................................................................ 14
LIST OF ABBREVIATIONS AND DEFINITIONS................................................................19
1
INTRODUCTION............................................................................................................... 21
1.1 Study Background........................................................................................................... 21
1.1.1 Disease background............................................................................................... 21
1.1.2 Investigational drug................................................................................................23
1.1.2.1 Description of investigational drug..............................................................23
1.1.2.2 Preclinical studies........................................................................................ 24
1.2 Study Principles and Risk/Benefit Assessment...............................................................26
1.2.1 Study principles and dose selection....................................................................... 26
1.2.2 Risk/benefit assessment......................................................................................... 27
2
STUDY OBJECTIVES....................................................................................................... 28
2.1 Primary Objective............................................................................................................28
2.2 Secondary Objectives......................................................................................................28
2.3 Exploratory Objectives....................................................................................................28
3
STUDY PLAN......................................................................................................................29
3.1 Overview of Study Design.............................................................................................. 29
3.2 Study Design Discussion.................................................................................................30
4
STUDY POPULATION...................................................................................................... 31
4.1 Inclusion Criteria.............................................................................................................31
4.2 Exclusion Criteria............................................................................................................32
4.3 Screening Failure.............................................................................................................34
4.4 Subject Restrictions.........................................................................................................34
4.5 Subject Withdrawal and Replacement............................................................................ 34
5
STUDY TREATMENT.......................................................................................................36
5.1 Therapies by Study Drugs............................................................................................... 36
5.2 Chemotherapy................................................................................................................. 36
5.3 Dose Adjustment of Each Study Drug............................................................................ 36


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5.3.1 General principles.................................................................................................. 36
5.3.2 Dose adjustments of study drugs........................................................................... 39
5.3.3 Dose adjustments of chemotherapy....................................................................... 44
5.4 Study Drug Properties..................................................................................................... 48
5.6 Packaging, Labeling, and Storage................................................................................... 49
5.7 Subjects Allocation..........................................................................................................49
5.8 Blinding...........................................................................................................................50
5.9 Concomitant Medications and Treatments......................................................................50
5.9.1 Prohibited medications...........................................................................................50
5.9.2 Medications allowed.............................................................................................. 50
5.9.3 Treatment after study treatment............................................................................. 51
5.10 Treatment Compliance.................................................................................................. 51
5.11 Drug Return and Destruction........................................................................................ 51
5.12 Study Drug-Related Records.........................................................................................51
6
STUDY PROCEDURE....................................................................................................... 52
6.1 Screening Visits (D -28 to D -1)..................................................................................... 53
6.2 Baseline Visits (D1 of cycle 1)........................................................................................54
6.3 Cycle 2 (week 4 ± 3 days)...............................................................................................55
6.4 Cycle 3 (week 7 ± 3 days)...............................................................................................55
6.5 Cycle 4 (week 10 ± 3 days).............................................................................................56
6.6 Cycle 5 (week 13 ± 3 days).............................................................................................56
6.7 Cycle 6 (week 16 ± 3 days).............................................................................................57
6.8 Cycle 7 and Subsequent Treatment Cycles (±3 Days)....................................................57
6.9 End-Of-Treatment Visit.................................................................................................. 58
6.10 Disease Progression Visit..............................................................................................58
6.11 Survival Follow-Up.......................................................................................................59
6.12 Study Completion..........................................................................................................59
6.13 Tumor Assessment........................................................................................................ 60
6.14 Clinical Laboratory Evaluations....................................................................................60
6.15 Vital Signs, Physical Examinations, and Other Safety Assessments............................62
6.15.1 Vital signs............................................................................................................ 62


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6.15.2 Height and weight................................................................................................ 64
6.1.5.3 Physical examinations.........................................................................................64
6.15.4 12-Lead ECG....................................................................................................... 65
6.15.5 Immunogenicity assessment.................................................................................66
6.15.6. Pharmacokinetics/pharmacodynamics................................................................ 66
6.15.6.1 Pharmacokinetics.............................................................................................. 66
6.15.6.2 Pharmacodynamics........................................................................................... 66
6.15.7 EGFR testing........................................................................................................66
7
STUDY ASSESSMENTS.................................................................................................... 68
7.1 Efficacy Assessment........................................................................................................68
7.1.1 Primary efficacy endpoint......................................................................................68
7.1.2 Secondary efficacy endpoints................................................................................ 68
7.2 Safety Assessments......................................................................................................... 69
7.2.1 Adverse events....................................................................................................... 69
7.2.1.5 Management and follow-up of adverse events............................................ 71
7.2.1.6 Adverse event of special interest and expedited reporting.......................... 72
7.2.1.7 Pregnancy.....................................................................................................72
7.2.1.8 Time limits of documenting and reporting AEs.......................................... 73
8
STATISTICS........................................................................................................................77
8.1 Sample Size Determination.............................................................................................77
8.2 Statistical Population.......................................................................................................77
8.3 General Principles for Statistical Analyses..................................................................... 78
8.4 Statistical Methods.......................................................................................................... 78
8.4.1 Adjustments for covariates.....................................................................................78
8.4.2 Managing dropouts and missing data.....................................................................78
8.4.3 Multi-center study..................................................................................................78
8.4.4 Multiple comparisons and adjustments to multiplicity..........................................78
8.5 Statistical Analyses..........................................................................................................78
8.5.1 Subject distribution................................................................................................ 78
8.5.2 Demographics and other baseline characteristics.................................................. 79
8.5.3 Compliance and drug exposure..............................................................................79


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8.5.4 Efficacy.................................................................................................................. 79
8.5.4.1 Primary efficacy endpoint............................................................................79
8.5.4.2 Secondary efficacy endpoints...................................................................... 79
8.5.4.3 Sensitivity analysis...................................................................................... 80
8.5.4.4 Antibody and efficacy analysis....................................................................80
8.5.5 Exploratory analysis...............................................................................................80
8.5.6 Interim analysis......................................................................................................81
8.5.7 Stratified analysis...................................................................................................81
8.5.8 Safety analysis........................................................................................................81
8.5.8.2 Laboratory tests............................................................................................81
8.5.8.3 ECG examinations.......................................................................................81
8.5.8.4 Vital signs, physical examinations, and other safety examinations.............81
8.5.8.5 Concomitant medications............................................................................ 81
9
QUALITY ASSURANCE AND QUALITY CONTROL.................................................82
9.1 Clinical Monitoring......................................................................................................... 82
9.2 Data Management/Coding...............................................................................................83
9.3 Audits and Inspections.................................................................................................... 84
10
ETHICS................................................................................................................................ 85
10.1 Independent Ethics Committee..................................................................................... 85
10.2 Implementation of Ethical Principles............................................................................85
10.3 Subject Information and Informed Consent.................................................................. 86
10.4 Protection of Subject Data.............................................................................................86
11
STUDY MANAGEMENT...................................................................................................87
11.1 Organizational Structure................................................................................................87
11.1.1 Independent review committee............................................................................ 87
11.2 Archiving of Study Documents.....................................................................................87
11.3 Access to Source Data/Documents................................................................................88
11.4 Protocol Revisions.........................................................................................................88
11.5 Investigator's Responsibilities.......................................................................................88
11.6 Study Termination.........................................................................................................89
11.7 Publishing Policies........................................................................................................ 89


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11.8 Finance and Insurance...................................................................................................89
12
REFERENCES.................................................................................................................... 90
13
APPENDIX...........................................................................................................................91
13.1 Appendix I.....................................................................................................................91
13.2 Appendix II....................................................................................................................92
13.3 APPENDIX 3................................................................................................................ 93
14 INVESTIGATOR SIGNATURE PAGE............................................................................ 107
LIST OF TABLES
Table 1. Schedule of follow-up visits............................................................................................11
Table 2. Dose adjustments of paclitaxel and carboplatin (febrile neutropenia)............................ 45
Table 3. Dose adjustments of paclitaxel and carboplatin (thrombocytopenia)..............................45
Table 4. Dose adjustment of paclitaxel (hepatotoxicity)............................................................... 46
Table 5. Dose adjustment of paclitaxel (neurotoxicity).................................................................47
Table 6. Study drugs......................................................................................................................49
Table 7. Correlation between AEs and investigational drugs............................................................. 70
Table 8. Reporting and follow-up of adverse events.....................................................................73
Table 9. Organizational structure...................................................................................................87
LIST OF FIGURE
Figure 1. Study design schematic.................................................................................................. 30


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LIST OF ABBREVIATIONS AND DEFINITIONS
Abbreviations
Definitions
AE
Adverse event
AESI
Adverse event of special interest
ADA
Anti-drug antibody
ALT
Alanine aminotransferase
AUC
Area under the curve
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
CFDA
China Food and Drug Administration (now National Medical
Products Administration)
CQA
Clinical quality assurance
CR
Complete response
CRA
Clinical research associate
CRO
Contract research organization
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DCR
Disease control rate
DOR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data collection
EGFR
Epithelial growth factor receptor
FAS
Full analysis set
GCP
Good Clinical Practice
HBsAg
Hepatitis B surface antigen
HBV-DNA
Hepatitis B virus deoxyribonucleic acid
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Hazard ratio
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
INR
International normalized ratio
ITT
Intention-to-treat


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NCCN
National Comprehensive Cancer Network
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PK
Pharmacokinetics
PP
Per-protocol
PR
Partial response
PRES
Posterior Reversible Encephalopathy Syndrome
PTT
Partial thromboplastin time
SAE
Serious adverse event
SD
Stable disease
SOP
Standard operating procedure
SS
Safety set
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
VEGF
Vascular endothelial growth factor


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1 INTRODUCTION
1.1 Study Background
1.1.1 Disease background
Lung cancer has the highest incidence and mortality globally among all cancers. According to the
2012 Global Cancer Statistics (GLOBOCAN 2012) published by International Agency for
Research on Cancer, there were approximately 1.8 million new lung cancer cases worldwide,
which accounted for 13% of the global newly-diagnosed cancers, and 58% of these cases occurred
in underdeveloped areas1. According to the data released by the National Central Cancer Registry
of China in 2015, lung cancer was the most prevalent malignancy in China in 2011, with about
650,000 new cases every year. Lung cancer was also the leading cause of death, with about
520,000 deaths per year2. The limited clinical treatment of lung cancer is the main reason for its
poor prognosis. There is a huge demand for new types of lung cancer treatment drugs.
Approximately 85–90% of lung cancers are non-small cell lung cancer (NSCLC) and patients
with NSCLC are usually in the advanced stages when diagnosed3. According to the Chinese
guidelines for the diagnosis and treatment of primary lung cancer, anatomic pulmonary resection
is the mainstay of treatment for early stage lung cancers4. However, despite surgery, some
patients develop distance metastases that eventually lead to death5. Surgery is not possible for
most patients with clearly diagnosed stage IIIb and IV as well as some patients with stage IIIa
NSCLC4. Comprehensive treatment based on systemic therapy is used to maximize patient
survival, control progressive disease, and improve the quality of life6.
In recent years, anti-tumor therapies have entered a new era with the emergency of targeted
drugs. Some of these targeted drugs have demonstrated satisfactory efficacy in the treatment of
advanced NSCLC. These targeted drugs include monoclonal antibodies and tyrosine kinase
inhibitors (TKIs), mostly targeting epidermal growth factor receptors (EGFRs) and vascular
endothelial growth factor (VEGF), such as bevacizumab, cetuximab, gefitinib, erlotinib, and
icotinib. Monoclonal antibodies have become the drugs of choice in various treatment guidelines
due to the good targeting ability, low drug resistance, and good patient tolerability. Bevacizumab
combination chemotherapy is a first-line therapy of NSCLC recommended by the National
Comprehensive Cancer Network (NCCN)7. Additionally, bevacizumab in combination with
paclitaxel/carboplatin has also been approved as the first-line therapy of unresectable advanced,
metastatic, or relapsed non-squamous NSCLC by China Food and Drug Administration (CFDA)
on Jul. 9, 20156.


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Compared with traditional chemotherapy that directly inhibit or kill tumor cells, anti-angiogenic
drugs have the following unique advantages8:

The targets are genetically stable vascular endothelial cells (VECs) rather than highly
heterogeneous tumor cells, thus leading to lower drug resistance;

The number of tumor-induced VECs is far less than that of tumor cells, and the efficacy
is preferable targeting on VECs and their cytokines;

Normal VECs are quiescent, whereas tumor VECs are active in proliferation. Anti-
angiogenic therapy targets activated cells and avoids damage to normal VECs, thus
leading to better targeting ability;

Anti-angiogenic therapy can normalize the tumor vessels and thereby reduce the
pressure in tumor tissues. This enhances the delivery of chemotherapeutic agents into
tumor tissues, thus increasing the efficacy of chemotherapy.
Angiogenesis is a basic biological characteristic of tumors. The growth of both solid and
hematologic tumors are depended on angiogenesis regardless of the nature of tumor cells.
Therefore, anti-angiogenic therapy is broad-spectrum and applicable to various tumors.
Bevacizumab is a recombinant humanized monoclonal antibody that selectively binds to human
VEGF and blocks its biological activity. Bevacizumab consists of a framework region of a
human antibody and a humanized murine antigen binding region that can inhibit the binding of
VEGF to its receptors on epithelial cells, Flt-1 and KDR. By blocking the activity of VEGF and
reducing tumor angiogenesis, tumor growth is inhibited9.
In a study conducted by the Estern Cooperative Oncology Group (ECOG), compared with
chemotherapy alone (paclitaxel/ carboplatin), bevacizumab in combination with paclitaxel/carboplatin
significantly increased the overall survival (OS) (median: 12.3 vs. 10.3 months), progression-free
survival (PFS) (median: 6.2 vs. 4.5 months), and overall response rate (ORR) (35% vs. 15%) in
patients with advanced, metastatic, or relapsed non-squamous NSCLC10. In another foreign
AVAiL study, different doses of bevacizumab (7 and 15 mg/kg) in combination with
chemotherapy (cisplatin and gemcitabine) and placebo combine with chemotherapy were
compared for the treatment of non-squamous NSCLC. The study found that the two
bevacizumab groups had significantly increased the PFS (median: 6.7 months (7.5 mg/kg
combination chemotherapy group) vs. 6.5 months (15 mg/kg combination chemotherapy group)
vs. 6.1 months (placebo combination chemotherapy group)) and the ORR (37.8% (7.5 mg/kg
combination chemotherapy group) vs. 34.6% (15 mg/kg combination chemotherapy group) vs.
21.6% (placebo combination chemotherapy group)) in patients with locally advanced, metastatic,
or relapsed non-squamous NSCLC11. In a BEYOND study conducted in China, compared with


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placebo in combination with paclitaxel/carboplatin, bevacizumab in combination with
paclitaxel/carboplatin significantly increase the PFS (median: 9.2 vs. 6.5 months), OS (median:
24.3 vs. 17.7 months), and the ORR (54% vs. 26%) in patients with advanced or relapsed non-
squamous NSCLC12.
In China, the antibodies and fusion proteins targeting VEGF are research hotspots. However,
since 2006, the clinical efficacies of various drugs have not been verified and no products have
been marketed. Considering the complexity of macromolecular drugs and the limitations of drug
development capability in China, advanced technologies in antibody development, production,
and quality control is required to develop high-quality VEGF inhibitors that are safe and
effective. IBI305 has showed high similarity to bevacizumab in various pharmaceutical and
nonclinical studies (refer to Investigator's Brochure [IB]). Besides, the efficacy and safety of
bevacizumab for treatment of locally advanced, metastatic or relapsed lung cancer have been
verified. The relevant domestic and external pivotal clinical studies are referable for the protocol
design of IBI305 clinical study. In summary, the clinical study of IBI305 for treatment of
NSCLC has a solid foundation and relatively low risks. The successful development of IBI305
indicates an additional first-line targeted drug for lung cancer in China, providing doctors and
patients with more therapeutic options.
1.1.2 Investigational drug
1.1.2.1 Description of investigational drug
IBI305 is a recombinant humanized anti-VEGF monoclonal antibody injection developed by
Innovent Biologics (Suzhou) Co., Ltd. (hereafter as sponsor) that specifically binds human
VEGF. The molecular weight of IBI305 is 149 KDa. IBI305 specifically binds to VEGF-A,
inhibits the binding of VEGF-A to VEGF-R1 and VEGF-R2, blocks the signaling pathways such
as PI3K/Akt/PKB and Ras-Raf-MEK-ERK. IBI305 also inhibits the growth, proliferation, and
migration of VECs and angiogenesis, decreases the vascular permeability, blocks blood supply to
tumor tissues, inhibits the proliferation and metastasis of tumor cells, and induces the apoptosis
of tumor cells, thereby generates anti-tumor effects. The main active ingredient is recombinant
humanized anti-VEGF monoclonal antibody and excipients include sodium acetate, sorbitol, and
polysorbate 8013. Refer to the Investigator's Brochure for the detailed structure and
physicochemical properties of IBI305.


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1.1.2.2 Preclinical studies
Pharmaceutical studies
The pharmaceutical studies showed that stability, primary structure, higher-order structure,
oligosaccharide distribution, charge variant, and product-related impurities of IBI305 are highly
similar to those of bevacizumab, and the process-related impurities meet the proposed
specification. Therefore, IBI305 is considered to have highly similar protein properties and
product quality to bevacizumab13.
Pharmacodynamic studies
In vitro and in vivo pharmacodynamic (PD) studies of IBI305 showed the following findings:
1)
Target: IBI305 displayed specifically high-affinity binding to recombinant human
VEGF-A with an affinity constant same as that of bevacizumab, indicating that IBI305,
the same as bevacizumab, is a specific human VEGF blocker with a clear target.
2)
Specificity: IBI305 displayed specifically high-affinity binding to recombinant human
VEGF-A, medium-affinity binding to canine VEGF-A, but low-affinity binding to
human VEGF-B, VEGF-C, VEGF-D, PlGF, suggesting that IBI305 recognizes specific
targets and has low off-target toxicity risk; no obvious affinity to mouse VEGF-A164
and rat VEGF-A164, suggesting that IBI305 has high species specificity.
3)
Mechanism of action: IBI305 specifically binds to VEGF-A and inhibits the activation
of VEGFR-2 and ERK1/2, blocks the proliferation and migration of HUVEC, and
inhibits the sprouting from rat aortic ring, suggesting that IBI305 antagonizes VEGF-
A-induced signaling pathway to block the proliferation and migration of VECs and
inhibit angiogenesis, which leads to the reduction of nutritional supply and metastasis
of tumor.
4)
Anti-tumor effects: IBI305 significantly inhibits the growth of human colon cancer
Ls174t and lung cancer NCI-H460 cells in xenografts in nude mice, indicating that
IBI305 has significant anti-tumor effects.
Results from in vitro and in vivo studies of IBI305 showed highly similarity with that of
bevacizumab designed simultaneously, demonstrating that the target, mechanism of action,
and anti-tumor effects of IBI305 are highly similar to bevacizumab13.


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Pharmacokinetic studies
In vitro and in vivo pharmacokinetic (PK) studies of IBI305 showed the following findings:
1)
IBI305 showed no significant cross-reactivity with normal human tissues and
cynomolgus monkey tissues, and only cross-reacted with the positive-control. i.e.
human angiosarcoma tissue, suggesting that IBI305 is highly specific to cancer tissues
rather than normal human tissues and has very low on-target toxicity.
2)
Linearity: With single dose or repeated doses of IBI305 (2-50 mg/kg) vis intravenous
injection in cynomolgus monkeys, the test showed significant PK, thus reducing the
suddenly rising toxicity risks with increased clinical doses.
3)
Immunogenicity: With single dose or repeated doses of IBI305 or bevacizumab via
intravenous injection in cynomolgus monkeys, the test showed abnormal changes of
drug concentration-time curves in several animals. The anti-drug antibody (ADA) test
results showed that IBI305 has a medium immunogenicity.
4)
Accumulation: With repeated doses of IBI305 or bevacizumab via intravenous
injection in cynomolgus monkeys, the test showed that drug exposure of the last
dose was significantly higher than that of the first dose, and the steady-state drug
concentration after repeated doses was higher than that after a single dose, suggesting
that the drug may be accumulated in body.
The results of tissue cross-reactivity and PK/toxicokinetic studies in cynomolgus monkeys
indicated that IBI305 and bevacizumab have similar characteristics in tissue cross-reactivity and
PK/toxicokinetics13.
Toxicological studies
Toxicological studies of IBI305 showed the following findings:
1)
Single dose: With single dose of IBI305 (up to 300 mg/kg) via intravenous injection in
cynomolgus monkeys, the test showed good tolerability without any abnormal clinical
symptoms and toxicity. The dose was about 48 times the proposed clinical dose for
human based on body surface area. In the safety pharmacology test, with single dose of
IBI305 (50 mg/kg) via intravenous injection in cynomolgus monkeys, the test showed
no significant effects on the central nervous system, respiratory system, and
cardiovascular system, suggesting that the single dose of IBI305 via intravenous
injection has a high safety.


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2)
Repeated doses: With repeated doses of IBI305 (up to 50 mg/kg) via intravenous
injection twice weekly for 9 consecutive doses in cynomolgus monkeys, equivalent to
20 times the proposed clinical dose for humans (based on the weight), the test showed
extremely mild to mild linear growth arrest of metaphyseal lines at knee joint and
disordered chondrocyte proliferation, extremely mild increases in macrophage count
in white pulp of spleen, pulmonary (including bronchial) hemorrhage, and deposits of
hemosiderin in lymphoid tissue of bronchial mucosa, indicating that the target organ
toxicities are mainly in the bone, spleen, and lungs.
3)
Immunotoxicity and immunogenicity: With repeated doses of IBI305 via intravenous
injection twice weekly for 9 consecutive doses in cynomolgus monkeys, the test
showed medium immunotoxicity to the spleen. Different doses of IBI305 may result in
the production of ADAs, a portion of which are neutralizing antibodies (NAbs),
indicating that IBI305 has medium immunotoxicity and immunogenicity.
4)
Local irritation test: With repeated dose of IBI305 via intravenous injection in
cynomolgus monkeys, the test showed no irritation at the injection site, suggesting that
administration of IBI305 via intravenous injection is safe and feasible.
5)
In vitro hemolysis assay: With maximum proposed clinical concentration of IBI305
(9 mg/mL), the assay showed no hemolysis, suggesting that IBI305 is suitable for
intravenous injection.
IBI305 has high similarity with bevacizumab in safety pharmacology, long-term toxicity,
immunotoxicity, immunogenicity, local irritation, and hemolysis13.
1.2 Study Principles and Risk/Benefit Assessment
1.2.1 Study principles and dose selection
A biosimilar drug refers to a therapeutic biological product that is similar in quality, safety and
efficacy with an approved reference drug14. IBI305, developed and sold in the market by the
sponsor, is a bevacizumab biosimilar, and has the same administration method and indications
as bevacizumab.


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This study is conducted in accordance with the "Guidelines on Development and Evaluation of
Bosimilars (for Trial Version)" issued by the NMPA (formerly CFDA)14. The doses of IBI305
selected in this study are based on the preclinical studies that showed highly similarity between
IBI305 and bevacizumab in pharmacology, PD, PK and toxicology (refer to the Investigator's
Brochure for details). Besides, the efficacy and safety of bevacizumab for treatment of advanced,
metastatic or relapsed non-squamous NSCLC have been verified, and the indications have also
been approved in China. Therefore, the dose and administration of IBI305 is similar to
bevacizumab in this study, that is, 15 mg/kg intravenously on D1 of every 3-week cycle
when used in combination with chemotherapy (paclitaxel and carboplatin). In the subsequent
maintenance monotherapy therapy, IBI305 will be given intravenously at a dose of 7.5 mg/kg on
the first day of every 3-week cycle. This design of this study is to further demonstrate that
IBI305 is similar to bevacizumab in clinical efficacy, safety, and immunogenicity in subjects
with advanced, metastatic or relapsed non-squamous NSCLC.
1.2.2 Risk/benefit assessment
IBI305 is a bevacizumab biosimilar developed by the sponsor. Based on the clinical pharmacology
and toxicology characteristics of IBI305, the risks and benefits of IBI305 are expected to be similar
to bevacizumab.
The treatment-related risks of bevacizumab are detailed in its prescribing information. This study
is the first human study of IBI305 so that unexpected adverse reactions will be possible. The
design of this study ensures the minimized subject risks by close monitoring of the adverse
events (AEs) before, during, and after the infusion of the investigational drugs. Once an adverse
reaction occurs, the investigator will immediately take appropriate action for the subject safety.
The platinum-based therapy is the standard first-line regimen of advanced NSCLC4. This study
uses the combination of paclitaxel/carboplatin, ensuring the basic anti-tumor therapy for subjects.


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2 STUDY OBJECTIVES
2.1 Primary Objective
The primary objective of this study is to compare the objective response rate (ORR) of IBI305
plus paclitaxel/carboplatin versus bevacizumab plus paclitaxel/carboplatin for the treatment of
advanced or relapsed non-squamous NSCLC.
2.2 Secondary Objectives
Secondary objectives include:

To compare the duration of response (DOR), progression-free survival (PFS), disease
control rate (DCR), and overall survival (OS) in subjects with advanced or relapsed
non-squamous NSCLC treated by IBI305 plus paclitaxel/carboplatin versus
bevacizumab plus paclitaxel/carboplatin

To compare the safety and immunogenicity of IBI305 plus paclitaxel/carboplatin
versus bevacizumab plus paclitaxel/carboplatin for the treatment of advanced or
relapsed non-squamous NSCLC
2.3 Exploratory Objectives

To compare the population pharmacokinetics (PPK) characteristics of IBI305 and
bevacizumab in subjects with advanced or relapsed non-squamous NSCLC

To compare the pharmacodynamics (PD) characteristics of IBI305 and bevacizumab in
subjects with advanced or relapsed non-squamous NSCLC


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3 STUDY PLAN
3.1 Overview of Study Design
This is a randomized, double-blind, active-controlled, and multi-center phase III study. A total of
436 subjects across 35 study sites with non-squamous NSCLC will be planned, randomized in a
1:1 ratio into the IBI305 plus paclitaxel/carboplatin group or bevacizumab plus paclitaxel/carboplatin
group, and stratified according to age (< 60 vs. ≥60 years old) and epidermal growth factor
receptor (EGFR) status (wild type vs. unknown type). Each treatment cycle is 3 weeks for both
groups. 15 mg/kg IBI305 or bevacizumab is administered on D1 of each cycle along with
paclitaxel/carboplatin. Subjects will receive up to 6 treatment cycles of combination therapy until
PD, unacceptable toxicity, withdrawal of informed consent, loss of follow-up, or death
(whichever comes first). Then subjects received maintenance monotherapy, that is, discontinuing
paclitaxel/carboplatin while continuing maintenance therapy with IBI305 or bevacizumab. The
maintenance monotherapy continues every 3 weeks. On D1 of each treatment cycle, subjects will
be administered 7.5 mg/kg of either IBI305 or bevacizumab until PD, unacceptable toxicity,
withdrawal of informed consent, lost to follow-up, death, or end of study (whichever comes first).
After discontinuing the study drug, subjects will return to the study site 28 days (± 7 days) after
the last dose for an end-of-treatment visit. If the subjects discontinue the study treatment for
reasons other than PD, subsequent follow-up will be continued until PD, withdrawal of informed
consent, start of other anti-tumor therapies, loss of follow-up, death, or end of study. If the
subjects discontinue the study treatment for PD, the investigator will make telephone follow-up
every 12 weeks (± 7 days) to collect information of subsequent anti-tumor therapies and survival.
A CT or an MRI will be performed every 6 weeks (± 7 days) until PD, withdrawal of informed
consent, start of other anti-tumor therapies, loss of follow-up, death, or end of study. The method
for subsequent imaging examination should be consistent with that at baseline, and the chest,
abdomen and pelvis of the subject must be scanned. Each assessment must be completed within
7 days from the most recent visit. The investigators then perform the evaluation based on the
RECIST v1.1 criteria to determine whether the subject can continue receiving the next cycle of
treatment. Furthermore, the independent tumor evaluation committee (Section 11.1.1) will also
evaluate tumor response according to the RECIST v1.1. If the subjects discontinue the study
treatment for reasons other than PD, subsequent tumor evaluation should be continued according
to the study procedures until PD, withdrawal of informed consent, start of other anti-tumor
therapies, loss of follow-up, death or, end of study.
The study design is shown in Figure 1.


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Figure 1. Study design schematic
3.2 Study Design Discussion
This is a randomized, double-blind study, and bias in treatment groups is avoided. Furthermore,
the CT/MRI images of each subject will be evaluated by an independent tumor evaluation committee
according to the RECIST v1.1 to ensure consistency in evaluation.
Screening
period
Combination therapy (once every 3 weeks)
IBI305 or bevacizumab plus
Paclitaxel + carboplatin
Follow-
up
Monotherapy
(once every 3 weeks) IBI305 or
Bevacizumab
End-of-treatment visit
(28 days (±7 days) after
last dose)
Cycle n
D-28
to
D-1
Cycle 1
randomiz
ation
(D1)
Cycle 2
Cycle 3
Cycle 6
Cycle 7
Post-treatment follow-up


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4 STUDY POPULATION
4.1 Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be enrolled in the study:
1)
Sign the informed consent form
2)
Male or female ≥18 and ≤70 years old
3)
Histologically or cytologically confirmed unresectable locoregionally advanced (stage
IIIb), metastatic (stage IV), or relapsed non-squamous NSCLC; mixed tumors should
be categorized according to the main cell types
4)
Histologically or cytologically confirmed EGFR wild type
5)
Must have at least one measurable target lesion (as per RECIST 1.1)
6)
Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0–1
7)
Expected survival ≥6 months
8)
Laboratory results during screening:
Routine blood test: WBC ≥3.0 × 109/L, ANC ≥1.5 × 109/L, platelets ≥100 × 109/L,
and hemoglobin ≥90 g/L
Hepatic function: TBIL < 1.5 × ULN; ALT and AST < 2.5 × ULN for subjects
without liver metastasis, or ALT and AST < 5 × ULN for subjects with liver
metastasis
Renal function: SCr ≤1.5 × ULN or CrCl ≥50 mL/min, and urine protein < 2 +
in routine urinalysis. Subjects with urine protein ≥2+ at baseline must have
undergone 24 h urine collection with total protein content <1 g
INR ≤1.5 and PTT or aPTT ≤1.5 × ULN within 7 days prior to the study treatment
9)
Able to comply with study protocol
10) Female and male subjects of childbearing age, and partners of these male subjects must
agree to use effective contraceptive measures (such as abstinence, sterilization, oral
contraceptives, medroxyprogesterone injections or contraceptive implants) during the
study and for 6 months after the infusion of the study drug


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4.2 Exclusion Criteria
Subjects meeting any of the followings are not enrolled in the study:
1)
Prior chemotherapy or targeted therapy (such as monoclonal antibody or tyrosine
kinase inhibitor) for the treatment of the current stage of disease (Stage IIIb not suitable
for multidisciplinary treatment, stage IV or relapsed disease). Prior surgery and
radiotherapy are permitted, provided that the criteria outlined in the study protocol are
met. Subjects who received prior adjuvant therapy and relapsed within 6 months are not
eligible
2)
Mixed non-small cell and small cell carcinoma, or mixed adenosquamous carcinoma
predominantly containing squamous cell carcinoma component
3)
Histologically or cytologically confirmed EGFR mutation type. Subjects with unknown
EGFR status for various reasons could be enrolled.
4)
History of hemoptysis within 3 months prior to screening, with a volume of blood
greater than 2.5 mL
5)
Radiographic evidence of tumor invasion in great vessels. The investigator or the
radiologist must exclude subjects with tumors that are fully contiguous with,
surrounding, or extending into the lumen of a great vessel (such as pulmonary artery or
superior vena cava)
6)
History of brain metastasis, spinal cord compression, or carcinomatous meningitis, or
brain metastasis confirmed by CT or MRI during screening
7)
Subjects who received radical thoracic radiation therapy within 28 days prior to
enrollment; subjects who received palliative radiation for non-thoracic bone lesions
within 2 weeks prior to the first dose of the study drug
8)
Subjects with severe skin ulcers or fracture, or having major surgery within 28 days
prior to randomization or expecting to have major surgery during the study
9)
Subject who received minor surgery (including catheterization) within 48 h prior to the
first dose of the study drug
10) Currently or recently (within 10 days prior to the first dose of study drug) used aspirin
(> 325 mg/day) or other nonsteroidal anti-inflammatory drugs known to inhibit platelet
function
11) Currently or recently (within 10 days prior to the first dose of study drug) received
treatment with full dose oral or parenteral anticoagulants or thrombolytic agents.


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However, anticoagulants for prophylaxis are accepted.
12) Subjects with inherited hemorrhagic tendency or coagulopathy, or history of thrombosis
13) Uncontrolled hypertension (systolic greater than 150 mmHg and/or diastolic greater
than 100 mmHg), history of hypertensive crisis or hypertensive encephalopathy
14) Any unstable systemic disease including but not limited to: active infection, unstable
angina, cerebrovascular accident or transient cerebral ischemia (within 6 months prior
to screening), myocardial infarction (within 6 months prior to screening), cardiac
failure congestive (NYHA Class ≥II), severe arrhythmia requiring medication, and
liver, kidney or metabolic disease
15) History of the following diseases within 6 months prior to screening: gastrointestinal
ulcers, gastrointestinal perforation, corrosive esophagitis or gastritis, inflammatory
bowel disease or diverticulitis, abdominal fistula, or intra-abdominal abscess
16) Subjects with tracheoesophageal fistula
17) Clinically significant third spacing (such as ascites or pleural effusion that are
uncontrollable by drainage or other treatments)
18) Subjects with pulmonary fibrosis history or active pneumonia shown on CT during
screening
19) History of malignant tumors other than NSCLC within 5 years prior to randomization,
except for adequately treated cervical carcinoma in situ, basal or squamous cell skin
cancer, locoregional prostate cancer after radical surgery, ductal carcinoma in situ after
radical surgery
20) Subjects with autoimmune disease
21) Subjects with positive test result of HBsAg, and peripheral blood HBV DNA titer ≥1 ×
103 copies/L; subjects with positive test result of HBsAg and peripheral blood HBV
DNA titer < 1 × 103 copies/L are eligible if the investigator determined that the subject's
chronic hepatitis B is table and participation in the study would add no further risks to the
subject
22) Subjects who are tested positive for HCV antibody, HIV antibody or syphilis
23) Subjects with known history of allergic diseases or allergic physique
24) Received treatment with other investigational drugs or participated in another
interventional study within 30 days prior to screening
25) History of alcohol or drug abuse


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26) Female subjects who are pregnant or breastfeeding, or expected to be pregnant or
breastfeeding during the study
27) Known allergies to bevacizumab or any of its excipients, or any chemotherapeutic
agents
28) Other conditions unsuitable for the inclusion as determined by the investigator
4.3 Screening Failure
Screening failure is that the subject who has signed the informed consent form fails to meet the
inclusion criteria. Subjects with screening failure will not get a randomization number. The
reasons of screening failure will be documented in the electronic case report forms (eCRFs).
4.4 Subject Restrictions
Female subjects of childbearing age must take effective contraceptive measures during the study
and 6 months after the last dose.
Male subjects must take effective contraceptive measures during the study and 6 months after the
last dose to avoid the pregnancy of their partners.
Restrictions on the use of medication during the study are shown in Section 5.9.
4.5 Subject Withdrawal and Replacement
All subjects may withdraw from this study at any time, with or without a reason. Subjects who
withdraw from the study will not be subjected to discrimination or retaliation, and their medical
treatment will not be affected.
Subjects may discontinue the study treatment or withdraw from the study under the following
circumstances:

Unacceptable toxicity

Progressive disease

Investigator believes that the subject should withdraw from the study. If an unacceptable
adverse event (AE) occurs and the investigator believes that the subject should
withdraw from the study, the study treatment should be discontinued and appropriate
measures should be taken. In addition, the sponsor or personnel designated by the
sponsor should be notified.

Withdrawal of informed consent form by the subject


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
Serious protocol deviation determined by the investigator and/or sponsor

Poor protocol compliance

Study termination by the investigator or sponsor for any reason

Enrollment error* (enrollment of subjects who have violated the inclusion/exclusion
criteria)

Use of prohibited concomitant medications or other medications that the investigator
believes that it may result in toxicities or may affect study results

Subject lost to follow-up

Death of subject
* If the subject is determined by the investigator and the sponsor's doctor to be medically suitable
to continue with the study drugs without any risk or inconvenience, the mistakenly enrolled or
randomized subject will continue with the study treatment and assessments.
In any cases, reasons for withdrawal must be documented in the eCRFs. If the subject withdraws
from the study prematurely for any reason, the investigator should make every effort to persuade
the subject to receive the corresponding assessment, and continue the follow-up of all unresolved
AEs based on the AE reports and follow-up requirements (Table 2):

If the subject withdraws during the study, the series of assessments listed under the End
of Treatment Visit (Section 6.9) should be performed

If the subject withdraws after the end of the treatment visit and has not experienced PD,
the series of assessments listed under the Follow-Up for PD (Section 6.10) should be
performed (tumor assessment is not required to be repeated if it has been performed
within 6 weeks prior to this follow-up)

If the subject withdraws during the follow-up for survival, the information of subsequent
anti-tumor therapies and survival should be collected by telephone follow-up only
Subjects who withdraw their informed consent are not to be contacted again unless they clearly
indicate the willingness to be contacted. The sponsor may use the clinical study data obtained
before the withdrawal of informed consent.
Subjects who have been randomized will not be replaced.


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5 STUDY TREATMENT
5.1 Therapies by Study Drugs
The study drugs of this study are IBI305 and bevacizumab.
In this study, the dose of IBI305 or bevacizumab during combination therapy with chemotherapy
is 15 mg/kg, while the dose during maintenance monotherapy is 7.5 mg/kg. The study drugs are
administered intravenously on D1 of each 3-week cycle until PD, unacceptable toxicity,
withdrawal of informed consent, loss to follow-up, death, or end of study (whichever comes first).
The duration of the first dose of IBI305 or bevacizumab should be 90 min (± 15 min). If the
first infusion is well-tolerated by the subject, then the duration of the second infusion can be
shortened to 60 min (± 15 min). If the 60 min infusion is also well-tolerated by the subject, then
the subsequent infusions can be completed within 30 min (± 15 min).
5.2 Chemotherapy
Paclitaxel will be administered after the IBI305 or bevacizumab infusion is completed, then
followed by carboplatin:
Paclitaxel: 175 mg/m² administered via intravenous infusion for 3 h (may be adjusted according
to clinical practice of each study site) on D1 of every 3-week cycle for up to 6 cycles until PD,
unacceptable toxicity, withdrawal of informed consent, loss of follow-up, or death.
Carboplatin: AUC 6.0, the infusion time is based on the standard practice of each study site,
administered on D1 of every 3-week cycle for up to 6 cycles until PD, unacceptable toxicity,
withdrawal of informed consent, loss of follow-up, or death.
The chemotherapeutic agents are supplied by the sponsor.
Formulas for calculating surface area, creatinine clearance and carboplatin dose are shown in
Section 13.2.
5.3 Dose Adjustment of Each Study Drug
5.3.1 General principles
The reasons for dose adjustments or delayed administration, measures taken, and
results should be documented in the medical records and eCRFs


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If the concomitant symptoms exist at baseline, the investigator will determine whether
the dose should be adjusted according to the change in severity of toxicity. For example,
if the subject has Grade 1 "weakness" at baseline and Grade 2 "weakness" during the
study treatment, the dose should be adjusted based on Grade 1 toxicity since the
severity has increased by one grade
If several toxic reactions of different grades or severity occur simultaneously, the dose
will be adjusted according to the highest observed grade/severity
If a dose adjustment is required solely due to abnormal lab test results, then the dose
should be adjusted based on the measured values obtained prior to the start of the
treatment cycle
If the investigator determines that the toxicity is unlikely to further develop into a
serious or life-threatening event, the current dose will be continued without any
adjustments or treatment interruptions. In addition, dose adjustments or treatment
interruptions will not be performed for non-hemolytic anemia as the symptoms can be
alleviated through blood transfusions.
If the investigator determines that a toxicity is caused by a specific therapeutic drug,
then the dose adjustments of other drugs are not required
Discontinuation of one or two therapeutic drugs before PD will not affect the continued
treatment with other drugs
Dose reductions or adjustments of IBI305 or bevacizumab are not permitted.
Subsequent therapeutic dose will not be adjusted according to weight change, unless
the subject weight has changed by ≥10% from baseline
Once the dose of any chemotherapeutic agents is reduced, the original dose should no
longer be adopted
If any but not all of the therapeutic drug (IBI305, bevacizumab or chemotherapeutic
agents) treatments is interrupted due to toxicity, then this treatment will be considered
as a treatment cycle
If the administration of any one of the chemotherapeutic agents is delayed for more
than 3 weeks, the subject should permanently discontinue that chemotherapeutic agent


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If IBI305/bevacizumab is continued/infused after a delay for more than 3 weeks, the
investigator must discuss with the sponsor


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5.3.2 Dose adjustments of study drugs
Dose adjustments of IBI305 or bevacizumab are not permitted except for the adjustments
(adjusted to 7.5 mg/kg for maintenance monotherapy) specified in the study protocol. The dose
of IBI305 or bevacizumab is calculated according to the subject weight at baseline (prior to the
first dose), and remains unchanged throughout the study, unless the subject weight has changed
by ≥10% from baseline.
If an infusion reaction occurs during a 60-minute infusion, the infusion time should be extended
to 90 minutes for all subsequent infusions. Likewise, if an infusion reaction occurs during a 30-
minute infusion, the infusion time should be extended to 60 minutes for all subsequent infusions.
IBI305 or bevacizumab in combination with paclitaxel/carboplatin will be administered every
3-week treatment cycle for 6 cycles. If PD is not observed in subject during treatment, then the
subject will continue to receive IBI305 or bevacizumab as maintenance monotherapy every 3-
week treatment cycle until PD, unacceptable toxicity, withdrawal of informed consent, loss of
follow-up, death, or end of study (whichever comes first).
If IBI305 or bevacizumab is permanently discontinued due to unacceptable toxicity or subject
refusal to continue the study drugs during the combination therapy, then the subject will continue
to receive the chemotherapy (paclitaxel/carboplatin) until 6 treatment cycles are completed as
determined by the investigator. If any one of the chemotherapeutic agents (paclitaxel or carboplatin)
is prematurely discontinued due to unacceptable toxicity, the subject can continue to receive
IBI305 or bevacizumab treatment until PD, unacceptable toxicity, withdrawal of informed
consent, loss of follow-up, or death (whichever comes first).
When a Grade 3 or 4 IBI305- or bevacizumab-related toxicity is observed, the investigators
should determine whether to continue or terminate IBI305 or bevacizumab treatment according
to the followings:
First occurrence:
IBI305 or bevacizumab administration should be interrupted until toxicity symptoms return to
baseline level or are at least reduced to the Common Terminology Criteria for Adverse Events
(CTCAE) Grade 1 or lower (except for the special circumstances listed below)
Note that when Grade 4 febrile neutropenia and/or thrombocytopenia occur(s), IBI305
or bevacizumab administration should be interrupted until the symptoms return to
baseline levels or at least reduced to CTCAE Grade 1 or lower, since these events
increase the risk of hemorrhage.


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Re-occurrence in re-administration:
If Grade 3 IBI305- or bevacizumab-related toxicity occurs again, the investigator
should assess the risk/benefit of study drug continuation for the subject. If such toxicity
re-occurs again after re-administration, IBI305 or bevacizumab should be permanently
discontinued
If Grade 4 IBI305- or bevacizumab-related toxicity occurs again, IBI305 or
bevacizumab should be permanently discontinued
Measures should be taken in the following special circumstances (classified based on CTCAE
version 4.03):
Hemorrhage
Subjects with Grade 3 or 4 hemorrhages should be treated accordingly and permanently
discontinue the study treatment
Thrombosis/embolism

Subjects with arterial thrombosis of any severity grades should permanently
discontinue the study treatment

Subjects with Grade 4 venous thrombosis should permanently discontinue the
study treatment

Subjects with Grade 3 venous thrombosis should interrupt the study treatment. If
the anticoagulant therapy at the planned therapeutic dose is < 2 weeks, the study
treatment should be interrupted until the anticoagulant therapy is completed. If
the anticoagulant therapy at the planned therapeutic dose is > 2 weeks, IBI305
or bevacizumab administration should be interrupted for 2 weeks, and the study
treatment can be restarted during the anticoagulant therapy if the following criteria
are met:
- INR is within the target range (usually 2-3) prior to restarting of study treatment
- Subjects must not have experienced Grade 3 or 4 hemorrhage since enrollment
- No signs of great vessel invasion or adjacency to great vessels from previous
tumor assessments
Note: Therapeutic dose of anticoagulant therapy is defined as the escalating dose of
warfarin or other anticogulants until INR is maintained at no less than 1.5 (usually


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2-3). The warfarin dose should be documented in the eCRFs, and the INR of
subjects receiving anticoagulant therapy should be monitored during the treatment.
Hypertension
BP should be measured frequently to monitor the occurrence and exacerbation of hypertension.
Subjects should remain at resting position for at least 5 min before BP measurement.
Grade 1 hypertension: Asymptomatic transient (< 24 h) increase in BP (> 20 mmHg
diastolic blood pressure), or > 150/100 mmHg in this measurement, but previous BP
was within normal range. No interventions are required.
Grade 2 hypertension: Repeated or sustained (> 24 h) or symptomatic BP increase (>
20 mmHg diastolic blood pressure), or > 150/100 mmHg in this measurement, but
previous BP was within normal range. One antihypertensive drug can be used. Once
BP is lowered to < 150/100 mmHg, the subject may continue the study treatment.
Grade 3 hypertension: Requires more than one antihypertensive drugs or more potent
treatment. Study treatment should be interrupted in case of persistent or symptomatic
hypertension; study treatment should be permanently discontinued for uncontrollable
hypertension.
Grade 4 hypertension: Life-threatening (i.e. hypertensive crisis). The study treatment
should be permanently discontinued in case of Grade 4 hypertension. The dose of all
antihypertensive agents used should be documented during each visit.
The dose of antihypertensive agents used should be documented during each visit. If the subject
remains hypertensive despite treatment discontinuation, BP and antihypertensive agents used
should be monitored every 3 months until BP returns to normal or end of study.
Posterior reversible encephalopathy syndrome (PRES)
There have been a few reports of subjects with signs and symptoms consistent with PRES after
study treatment. This is a rare neurological disease and its signs and symptoms include epilepsy,
headache, altered mental status, visual impairment, or cortical blindness, with or without
hypertension. Subjects with PRES should permanently discontinue the study treatment.
Proteinuria
Urinalysis dipstick test should be performed prior to each IBI305 or bevacizumab infusion unless
24-h proteinuria test has already been performed.


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First occurrence of proteinuria:
The urinalysis dipstick test should be performed if:
Urine protein is < 2+, continue study treatment as scheduled, no additional tests are
required.
Urine protein is ≥2+ (strip test), continue study treatment as scheduled, and a 24-h
urine protein test should be performed within 3 days prior to the next treatment cycle:

If 24-h urine protein is < 2 g, continue study treatment as scheduled, and perform
urinalysis dipstick test before each scheduled dose.

If 24-h urine protein is > 2 g, the current study treatment is interrupted, and a 24-h
urine protein test should be performed within 3 days prior to the next planned dose.
Study treatment is delayed until 24-h urine protein is ≤2 g, and a 24-h urine protein
test prior to each subsequent dose is performed until urine protein is reduced to ≤
1 g/24 h. Interrupt study treatment only when 24-h urine protein is > 2 g.
Second and subsequent occurrence of proteinuria:
< 3+ (strip test): continue study treatment as scheduled, no additional tests are required.
Urine protein is ≥3+ (strip test), continue study treatment as scheduled, and a 24-h
urine protein test should be performed within 3 days prior to the next treatment cycle:

If 24-h urine protein ≤2 g, continue study treatment as scheduled.

If 24-h urine protein is > 2 g, the current study treatment is interrupted, and a 24-h urine
protein test should be performed within 3 days prior to the next planned dose. Study
treatment is delayed until 24-h urine protein is ≤2 g, and a 24-h urine protein test
prior to each subsequent dose is performed until urine protein is reduced to ≤
1 g/24 h. Interrupt study treatment only when 24-h urine protein is > 2 g.
Nephrotic syndrome (Grade 4): Study treatment is permanently discontinued
Gastrointestinal perforation
If gastrointestinal perforation occurs, appropriate measures should be taken and the study
treatment should be permanently discontinued.
Wound healing complications
The study treatment should not begin within 28 d after a major surgery, or before the surgical


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wound is fully healed. If a complication of wound healing occurs during study treatment, the
study treatment should be interrupted until the wound is fully healed. If an elective surgery is
required, the study treatment should be interrupted.
Abdominal abscess or fistula
If abdominal abscess or fistula occurs, the study treatment should be discontinued. However, the
investigator will determine whether study treatment will be continued if the above AE is resolved.


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Infusion-related and allergic reactions:
Infusion-related reactions after first dose of the study drug is uncommon (< 3%), and the incidence
of a severe reaction is only 0.2%.
If a mild (grade 1 or 2) reaction (such as fever, chills, headache, and nausea) occurs, pretreatment
prior to subsequent administration should be performed and infusion time should not be reduced.
If the subject is well-tolerated during infusion after pretreatment, the infusion time can be
reduced by 30 minutes (+10 minutes) for subsequent administration with pretreatment. If an
infusion-related AE occurs during a 60-minute infusion, the subsequent infusion should be
completed within 90 minutes (+15 minutes) with pretreatment. Likewise, if an infusion-related
AE occurs during a 30-minute infusion, the subsequent infusion should be completed in 60 minutes
(+10 minutes) with pretreatment. If a subject has a grade 3 infusion-related reaction, the study
treatment should be interrupted and not be restarted on the same day. However, since there lacks
the dose adjustment method for grade 3 infusion-related reactions, the investigators may decide
to either discontinue the study drug or perform pretreatment, and complete the infusion within
90 minutes (+15 minutes). If an adverse reaction still occurs during a 90-minute infusion, the
infusion should be continued at a slower rate and then gradually returned to a 90-minute infusion.
If the investigator is uncertain about the handling, the study treatment should be discontinued.
When the study treatment is restarted, the subject should be closely monitored based on routine
clinical practice until the possible time of adverse reaction has passed. If a subject has a grade 4
infusion-related reaction, the study treatment should be discontinued.
An allergic reaction is defined as the vascular collapse or shock (systolic BP < 90 mmHg,
unresponsive to rehydration) that occurs within 30 minutes of a study drug infusion caused by
an allergy, with or without respiratory distress. Skin reactions include pruritus, urticaria, and
angioedema. Subjects with allergic reactions should discontinue the study treatment.
5.3.3 Dose adjustments of chemotherapy
Paclitaxel and carboplatin should be administered according to the study site guidelines and local
prescribing information. For the specific information for use, preparation, and storage of
paclitaxel and carboplatin, refer to the prescribing information and local dosing information.
Carboplatin-based chemotherapies have a relatively high incidence of emesis. Therefore,
antiemetics for prophylaxis can be used.
Hematological toxicity:
Absolute neutrophil count (ANC; dose can only be reduced when febrile neutropenia occurs.
ANC must be ≥1.5 × 109/L and platelet count ≥100 × 109/L on D1 of each treatment cycle)


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Table 2. Dose adjustments of paclitaxel and carboplatin (febrile neutropenia)
Dose Adjustments of Paclitaxel/Carboplatin
ANC (D1 of each treatment cycle)
< 1.5 x 109/L
≥1.5 x 109/L
Febrile neutropenia
(regardless of duration)
0
Paclitaxel = 150 mg/m2
Carboplatin = AUC 4.5
Platelet count:
Table 3. Dose adjustments of paclitaxel and carboplatin (thrombocytopenia)
Lowest Level After Last Dose
Dose Adjustments of Paclitaxel/Carboplatin
Platelet count (D1 of each treatment cycle)
< 100 x 109/L
≥100 x 109/L
< 25 × 109/L or
< 50 × 109/L with hemorrhage or
requires blood transfusion
0
Paclitaxel = 150 mg/m2
Carboplatin = AUC 4.5
Once the chemotherapeutic dose is reduced due to febrile neutropenia or thrombocytopenia
(platelet count < 25 × 109/L or < 50 × 109/L with hemorrhage or blood transfusion required), the
original dose should no longer be adopted. If dose reduction is required due to another incident
of febrile neutropenia or thrombocytopenia, the dose of paclitaxel and carboplatin will be
reduced to 100 mg/m2 and AUC 3.0, respectively. If the dose reduction is required for the third
time, the chemotherapy should be immediately discontinued.
If the dose adjustment is required when ANC and thrombocytopenia occur concurrently, the low-
dose chemotherapy should be adopted.
Chemotherapy may be delayed for up to 3 weeks. If after the chemotherapy has been delayed for
3 weeks, ANC does not reach ≥1.5 × 109/L and platelet count does not reach ≥100 × 109/L on
D1 of the scheduled chemotherapy, the chemotherapy should be permanently discontinued. If the
above values have been reached, the next course of chemotherapy should be continued.
The investigator should monitor the subject closely for toxicity with particular attention to early
and evident signs of myelosuppression, infection, or febrile neutropenia to timely and
appropriately treat the complications.
Subjects should be informed to pay attention to these signs and receive treatment as soon as possible.


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If the chemotherapy must be interrupted due to hematological toxicity, the complete blood count
should be performed regularly (including WBC differentials) until all the counts reach the
minimum requirements for treatment continuation. Thereafter the scheduled treatment plan will
be performed.
Dose adjustments are not required for anemia. However, treatment based on guidelines of each
clinic should be performed.
Gastrointestinal toxicity
Antiemetics will be used to control nausea and/or emesis. If grade 3 or 4 nausea and/or emesis
occur(s) despite of antiemetics, the chemotherapeutic dose should be reduced by 20% for the
next treatment cycle. The dose should be returned to the initial level as possible if the subject is
tolerated.
If the subject experiences stomatitis on D1 of any treatment cycle, the chemotherapy should be
interrupted until the symptoms resolve. If the stomatitis has not resolved after 3 weeks, the
chemotherapy should be permanently discontinued (refer to CTCAE version 4.03). If an acute
Grade 3 stomatitis occurs, the chemotherapeutic dose should be reduced to 75% of the proposed
dose when symptoms resolve.
Hepatotoxicity (Paclitaxel)
The paclitaxel dose should be determined based on the lab values measured on D1 of each
treatment cycle.
Table 4. Dose adjustment of paclitaxel (hepatotoxicity)
AST
Total bilirubin
Paclitaxel Dose
≤5 x UNL
and
WNL
175 mg/m2
> 5 x UNL
or
> UNL ~ 1.5 x UN
150 mg/m
> 1.5 x UN
0
If paclitaxel is interrupted due to hepatotoxicity, carboplatin should also be interrupted until
paclitaxel is restarted. Paclitaxel will be interrupted for up to 3 weeks. If the subject's hepatic
function does not return to the acceptable ranges in 3 weeks, paclitaxel should be permanently
discontinued. The carboplatin dose will not be adjusted when hepatotoxicity occurs.


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The investigators should avoid PD due to abnormal hepatic enzyme levels as possible. If PD
occurs, all the study drugs should be permanently discontinued, including chemotherapy.
Cardiovascular toxicity (paclitaxel)
The arrhythmia in subjects was infrequent in previous clinical studies. However, most subjects
were asymptomatic and electrocardiographic monitoring was not required. Asymptomatic
transient bradycardia was observed in 29% of subjects, but significant atrioventricular block was
rare. Cardiac events should be treated as follows:
Asymptomatic bradycardia: no intervention indicated
Symptomatic arrhythmia during infusion: Discontinue paclitaxel infusion and perform
routine treatment of arrhythmia. Discontinue subsequent paclitaxel treatment.
Document this AE in the AE Report Form of eCRF.
Chest pain and/or symptomatic hypotension (< 90/60 mmHg or rehydration therapy
required): discontinue the paclitaxel infusion. Perform electrocardiography (ECG). If
hypersensitivity reaction is suspected, administer diphenhydramine and dexamethasone
via intravenous infusion. If the chest pain is not considered as cardiogenic, epinephrine
or bronchodilators will be administered. Document this AE in the AE Report Form of
eCRF. Discontinue subsequent paclitaxel treatment and provide symptomatic treatment.
Consult a cardiologist if needed.
Neurotoxicity (paclitaxel)
The dose of paclitaxel should be adjusted according to Table when neuropathy occurs. The dose
adjustment of carboplatin is not needed when neurotoxicity occurs.
Table 5. Dose adjustment of paclitaxel (neurotoxicity)
Toxicity Grade (CTCAE version 4.03)
Paclitaxel dose adjustment
Grade 1 or below
175 mg/m2
2
Interrupt treatment until return to grade 1, then reduce dose to 140 mg/m2
(20% of reduction) and restart infusion
Grade 3 or above
Interrupt treatment until return to grade 1, then reduce dose to 125 mg/m2
(30% of reduction) and restart infusion.
Once the dose is reduced due to neurotoxicity, the original dose should no longer be adopted.


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If the neurotoxicity does not return to grade 1 after paclitaxel interruption for 3 weeks, paclitaxel
should be permanently discontinued.
Allergic reactions/hypersensitivity reactions (paclitaxel)
Note: Prophylaxis for hypersensitivity reactions (see below) and close monitoring of vital signs
are recommended for subjects with history of mild to moderate hypersensitivity reactions when
hypersensitivity reactions reoccur.
Mild symptoms: complete paclitaxel infusion. Close monitoring; no treatment indicated.
Moderate symptoms: Interrupt paclitaxel infusion, administer diphenhydramine 25–
50 mg and dexamethasone 10 mg via intravenous infusion. Once symptoms have
resolved, resume paclitaxel infusion at a slower rate (20 mL/hour for 15 minutes, then
at 40 mL/hour for 15 minutes, and if no further symptoms develop, continue at original
rate until infusion is complete). Document this AE in the AE Report Form of eCRF. If
symptoms reoccur, interrupt the paclitaxel infusion and permanently discontinue
subsequent paclitaxel infusion.
Severe and life-threatening symptoms: Interrupt paclitaxel infusion, administer
diphenhydramine and dexamethasone via intravenous infusion (as above). Use
epinephrine or bronchodilators if indicated. Document this AE in the AE Report Form
of eCRF. Subsequent courses of paclitaxel infusion should be permanently
discontinued.
Moderate or severe hypersensitivity reactions should be documented as AEs.
Other toxicities
If other unmentioned grade 3–4 toxicities occur, the chemotherapy should be interrupted until
symptoms resolve or return to grade 1. Thereafter restart the infusion at 50% of the original dose
(which should no longer be adopted). If the toxicity does not return to grade 1 after an
interruption for 3 weeks, the chemotherapy should be permanently discontinued. Dose
adjustments are not recommended for grade 1 and 2 toxicities.
5.4 Study Drug Properties
IBI305 is a bevacizumab biosimilar. The active ingredient of both drugs is recombinant humanized
anti-VEGF monoclonal antibody; Bevacizumab is the standard commercially available drug, provided
by the sponsor.


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Detailed information on the study drugs is shown in Table .
Table 6. Study drugs
Study Drugs
Dosage Form and
Strength
Excipient
Appearance
Manufacturer
IBI305
4 mL: 100 mg
Sodium acetate,
sorbitol, and
polysorbate 80
Sterile solution for
intravenous injection
pH 5.2
Clear, colorless liquid, no
foreign matters, no floc
or precipitation
Innovent Biologics (Suzhou)
Co., Ltd.
Bevacizumab 4 mL: 100 mg
α,α-trehalose
dihydrate, sodium
dihydrogen phosphate
monohydrate,
disodium hydrogen
phosphate,
polysorbate 20, and
sterile water for
injection
Sterile solution for
intravenous injection
pH 5.9–6.3
Clear to slight
opalescent, colorless to
light brown
Roche Pharma (Schweiz)
Ltd.
5.5 Preparation and Distribution
IBI305 or bevacizumab is diluted in 0.9% sodium chloride solution by the pharmacist or research
nurse before infusion. Check the particles and discoloration prior to administration.
The investigator should ensure that the pharmacist or research nurse administers the study drugs
according to study protocol.
5.6 Packaging, Labeling, and Storage
The sponsor should package and label the study drugs according to appropriate local regulations.
All study drugs (IBI305 and bevacizumab) must be stored at 2–8 °C away from light. The study
drugs should be stored in a safe zone only accessible by authorized staff prior to dispensation to
the subjects.
5.7 Subjects Allocation
After confirming that the subject meets all of the inclusion and exclusion criteria, the study site
will log in the Interactive Web Response System (IWRS) and enter the subject information into
the IWRS. The IWRS will allocate a random number to the subject and provide a medication
number. Stratified randomization is used in this study. Stratifying factors include age (< 60 vs.
≥60 years old) and EGFR status (wild vs. unknown type).


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5.8 Blinding
This is a randomized, double-blind, and active-controlled study, and only relevant study
personnel had access to the randomization numbers. A non-blinded pharmacist or research nurse
will prepare the medications since IBI305 and bevacizumab do not have an identical appearance.
The pharmacist or research nurse who is responsible for preparing the study drugs is not allowed
to disclose any information regarding treatment allocation to the subject, the subject's family
members, or other personnel including the physician and the relevant study staff.
Unblinding: Subject unblinding should only be performed after database locking.
Emergency unblinding: In case of an emergency where the investigator must know the
medication given to a particular subject, the investigator will unblind the subject via the IWRS
and immediately inform the sponsor and CRO. The reasons for unblinding, date, and outcomes
should be documented in the source document and eCRF of the subject.
5.9 Concomitant Medications and Treatments
All medications except for the study drugs, including other chemotherapies not specified in the
study, Chinese herbal medicines, and other non-traditional therapies, are considered concomitant
medications. All concomitant medications used within 30 days prior to screening should be
documented in the eCRFs, including the information of generic name, route of administration,
start date, end date, and indication.
5.9.1 Prohibited medications
No other anti-tumor therapies or medications with anti-tumor indications, including Chinese
herbal medicine, radiotherapy, or other investigational drugs, are allowed during this study other
than IBI305, bevacizumab, paclitaxel, and carboplatin.
Severe myelosuppression is possible after chemotherapy. Granulocyte colony-stimulating factor
or granulocyte-macrophage colony-stimulating factor are not allowed to be used prophylactically
in the first treatment cycle.
5.9.2 Medications allowed
Prophylactic use of anti-emetics, glucocorticoids, or other treatments targeting toxicities is permitted
during the study. Unconventional treatments (such as acupuncture) and vitamins/microelements are
permitted if their use does not affect the study endpoints as determined by the investigators.


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Starting from the 2nd chemotherapy cycle, granulocyte colony-stimulating factor or granulocyte-
macrophage colony-stimulating factor are allowed to be used prophylactically to prevent severe
myelosuppression.
5.9.3 Treatment after study treatment
Subsequent therapy after the end of study treatment should be determined by the subject's
attending doctor.
5.10 Treatment Compliance
Subjects should receive treatment at the study site. The dose and time of administration of
IBI305 or bevacizumab and paclitaxel/carboplatin should be documented in the source records
and eCRFs during each treatment cycle. Reasons for dose adjustments, therapy delay, and
therapy discontinuation should be documented. Treatment compliance is monitored by
medication dispensing and return records, medical records, and eCRFs.
5.11 Drug Return and Destruction
The containers, vials, infusion bags, and syringes of used and partially used drugs can be
destroyed on-site according to the appropriate guidelines and operating procedures established
by study sites and local agencies.
Unless the contents have significant safety issues requiring immediate destruction in accordance
with local regulations, all the unused drugs should be returned and destroyed based on the
requirements of sponsor.
5.12 Study Drug-Related Records
The designated personnel of the study sites should make timely records of receiving, dispensing,
using, storing, returning, and destroying the study drugs in accordance with the relevant
regulations and guidelines.


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6 STUDY PROCEDURE
The detailed procedures of this study are shown in Table 1. Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
.
6.1 Screening Visits (D -28 to D -1)
Complete the screening visits within 28 days prior to study treatment commencement. The
following procedures must be completed during screening to ensure that subject meets the
requirements for participating in this study:

Sign the ICF

Record the demographics, including age, ethnicity, and gender

Record the past medical history, including smoking history

Record the history of anti-tumor therapies

Record the concomitant medications (within 30 days prior to screening)

Record the vital signs

Measure the height and weight (including BMI)

ECOG score

Physical examination

12-Lead ECG

Hepatitis B panel, anti-HCV, anti-HIV, and syphilis tests

Clinical laboratory tests (routine blood test, coagulation test, blood chemistry, and
urinalysis)


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
Blood pregnancy test (for female subjects of childbearing age only)

Imaging examinations (CT or MRI: Head, chest, abdomen, and pelvis cavity)*

EGFR test#

Review the inclusion/exclusion criteria

Record the AEs and concomitant medications
* Retests are not required if the tests have been performed within 28 days prior to the first dose,
unless the investigators suspect changes in tumor burden. Imaging results during screening will
be used as the baseline data. The same method of imaging test is used at baseline and during
follow-up. Imaging evaluations of the chest, abdomen, and pelvis are required.
# If the subject has been tested for EGFR of tumor sample at the study site with documentation,
the subject will not be required for retest.
6.2 Baseline Visits (D1 of cycle 1)
D1 refers to the day of receiving the first dose of the study drugs. Eligible subjects meeting the
inclusion criteria will return to the study site and complete the following procedures:

Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests * (routine blood test, blood chemistry, and urinalysis)

Confirm the inclusion/exclusion criteria
* If clinical laboratory screening tests (routine blood test, blood chemistry, urinalysis) are
performed within 7 days prior to the first dose, then the results of the screening test can be
used as baseline.
If the subject meets the inclusion criteria, the following procedures should be complete:

Randomization and grouping

Immunogenicity test (within 1 h prior to the study drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Pharmacokinetic (PK) blood sampling (within 1 h prior to the study drug infusion,


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immediately after the study drug infusion [+5 min])

VEGF blood sampling (within 1 h prior to the study drug infusion)

Record the AEs and concomitant medications
6.3 Cycle 2 (week 4 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study drug infusion)

VEGF blood sampling (within 1 h prior to the study drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
6.4 Cycle 3 (week 7 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)


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
Record the AEs and concomitant medications
Imaging tests (CT or MRI) should be done every 6 weeks (±7 days), and tumor assessment
should be completed within 7 days prior to this visit to determine whether the study treatment
should be continued.
6.5 Cycle 4 (week 10 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study drug infusion)

Immunogenicity test (within 1 h prior to the study drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
6.6 Cycle 5 (week 13 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study drug infusion)


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
Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
Imaging tests (CT or MRI) should be done every 6 weeks (±7 days), and tumor assessment
should be completed within 7 days prior to this visit to determine whether the study treatment
should be continued.
6.7 Cycle 6 (week 16 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study drug infusion)

VEGF blood sampling (within 1 h prior to the study drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
6.8 Cycle 7 and Subsequent Treatment Cycles (±3 Days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Maintenance monotherapy will start from week 7 and the dose of study drug will be adjusted to
7.5 mg/kg. Subjects should complete the following procedures during each visit:

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG


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
Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Study drug infusion (IBI305 or bevacizumab)

Record the AEs and concomitant medications
Imaging tests (CT or MRI) should be done every 6 weeks (±7 days), and tumor assessment
should be completed within 7 days prior to this visit to determine whether the study treatment
should be continued.
6.9 End-Of-Treatment Visit
The end of treatment visit in study sites will be conducted in 28 days (±7 days) after the last dose
of study drug. Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Immunogenicity test

PD blood sampling

Blood pregnancy test (for female subjects of childbearing age only)

Tumor assessment (CT or MRI, completed within 7 days prior to this visit; not required
to be repeated if it has been performed within 6 weeks prior to this visit)

Subsequent anti-tumor therapy

Record the AEs and concomitant medications
If the subject has not experienced PD, the subsequent follow-up for PD will be performed
(Section 6.10). If the subject has experienced PD, the subsequent follow-up for survival will be
performed (Section 6.11).
6.10 Disease Progression Visit
If the study drugs are discontinued for reasons other than PD, the end of treatment visit in study
sites will be conducted in 28 days after the last dose of study drug, and tumor assessments should
be conducted every 6 weeks (±7 days) until PD if possible (after which, follow-up for survival
will be conducted [Section 6.11]), withdraw of informed consent, loss to follow-up, death,


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start of other anti-tumor therapies, or end of study. During the visit, vital signs and weight
measurements will be performed, and any subsequent anti-tumor therapies will be documented.
6.11 Survival Follow-Up
The investigator will make telephone follow-up every 12 weeks (±7 days) to collect the
information of subsequent anti-tumor therapies and survival until withdrawal of informed
consent, loss to follow-up, death, or end of study.
6.12 Study Completion
The end of this study will be the18th month after randomization of the last subject. If the subjects
continue to receive the study drug treatment before this cut-off time, the treatment should be
discontinued and the end of treatment visit should be completed (Section 6.9).


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6.13 Tumor Assessment
Imaging tests (CT or MRI) of the brain, chest, abdomen, and pelvis are required at baseline. If
these tests are performed within 28 days prior to the first dose of the study drug, they do not need
to be repeated unless the investigator believes that there have been changes in the subject's tumor
burden. After the start of treatment, imaging tests are performed once every 6 weeks (±7 days)
and have to be completed within 7 days prior to the scheduled visits, until progressive disease,
start of other treatment, withdrawal of informed consent, loss to follow-up, death, or study
completion. The same method of imaging test was used at baseline and during follow-up.
Imaging evaluations of the chest, abdomen, and pelvis are required.
The investigator should perform a tumor assessment based on RECIST v1.1 (Section 13.3) prior
to each dose to determine whether the subject should continue with the next round of treatment.
An independent review committee will also assess the tumor response (Section 11.1.1). Imaging
tests will not be rescheduled if the study drugs or chemotherapeutic agents are interrupted due to
toxicities. Every effort should be made to continue the schedule for imaging tests even for
subjects who discontinue one or two study treatment(s) due to drug-related toxicities.
If subject experience PD according to the RECIST v1.1 criteria, the attending doctor should
discuss with the subject regarding subsequent routine cancer therapies.
6.14 Clinical Laboratory Evaluations
Clinical laboratory tests will be conducted at the laboratories of each study site. Sample collection
and analysis should be performed according to the requirements of each laboratory.
The following laboratory tests should be conducted according to the study procedures (Table 1.
Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
):
Routine blood test: hemoglobin, hematocrit, WBC and differentials (including


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absolute neutrophil and lymphocyte counts), platelets, and RBC
Routine coagulation test (baseline test): INR, aPTT, or PTT
➢
Blood chemistry: Creatinine, blood urea nitrogen, total protein, albumin, total
bilirubin, alkaline phosphatase, aspartate aminotransferase (AST), alanine
aminotransferase (ALT), fasting blood glucose, sodium, potassium, chloride,
calcium, phosphorus, and magnesium
➢
Urinalysis: Specific gravity, pH, glucose, protein, occult blood, and leukocytes
➢
Pregnancy test: Serum pregnancy tests are performed on women of childbearing age
during screening and the end-of-treatment visit.
These tests are carried out at the laboratory of each trial site.
For subsequent visits, all laboratory tests need to be completed within 3 days prior to the
administration. During the study, the frequency of these laboratory tests will be increased if
safety is a concern. The investigator should review the laboratory test results throughout the
study to determine whether the results are clinically significant. The investigator should assess
the changes in laboratory test results. If the investigator considers a laboratory test result to be
abnormal and of clinical significance, it is considered as an AE.
6.15 Vital Signs, Physical Examinations, and Other Safety Assessments
6.15.1 Vital signs
Vital signs include pulse, BP, temperature, and respiratory rate. The subject must rest for at least
5 minutes prior to each vital sign assessment.
Vital signs will be assessed according to the Schedule of Activities (Table 1. Schedule of follow-
up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
). During the study, the investigator may increase the frequency of vital sign measurement if


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safety is a concern.
6.15.2 Height and weight
Height is only measured during screening. Weight is measure during each visit.
6.1.5.3 Physical examinations
The following organs/systems will be examined according to the Schedule of Activities (Table 1.
Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
x
x
x
x
x
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
(IBI305 or
bevacizumab) j
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
): general condition, head (eyes, ears, nose, and throat), neck and thyroid, respiratory system,
cardiovascular system, abdomen, nervous system, skeletal muscles and limbs, as well as
lymphatic system and skin.
6.15.4 12-Lead ECG
12-lead ECG will be performed during screening. During the study, each medication visit
requires an ECG examination. The following ECG parameters should be documented: HR, PR-
interval, QRS-complex, QT-interval, and QTc-interval. The subject must be in the supine
position for at least 5 minutes prior to undergoing the 12-lead ECG. All ECG are evaluated by
qualified physicians. All clinically significant abnormal findings should be reported as AEs.


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6.15.5 Immunogenicity assessment
Immunogenicity tests will be performed in all subjects at 3 blood sampling time points: Within 1
hour prior to the first dose of the study treatment (IBI305/bevacizumab) in C1, within 1 hour
prior to the administration of the study treatment in C4, and during the end-of-treatment visit.
Blood specimens that are positive for anti-drug antibodies (ADA) after dosing will be further
tested for neutralizing antibodies (NAb). Samples were tested at the designated central laboratory.
6.15.6. Pharmacokinetics/pharmacodynamics
6.15.6.1 Pharmacokinetics
Study sites that are implementing version 2.0 of the study protocol should collect PK samples
until 140 subjects in this study meet the requirements for PPK assessment (based on the written
notice of the sponsor). There are 6 PK sampling time points: Within 1 h prior to the first dose of
the study treatment (IBI305/bevacizumab) in C1, immediately after the first infusion (within 5
minutes), within 1 h prior to the dose in C2, within 1 hour prior to the dose in C4, within 1 h
prior to the dose in C5, and within 1 h prior to the dose in C6. Serum will be separated from the
samples at the study site and the serum samples will be analyzed at the designated central
laboratory.
6.15.6.2 Pharmacodynamics
Study sites that are implementing version 2.0 of the study protocol should collect PD samples
until 140 subjects in this study meet the requirements for VEGF testing (based on the written
notice of the sponsor). There are 4 VEGF sampling time points: within 1 h prior to the first dose
of the study treatment (IBI305/bevacizumab) in C1, within 1 h prior to the dose in C2, within 1 h
prior to the dose in C6, and during the end-of-treatment visit. Samples were tested at the
designated central laboratory.
6.15.7 EGFR testing
EGFR mutation testing histologically or cytologically will be performed in all subjects (if the
subject has been tested for EGFR at the study site histologically or cytologically with
documentation, the subject will not be required to be retested). The testing will be conducted at
the laboratory of each study site or a qualified third-party laboratory.


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7 STUDY ASSESSMENTS
7.1 Efficacy Assessment
7.1.1 Primary efficacy endpoint

Objective response rate (ORR)
ORR will be assessed using RECIST v1.1. ORR is defined as the proportion of subjects whose
tumor volume has reduced to a predetermined value for a minimum time limit, including patients
who achieved complete response (CR) and partial response (PR). The cutoff date for the primary
efficacy endpoint analysis of this study is 6 months after subject randomization.
7.1.2 Secondary efficacy endpoints

Duration of response (DOR)

Progression-free survival (PFS)

Disease control rate (DCR)

Overall survival (OS)
Each endpoint will be assessed using RECIST v1.1.
DOR is defined as the time from initial tumor response (CR or PR) to PD or death before PD;
Subjects with CR or PR who do not progress or die will be censored on the date of the last tumor
assessment.
PFS is defined as the time from the date of randomization to the date of PD or death; Subjects
who do not progress or die will be censored on the date of the last tumor assessment.
DCR is defined as the proportion of patients whose tumor volume has reduced to a
predetermined value for a minimum time limit, including patients who achieved CR, PR, and SD.
OS is defined as the time from the date of randomization to the date of death of any cause. For
subjects that are alive on the date of study completion or are lost to follow-up, their survival time
will be censored at the date of last contact.


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7.2 Safety Assessments
7.2.1 Adverse events
7.2.1.1 Definition
Adverse event
An AE refers to any untoward medical occurrence in a subject after signing the informed consent
form, and does not necessarily have a causal relationship with the treatment. Thus, an AE can be
any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or
disease, whether considered drug related.
Abnormalities resulting from PD are not considered as AEs.
Serious adverse event
A SAE refers to an AE meeting at least one of the followings:
(1) Lead to death, except for deaths caused by PD.
(2) Life-threatening (a "life-threatening event" is defined as an AE when the subject is at
immediate risk of death at the time, but does not include the case that may lead to death
only when the event worsens).
(3) Requires hospitalization or prolonged hospitalization, excluding an emergency or
outpatient visit. Subjects with existing diseases or conditions prior to the enrollment
that do not worsen during the study, and having hospitalization and/or surgery that was
scheduled before the study or during the study do not meet the SAE criterion.
Hospitalizations resulting from PD are not considered as SAEs.
(4) Results in permanent or severe disability/incapacity.
(5) Results in congenital anomalies/birth defects.
(6) Other important medical events: The event that does not result in death, is not life-
threatening or does not require hospitalization, but may jeopardize the health of
subjects and require medical intervention to prevent the SAEs above, is considered as
an SAE
7.2.1.2 Severity of adverse events
The severity of AEs is evaluated using the 5-level criteria of NCI CTCAE v4.03.
For AEs not included in CTCAE v4.03, use the following CTCAE general guidelines:


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
Grade 1: Mild; asymptomatic or mild signs; clinical or diagnostic observations only;
medical intervention not indicated.

Grade 2: Moderate; minimal/local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily life (such as cooking, shopping, using the
phone, financial management, etc.).

Grade 3: Severe or clinically significant but not immediately life-threatening;
hospitalization or prolonged hospitalization indicated; disability; limited ability of self-
care (such as bathing, dressing, undressing, eating, using the toilet, taking medication),
but not bedridden.

Grade 4: Life-threatening consequences; urgent intervention indicated.

Grade 5: Death related to AE
7.2.1.3 Relationship between adverse events and the investigational drug
The relationship between the study drugs and AEs can be determined using the followings:
Table 11. Correlation between AEs and investigational drugs
Correlation
CRITERIA
Related

The occurrence of the AE is reasonably related to the time sequence of
dosing;

The investigational drug can more reasonably explain the AE than the
other causes (such as the pre-existing disease of the subject, environment,
toxicity, or other treatment received);

The AE resolves or is alleviated after treatment interruption or dose
reduction;

The AE is consistent with the known type of AEs of the suspicious drug or
similar drugs;

The AE occurs again after the drug administration is resumed.
Possibly related

The occurrence of the AE is reasonably related to the time sequence of
dosing;

The investigational drug can be used to explain the AE with the same
level of rationality as other reasons (such as the pre-existing disease of the
subject, environmental or toxic factors, or other treatments received by the
subject);

The AE resolves or is alleviated after treatment interruption or dose
reduction (if applicable).
Possibly not related

Other reasons can more reasonably explain the AE than the investigational
drug (such as the pre-existing disease of the subject, environmental or
toxic factors, or other treatments received by the subject);

The AE does not resolve or be alleviated after treatment interruption or
dose reduction (if applicable), or the situation is unclear;

The AE does not occur again or the situation of the AE is unknown after
the drug administration is resumed.


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Unrelated

The occurrence of the AE is not reasonably related to the time sequence of
dosing, or

The AE has other obvious causes (such as the pre-existing disease of the
subject, environmental or toxic factors, or other treatments received by the
subject).
Cannot be determined

The above information is unclear and cannot be determined based on the
available information. Further follow-up information is not accessible to
the investigator.
7.2.1.4 Serious adverse event reporting
The investigator should immediately take appropriate medical measures to treat any SAE that
occurs during the trial. And the SAE should be recorded in the tables of adverse events and
serious adverse events in the eCRF and source documents; regardless of whether the SAE is
related to the treatment, the investigator must submit the completed SAE report form to the
sponsor within 24 hours of noticing the event. The investigator shall urgently perform visit on
missing information and provide a complete SAE report for events that result in death or are life-
threatening.
Contact information for the reporting of SAE/pregnancy to the sponsor:
Fax: 021-31652800
SAE reporting email: drugsafety@innoventbio.com
When submitting the SAE report by email, it is recommended for the investigator to encrypt the
report file and send the report file and password in separate emails.
At the same time, the investigator should follow the SAE reporting procedures issued by relevant
regulatory authorities or the independent ethics committee.
The investigator should follow up the SAE until it disappears or recovers to a result that the
investigator believes it can be explained without further follow-ups, such as clinical stability or
improvement. The time limit for the follow-up report and the report of answered queries is the
same as that for the initial report.
7.2.1.5 Management and follow-up of adverse events
The investigator is responsible for providing appropriate medical treatment for all AEs (Indicate
the actions taken, such as suspension/termination of the investigational drug, dose modification,
drug therapy, etc.). When an AE occurs, the investigator should actively take appropriate
measures to ensure the safety of the subject. All AEs observed from the signing of the ICF
to the time specified in the protocol (Table 2) must be followed.


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The investigator should report any SAE that occurs after the time specified in the protocol (Table 2)
and is suspected of being related to the investigational drug to the sponsor.
7.2.1.6 Adverse event of special interest and expedited reporting
The AESI for this study include:

Gastrointestinal perforation

Procedural and wound healing complications

Hemorrhage

Fistula

Hypertension

Thrombotic event

Posterior reversible encephalopathy syndrome (PRES)

Proteinuria

Infusion-related reaction

Ovarian failure

Cardiac failure congestive
Among them, Grade 2 gastrointestinal perforation, procedural and wound healing complications,
hemorrhage, fistula, arterial thrombotic events and proteinuria, and all above adverse events of
special interest (AESIs) of Grade 3 and above should be reported as AESIs to the sponsor in
accordance with the SAE reporting time limit and procedures (see 7.2.1.4 for details) even if they
do not meet the SAE definition.
7.2.1.7 Pregnancy
Bevacizumab may be harmful to the fetus. Subjects or female partners of male subjects must use
an effective form of contraception during the 6 months after the last dose. If any female subject or
the female partner of any male subject becomes pregnant during the study, the drug should be
discontinued immediately and the investigator should be notified. The investigator should report
the pregnancy to the sponsor within 24 h of knowing the event by filling out the pregnancy form.
The Investigator should also discuss with the subject (and the female partner of the male subject)
regarding the risk of continuing pregnancy and its possible impact on the fetus. The investigator
should follow up the pregnancy to determine its outcome (including abortion) and the status of the
mother and the baby for not less than 8 weeks after delivery, and report the follow-up results as the


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pregnancy follow-up report to the sponsor according to the procedure and time limit the same as
those for the first report. Complications and termination of pregnancy due to medical reasons
should be reported as AE or SAE. A spontaneous abortion should be reported as an SAE. For any
congenital abnormalities/birth defects or SAEs of the mother and child during the perinatal period,
they should be recorded and reported in accordance with the procedure and time limit for reporting
SAEs.
The investigator should pay attention to any pregnancy-related SAE that occurs after study
completion. Any SAE that the investigator believes may be related to the study treatment should
be reported immediately to the sponsor.
7.2.1.8 Time limits of documenting and reporting AEs
All AEs occurring from the time the subject signs the informed consent form to the time
specified in the protocol (Table 2) (including SAEs and non-SAEs), regardless of their severity,
must be collected and recorded on the AE page of the eCRF.
Table 12. Reporting and follow-up of adverse events
Reporting time limit
Visit time limit
AEs
From signing of the informed consent form to 3
months after the last dose of the study treatment
Until resolved or explainable stable
determined by the investigator
Adverse events of
special interest (AESIs)
From signing of the informed consent form to 3
months after the last dose of the study treatment
Until resolved or explainable stable
determined by the investigator
Serious adverse event
From signing of the informed consent form to 3
months after the last dose of the study treatment
Until resolved or explainable stable
determined by the investigator
Pregnancy
From the first dose until 6 months after the last dose
of the study treatment
Until the outcome of the event is
available, and the health conditions of
the newborn should be followed up
for at least 2 months according to the
protocol
7.2.1.9 Precautions for AE documentation
Diagnosis, signs, and symptoms
If a diagnosis is already made, the eCRF should record the diagnosis instead of individual
symptoms and signs (such as hepatic failure rather than jaundice, transaminase increased, and
asterixis). However, if the signs and symptoms cannot be attributed to a definitive diagnosis, each
independent event should be documented in the eCRFs as an AE or SAE. Update the report with
visit information if a diagnosis is confirmed later.


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AEs secondary to other events
Generally, AEs secondary to other events (such as result of another event or clinical sequelae)
should be documented as the primary event, unless the event is severe or an SAE. However,
clinically significant secondary events should be recorded as independent adverse events in the
eCRFs if they occur at different times than the primary event. If the relationship between events is
unclear, document them as separate events in the eCRFs.
Ongoing or recurrent AEs
An ongoing AE refers to an event that does not resolve and is ongoing between two assessment
time points. These AEs should only be documented once in the eCRFs. The initial severity should
be documented, and the information should be updated if the event exacerbates.
Recurring AEs refer to AE that have resolved between the two time points of assessment but
subsequently occur. These events should be independently documented in the eCRFs.
Abnormalities in laboratory tests/vital signs
Not all abnormalities in laboratory tests/vital signs should be reported as AEs. Only the
abnormalities in laboratory tests/vital signs that meet the following criteria are reported as AEs:

Accompanied with clinical symptoms

Lead to changes in the dose of the study treatment (such as dose adjustment, dose
interruption, or permanent drug withdrawal)

Require medical intervention or changes in concomitant therapy

Judged by the investigator as clinically significant
It is the responsibility of the investigator to review all abnormal laboratory test results and vital
signs, and to determine whether each abnormal laboratory test result or vital signs should be
reported as AEs.
If clinically significant laboratory abnormalities or abnormal vital signs are characteristic of a
disease or syndrome (such as increased levels of alkaline phosphatase and total bilirubin caused by
cholecystitis that are higher than 5 times the upper limit of normal), only the diagnosis is recorded
on the AE report of the eCRF (i.e., cholecystitis). Conversely, the laboratory abnormalities or
abnormal vital signs are recorded on the AE report of the eCRF, and it should be indicated that
whether the test value is above or below the normal range (for example, it should be recorded as
"blood potassium increased" instead of "blood potassium abnormal"). If there is a standard clinical
term corresponding to the laboratory abnormalities or abnormal vital signs, the clinical term should
be recorded on the eCRF (such as "anemia", instead of "hemoglobin decreased"). The same
clinically significant laboratory abnormalities or abnormal vital signs found during multiple
follow-ups should not be repeatedly recorded as AEs or SAEs in the eCRF unless there is a change


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in its severity or etiology.
Death
During the entire course of the study, all the deaths that occurred within 90 days after the last dose
were documented in the Death Report Form in the eCRFs and reported to the sponsor timely,
regardless of the causality with the investigational drug.
When recording a death event, if there is an AE leading to the death, a single medical concept
should be used on the AE report of the eCRF to record the event leading to the death, and the event
should be reported as an SAE in an expedited manner; if the cause of the death is unknown at the
time of reporting , "Death with Unknown Cause" should be recorded on the AE report of the eCRF.
The "Death with Unknown Cause" should be reported as an SAE in an expedited manner before
further investigation is carried out to find the exact cause of death.
If the cause of death is confirmed to be PD, then the event should not be documented and reported
as an AE/SAE. However, the event should be documented in the Mortality Report Form of the
eCRF and reported to the sponsor timely.
Pre-existing medical conditions
Symptoms/signs presenting during the screening period will be recorded and reported as AEs only
if their severity, frequency, or property becomes aggravated (except for worsening of the studied
disease). The relative change should be documented, such as "increased frequency of headaches".
Hospitalization and prolonged hospitalization, or surgery
Any AE that results in hospitalization or prolonged hospitalization should be documented and
reported as an SAE, except for the following situations:

Hospitalization or prolonged hospitalization as required by study protocol (such as for dose
administration, efficacy evaluation, etc.)

Hospitalization due to a pre-existing medical condition that remains stable, e.g. elective
surgery/therapy scheduled prior to the study.
However, elective surgery/therapy required because of the exacerbated condition during the study
(e.g. surgery/therapy required earlier than scheduled) should be considered as an AE.
The investigator should fill in all required information, including AE terms
(diagnostic terms, or the record of symptoms and signs including laboratory test abnormalities if
there is no diagnosis), start date, end date, severity level, whether it is an AESI, measures taken for
the investigational product, treatment given for the AE, outcome, seriousness, and relationship with
the investigational product. If the signs and symptoms cannot be attributed to a definitive diagnosis,
each AE should be documented independently.


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Progressive disease
For any event, if it can be clearly determined that the event is caused by progressive disease, the
event is not reported as an AE. Hospitalization or death caused by progressive disease does not
need to be reported in an expedited fashion.
Lack of efficacy
When the disease treated by the study treatment deteriorates, it may not be possible to determine
whether it is due to the lack of efficacy or the occurrence of an adverse event. In this case, unless
the investigator believes that the deterioration of the condition is related to the study treatment,
such changes are all regarded as the lack of efficacy rather than adverse events.
Overdose
When there is an accompanying AE, the AE should be recorded; when there is not accompanying
AE, the overdose should be recorded on the eCRF.


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8 STATISTICS
8.1 Sample Size Determination
A number of 218 subjects for each group (436 subjects in total) can provide 80% test power to
confirm the clinical equivalence between the treatments of IBI305 in combination with
paclitaxel/carboplatin and bevacizumab in combination with paclitaxel/carboplatin.
The sample size is estimated based on the following assumptions:

The ORRs between IBI305 and bevacizumab group are equivalent

The ORR of subjects in the bevacizumab groups is set to 50.0%

The equivalence margin is taken as (-12.5%, 16.7%)

The significance level of the two one-side test is 0.05

1:1 randomization
Based on the above hypotheses, a number of 218 subjects for each group is required (436
subjects in total). The sample size was estimated using PASS 2013.
8.2 Statistical Population
Intention-to-Treat (ITT): All randomized subjects.
Full Analysis Set (FAS): All randomized subjects who received at least one dose of the study
treatment. This dataset is used as the primary analysis set for efficacy assessment.
Per-Protocol (PP): Based on the FAS, subjects with the predetermined minimum drug exposure
and without any predetermined major protocol deviations. This dataset is used as the secondary
analysis set for efficacy assessment.
Safety set (SS): Includes all randomized subjects who received at least one dose of the study
treatment and have safety evaluation data. This data set is used for the safety evaluation of this
study.
PK analysis set (PKAS): Includes subjects in the FAS with at least one PPK measured value.
Pharmacodynamic analysis set (PDAS): Includes all subjects in the FAS set with at least one PD
measured value.


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8.3 General Principles for Statistical Analyses
For continuous variables, descriptive statistics should include the count, mean, standard
deviation, median, maximum, and minimum. For categorical variables, descriptive statistics will
include the frequency as well as the absolute or relative percentage. Statistical analyses will be
carried out using SAS 9.4.
8.4 Statistical Methods
8.4.1 Adjustments for covariates
Not applicable.
8.4.2 Managing dropouts and missing data
The analyses of primary and secondary endpoints will include data from dropouts. The management
of missing data is described in the Statistical Analysis Plan.
8.4.3 Multi-center study
Since this is a multicenter study, the primary endpoint (ORR) will be listed according to study
sites and treatment groups. However, individual equivalence analysis will not be conducted.
Trial sites with fewer than 5 ITT subjects per treatment group will need to be combined for
analysis. Details will be discussed in the data review meeting.
8.4.4 Multiple comparisons and adjustments to multiplicity
The α adjustment for multiple comparisons is not considered.
8.5 Statistical Analyses
8.5.1 Subject distribution
Refer to Figure 1: Study design schematic for the schedule of activities. The number and
percentage of patients who have completed or dropped out of the study (including the reason for
dropouts such as loss to follow-up, AEs, and poor compliance) are summarized based on
treatment groups.
The number and percentage of subjects in each analysis set are calculated based on treatment groups.
The number and percentage of protocol deviations are calculated based on treatment groups.


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8.5.2 Demographics and other baseline characteristics
Demographic information such as age, height, sex, and weight, and other baseline characteristics
such as disease history (including NSCLC diagnosis, staging, previous cancer treatment, and
target and nontarget lesions) are summarized using descriptive statistics.
8.5.3 Compliance and drug exposure
The required dose and the actual dose must be documented in the eCRF. Subject compliance is
calculated based on the ratio of the actual dose (number of doses) to the required dose (number
of doses). Subject compliance is classified into the following categories: < 80%, 80–120%, and >
120%. The number and percentage of subjects in each category will be summarized.
8.5.4 Efficacy
The efficacy analysis will be based on the FAS. Results of the PP set will also be presented.
8.5.4.1 Primary efficacy endpoint
The primary objective of this study is to determine the clinical equivalence between IBI305 +
paclitaxel/carboplatin and bevacizumab + paclitaxel/carboplatin for the treatment of advanced or
relapsed non-squamous non-small cell lung cancer (NSCLC). The primary endpoint is objective
response rate (ORR). ORR is defined as the incidence of patients with confirmed complete
response (CR) or partial response (PR), when a validated imaging method and RECIST v1.1
are used to evaluate target and non-target lesions. Subjects without tumor assessments beyond
baseline will be considered unresponsive to treatment. Subjects qualified for the evaluation of
CR or PR must have at least one measurable lesion according to RECIST v1.1. The evaluation
of clinical equivalence will be based on the ORR provided by the independent review committee
(IRC). Results provided by the investigator will be used for sensitivity analysis.
Clinical equivalence will be declared if the 90% confidence interval of the difference in ORR
between IBI305 and bevacizumab groups falls within the preset margin of (-12.5%, 16.7%).
The ORR and corresponding 95% confidence interval of the two treatment groups, the ORR
difference and the 90% confidence interval, as well as the ORR ratio between the two groups and
the 90% confidence interval will be estimated using the generalized linear model (GLM, which
includes treatment groups and stratification factors).
8.5.4.2 Secondary efficacy endpoints
The secondary endpoints for this study include DOR, DCR, progress-free survival (PFS), and
overall survival (OS).


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DCR is defined as the incidence of patients with confirmed complete response (CR), partial
response (PR), and stable disease (SD), when a validated imaging method and RECIST v1.1 are
used to evaluate target and non-target lesions.
DOR is defined as the time from initial tumor response (CR or PR) to PD or death; Subjects with
CR or PR who do not progress or die will be censored on the date of the last tumor assessment.
OS refers to the time from the date of randomization to the date of death (of any cause). For
subjects who are still alive at the time of the analysis, their survival time is censored on the last
known alive date. PFS refers to the time from the date of randomization to the date of first
documented PD or death, whichever occurs first. The investigator will assess PD using RECIST
v1.1. Subjects who do not progress or die will be censored on the date of the last tumor
assessment. Subjects without tumor assessments after baseline are censored on their date of
randomization.
Median OS and its 95% CI will be estimated using the Kaplan-Meier method. The survival curve
will be plotted. The hazard ratio (HR) between the two groups and its 95% CI will be estimated
using a Cox model. The Cox model includes treatment groups and stratification factors. DOR
and PFS will be analyzed using the same method as for OS. DCR will be analyzed using the
same method for primary efficacy endpoints, but an equivalence test will not be conducted.
8.5.4.3 Sensitivity analysis
The center effect (fixed or random) will be considered in the primary and secondary endpoints
analysis models (GLM or Cox).
8.5.4.4 Antibody and efficacy analysis
Subjects who develop antibodies during the clinical study will be summarized in detail. The
difference in efficacy between subjects with and without antibodies will be compared if
necessary.
Changes in PK parameters and steady-state trough concentrations of subjects with positive ADA
are analyzed.
8.5.5 Exploratory analysis
Pharmacodynamic parameters: The changes in the serum VEGF level at different time points are
described, and inter-group comparisons are carried out when necessary (based on the PD dataset)
Steady-state trough concentrations of the drug: The level of trough concentration is described
and inter-group comparisons are carried out when necessary (based on the PPK dataset)


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8.5.6 Interim analysis
No interim analysis is planned for this study.
8.5.7 Stratified analysis
Efficacy analysis of different levels of subjects is conducted based on the random stratification
factors
8.5.8 Safety analysis
The safety analysis is based on the safety analysis set.
8.5.8.1 Adverse events
All adverse events (AE) will be coded using MedDRA and graded using CTCAE v4.03. All
TEAEs, TEAEs ≥grade 3, SAEs, drug-related TEAEs, drug-related SAEs, TEAEs resulting in
the termination of study drugs, TEAEs resulting in the termination of study, and AESIs will be
listed based on system organ class, preferred terms, and groups and the corresponding numbers
and percentages of subjects will be summarized. In addition, the severity of TEAEs and
relevance to the study drugs will also be summarized system organ class, preferred terms, and
treatment groups.
8.5.8.2 Laboratory tests
All laboratory test results and changes relative to baseline will be summarized by scheduled time
point and treatment group using descriptive statistics. Laboratory abnormalities will be listed.
8.5.8.3 ECG examinations
Results of ECG and changes relative to baseline will be summarized using descriptive statistics.
8.5.8.4 Vital signs, physical examinations, and other safety examinations
Descriptive statistics of vital signs and relative changes from baseline are shown.
Results of physical examinations are listed by treatment groups.
8.5.8.5 Concomitant medications
Concomitant medications are non-study medications that meet one of the followings:
(1)
Any drug therapy started during or after the first dose of the study treatment;
(2)
Any drug therapy started before the first dose of the study treatment and continued after
the first dose of the study treatment. Concomitant medications are listed by treatment
groups.


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9 QUALITY ASSURANCE AND QUALITY CONTROL
According to GCP principles, the sponsor is responsible for implementing and maintaining
quality assurance and quality control systems based on standard operating procedures (SOP),
to ensure that the implementation of the clinical trial and the collection, documentation, and
reporting of trial data is in accordance with the protocol, GCP, and applicable regulatory
requirements.
To ensure that the data is reliable and processed correctly, there should be quality control for
every step during the data processing.
In addition, the Clinical Quality Assurance (CQA) Department of the sponsor and/or CRO may
conduct regular audits of the study process, including but not limited to auditing the study site,
on-site visits, central laboratory, suppliers, clinical database, and the final clinical study report.
Regulatory authorities may also conduct inspections during the trial or at any time after the trial
is completed. The investigator and the research institution must allow the sponsor's representative
and regulatory authorities to review source data.
9.1 Clinical Monitoring
The sponsor has authorized Wuxi Clinical Co., Ltd. to conduct clinical monitoring for this study.
The clinical research associate (CRA) should follow the SOPs of Wuxi Clinical Co., Ltd. when
carrying out monitoring, and has the same rights and responsibilities as the sponsor's monitor.
The CRA should maintain regular communication with the investigator and the sponsor.
Before the start of the study, the associate monitor assess the qualifications of each study site,
and report issues related to facilities, technical equipment, or medical staff to the sponsor. During
the study, the CRA will be responsible for confirming whether written informed consent is
obtained from all subjects, and whether data documentation is accurate and complete. At the
same time, the CRA will compare data entered in to the eCRF with source data, and notify the
investigator of any errors or omissions. The CRA will also verify protocol compliance of the
study site, as well as the dispensing and storage of investigational drugs to ensure protocol
requirements are met.
The monitoring visit will be conducted in accordance with applicable statutes and regulations.
Each site receives regular monitoring visits from the time the subjects are enrolled. The CRA
should submit a written report to the sponsor after each monitoring visit to the study site.


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9.2 Data Management/Coding
The Data Management and Biostatistics Department of Wuxi Clinical Co., Ltd will process data
generated from this study in accordance with relevant SOPs.
This study will use an electronic data capture (EDC) system. Trial data will be entered into the
eCRF by the investigator or authorized study personnel. Prior to launching of the study site or
data entry, the investigator and authorized study personnel will receive appropriate training, and
appropriate safety measures will be taken.
All data are input in Chinese. The eCRF should be completed during or soon after each visit, and
should be constantly updated to ensure that it reflects the latest status of the subject. To avoid
discrepancies in outcome assessments between different evaluators, ensure that baseline and all
subsequent efficacy and safety assessments for the same subject are performed by the same
person. The investigator must review trial data to ensure the accuracy and correctness of all data
entered into the eCRF. During the study, the investigator should document any evaluations that
are not conducted, or any information that is not available, applicable, or known. The
investigator needs to sign all verified data electronically.
The CRA will review the eCRF, and evaluate its completeness and consistency. The CRA will
also compare the eCRF with the source documents to ensure the consistency of critical data. Data
entry, corrections, or modifications are completed by the investigator or designated staff. The
CRA do not have access to data entry. The data in eCRF is submitted to the data server, and any
changes to the data will be documented in the audit trail, including the reason for the change, the
name of the operator, as well as the time and date of the change. The roles and permissions of
study personnel responsible for data entry will be predetermined. The CRA or data manager will
submit data queries in the EDC system, and study personnel shall respond to the queries. The
EDC system will record the audit trail of each query, including the name of the investigator, as
well as the time and date.
Unless otherwise specified, the eCRF should be considered simply as a form for data collection
and not a source document. A source file is used by the investigator or hospital, relevant to the
subject, and can prove the existence of the subject, inclusion criteria, and all records of
participation in the study, including laboratory records, ECG results, memorandum, pharmacy
dispensing records, and subject folders.


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The investigators are required to maintain all source documents and to offer the documents to the
CRA for review during each visit. In addition, the investigator must submit a complete eCRF for
each subject, regardless of the duration of the subject's participation in the study. The study
number and subject number in all supporting documents (such as laboratory records or hospital
records) submitted along with the eCRF should be carefully verified. All personal privacy
information (including the name of the subject) should be deleted or be made indecipherable in
order to protect subject privacy.
The investigator could be automatically added to the eCRF with his/her user ID. The investigators
verify that the record have been reviewed and that the data are accurate with an electronic
signature. The electronic signature is completed with the investigator's user ID and password.
The system automatically attaches the date and time of the signature. The investigator could not
share the user ID and password with other personnel. If data in the eCRF need to be modified,
the procedures defined by the EDC system have to be followed. All modifications and reasons
for the changes are recorded in the audit trail.
Training on the EDC system will be provided to study personnel at the study site.
Adverse events, and concurrent diseases/medical history will be coded. The medical dictionary
used for coding will be described in the Clinical Study Report (CSR).
9.3 Audits and Inspections
The sponsor or its representative (WuXi Clinical Co., Ltd) may conduct quality assurance audits
on the study site, database, and relevant study-related documents. Also, regulatory authorities
may also decide to inspect the study site, database, and relevant study-related documents at its
own discretion. The aim of audits and inspections is to systematically and independently check
all study-related procedures and documents to ensure that the clinical study is being carried out
in accordance with requirements of the trial protocol, GCP, Declaration of Helsinki, and
applicable regulations. The investigator must inform the sponsor immediately when an
inspection notice is received from the regulatory authorities.


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10 ETHICS
10.1 Independent Ethics Committee
The sponsor and its designated personnel will prepare all documents to be submitted to the
independent ethics committee (IEC) of each study site. The trial protocol, informed consent form
(ICF), investigators brochure, subject recruitment material or advertisements (if applicable), as
well as other documents required by regulations must be submitted to the IEC for approval. Prior
to the start of the study, written approval from the IEC must be obtained and provided to the
sponsor. The IEC approval must clearly state the title, number, and version of the study protocol
as well as the version of other documents (e.g. ICF) and the date of approval. The investigator
must notify the sponsor of the IEC's written comments concerning delays, suspension and re-
approval.
The study site must follow the requirements of the IEC. IEC requirements may include
submitting the revised protocol, ICF, or subject recruitment material to the IEC for approval,
local regulatory requirements for safety reports, and regular reports, updates, and submitting the
final report as per IEC requirements. The above documents as well as the IEC approval must be
provided to the sponsor or its designated personnel.
10.2 Implementation of Ethical Principles
The study process and the acquisition of informed consent should comply with the Declaration of
Helsinki, relevant GCP requirements (CPMP/ICH/135/95), and applicable statutes and
regulations related to drugs and data protection in the country in which the study is conducted.
The GCP is an international ethical and scientific quality standard for designing, conducting,
recording and reporting clinical trials that involve the participation of human subjects. To protect
the rights, safety, and healthy of subjects, this study will be carried out in accordance with GCP
and applicable national regulations, as well as ethical principles outlined in the Declaration of
Helsinki.
The investigator is required to follow the procedures specified in this protocol and must not
change the procedures without the permission from the sponsor. Protocol deviations will be
reported in accordance with the requirements of each ethics committee.


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10.3 Subject Information and Informed Consent
Prior to undergoing any study procedure, the ICF should be used to explain to potential participants
the potential risks and benefits of this study. The informed consent form should be in a language
that is simple and be easy to understand. The ICF should state that informed consent is voluntary,
emphasize the potential risks and benefits of participating in this study, and that the subject may
withdraw from the study at any time. The investigator may only enroll a subject after fully
explaining the details of the study, answering questions to the subject's satisfaction, giving
the subject sufficient time for consideration, and obtaining written consent from the subject or
his/her legal representative. All signed ICF must be retained in the investigator's documents or
the subject's folder.
The investigator is responsible for explaining the contents of the ICF and obtaining the ICF
signed and dated by the subject or his/her legal representative prior to starting the study. The
investigator should provide the subject with a copy of the signed ICF. The investigator must
document the informed consent process in the source document of the trial.
10.4 Protection of Subject Data
Information about data protection and privacy protection will be included in the ICF (or in some
cases, in a separate document).
Study personnel must ensure that the privacy of clinical trial subjects are protected. In all
documents submitted to the sponsor, the clinical trial subjects must only be identified with
subject number and not with the full name.
Additional precautions should be taken to ensure the confidentiality of the documents and
to prevent the identification of subjects based on genetic data. However, under special
circumstances, some personnel may be permitted to see the genetic data and personal
identification number of a subject. For example, in the event of a medical emergency, the
sponsor, designated physician, or investigator will have access to the subject identification code
and the subject's genetic data. In addition, regulatory agencies may request access to relevant
documents.


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11 STUDY MANAGEMENT
11.1 Organizational Structure
Refer to Table 3 for relevant collaborating parties.
Table 13. Organizational structure
Sponsor
Innovent Biologics (Suzhou) Co., Ltd.
No. 168 Dongping Street, Suzhou Industrial Park, Jiangsu, China
Telephone: (+86) 0512-69566088
Contract research
organization
WuXi Clinical Development Services (Shanghai) Co., Ltd.
19F, Building A, SOHO Fuxing Plaza, 388 Madang Road, Shanghai
Tel: (+86) 21-23158000
Data management and
biostatistics
WuXi Clinical Development Services (Shanghai) Co., Ltd.
19F, Building A, SOHO Fuxing Plaza, 388 Madang Road, Shanghai
Tel: (+86) 21-23158000
11.1.1 Independent review committee
Central imaging evaluation will be performed by Parexel China Co., Ltd. The CT/MRI images of
each subject will be evaluated using RECIST v1.1.
11.2 Archiving of Study Documents
Clinical trial documents (protocol and amendments, completed eCRFs, signed ICFs, etc.) must
be retained and managed as per GCP requirements. The study site must retain these documents
for 5 years after the completion of the study. The sponsor should retain clinical trial data for
5 years after the investigational drug is approved for marketing.
Study documents should be retained properly for future access or data traceability. Safety and
environmental risks should be considered when retaining documents.
The documents associated with the study may only be destroyed with the written consent of the
sponsor and the investigator. Study documents may be transferred to other parties that comply
with or other locations that meet retention requirements only after the sponsor is notified and
written consent thereof is obtained.


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11.3 Access to Source Data/Documents
Source data refers to source records of subject data obtained from a clinical study. These source
records are source documents, which include but are not limited to medical records (hospital
records, nursing records, pharmacy dispensing records, etc.), electronic data, screening logs,
laboratory test results, as well as medical device test results (ECG, CT/MRI, etc.). All source
documents associated with the trial are retained by the study site and the investigator. The
original ICFs will be retained according to standard practices developed by the clinical trial
institution.
The investigator will prepare sufficient and accurate source documents for each randomized
subject in order to document all examination results and other relevant data, and retain these
documents properly.
During the study, the CRA will conduct on-site visits to verify protocol compliance, EDC data
entry, documentation of subjects' medical history, drug inventory, and whether the study is
carried out in accordance with applicable regulations. In addition, regulatory authorities, IRB,
IEC, and/or the quality assurance department of the sponsor will verify source data and/or
conduct on-site audits or inspections. The investigator should allow direct access to documents
associated with the study, including medical records of subjects.
11.4 Protocol Revisions
The sponsor and the investigator must both agree on any appropriate protocol revisions during
the course of the study. The sponsor shall ensure that the protocol revision is submitted to the
regulatory authority in a timely manner.
All protocol revisions must be submitted to the IEC, and if needed, to regulatory authorities for
approval. Revisions may only be implemented after approval from the IEC and regulatory
authorities (if needed) is obtained (except for changes to eliminate immediate risks to subjects).
11.5 Investigator's Responsibilities
The investigator will conduct this study in accordance with the protocol, ethical principles of the
Declaration of Helsinki, Chinese GCP, and applicable regulations. Details of the investigator's
responsibilities are list in Chapter 5 (Investigator's Responsibilities) of the Chinese GCP (NMPA
order No. 3).


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11.6 Study Termination
The study may be terminated after a discussion between relevant parties if the investigator or the
sponsor becomes aware of circumstances or events that could jeopardize the subjects if the study
is continued. The sponsor may also decide to terminate the study even without such findings.
Reasons for study termination include but are not limited to:

Unexpected, serious, or unacceptable risks to enrolled subjects

Slow recruitment

The sponsor decides to suspend or discontinue the development of the drug
11.7 Publishing Policies
All the data generated in this study is the confidential information owned by the sponsor. The
sponsor has the right to publish study results. The investigator shall not publish any data relevant
to this study (posters, abstracts, papers, etc.) without prior communication with the sponsor.
Information on the publishing policies of the sponsor and investigator will be described in the
clinical trial agreement.
11.8 Finance and Insurance
The sponsor will purchase insurance for subjects participating in the study in accordance with
local regulations, and bear the cost of treatment and corresponding financial compensation for
the subjects who suffer injury during the study due to the investigational drug or the study
process. Insurance related terms shall be saved in the study folder.


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12 REFERENCES
1.
GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. Apr.
11, 2016: http://globocan.iarc.fr/Default.aspx
2.
陈万青，郑荣寿，曾红梅，等. 2011 年中国恶性肿瘤发病和死亡分析. 中国肿瘤.
2015;24(1):1-10.
3.
GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. Apr.
11, 2016: http://www.cancer.org/acs/groups/cid/documents/webcontent/003115-pdf.pdf
4.
支修益，石远凯，于今明. 中国原发性肺癌诊疗规范（2015 年版）. 中华肿瘤杂志.
2015;37(1):67-78.
5.
Pisters KMW and Chevalier TL. Adjuvant Chemotherapy in Completely Resected Non–
Small-Cell Lung Cancer. J Clin Oncol. 2005;23:3270-3278.
6.
石远凯，孙燕，于今明，等. 中国晚期原发性肺癌诊治专家共识（2016 年版）. 中国
肺癌杂志. 2016;19(1):1-15.
7.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN
Guidelines®) Non-Small Cell Lung Cancer (Version 4. 2016). Apr. 11, 2016:
http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
8.
郝希山，魏于全. 肿瘤学（第二版）. 北京: 人民卫生出版社. 108; 2010.
9.
Package insert of bevacizumab (Nov. 25, 2015). Apr. 11, 2016:
http://www.roche.com.cn/content/dam/roche_china/zh_CN/pdf/product/Avastin_20151125_
IM %20PI%20CDS32.0-33.0.pdf
10. Sandler A., Gray R., Perry MC., et al. Paclitaxel-carboplatin alone or with bevacizumab for
non-small-cell lung cancer. N Engl J Med. 2006;355:2542-2550.
11. Reck M., von Pawel J., Zatloukal P., et al. Overall survival with cisplatin-gemcitabine and
bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer:
results from a randomized phase III trial (AVAiL). Annals of Ocology. 2010;21:1804-1809.
12. Zhou CC., Wu YL., C GY., et al. BEYOND: A randomized, double-blind, placebo-
controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab
or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung
cancer. J Clin Oncol. 2015;33:2197-2204.
13. IBI305 研究者手册. 信达生物制药（苏州）有限公司. 2016 年5 月11 日.
14. Technical Guidelines for Development and Evaluation of Biosimilars by NMPA (Trial). Apr. 21,
2016: http://www.sda.gov.cn/WS01/CL1616/115104.html


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13 APPENDIX
13.1 Appendix I
Eastern Cooperative Oncology Group (ECOG) Performance Status Score
Score
Performance Status
0
Fully active, and able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activities but able to move around easily and carry out work of
a light or sedentary nature, e.g. light house work or office work
2
Capable of moving around easily and self-care but unable to carry out any work activities; up and
about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or wheelchair more than 50% of waking hours
4
Bedridden and incapable of self-care
5
Death
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative
Oncology Group. Am J Clin Oncol. 1982;5:649-655.


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13.2 Appendix II
Calculation of body surface area
Body surface are (m2) = 0.00616 height (cm) + 0.01286 weight (kg) - 0.1529
Creatinine Clearance (Cockroft-Gault Equation)
Ccr (mL/min) = [(140 - age) x weight (kg)]/[72 x Scr (mg/dL)]
Female subjects: results × 0.85
1 mg/dL = 88.41 µmol/L
Carboplatin Dose (Calvert Equation)
Carboplatin dose (mg) = target AUC (mg/mL/min) × [creatinine clearance rate (mL/min) + 25]


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13.3 APPENDIX 3
RECIST v1.1
1
MEASURABILITY OF TUMOR AT BASELINE
1.1
Definitions
At baseline, tumor lesions/lymph nodes will be categorized as measurable or not measurable as
follows:
1.1.1
Measurable
Tumor lesions: must be accurately measured in at least one dimension (longest diameter in the
plane of measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm)

10 mm caliper measurement by clinical exam (lesions which cannot be accurately
measured with calipers should be documented as not measurable).

20 mm by chest X-ray.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will
be measured and followed.
1.1.2
Not measurable
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes
with a short axis ≥10 and <15 mm) as well as truly not measurable lesions. Lesions considered
truly not measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion,
inflammatory breast disease, lymphangitis involving the skin or lungs, abdominal masses/
abdominal organomegaly identified by physical exam but not measurable by reproducible
imaging techniques.
1.1.3
Special considerations regarding measurable bone lesions, cystic lesions, and lesions
with prior locoregional treatment:
Bone lesions:

Bone scan, PET scan or plain films are not considered adequate imaging
techniques to measure bone lesions. However, these techniques can be used to
confirm the presence or disappearance of bone lesions.


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
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue
components, that can be evaluated by cross sectional imaging techniques (such as
CT or MRI) can be considered as measurable lesions if the soft tissue
components meet the definition of measurability described above.

Blastic bone lesions are not measurable.
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not
be considered as malignant lesions (neither measurable nor not measurable) since
they are, by definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as
measurable lesions, if they meet the definition of measurability described above.
However, if noncystic lesions are present in the same patient, these noncystic
lesions are preferred for selection as target lesions.
Lesions with prior locoregional treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to
other locoregional therapy are usually not considered measurable, unless there
has been demonstrated progression in the lesion. The study protocol should detail
the conditions under which such lesions would be considered measurable.
1.2
Specifications by Methods of Measurements
1.2.1
Measurement of lesions
All measurements should be documented with metric symbols. Calipers should be used if clinical
assessments are required. All baseline evaluations should be performed as close as possible to
the beginning of the treatment but never more than 4 weeks before the beginning of the treatment.
1.2.2
Method of assessment
The same method of assessment and the same technique should be used to characterize each
identified and reported lesion at baseline and during follow-up. Imaging evaluation should
always be done rather than clinical examination unless the lesion(s) being followed cannot be
imaged but are assessable by clinical examination.
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial
and its diameter is ≥10 mm as assessed using calipers (e.g. skin nodules). For skin lesions,
documentation by color photography including a plotting scale to estimate the size of the lesion
is recommended. As noted above, when lesions can be evaluated by both clinical examination
and imaging evaluation, the latter should be undertaken since it is more objective and may also


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be reviewed at the end of the study.
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.
However, lesions on chest X-ray may be considered measurable if they have clear boundaries
and are surrounded by aerated lung tissues.
CT and MRI: CT is the best currently available and reproducible method to measure lesions
selected for response assessment. This guideline has defined measurability of lesions on CT scan
based on the assumption that CT slice thickness is 5 mm or less. When CT scans have a slice
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice
thickness. MRI is also acceptable in certain situations (e.g. for body scans).
Ultrasound: Ultrasound should not be used for measuring lesion size and should not be used as
a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for
independent review at a later date and, because they are operator dependent, it cannot be
guaranteed that the same technique and measurements will be taken from one assessment to the
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT
or MRI is recommended. If there is concern about radiation exposure at CT, MRI may be used
instead of CT in selected instances.
Endoscopy and laparoscopy: The utilization of these techniques is not recommended for
objective tumor evaluation. However, they can be used to confirm complete pathological
response when biopsies are obtained or to determine relapse in trials where recurrence following
complete response or surgical resection is an endpoint.
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If
markers are initially above the upper limit of normal, however, they must normalize for a patient
to be considered in complete response. Because tumor markers are disease specific, instructions
for their measurement should be incorporated into the protocol on a disease specific basis.
Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response
(in recurrent prostate cancer) have been published. In addition, the Gynecologic Cancer
Intergroup has developed CA125 progression criteria which are to be integrated with objective
tumor assessment for use in first-line trials in ovarian cancer.
Cytology and histology: These techniques can be used to differentiate between PR and CR in rare
cases if required by the protocol (for example, residual lesions in tumor types such as seminoma,
where known residual benign tumors can remain). When effusions are known to be a potential
adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors),
cytological confirmation of the neoplastic origin of any effusion that appears or worsens during


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treatment can be considered if the measurable tumor has met criteria for response or stable
disease in order to differentiate between response (or stable disease) and progressive disease.
2.
TUMOR RESPONSE EVALUATION
2.1
Assessment of Overall Tumor Burden and Measurable Disease
To assess objective response or future progression, it is necessary to estimate the overall tumor
burden at baseline and use this as a comparator for subsequent measurements. Only patients with
measurable disease at baseline should be included in regimens where objective tumor response is
the primary endpoint. Measurable disease is defined by the presence of at least one measurable
lesion. In studies where the primary endpoint is tumor progression (either time to progression or
proportion with progression at a fixed date), the protocol must specify if entry is restricted to
those with measurable disease or whether patients having non-measurable disease only are also
eligible.
2.2
Baseline Documentation of "Target" and "Non-Target" Lesions
When more than one measurable lesion is present at baseline, all lesions (five lesions at most,
and two lesions per organ at most) representative of all involved organs should be identified as
target lesions and will be recorded and measured at baseline (This means in instances where
patients have only one or two organ sites involved, a maximum of two and four lesions
respectively will be recorded).
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be
representative of all involved organs, and should be those with reproducible repeated
measurements. It may be the case that, the largest lesion does not have reproducible
measurements, in which circumstance the next largest lesion with reproducible measurements
should be selected.
Lymph nodes merit special mention since their normal anatomical structures may be visible by
imaging even if not involved by tumor. Pathological nodes which are defined as measurable and
may be identified as target lesions must have a short axis of ≥15 mm by CT scan. Only the short
axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter
normally used by radiologists to judge if a node is invaded by solid tumor. Nodal size is
normally reported as two dimensions in the plane in which the image is obtained (for CT scan
this is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal or
coronal). The smaller of these measures is the short axis. For example, an abdominal node which
is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies as a malignant
measurable node. In this example, 20 mm should be reported as the node measurement. All other
pathological nodes (those with a short axis ≥10 mm but < 15 mm) should be considered non-


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target lesions. Lymph nodes that have a short axis < 10 mm are considered non-pathological and
should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions; short axis for nodal lesions) for all target
lesions will be calculated and reported as the baseline sum of diameters. If lymph nodes are to be
included in the sum, then as noted above, only the short axis is added into the sum. The baseline
sum of diameters will be used as reference to further characterize any objective tumor regression
in the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as
non-target lesions and should also be recorded at baseline. Measurements are not required and
these lesions should be recorded as "present", "absent", or in rare cases "unequivocal
progression". In addition, it is possible to record multiple target lesions involving the same organ
as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple
liver metastases’).
2.3
Response Criteria
2.3.1
Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes
(whether target or non-target) must have a reduced short axis of <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions vs. the
baseline sum of diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions vs.
the smallest sum during the study (this includes the baseline sum if that is the smallest). In
addition to the relative increase of 20%, the sum must also have an absolute increase of at least
5 mm. (Note: The appearance of one or more new lesions is also considered progression).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to
qualify for PD, using the smallest sum of diameters during the study as reference.
2.3.2
Special notes on the assessment of lymph nodes which are target lesions
Lymph nodes identified as target lesions should always have the actual short axis measurement
recorded (measured in the same anatomical plane as during the baseline examination), even if the
nodes regress to below 10 mm at the time of the study. This means that when lymph nodes are
included as target lesions, the "sum" of lesions may not be zero even if complete response
criteria are met, since a normal lymph node is defined as having a short axis of <10 mm. Case
report forms or other data collection methods may therefore be designed to have target nodal
lesions recorded in a separate section where, in order to qualify for CR, each node must have a


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short axis of <10 mm. For PR, SD, and PD, the actual short axis measurement of the nodes is to
be included in the sum of target lesions.
Target lesions that are "too small to measure". During the study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent
evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or lymph nodes
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist
may not feel comfortable assigning an exact measurement and may report them as being "too
small to measure". When this occurs it is important that a value be recorded on the case report
form. If it is the opinion of the radiologist that the lesion has probably disappeared, the
measurement should be recorded as 0 mm. If the lesion is believed to be present and is faintly
seen but too small to measure, a default value of 5 mm should be assigned (Note: It is less likely
that this rule will be used for lymph nodes since they usually have a definable size when normal
and are frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is
believed to be present and is faintly seen but too small to measure, a default value of 5 mm
should be assigned in this circumstance as well). This default value is derived from the 5 mm CT
slice thickness (but should not be changed with varying CT slice thickness). The measurements
of these lesions are potentially non-reproducible, therefore providing this default value will
prevent false responses or progressions caused by measurement errors. To reiterate, however, if
the radiologist is able to provide an actual measurement, that value should be recorded, even if it
is below 5 mm.
Lesions that split or coalesced at the time of treatment. When non-nodal lesions fragment, the
longest diameters of the fragmented portions should be added together to calculate the target lesion sum.
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such that
they are no longer separable, the vector of the longest diameter in this instance should be the maximal
longest diameter for the "coalesced lesion".
2.3.3
Evaluation of non-target lesions
This section provides the definitions of the criteria used to determine the tumor response for the
group of non-target lesions. While some non-target lesions may actually be measurable, they do
not need to be measured and instead should be assessed only qualitatively at the time points
specified in the protocol.
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor
marker level. All lymph nodes must be non-pathological in size (short axis <10 mm).
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor
marker level above the normal limits.


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Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: The
appearance of one or more new lesions is also considered progression).
2.3.4
Special notes on the assessment of progression of non-target lesions
The concept of progression of non-target disease requires additional explanation as follows: When
the patient also has measurable lesions. In this setting, to achieve ‘unequivocal progression’ on the
basis of the non-target lesion, there must be an overall level of substantial worsening in non-target
disease such that, even in the presence of SD or PR of the target disease, the overall tumor burden
has increased sufficiently to merit discontinuation of therapy. A minimal increase in the size of one
or more non-target lesions is usually not sufficient to quality for unequivocal progression status.
The designation of overall progression solely on the basis of change in non-target lesions in the
face of SD or PR of target disease will therefore be extremely rare.
When the patient has only lesions that are not measurable. This circumstance arises in some
phase III trials when the presence of measurable lesions is not a criterion for study enrollment.
The same general concepts apply here as well. However, in this instance there are no measurable
lesions to factor into the interpretation of an increase in non-measurable lesion burden. Because
worsening in non-target lesion cannot be easily quantified (by definition: if all lesions are truly
not measurable), a useful test that can be applied when assessing patients for unequivocal
progression is to consider if the increase in overall lesion burden based on the change in non-
measurable disease is comparable in magnitude to the increase that would be required to declare
PD for measurable disease: i.e. an increase in tumor burden representing an additional 73%
increase in volume (which is equivalent to a 20% increase of diameter in a measurable lesion).
Examples include an increase in pleural effusion from "trace" to "large amount", an increase in
lymphangitic lesion from localized to widespread, or a description in the protocol such as
"sufficient to require a change in therapy". If ‘unequivocal progression’ is seen, the patient
should be considered to have had overall PD at that point. While it would be ideal to have
objective criteria to apply to diseases that are not measurable, the very nature of these diseases
makes it impossible to do so, therefore the increase must be substantial.
2.3.5
New lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on the detection of new lesions are important. There are no specific criteria for the
identification of new radiographic lesions; however, the finding of a new lesion should be
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging
modality or findings thought to represent something other than tumors (for example, some new
bone lesions which may be simply healed or flare of pre-existing lesions). This is particularly


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important when the patient’s baseline lesions show partial or complete response. For example,
necrosis of a liver lesion may be reported by a CT scan as a "new" cystic lesion, while it is
actually not.
A lesion identified during a follow-up in an anatomical location that is not discovered during the
baseline scan is considered a new lesion and will indicate disease progression. For example, a
patient with a visceral disease at baseline has a brain CT or MRI which reveals metastases. The
patient's brain metastases are considered evidence of PD even if he/she does not have brain
imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents a truly new lesion. If repeat scans confirm there is
definitely a new lesion, then progression should be declared using the date of the initial scan.
While FDG-PET response assessments need additional studies, it is sometimes reasonable to
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of
progression (particularly possible "new" lesions). New lesions on the basis of FDG-PET imaging
can be identified as follows:
a.
A negative FDG-PET at baseline and a positive FDG-PET at follow-up is a sign of PD
based on a new lesion.
b.
No FDG-PET at baseline and a positive FDG-PET at follow-up:
If the positive FDG-PET at follow-up corresponds to a new lesion site confirmed by
CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new lesion
site on CT, additional follow-up CT scans are needed to determine if there is truly
progression at that site (if so, the date of PD will be the date of the initial abnormal
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing
lesion site on CT that is not progressing according to the anatomic images, this is not PD.
2.4
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until
the end of treatment, taking into account any requirement for confirmation. On occasion a
response may not be documented until after the end of therapy, so the study protocol should
clearly state if post-treatment assessments are to be considered when determining best overall
response. The study protocol must specify how any new therapy introduced before progression
will affect best response designation. Assignment of best overall response for the patient will
depend on the findings of both target and non-target lesions and will also take into consideration
the appearance of new lesions. Furthermore, depending on the nature of the study and the


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protocol requirements, confirmatory measurement may also be required. Specifically, in non-
randomized trials where response is the primary endpoint, confirmation of PR or CR is needed to
determine which one is the "best overall response".
2.4.1
Time point response
It is assumed that at each time point specified by the study protocol, a response assessment
occurs. Table 1 on the next page provides a summary of the overall response status calculation at
each time point for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used.
2.4.2
Missing assessments and non-evaluable targets
When no imaging/measurement is done at a particular time point, the patient is not evaluable
(NE) at that time point. If only a subset of lesion measurements is made at an assessment, usually
the case is also considered NE at that time point, unless a convincing argument can be made that
the missing lesion(s) would not change the response at the assigned time point. This would be
most likely to happen in the case of PD. For example, if a patient has a baseline sum of 50 mm
with three measured lesions and at follow-up only two lesions are assessed and with a sum of 80
mm, the patient will have achieved PD status, regardless of the contribution of the missing lesion.
2.4.3
Best overall response: all time points
The best response is determined once all the data for the patient is obtained.
Best response determination in trials where confirmation of complete or partial response is not
required: Best response in these trials is defined as the best response across all time points (for
example, the best overall response of a patient who has SD at the first assessment, PR at the
second, and PD at the last is PR). When SD is believed to be best response, it must also meet the
minimum time from baseline specified by the protocol. If the minimum time is not met,
otherwise SD is the best time point response, the patient’s best response depends on subsequent
assessments. For example, if a patient has SD at the first assessment, PD at the second and does
not meet the minimum duration for SD, his/her best response is PD. The same patient lost to
follow-up after the first SD assessment would be considered not evaluable.
Best response determination in trials where confirmation of complete or partial response is
required: Complete or partial responses may be claimed only if the criteria for each are met at a
subsequent time point specified in the protocol (generally 4 weeks later). In this circumstance,
the best overall response can be interpreted as in Table 3.


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2.4.4
Special notes on response assessment
When nodal lesions are included in the sum of target lesions and the nodes decrease to "normal"
size (<10 mm), they may still have a measurement reported on scans. This measurement should
be recorded even if the nodes are normal in size in order not to overstate progression should it be
based on the increase in size of the nodes. As noted earlier, this means that patients with CR may
not have a total sum of "zero" on the case report form (CRF).
In trials where confirmation of response is required, repeated "NE" time point assessments may
complicate best response determination. The analysis plan for the trial must explain how missing
data/assessments will be addressed in the determination of response and progression. For
example, in most trials it is reasonable to consider a patient with time point responses of PR-NE-
PR as a confirmed response.
Patients with a global deterioration of health status requiring discontinuation of treatment without
objective evidence of disease progression at that time should be reported as "symptomatic
deterioration". Every effort should be made to document objective progression even after
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective
response. Instead, it is a reason for stopping the study treatment. The objective response status of
this type of patients is to be determined by evaluation of target and non-target lesions as shown
in Table 1–3.
Conditions that define "early progression, early death, and non-evaluability" are study specific
and should be clearly described in each study protocol (depending on treatment duration and
treatment periodicity).
In some circumstances it may be difficult to distinguish a residual lesion from normal tissues.
When the evaluation of complete response depends upon this determination, it is recommended
that the residual lesion be investigated (by fine needle aspirate/biopsy) before assigning a status
of complete response.
Like a biopsy, FDG-PET may also be used to upgrade a response to a CR in cases where a
residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-
PET in this circumstance should be pre-defined in the protocol and supported by disease specific
medical literature for the indication. However, it must be acknowledged that both approaches
may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.


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Table 1. Time point response: patients with target (+/– non-target) disease.
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or
No
PR
Not all were evaluated
SD
Non-PD or
No
SD
Not all were evaluated
Not all were
evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not evaluable
Table 2. Time point response: patients with non-target disease only.
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PDa
Not all were evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease, and NE = not evaluable.
a "Non-CR/non-PD" is preferred over "stable disease" for non-target disease, since SD is increasingly used as an
endpoint for assessment of efficacy in some trials, thus assigning this category in the absence of measurable
lesions is not advised.
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at
the next scheduled assessment, progression is confirmed, the date of progression should be the
earlier date when progression is suspected.


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Table 3. Best overall response when confirmation of CR and PR required.
Overall response
First time point
Overall response
Subsequent time
point
Best overall response
CR
CR
CR
CR
PR
SD, PD, or PRa
CR
SD
SD provided that the minimum duration for SD is met, otherwise PD
CR
PD
SD provided that the minimum duration for SD is met, otherwise PD
CR
NE
SD provided that the minimum duration for SD is met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided that the minimum duration for SD is met, otherwise PD
PR
NE
SD provided that the minimum duration for SD is met, otherwise NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not
evaluable.
a If CR is truly achieved at the first time point, then any lesions seen at a subsequent time point, even those meeting
PR criteria relative to baseline, make the disease PD at that time point (since lesions must have reappeared after
CR). Best response would depend on whether the minimum duration for SD is met. However, sometimes CR may
be claimed and subsequent scans suggest small lesions are likely still present, while in fact the patient have PR
instead of CR at the first time point. Under these circumstances, CR should be changed to PR and the best response
is PR.
2.5 Frequency of Tumor Re-Evaluation
Frequency of tumor re-evaluation during treatment should be protocol specific and adapted to the
type and schedule of treatment. However, for phase II studies where the beneficial effect of the
treatment is not known, follow-up every 6–8 weeks (timed to coincide with the end of a cycle) is
reasonable. Smaller or greater time intervals may be justified for certain regimens or circumstances.
The study protocol should specify which organ sites are to be evaluated at baseline (usually those
most likely to be involved with metastatic disease for the tumor type under study) and how
often evaluations are repeated. Normally, all target and non-target sites are evaluated at each
assessment. Under certain circumstances, some non-target organs may be evaluated less frequently.
For example, bone scans may need to be repeated only when complete response is identified in
the target lesion or when progression is suspected.


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After the end of the treatment, the need for repeated tumor evaluations depends on whether the
trial has a goal such as a certain response rate or a certain time to an event (progression/death).
If ‘time to an event’ (e.g. time to progression, disease-free survival, progression-free survival) is
the main endpoint of the study, then routine scheduled re-evaluation of lesion sites specified by
the protocol must be carried out. In randomized comparative trials in particular, the scheduled
assessments should be performed on time (for example: every 6–8 weeks during the treatment or
every 3–4 months after the treatment) and should not be affected by treatment delays, holidays or
any other events that might lead to imbalance in the timing of disease assessment between
treatment arms.
2.6 Confirmation of Measurements/Duration of Response
2.6.1 Confirmation
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is
required to ensure responses identified are not the result of measurement errors. This will also
permit appropriate interpretation of results in the context of historical data. Response
confirmation has been traditionally required in such trials. However, in all other circumstances,
i.e. in randomized trials (phase II or III) or studies where stable disease or progression are the
primary endpoints, confirmation of response is not required since it will not add value to the
interpretation of trial results. However, elimination of the requirement for response confirmation
may increase the importance of central review to protect against bias, in particular in studies
which are not blinded.
In the case of SD, measurements after study entry must have met the minimum interval for SD
(generally not shorter than 6–8 weeks) defined in the study protocol at least once.
2.6.2 Duration of overall response
The duration of overall response is measured from the time CR/PR measurement criteria are first
met CR/PR (whichever is first documented) until the date when recurrent or progressive disease
is objectively documented for the first time (using the shortest time to progressive disease
documented during the study as reference).
The duration of overall complete response is measured from the time CR measurement criteria
are first met until the date when recurrent disease is objectively documented for the first time.
2.6.3 Duration of stable disease
Stable disease is measured from the start of the treatment (in randomized trials, from the date
of randomization) until the criteria for progression are met, using the smallest sum during the
study as reference (if the baseline sum is the smallest, then it is used as the reference for the
calculation of PD).


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The clinical relevance of the duration of stable disease varies with different studies and diseases.
If the proportion of patients achieving stable disease for a minimum period of time is an endpoint
of importance in a particular trial, the protocol should specify the minimal time interval required
between two measurements for the determination of stable disease.
Note: The duration of response and stable disease as well as the progression-free survival are
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of the
guidelines to define a standard follow-up frequency. The frequency should take into account
many parameters including disease types and stages, treatment periodicity, and standard practice.
However, limitations of the precision of the measured endpoint should be taken into account if
comparisons between trials are to be made.


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14 INVESTIGATOR SIGNATURE PAGE
Protocol Title: A randomized, double-blind, multi-center phase III study comparing the efficacy
and safety of IBI305 plus paclitaxel/carboplatin vs. bevacizumab plus paclitaxel/carboplatin in
treatment-naive patients with advanced or relapsed non-squamous NSCLC.
Protocol No.: CIBI305A301
This protocol is a trade secret owned by Innovent Biologics (Suzhou) Co., Ltd. I have read and
fully understood this protocol, and agree to conduct this study in accordance with the
requirements found in this protocol and the Good Clinical Practice, and in compliance with
relevant laws and regulations and the Declaration of Helsinki. At the same time, I promise not to
disclose any confidential information associated with this study to any third party without the
written consent of Innovent Biologics (Suzhou) Co., Ltd.
Instructions for the Investigator: Please sign and date this signature page, type the investigator's name and job
title, as well as the name of the study site, and return this document to Innovent Biologics (Suzhou) Co., Ltd.
I have read the entire contents of this study protocol and shall perform the study as required:
Investigator's signature:
Date:
Name (in Print):
Job Title:
Name and Address of Study Site:


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Original text
After revision
Reason for amendment
Cover:
Version Date/No.:
Jun. 02, 2016/Version 1.0
Version Date/No.:
Sep. 26, 2016/Version 2.0
Jun. 02, 2016/Version 1.0

The revision history of
the protocol is added
Cover:
Sponsor Contact:
Zhou Hui (Medical Director)
Tel: (+86) 021-31652896
E-mail: hui.zhou@innoventbio.com
Hou Jiagang (Clinical Operations Director)
Tel: (+86)0512-69566088-8062
E-mail：jiagang.hou@innoventbio.com
Sponsor Contact:
Zhou Hui, Medical Director
Tel: (+86) 021-31652896
E-mail: hui.zhou@innoventbio.com

The contact of sponsor
is updated
Cover:
This document is only for the review of investigators, research
consultants or relevant personnel, and independent ethics
committee. Without the written approval of the sponsor, the
Confidentiality Statement
This document is the confidential information of Innovent

The confidentiality
statement is updated


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contents of this document shall not be disclosed to any third
party.
Biologics (Suzhou) Co., Ltd.
The content of this document shall not be disclosed to any person
other than the investigators, research consultants or related
personnel, and Institutional Review Board/Independent Ethics
Committee.
The information contained in this document must not be used for
any purpose, except for the evaluation or conduction of this study,
without the written consent of the sponsor.
P3: Study Objectives

To compare the safety and immunogenicity of IBI305
plus paclitaxel/carboplatin versus bevacizumab plus
paclitaxel/carboplatin for the treatment of advanced or
relapsed non-squamous NSCLC
Exploratory objectives:

To compare the population pharmacokinetics (PPK)
of IBI305 and bevacizumab in subjects with
advanced or recurrent non-squamous NSCLC

To compare the PD of IBI305 and bevacizumab in
subjects with advanced or recurrent non-squamous
NSCLC

Based on the
recommendations of
CDE, the
pharmacokinetic and
pharmacodynamic
evaluations are added
as the objectives of the
exploratory study
P4: Study design
This is a randomized, double-blinded, multi-center phase III
study. A total of 436 subjects with non-squamous NSCLC will be

Based on the
recommendations of


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This is a randomized, double-blinded, multi-center phase III
study. The study planned to enroll and randomize 400 subjects
with non-squamous NSCLC in a 1:1 ratio to IBI305 plus
paclitaxel/carboplatin group or bevacizumab plus
paclitaxel/carboplatin group. Stratifying factors include age (<
60 vs. ≥60 years old) and EGFR status (wild type vs. mutant
type).
enrolled, randomized in a ratio of 1:1 to either IBI305 in
combination with paclitaxel/carboplatin group or bevacizumab in
combination
with
paclitaxel/carboplatin
group,
and
the
stratification factors include age (< 60 vs. ≥60 years old) and
EGFR status (wild type vs. unknown type).
CDE, the sample size
is increased and the
stratification factors
are updated to include
the wild type vs.
unknown type
P4: Study design
Then subjects received monotherapy, that is, discontinuing
paclitaxel/carboplatin while continuing therapy with IBI305 or
bevacizumab. The monotherapy continues every 3 weeks.
Then subjects received maintenance monotherapy, that is,
discontinuing paclitaxel/carboplatin while continuing therapy
with IBI305 or bevacizumab. The maintenance monotherapy
continues every 3 weeks.

Clarify that
monotherapy refers to
maintenance
monotherapy
P4: Number of Subjects
400 cases
436 cases

Based on the
recommendations of
CDE, the sample size
is increased
P5: Diagnosis and main inclusion criteria:
4) Histologically confirmed EGFR wild type
5) Histologically confirmed EGFR mutation type, but subjects
who have not received EGFR-TKI treatment due to various
4) Histologically or cytologically confirmed EGFR wild type

Subjects carrying
mutant type EGFR are
excluded


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reasons
P5: Exclusion Criteria
None
3) Histologically or cytologically confirmed EGFR mutation
type. Subjects with unknown EGFR status for various reasons
could be enrolled

Subjects carrying
mutant type EGFR are
excluded
P7: Investigational Drug, Dosage, and Route of Administration
IBI305: 15 mg/kg in combination chemotherapy and 7.5 mg/kg
monotherapy, administered via intravenous infusion on D1 of
every 3-week treatment cycle until PD, unacceptable toxicity,
withdrawal of informed consent, lost to follow-up, death, or end
of study (whichever comes first)
IBI305: 15 mg/kg in combination chemotherapy and 7.5 mg/kg in
maintenance monotherapy, administered via intravenous infusion
on D1 of every 3-week treatment cycle until PD, intolerable
toxicity, withdrawal of informed consent, loss to follow-up, death,
or end of study (whichever comes first)

Clarify that
monotherapy refers to
maintenance
monotherapy
P7: Control Drug, Dosage, and Route of Administration:
Bevacizumab: 15 mg/kg in combination chemotherapy and 7.5
mg/kg monotherapy, administered via intravenous infusion on
D1 of every 3-week treatment cycle until PD, unacceptable
toxicity, withdrawal of informed consent, lost to follow-up,
death, or end of study (whichever comes first)
Bevacizumab: 15 mg/kg in combination chemotherapy with and
7.5
mg/kg in
maintenance
monotherapy,
administered via
intravenous infusion on D1 of every 3-week treatment cycle until
PD, intolerable toxicity, withdrawal of informed consent, loss to
follow-up, death, or end of study (whichever comes first)

Clarify that
monotherapy refers to
maintenance
monotherapy


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P8:
None
PK/PD Endpoints:

Population PK parameters, including steady-state trough
concentrations after repeated doses

Changes of serum VEGF at different time points

Based on the
recommendations of
CDE, the endpoints for
the pharmacokinetic
and pharmacodynamic
analysis are added
P8：Sample size calculation:
A number of 200 subjects for each group (400 subjects in total)
will provide over 80% power to confirm the clinical equivalence
between IBI305 plus paclitaxel/carboplatin and bevacizumab
plus paclitaxel/carboplatin. Estimation of sample size: If the
significance level of the two one-sided test is 0.05, the ORR
between IBI305 and bevacizumab group is about 54.4%, with an
equivalence margin of (-15%, 15%). Based on the above
assumptions, 189 subjects are required for each group (378
subjects in total). The sample size is expanded to 200 subjects
for each group (400 subjects in total) after taking dropouts into
consideration.
A number of 218 subjects for each group (436 subjects in total)
can provide 80% test power to confirm the clinical equivalence
between the treatments of IBI305 in combination with
paclitaxel/carboplatin and bevacizumab in combination with
paclitaxel/carboplatin. Estimation parameters for sample size:
The significance level of the two-sided test is 0.05, the ORR of
subjects in the IBI305 and bevacizumab groups is about 50.0%,
and the equivalence margin is taken as (-12.5%, 16.7%). Based on
the above hypothesis, each group requires 218 subjects (436
subjects in total).

Based on the
recommendations of
CDE, the statistical
hypotheses are updated
and the sample size is
increased
P8：Efficacy analysis:
Clinical equivalence will be determined by whether the 90%
Clinical equivalence will be determined by whether the 90%

Based on the
recommendations of


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confidence interval (CI) of the difference in ORR between the
IBI305 and bevacizumab arms falls within the preset margin of
(-15% to 15%).
confidence interval of the difference in ORR between the subjects
in the IBI305 and bevacizumab groups falls within the set margin
(-12.5%, 16.7%).
CDE, the statistical
hypotheses are updated
P8
None
PK/PD exploratory analysis: Mainly based on description,
and inter-group comparison will be carried out if necessary.

Based on the
recommendations of
CDE, the analytical
methods for
pharmacokinetic and
pharmacodynamic
evaluations are added
Table 1. Schedule of follow-up visits
12-Lead ECG:
C2D1-Progressive disease follow-up; If clinically indicated
12-Lead ECG:
C2D1 C2D1 C3D1 C4D1 C5D1 C6D1
C7 until the end of treatment

The frequency of ECG
examinations is
increased to detect the
occurrence of
myocardial ischemia
Table 1. Schedule of follow-up visits
None
Pharmacokinetics (PK):
C1D1 C2D1 C4D1 C5D1 C6D1

Based on the
recommendations of
CDE, pharmacokinetic
collection time points
are added


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Table 1. Schedule of follow-up visits
None
VEGF detection:
C1D1 C2D1 C6D1; end-of-treatment

Based on the
recommendations of
CDE,
pharmacodynamic
collection time points
are added
Table 1. Schedule of follow-up visits
None
l. Study sites that are implementing version 2.0 of the study
protocol should collect PK samples until 140 subjects in this
study meet the requirements for PPK assessment (based on
the written notice of the sponsor). There are 6 PK sampling
time points: Within 1 h before the first dose of the study drug
(IBI305/bevacizumab) in C1, immediately after the first
infusion (within 5 minutes), within 1 h prior to the dose in
C2, within 1 h prior to the dose in C4, within 1 hour prior to
the dose in C5, and within 1 h prior to the dose in C6. Serum
will be separated from the samples at the study site and the
serum samples will be analyzed at the designated central
laboratory.

Based on the
recommendations of
CDE, pharmacokinetic
collection time points
are added
Table 1. Schedule of follow-up visits
None
m. Study sites that are implementing version 2.0 of the study
protocol should collect PD samples until 140 subjects in this
study meet the requirements for VEGF testing (based on the
written notice of the sponsor). There are 4 VEGF sampling
time points: Within 1 h prior to the first dose of the study

Based on the
recommendations of
CDE,
pharmacodynamic


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drug (IBI305/bevacizumab) in C1, within 1 h prior to the
dose in C2, within 1 h prior to the dose in C6, and at the end
of treatment visit. Samples were tested at the designated
central laboratory.
collection time points
are added
P14 List of Abbreviations and Definitions
None
ADA Anti-Drug Antibody

Addition
P15 List of Abbreviations and Definitions
None
PK
Pharmacokinetics
PRES
Posterior Reversible Encephalopathy Syndrome

Addition
P20 Clinical studies
This study is the first study of IBI305 in humans.
Deleted from the original text

Clarification
P20
In the subsequent monotherapy therapy, IBI305 will be given
intravenously at a dose of 7.5 mg/kg
The dose is 7.5 mg/kg in the subsequent maintenance
monotherapy,

Clarify that
monotherapy refers to
maintenance
monotherapy
P21
None
2.3 Exploratory Objectives

To compare the population pharmacokinetics (PPK)
characteristics of IBI305 and bevacizumab in subjects
with advanced or relapsed non-squamous NSCLC

Based on the
recommendations of
CDE, the
pharmacokinetic and
pharmacodynamic


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
To compare the pharmacodynamics (PD)
characteristics of IBI305 and bevacizumab in subjects
with advanced or relapsed non-squamous NSCLC
evaluations are added
as the objectives of the
exploratory study
P22 Overview of Study Design
This is a randomized, double-blind, active-controlled, and
multi-center phase III study. A total of 400 subjects across 35
study sites with non-squamous NSCLC will be planned,
This is a randomized, double-blind, active-controlled, and multi-
center phase III study. This study plans to enroll 436 subjects with
non-squamous NSCLC at about 35 study centers in China

Based on the
recommendations of
CDE, the sample size
is increased
P22 Overview of Study Design
Then subjects received monotherapy, that is, discontinuing
paclitaxel/carboplatin while continuing therapy with IBI305 or
bevacizumab.
Then subjects received maintenance monotherapy, that is,
discontinuing
paclitaxel/carboplatin
while
continuing
maintenance
therapy
with
IBI305
or
bevacizumab.
Every
treatment cycle of the maintenance monotherapy lasts 3 weeks,

Clarify that
monotherapy refers to
maintenance
monotherapy
P24 Inclusion Criteria
4) Histologically confirmed EGFR wild type
5) Histologically confirmed EGFR mutation type, but subjects
who have not received EGFR-TKI treatment due to various
reasons
4) Histologically or cytologically confirmed EGFR wild type

Subjects carrying
mutant type EGFR are
excluded
P24 Inclusion Criteria
6) Must have at least one measurable target lesion (as per
5) Must have at least one measurable target lesion (as per
RECIST 1.1)

Correction


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RECIST 1.1)
P25 Exclusion Criteria
None
3) Histologically or cytologically confirmed EGFR
mutation type. Subjects with unknown EGFR status
for various reasons could be enrolled.

Subjects carrying
mutant type EGFR are
excluded
P29 Therapies by Study Drugs
In this study, the dose of IBI305 or bevacizumab during
combination therapy with chemotherapy is 15 mg/kg, while the
dose during monotherapy is 7.5 mg/kg.
In this study, the dose of IBI305 or bevacizumab is 15 mg/kg
when used in combination with chemotherapeutic drugs and 7.5
mg/kg in the maintenance monotherapy,

Clarify that
monotherapy refers to
maintenance
monotherapy
P29 Chemotherapy
Carboplatin: AUC 6.0 administered via intravenous infusion for
15-30 min (may be adjusted according to clinical practice of
each study site)
Carboplatin: AUC 6.0, the infusion time is based on the standard
practice of each study site.

Because the AUC of
carboplatin is 6.0, it
may cause adverse
events if the infusion is
completed within 15–
30 min due to the high
concentration of the
formulated liquid, the
provision is changed to
operate according to
the clinical practice of
each center.


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P30 Dose adjustments of study drugs
Dose adjustments of IBI305 or bevacizumab are not permitted
except for the adjustments (adjusted to 7.5 mg/kg for
monotherapy) specified in the study protocol.
Dose adjustments of IBI305 or bevacizumab are not permitted
except for the adjustments (the dose of maintenance
monotherapy is adjusted to 7.5 mg/kg) specified in the study
protocol.

Clarify that
monotherapy refers to
maintenance
monotherapy
P30 Dose adjustments of study drugs
If PD is not observed in subject during treatment, then the
subject will continue to receive IBI305 or bevacizumab as
monotherapy every 3-week treatment cycle
If the subject does not experience PD, the maintenance
monotherapy will be continued every 3-week treatment cycle

Clarify that
monotherapy refers to
maintenance
monotherapy
P32 Dose adjustments of study drugs
Reversible posterior leukoencephalopathy syndrome (RPLS)
There have been a few reports with signs and symptoms consist
with RPLS after study treatment. RPLS is a rare neurological
disease and its signs and symptoms include epilepsy, headache,
altered mental status, visual impairment, or cortical blindness,
with or without hypertension. Subjects with RPLS should
permanently discontinue the study treatment.
Posterior reversible encephalopathy syndrome (PRES)
There have been a few reports of subjects with signs and
symptoms consistent with PRES after study treatment. This is a
rare neurological disease and its signs and symptoms include
epilepsy, headache, altered mental status, visual impairment, or
cortical blindness, with or without hypertension. Subjects with
PRES should permanently discontinue the study treatment.

The description related
to PRES is updated
according to the latest
prescribing
information of
AVASTIN
P37 Other toxicities
Investigator should closely monitor toxicities in subjects during
chemotherapy. Before the start of next chemotherapy cycle, the
Deleted from the original text

The content has been
included in the
inclusion/exclusion


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laboratory test results must be:
ANC ≥1.5 × 109/L
Platelet count ≥100 × 109/L
Serum creatinine < 1.5 × ULN
Bilirubin ≤1.5 × ULN
ALT and AST ≤2.5 × ULN; ALT and AST < 5 × ULN in
subjects with liver metastasis
criteria, so the
description in the main
text is updated
P40 Treatment Compliance
The dosage and dosing time of IBI305 or bevacizumab and
paclitaxel + carboplatin in each treatment cycle should be
documented in the eCRFs. Reasons for dosing delay, dose
reduction or missed dossing should also be documented in the
eCRFs.
Treatment and protocol compliance refers to the subject's
voluntary compliance with each aspect of the protocol, including
compliance with blood collection for safety evaluation and
imaging examination for tumor assessment. If a subject does not
return for the scheduled follow-up visits, his/her participation in
the study may be terminated based on the opinions of the
Subjects should receive treatment at the study site. The dose
and time of administration of IBI305 or bevacizumab and
paclitaxel/carboplatin should be documented in the source
records and eCRFs during each treatment cycle. Reasons for dose
adjustments, therapy delay, and therapy discontinuation should
be documented. Treatment compliance is monitored by
medication dispensing and return records, medical records, and
eCRFs

The description related
to drug management is
updated


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primary investigator or sponsor.
P40 Study Drug Count
The investigator, other relevant stuff, or authorized pharmacists
should document the receipt and distribution of study drugs on
the study drug count table and ensure that the table is readily
available for inspection.
The study drugs are only for the use of study subjects.
At the end of the trial, all study drugs should be counted and
explanations for deviations should be provided in a written
document.
The investigator shall count all unused study drugs and
packaging materials, and return them to the sponsor or the
designated third party.
Used empty drug bottles/bags will be destroyed on-site
according to the institutional standards.
5.11 Drug Return and Destruction
The containers, vials, infusion bags, and syringes of used and
partially used drugs can be destroyed on-site according to the
appropriate guidelines and operating procedures established by
study sites and local agencies.
Unless the contents have significant safety issues requiring
immediate destruction in accordance with local regulations, all
the unused drugs should be returned and destroyed based on the
requirements of sponsor.
5.12 Study Drug-Related Records
The designated personnel of the study sites should make timely
records of receiving, dispensing, using, storing, returning, and
destroying the study drugs in accordance with the relevant
regulations and guidelines.

The description related
to drug management is
updated
P41 Screening Visits (D -28 to D -1)
Record the AEs

Record the AEs and concomitant medications

Update based on study
visit schedule
P42 Baseline Visits (D1 of cycle 1)
Record the vital signs

Record the vital signs

Update based on study
visit schedule


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Measure the weight
Physical examination
Clinical laboratory tests * (routine blood test, blood
chemistry, and urinalysis)
Immunogenicity test (ADAs and neutralizing antibodies)
Confirm the inclusion/exclusion criteria
Record the AEs and concomitant medications
* If clinical laboratory screening tests (routine blood test, blood
chemistry, urinalysis) are performed within 7 days prior to the
first dose, then the results of the screening test can be used as
baseline.
If the subject meets the inclusion criteria, the following
procedures should be complete:
Randomization and grouping
Study drug infusion (IBI305 or bevacizumab)
Chemotherapeutic drug infusion (paclitaxel + carboplatin)
Record the AEs and concomitant medications

Measure the weight

Physical examination

Clinical laboratory tests * (routine blood test, blood
chemistry, and urinalysis)

Confirm the inclusion/exclusion criteria
* If clinical laboratory screening tests (routine blood test, blood
chemistry, urinalysis) are performed within 7 days prior to the
first dose, then the results of the screening test can be used as
baseline.
If the subject meets the inclusion criteria, the following
procedures should be complete:

Randomization and grouping

Immunogenicity test (within 1 h prior to the study drug
infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel +
carboplatin)

Pharmacokinetic (PK) blood sampling (within 1 h
prior to the study drug infusion, immediately after
the study drug infusion [+5 min])


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
VEGF blood sampling (within 1 h prior to the study
drug infusion)

Record the AEs and concomitant medications
P42 Cycle 2 (week 4 ± 3 days)
Record the vital signs
Measure the weight
Physical examination
Clinical laboratory tests (routine blood test, blood chemistry,
and urinalysis)
Study drug infusion (IBI305 or bevacizumab)
Chemotherapeutic drug infusion (paclitaxel + carboplatin)
Record the AEs and concomitant medications

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood
chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study
drug infusion)

VEGF blood sampling (within 1 h prior to the study
drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel +
carboplatin)

Record the AEs and concomitant medications

Update based on study
visit schedule
P44 Cycle 5 (week 13 ± 3 days)

Record the vital signs

Update based on study


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Record the vital signs
Measure the weight
Physical examination
Clinical laboratory tests (routine blood test, blood chemistry,
and urinalysis)
Study drug infusion (IBI305 or bevacizumab)
Chemotherapeutic drug infusion (paclitaxel + carboplatin)
Record the AEs and concomitant medications

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood
chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study
drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel +
carboplatin)

Record the AEs and concomitant medications
visit schedule
P43 Cycle 3 (week 7 ± 3 days)
Record the vital signs
Measure the weight
Physical examination

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Update based on study
visit schedule
P43

Cycle 4 (week 10 ± 3 days)

Record the vital signs

Update based on study
visit schedule


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
Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests (routine blood test, blood
chemistry, and urinalysis)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel +
carboplatin)

Record the AEs and concomitant medications

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood
chemistry, and urinalysis)

PK blood sampling (within 1 h prior to the study
drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel +
carboplatin)

Record the AEs and concomitant medications
P43 Cycle 6 (week 16 ± 3 days)

Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests (routine blood test, blood
chemistry, and urinalysis)

Study drug infusion (IBI305 or bevacizumab)

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Clinical laboratory tests (routine blood test, blood
chemistry, and urinalysis)

Update based on study
visit schedule


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
Chemotherapeutic drug infusion (paclitaxel +
carboplatin)

Record the AEs and concomitant medications

PK blood sampling (within 1 h prior to the study
drug infusion)

VEGF blood sampling (within 1 h prior to the study
drug infusion)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel +
carboplatin)

Record the AEs and concomitant medications
P43 Cycle 7 and Subsequent Treatment Cycles (±3 Days)

Record the vital signs

Measure the weight

Physical examination

Record the vital signs

Measure the weight

Physical examination

12-Lead ECG

Update based on study
visit schedule
P43 End-Of-Treatment Visit

Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests (routine blood test, blood

Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests (routine blood test, blood

Update based on study
visit schedule


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chemistry, and urinalysis)

Immunogenicity test

Blood pregnancy test (for female subjects of
childbearing age only)

Tumor assessment (CT or MRI, completed within 7
days prior to this visit; not required to be repeated if it
has been performed within 6 weeks prior to this visit)

Subsequent anti-tumor therapy

Record the AEs and concomitant medications
chemistry, and urinalysis)

Immunogenicity test

PD blood sampling

Blood pregnancy test (for female subjects of
childbearing age only)

Tumor assessment (CT or MRI, completed within 7
days prior to this visit; not required to be repeated if it
has been performed within 6 weeks prior to this visit)

Subsequent anti-tumor therapy

Record the AEs and concomitant medications
P46 Study Completion
Completion of this clinical study is defined as 18 months after
the enrollment of the last subject.
The end of this study will be the18th month after randomization of
the last subject.

The definition of study
completion is clarified
P47 12-Lead ECG
The subject will undergo a 12-lead ECG during screening, and
also during the course of the study if deemed necessary by the
investigator.
12-lead ECG will be performed during screening. During the
study,
each medication visit requires an ECG examination.

Update based on study
visit schedule
P48Immunogenicity assessment
Blood samples are collected before the first dose, on D1 of
Cycle 4, and during the end-of-treatment visit for
immunogenicity assessment including testing of anti-drug
antibodies and neutralizing antibodies. Immunogenicity testing
Immunogenicity tests will be performed in all subjects at 3 blood
sampling time points: Within 1 hour prior to the first dose of the
study treatment (IBI305/bevacizumab) in C1, within 1 hour prior
to the administration of the study treatment in C4, and during the

The description of
blood sampling time
points for the
immunogenicity test is


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will be carried out at the relevant central laboratory. Details
regarding sample collection, processing, labeling, storage,
transport, and analysis are provided in the Central Laboratory
Manual.
end-of-treatment visit. Blood specimens that are positive for anti-
drug antibodies (ADA) after dosing will be further tested for
neutralizing antibodies (NAb). Samples were tested at the
designated central laboratory.
added
P48
None
6.15.6. Pharmacokinetics/pharmacodynamics
6.15.6.1 Pharmacokinetics
Study sites that are implementing version 2.0 of the study
protocol should collect PK samples until 140 subjects in this
study meet the requirements for PPK assessment (based on
the written notice of the sponsor). There are 6 PK sampling
time points: Within 1 h prior to the first dose of the study
treatment (IBI305/bevacizumab) in C1, immediately after the
first infusion (within 5 minutes), within 1 h prior to the dose
in C2, within 1 hour prior to the dose in C4, within 1 h prior
to the dose in C5, and within 1 h prior to the dose in C6.
Serum will be separated from the samples at the study site
and the serum samples will be analyzed at the designated
central laboratory.
6.15.6.2 Pharmacodynamics
Study sites that are implementing version 2.0 of the study
protocol should collect PD samples until 140 subjects in this

Based on the
recommendations of
CDE, the description
for the sampling at PK
and PD blood
collection points is
added


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study meet the requirements for VEGF testing (based on the
written notice of the sponsor). There are 4 VEGF sampling
time points: within 1 h prior to the first dose of the study
treatment (IBI305/bevacizumab) in C1, within 1 h prior to the
dose in C2, within 1 h prior to the dose in C6, and during the
end-of-treatment visit. Samples were tested at the designated
central laboratory.
P53 Adverse events
An adverse event is defined as any untoward medical occurrence
suffered by the subject of the clinical research, which does not
necessarily have a causal relationship with the treatment. An
adverse event can therefore be any unfavorable and unintended
sign (including an abnormal laboratory finding), symptom, or
disease temporally associated with the use of the investigational
drug, whether or not considered related to the investigational
drug
An AE refers to any untoward medical occurrence in a subject
after signing the informed consent form, and does not necessarily
have a causal relationship with the treatment. Thus, an AE can be
any unfavorable and unintended sign (including an abnormal
laboratory finding), symptom, or disease, whether considered
drug related.
Abnormalities resulting from PD are not considered as AEs.

The definition of
adverse events is
updated
P53 Serious adverse event
A serious adverse event does not necessarily have a causal
relationship with the investigational drug. It refers to any
untoward medical occurrence that (at any dose of the
investigational drug):
A SAE refers to an AE meeting at least one of the followings:
(1) Lead to death, except for deaths caused by PD.
(2) Life-threatening (a "life-threatening event" is defined as
an AE when the subject is at immediate risk of death at

Definition of serious
adverse event is
updated


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(1) Results in death.
(2) Is life-threatening (The term "life-threatening" refers to an
event in which the subject is at risk of death at the time of the
event; it does not refer to an event which hypothetically might
have caused death if it is more severe).
(3) Requires inpatient hospitalization or prolongation of existing
hospitalization: This does not include hospitalization and/or
surgical procedures scheduled to be conducted prior to or during
the study for a disease or disorder that exists prior to study
enrollment and has not worsened during the course of the study.
(4) Results in permanent or severe disability/incapacity.
(5) Results in congenital anomalies/birth defects.
(6) Other important medical events: Medical events that do not
necessarily result in death, are not life-threatening, and do not
require hospitalization, but may jeopardize the subject and may
require medical or surgical intervention to prevent one of the
aboves outcomes, are also considered SAEs.
Note: Hospitalization as a result of PD is not considered an
SAE.
Other Definitions
An adverse drug reaction (ADR) refers to any untoward
response related to the investigational drug after receiving any
the time, but does not include the case that may lead to
death only when the event worsens).
(3) Requires hospitalization or prolonged hospitalization,
excluding an emergency or outpatient visit. Subjects
with existing diseases or conditions prior to the
enrollment that do not worsen during the study, and
having hospitalization and/or surgery that was
scheduled before the study or during the study do not
meet the SAE criterion. Hospitalizations resulting
from PD are not considered as SAEs.
(4) Results in permanent or severe disability/incapacity.
(5) Results in congenital anomalies/birth defects.
(6) Other important medical events: The event that does not
result in death, is not life-threatening or does not
require hospitalization, but may jeopardize the health of
subjects and require medical intervention to prevent the
SAEs above, is considered as an SAE.


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dose.
An unexpected adverse drug reaction is any adverse reaction that
is not consistent with information known about the
investigational drug.
P53 Severity of adverse events
The severity of AEs will be assessed by CTCAE 4.03. The
classifications are as follows:

Grade 1 Mild; asymptomatic or mild symptoms;
clinical or diagnostic observations only; intervention
not indicated.

Grade 2 Moderate; minimal, local or noninvasive
intervention indicated; limiting age-appropriate
instrumental ADL (e.g. preparing meals, shopping for
groceries or clothes, using the telephone, managing
money, etc.)

Grade 3 Severe or medically significant but not
immediately life-threatening; hospitalization or
prolongation of hospitalization indicated; disabling;
limiting self care ADL (e.g. bathing, dressing and
undressing, feeding oneself, using the toilet, taking
medications, and not bedridden)
The severity of AEs is evaluated using the 5-level criteria of NCI
CTCAE v4.03.
For AEs not included in CTCAE v4.03, use the following CTCAE
general guidelines:

Grade 1: Mild; asymptomatic or mild signs; clinical or
diagnostic observations only; medical intervention not
indicated.

Grade 2: Moderate; minimal/local or noninvasive
intervention indicated; limiting age-appropriate
instrumental activities of daily life (such as cooking,
shopping, using the phone, financial management, etc.).

Grade 3: Severe or clinically significant but not
immediately life-threatening; hospitalization or
prolonged hospitalization indicated; disability; limited
ability of self-care (such as bathing, dressing,
undressing, eating, using the toilet, taking medication),

The description of the
NCI CTCAE v4.03
grading principles is
updated


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
Grade 4 Life-threatening; urgent intervention
indicated

Grade 5 Death related to AE
but not bedridden.

Grade 4: Life-threatening consequences; urgent
intervention indicated.

Grade 5: Death related to AE
P54 Relationship between adverse events and the investigational
drug
The relationship between the investigational drug and AE can be
classified into five categories: definitely related, probably
related, possibly related, unlikely related, and definitely
unrelated. Specific assessment criteria are as follows:
Table 7. Assessment criteria for causality between an adverse
event and the investigational drug
Parameters
Definitely
related
Probably
related
Possibly
related
Unlikely
related*
Definitely
not
related
Reasonable
temporal
relationship
Yes
Yes
Yes
Yes
No
The relationship between the study drugs and AEs can be
determined using the followings:

Judgment on the
correlation between
the AE and the
investigational product
is updated
Correlation
CRITERIA
Related

The occurrence of the AE is reasonably
related to the time sequence of dosing;

The investigational drug can more
reasonably explain the AE than the
other causes (such as the pre-existing
disease of the subject, environment,
toxicity, or other treatment received);

The AE resolves or is alleviated after
treatment interruption or dose
reduction;

The AE is consistent with the known
type of AEs of the suspicious drug or
similar drugs;

The AE occurs again after the drug
administration is resumed.


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Recognized
pharmacological
phenomenon
Yes
Yes
Yes
No
No
Positive
dechallenge
Yes
Yes
Yes or
No
Yes or
No
No
Positive
rechallenge
Yes
?**
?**
?**
No
Other
alternative
explanations
No
No
Yes
Yes
Yes
* Unlikely related = further observations required to make an
assessment;
? ** Rechallenge not permitted due to ethical reasons.
Possibly related 
The occurrence of the AE is reasonably
related to the time sequence of dosing;

The investigational drug can be used to
explain the AE with the same level of
rationality as other reasons (such as
the pre-existing disease of the subject,
environmental or toxic factors, or other
treatments received by the subject);

The AE resolves or is alleviated after
treatment interruption or dose
reduction (if applicable).
Possibly not
related

Other reasons can more reasonably
explain the AE than the investigational
drug (such as the pre-existing disease
of the subject, environmental or toxic
factors, or other treatments received by
the subject);

The AE does not resolve or be
alleviated after treatment interruption
or dose reduction (if applicable), or the
situation is unclear;

The AE does not occur again or the
situation of the AE is unknown after the
drug administration is resumed.
Unrelated

The occurrence of the AE is not
reasonably related to the time sequence
of dosing, or

The AE has other obvious causes (such
as the pre-existing disease of the
subject, environmental or toxic factors,


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or other treatments received by the
subject).
Cannot be
determined

The above information is unclear and
cannot be determined based on the
available information. Further follow-
up information is not accessible to the
investigator.
P54 Serious adverse event reporting
Any SAE that occurs during the trial should be reported in
accordance with SAE reporting procedures of regulatory
authorities or the ethics committee, regardless of whether the
event is related to treatment.
The investigator should take the following measures:

If necessary, take appropriate treatment measures
immediately;

Immediately (within 24 hours after becoming aware
of the event or obtaining new information about the
event) report the event to the sponsor's authorized
representative responsible for relevant safety
information using a method approved by the sponsor;

Document the SAE in the AE and SAE section of the
eCRF as well as in the source documents;

The investigator must immediately (within 24 hours)
submit the signed and dated SAE Report to the
independent ethics committee, NMPA (formerly
The investigator should immediately take appropriate medical
measures to treat any SAE that occurs during the trial. And the
SAE should be recorded in the tables of adverse events and
serious adverse events in the eCRF and source documents;
regardless of whether the SAE is related to the treatment, the
investigator must submit the completed SAE report form to the
sponsor within 24 hours of noticing the event. The investigator
shall urgently perform visit on missing information and provide a
complete SAE report for events that result in death or are life-
threatening.
Contact information for the reporting of SAE/pregnancy to the
sponsor: Fax: 021-31652800
SAE reporting email: drugsafety@innoventbio.com
When submitting the SAE report by email, it is recommended for
the investigator to encrypt the report file and send the report file

The time limit and
contact information for
the reporting of AEs
are updated


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CFDA), health administration department, and local
drug administration authorities;

Follow and document the course of the event, until the
event resolves or returns to baselines levels, or
becomes clinically stable.
In addition, the sponsor or its representative (such as CRO)
should report the SAE to the corresponding regulatory agencies
and other investigators in accordance with the requirements of
regulatory agencies and local regulations.
and password in separate emails.
At the same time, the investigator should follow the SAE reporting
procedures issued by relevant regulatory authorities or the
independent ethics committee.
The investigator should follow up the SAE until it disappears or
recovers to a result that the investigator believes it can be
explained without further follow-ups, such as clinical stability or
improvement. The time limit for the follow-up report and the
report of answered queries is the same as that for the initial
report.
P55 Management and follow-up of adverse events
All AEs observed from the signing of the ICF to the time
specified in the protocol (Table 8) must be followed. Refer to
Section 7.2.1.8 for the specific follow-up time.
Any AE observed from the time the subject signs the informed
consent form to the time specified in the protocol (Table 8) should
be recorded, reported, and visited in accordance with the
requirements of this protocol

The chapter of AEs is
updated
P55 Adverse events of special interest
The AESI for this study include:
Hypertension
Proteinuria
Gastrointestinal perforation
The AESI for this study include:

Gastrointestinal perforation

Procedural and wound healing complications

The chapter of AESIs
is updated


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Hemorrhage (cerebral hemorrhage, hematuria, and upper
gastrointestinal hemorrhage)
Cardiotoxicity
Thrombus
An AESI should also be reported as an SAE if the definition of
SAE is met.

Hemorrhage

Fistula

Hypertension

Thrombotic event

Posterior reversible encephalopathy syndrome
(PRES)

Proteinuria

Infusion-related reaction

Ovarian failure

Cardiac failure congestive
Among them, Grade 2 gastrointestinal perforation, procedural
and wound healing complications, hemorrhage, fistula, arterial
thrombotic events and proteinuria, and all above adverse events
of special interest (AESIs) of Grade 3 and above should be
reported as AESIs to the sponsor in accordance with the SAE
reporting time limit and procedures (see 7.2.1.4 for details) even
if they do not meet the SAE definition.
P55 Pregnancy
Any pregnancy during the study, though not an SAE, must be
reported using the Clinical Trial Pregnancy Report. To ensure
Bevacizumab may be harmful to the fetus. Subjects or female
partners of male subjects must use an effective form of
contraception during the 6 months after the last dose. If any 
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subject safety, the investigator must submit the report to the
sponsor or the sponsor's representative within 24 hours after
becoming aware of the event. Pregnancies must be followed to
determine the outcome (including early termination) and the
condition of the mother and the baby. Complications and
termination of pregnancy due to medical reasons should be
reported as AE or SAE. A spontaneous abortion should be
reported as an SAE.
female subject or the female partner of any male subject
becomes
pregnant during
the
study,
the drug
should be
discontinued immediately and the investigator should be notified.
The investigator should report the pregnancy to the sponsor
within 24 h of knowing the event by filling out the pregnancy form.
The Investigator should also discuss with the subject (and the
female partner of the male subject) regarding the risk of
continuing pregnancy and its possible impact on the fetus. The
investigator should follow up the pregnancy to determine its
outcome (including abortion) and the status of the mother and the
baby for not less than 8 weeks after delivery, and report the
follow-up results as the pregnancy follow-up report to the sponsor
according to the procedure and time limit the same as those for
the first report. Complications and termination of pregnancy due
to medical reasons should be reported as AE or SAE. A
spontaneous abortion should be reported as an SAE. For any
congenital abnormalities/birth defects or SAEs of the mother
and child during the perinatal period, they should be recorded
and reported in accordance with the procedure and time limit
for reporting SAEs.
and time limit of
pregnancy report are
updated
P55 Summary of adverse event collection, documentation, and
reporting
All adverse events that occur from the signing of the ICF to the
time specified in the protocol (Table 8) must be collected and
documented in the AE page of the eCRF regardless of severity
All AEs occurring from the time the subject signs the informed
consent form to the time specified in the protocol (Table 8)
(including SAEs and non-SAEs), regardless of their severity,
The reporting and follow-
up periods of AEs are
updated


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(all SAEs and non-serious AEs).
The investigator must fill out all the required information,
including the description of the AE, start date, end date, severity,
measures taken, outcome, seriousness, and causality with the
investigational drug. Each AE should be documented separately.
Table 8. Reporting and follow-up of adverse events
Reporting time
limit
Visit time limit
AEs
From the signing
of the ICF until 28
days after the last
dose of the study
treatment
Until resolution or
28 days after the
last dose of the
study treatment
Adverse events of
special interest
(AESIs)
From the signing
of the ICF until 6
months after the
last dose of the
study treatment
Until resolution or
6 months after the
last dose of the
study treatment
Serious adverse
event
From the signing
of the ICF until 6
months after the
last dose of the
study treatment
Until resolution
(treatment-related)
or 6 months after
the last dose of the
study treatment
(not treatment-
related)
Pregnancy
From the first
dose until 6
months after the
Until the end of
the event
must be collected and recorded on the AE page of the eCRF.
Table 18 . Report and follow-up of adverse events
Reporting Time Limit Visit Time Limit
AEs
From signing of the
informed
consent
form
to
3
months
after the last dose of
the study treatment
Until
resolved
or
explainable
stable
determined
by
the
investigator
AESI
From signing of the
informed
consent
form
to
3
months
after the last dose of
the study treatment
Until
resolved
or
explainable
stable
determined
by
the
investigator
SAE
From signing of the
informed
consent
form
to
3
months
after the last dose of
the study treatment
Until
resolved
or
explainable
stable
determined
by
the
investigator
Pregnancy
From the first dose
until 6 months after
the last dose of the
study treatment
Until the outcome of the
event is available, and the
health conditions of the
newborn
should
be
followed up for at least 2
months according to the


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last dose of the
study treatment
protocol
P55
None
Precautions for AE documentation
Diagnosis, signs, and symptoms
If a diagnosis is already made, the eCRF should record the
diagnosis instead of individual symptoms and signs
(such as hepatic failure rather than jaundice, transaminase
increased, and asterixis). However, if the signs and symptoms
cannot
be
attributed
to
a
definitive
diagnosis,
each
independent event should be documented in the eCRFs as an
AE or SAE. Update the report with visit information if a
diagnosis is confirmed later.
AEs secondary to other events
Generally, AEs secondary to other events (such as result of
another event or clinical sequelae)
should be documented as the primary event, unless the event
is severe or an SAE. However, clinically significant secondary
events should be recorded as independent adverse events in
the eCRFs if they occur at different times than the primary
event. If the relationship between events is unclear, document
them as separate events in the eCRFs.

The description of
adverse event records
is added


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Ongoing or recurrent AEs
An ongoing AE refers to an event that does not resolve
and is ongoing between two assessment time points. These AEs
should only be documented once in the eCRFs. The initial
severity should be documented, and the information should be
updated if the event exacerbates.
Recurring AEs refer to AE that have resolved between the two
time points of
assessment but subsequently occur. These events should be
independently documented in the eCRFs.
Abnormalities in laboratory tests/vital signs
Not all abnormalities in laboratory tests/vital signs should be
reported as AEs. Only the abnormalities in laboratory
tests/vital signs that meet the following criteria are reported as
AEs:

Accompanied with clinical symptoms

Lead to changes in the dose of the study treatment
(such as dose adjustment, dose interruption, or
permanent drug withdrawal)

Require medical intervention or changes in
concomitant therapy


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
Judged by the investigator as clinically significant
It is the responsibility of the investigator to review all
abnormal laboratory test results and vital signs, and to
determine whether each abnormal laboratory test result or
vital signs should be reported as AEs.
If clinically significant laboratory abnormalities or abnormal
vital signs are characteristic of a disease or syndrome (such as
increased levels of alkaline phosphatase and total bilirubin
caused by cholecystitis that are higher than 5 times the upper
limit of normal), only the diagnosis is recorded on the AE
report
of the eCRF (i.e., cholecystitis). Conversely, the
laboratory abnormalities or abnormal vital signs are recorded
on the AE report of the eCRF, and it should be indicated that
whether the test value is above or below the normal range (for
example,
it
should
be
recorded
as
"blood
potassium
increased" instead of "blood potassium abnormal"). If there is
a standard clinical term corresponding to the laboratory
abnormalities or abnormal vital signs, the clinical term should
be recorded on the eCRF
(such as "anemia", instead of "hemoglobin decreased"). The
same
clinically
significant
laboratory
abnormalities
or
abnormal vital signs found during multiple follow-ups should
not be repeatedly recorded as AEs or SAEs in the eCRF unless


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there is a change in its severity or etiology.
Death
During the entire course of the study, all the deaths that
occurred within 90 days after the last dose were documented
in the Death Report Form in the eCRFs and reported to the
sponsor
timely,
regardless
of
the
causality
with
the
investigational drug.
When recording a death event, if there is an AE leading to the
death, a single medical concept should be used on the AE
report of the eCRF to record the event leading to the death,
and the event should be reported as an SAE in an expedited
manner; if the cause of the death is unknown at the time of
reporting , "Death with Unknown Cause" should be recorded
on the AE report of the eCRF. The "Death with Unknown
Cause" should be reported as an SAE in an expedited manner
before further investigation is carried out to find the exact
cause of death.
If the cause of death is confirmed to be PD, then the event
should not be documented and reported as an AE/SAE.
However, the event should be documented in the Mortality
Report Form of the eCRF and reported to the sponsor timely.
Pre-existing medical conditions
Symptoms/signs presenting during the screening period will


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be recorded and reported as AEs only if their severity,
frequency,
or
property
becomes
aggravated
(except
for
worsening of the studied disease). The relative change should
be documented, such as "increased frequency of headaches".
Hospitalization and prolonged hospitalization, or surgery
Any
AE
that
results
in
hospitalization
or
prolonged
hospitalization should be documented and reported as an
SAE, except for the following situations:

Hospitalization or prolonged hospitalization as
required by study protocol (such as for dose
administration, efficacy evaluation, etc.)

Hospitalization due to a pre-existing medical
condition that remains stable, e.g. elective
surgery/therapy scheduled prior to the study.
However, elective surgery/therapy required because of the
exacerbated condition during the study (e.g. surgery/therapy
required earlier than scheduled) should be considered as an
AE.
The investigator should fill in all required information,
including AE terms
(diagnostic terms, or the record of symptoms and signs
including
laboratory
test
abnormalities
if
there
is
no


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diagnosis), start date, end date, severity level, whether it is an
AESI,
measures
taken
for
the
investigational
product,
treatment
given
for
the AE,
outcome,
seriousness, and
relationship with the investigational product. If the signs and
symptoms cannot be attributed to a definitive diagnosis, each
AE should be documented independently.
Progressive disease
For any event, if it can be clearly determined that the event is
caused by progressive disease, the event is not reported as an
AE. Hospitalization or death caused by progressive disease
does not need to be reported in an expedited fashion.
Lack of Efficacy
When the disease treated by the study treatment deteriorates,
it may not be possible to determine whether it is due to the
lack of efficacy or the occurrence of an adverse event. In this
case, unless the investigator believes that the deterioration of
the condition is related to the study treatment, such changes
are all regarded as the lack of efficacy rather than adverse
events.
Overdose
When there is an accompanying AE, the AE should be
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should be recorded
on the eCRF.
P57 Sample Size Determination
It will require 200 subjects in each treatment group (400 in total)
to demonstrate clinical equivalence between IBI305 +
paclitaxel/carboplatin and bevacizumab + paclitaxel/carboplatin
with more than 80% power.
The sample size is estimated based on the following
assumptions:

The actual difference in ORR between subjects in the
IBI305 and bevacizumab arms is 0

The ORR of subjects in the bevacizumab arm is about
54.4%

The equivalence margin is (-15%, 15%)

The significance level of the two one-side test is 0.05

1:1 randomization
Based on the above assumptions, 189 subjects are required for
each treatment group (378 in total). The sample size is expanded
to 200 subjects for each treatment group (400 in total) after
taking dropouts into consideration. The sample size was
estimated using PASS 2013.
A number of 218 subjects for each group (436 subjects in total)
can provide 80% test power to confirm the clinical equivalence
between
the
treatments
of
IBI305
in
combination
with
paclitaxel/carboplatin and bevacizumab in combination with
paclitaxel/carboplatin.
The
sample
size
was
estimated
based
on
the
following
assumptions:

The ORRs between IBI305 and bevacizumab group are
equivalent

The ORR of subjects in the bevacizumab groups is set
to 50.0%

The equivalence margin is taken as (-12.5%, 16.7%)

The significance level of the two-sided test is 0.05

The ratio of randomization is 1:1
Based on the above hypotheses, a number of 218 subjects for each
group is required (436 subjects in total). The sample size was
estimated using PASS 2013.

Based on the
recommendations of
CDE, the statistical
hypotheses and the
sample size are
updated


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P57 Statistical Population
Intention-to-Treat (ITT): All randomized subjects who received
the study treatment.
Intention-to-Treat (ITT): All randomized subjects.

The definition of ITT
is clarified
P57 Statistical Population
None
PK analysis set (PKAS): Includes subjects in the FAS with at
least one PPK measured value.
Pharmacodynamic analysis set (PDAS): Includes all subjects
in the FAS set with at least one PD measured value.

Based on the
recommendations of
CDE, the definitions
of analysis sets of
pharmacokinetic and
pharmacodynamic
evaluations are added
for the objectives of
the exploratory study
P58 Interim analysis
There is no interim analysis planned for this study.
Deleted from the original text

Correction
P58 Multiple comparisons and adjustments to multiplicity
Not applicable.
The α adjustment for multiple comparisons is not considered.

Clarification
P60 Antibody and efficacy analysis
Subjects who develop antibodies during the clinical study will
be summarized in detail. The difference in efficacy between
subjects with and without antibodies will be compared if
necessary.
Subjects who develop antibodies during the clinical study will be
summarized in detail. The difference in efficacy between subjects
with and without antibodies will be compared if necessary.

The analytical method
of immunogenicity is
updated


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Changes
in
PK
parameters
and
steady-state
trough
concentrations of subjects with positive ADA are analyzed.
P60
None
8.5.5 Exploratory analysis
Pharmacodynamic parameters: The changes in the serum
VEGF level at different time points are described, and inter-
group comparisons are carried out when necessary (based on
the PD dataset)
Steady-state trough concentrations of the drug: The level of
trough
concentration
is
described
and
inter-group
comparisons are carried out when necessary (based on the
PPK dataset)

Based on the
recommendations of
CDE, the
pharmacokinetic and
pharmacodynamic
evaluations are added
as analytical methods
for the objectives of
the exploratory study
P60 Interim analysis
No interim analysis is planned for this study.
No interim analysis is planned.

Correction
P60
None
8.5.7 Stratified analysis
Efficacy analysis of different levels of subjects is conducted
based on the random stratification factors

A stratified analysis is
added


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CLINICAL STUDY PROTOCOL
Study Title:
A randomized, double-blinded, multi-center phase III study
comparing the efficacy and safety of IBI305 plus paclitaxel/carboplatin
versus bevacizumab plus paclitaxel/carboplatin in treatment-naive
subjects with advanced or relapsed non-squamous non-small cell
lung cancer
Protocol No.:
CIBI305A301
Version and Date:
Version 1.0/Jun. 2, 2016
Product Name:
Recombinant anti-VEGF humanized monoclonal antibody
injection (IBI305)
Study Phase:
Phase III
Sponsor:
Innovent Biologics (Suzhou) Co., Ltd.
No. 168 Dongping Street, Suzhou Industrial Park, Jiangsu, China
Sponsor Contact:
Zhou Hui (Medical Director)
Tel: （+86）0512-69566088-8067
E-mail: hui.zhou@innoventbio.com
Hou Jiagang (Clinical Operations Director)
Tel: （+86）0512-69566088-8062
E-mail：jiagang.hou@innoventbio.com
Confidentiality Statement
This document is only for the review of investigators, research consultants or relevant personnel, and independent
ethics committee. Without the written approval of the sponsor, the contents of this document shall not be disclosed
to any third party.


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SIGNATURE PAGE
Protocol Title: A randomized, double-blinded, multi-center phase III study comparing the efficacy
and safety of IBI305 plus paclitaxel/carboplatin versus bevacizumab plus paclitaxel/carboplatin in
treatment-naive subjects with advanced or relapsed non-squamous non-small cell lung cancer
Protocol No.: CIBI305A301
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PROTOCOL SYNOPSIS
Sponsor/Company:
Innovent Biologics (Suzhou) Co., Ltd.
Investigational drug:
IBI305
Active Ingredient:
Recombinant anti-VEGF humanized monoclonal antibody
Study Title:
A randomized, double-blinded, multi-center phase III study comparing the efficacy
and safety of IBI305 plus paclitaxel/carboplatin versus bevacizumab plus
paclitaxel/carboplatin in treatment-naive subjects with advanced or relapsed non-
squamous non-small cell lung cancer
Protocol No.:
CIBI305A301
Coordinating Investigator:
Zhang Li
Coordinating Center:
Sun Yat-Sen University Cancer Center
Expected study duration: Each subject will receive treatment every 3-week
until progressive disease (PD), unacceptable toxicity, withdrawal of informed
consent, lost to follow-up or death (whichever comes first).
The end of the study is defined as the 18th month after the randomization of
the last subject.
Phase: III
Study Objectives:
Primary Objective:

To compare the objective response rate (ORR) of IBI305 plus paclitaxel/carboplatin versus bevacizumab
plus paclitaxel/carboplatin for the treatment of advanced or relapsed non-squamous non-small cell lung
cancer (NSCLC)
Secondary Objectives:

To compare the duration of response (DOR), progression-free survival (PFS), disease control rate (DCR),
and overall survival (OS) of IBI305 plus paclitaxel/carboplatin versus bevacizumab plus
paclitaxel/carboplatin for the treatment of advanced or relapsed non-squamous NSCLC

To compare the safety and immunogenicity of IBI305 plus paclitaxel/carboplatin versus bevacizumab
plus paclitaxel/carboplatin for the treatment of advanced or relapsed non-squamous NSCLC


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Study design:
This is a randomized, double-blinded, multi-center phase III study. The study planned to enroll and randomize
400 subjects with non-squamous NSCLC in a 1:1 ratio to IBI305 plus paclitaxel/carboplatin group or bevacizumab
plus paclitaxel/carboplatin group. Stratifying factors include age (< 60 vs. ≥60 years old) and EGFR status (wild
type vs. mutant).
Each treatment cycle is 3 weeks for both groups. 15 mg/kg IBI305 or bevacizumab is administered on D1 of each
cycle along with paclitaxel/carboplatin. Subjects will receive up to 6 treatment cycles of combination therapy until
PD, unacceptable toxicity, withdrawal of informed consent, loss to follow-up, or death (whichever comes first).
Then subjects receive monotherapy, that is, discontinuing paclitaxel/carboplatin while continuing therapy with
IBI305 or bevacizumab. The monotherapy continues every 3 weeks. On D1 of each treatment cycle, subjects will be
administered 7.5 mg/kg of either IBI305 or bevacizumab until PD, unacceptable toxicity, withdrawal of informed
consent, loss to follow-up, death, or end of study (whichever comes first).
During the study, a CT or an MRI will be performed every 6 weeks (± 7 days) and be determined whether the study
treatment will be continued by investigators at each site through tumor assessments until PD, withdrawal of
informed consent, lost to follow-up, death, start of other anti-tumor therapies, or end of study. If subjects discontinue
the study treatment for reasons other than PD, tumor assessments will be continued until PD, withdrawal of
informed consent, loss of follow-up, death, start of other anti-tumor therapies, or end of study. If subjects discontinue
the study treatment for PD, the investigators will make telephone follow-up every 12 weeks (± 7 days) to collect
information of subsequent anti-tumor therapies and survival until withdrawal of informed consent, lost to follow-up,
death, or end of study.
Number of Subjects:
400
Diagnosis and main inclusion
criteria:
Inclusion Criteria:
Subjects must meet all of the following inclusion criteria to be enrolled in the study:
1)
Sign the formed consent form
2)
Male or female ≥18 and ≤70 years old
3)
Histologically or cytologically confirmed unresectable locoregionally
advanced (stage IIIb), metastatic (stage IV), or relapsed non-squamous
NSCLC; mixed tumors should be categorized according to the main cell
types
4)
Histologically confirmed EGFR wild type
5)
Histologically confirmed EGFR mutation type, but subjects who have not
received EGFR-TKI treatment due to various reasons
6)
Must have at least one measurable target lesion (as per RECIST 1.1)
7)
Eastern Cooperative Oncology Group Performance Status (ECOG PS)
score of 0–1


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8)
Expected survival ≥6 months
9)
Laboratory results during screening:
Routine blood test: WBC ≥3.0 × 109/L, ANC ≥1.5 × 109/L,
platelets ≥100 × 109/L, and hemoglobin ≥90 g/L
Hepatic function: TBIL < 1.5 × ULN; ALT and AST < 2.5 × ULN
for subjects without liver metastasis, or ALT and AST < 5 × ULN
for subjects with liver metastasis
Renal function: SCr ≤1.5 × ULN or CrCl ≥50 mL/min, and urine
protein < 2+ in routine urinalysis. Subjects with urine protein ≥2+
from urinalysis dipstick at baseline, a 24-h urine should be collected
with total protein content < 1 g
INR ≤1.5 and PTT or aPTT ≤1.5 × ULN within 7 days prior to the
study treatment
10)
Able to comply with study protocol
11)
Female and male subjects of childbearing age, and partners of these male
subjects must agree to use effective contraceptive measures (such as
abstinence, sterilization, oral contraceptives, medroxyprogesterone
injections or contraceptive implants) during the study and for 6 months
after the infusion of the study drug
Exclusion Criteria:
Subjects meeting any of the followings will not enrolled in the study:
1)
Prior chemotherapy or targeted therapy (such as monoclonal antibody or
tyrosine kinase inhibitor) for the treatment of the current stage of disease
(Stage IIIb not suitable for multidisciplinary treatment, stage IV or
relapsed disease). Prior surgery and radiotherapy are permitted, provided
that the criteria outlined in the study protocol are met. Subjects who received
prior adjuvant therapy and relapsed within 6 months are not eligible
2)
Mixed non-small cell and small cell carcinoma, or mixed adenosquamous
carcinoma predominantly containing squamous cell carcinoma component
3)
History of hemoptysis within 3 months prior to screening, with a volume
of blood greater than 2.5 mL each time
4)
Radiographic evidence of tumor invasion in great vessels. The
investigator or the radiologist must exclude subjects with tumors that are
fully contiguous with, surrounding, or extending into the lumen of a great
vessel (such as pulmonary artery or superior vena cava)
5)
History of brain metastasis, spinal cord compression, or carcinomatous


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meningitis, or brain metastasis confirmed by CT or MRI during screening
6)
Subjects who received radical thoracic radiotherapy within 28 days prior
to enrollment; subjects who received palliative radiation for non-thoracic
bone lesions within 2 weeks prior to the first dose of the study drug
7)
Subjects with severe skin ulcers or fracture, or having major surgery
within 28 days prior to randomization or expecting to have major surgery
during the study
8)
Subject who received minor surgery (including catheterization) within
48 h prior to the first dose of the study drug
9)
Currently or recently (within 10 days prior to the first dose of study drug)
used aspirin (> 325 mg/day) or other nonsteroidal anti-inflammatory
drugs known to inhibit platelet function
10)
Currently or recently (within 10 days prior to the first dose of study drug)
received treatment with full dose oral or parenteral anticoagulants or
thrombolytic agents. However, anticoagulants for prophylaxis are accepted.
11)
Subjects with inherited hemorrhagic tendency or coagulopathy, or history
of thrombosis
12)
Uncontrolled hypertension (systolic greater than 150 mmHg and/or
diastolic greater than 100 mmHg), history of hypertensive crisis or
hypertensive encephalopathy
13)
Any unstable systemic disease including but not limited to: active
infection, unstable angina, cerebrovascular accident or transient cerebral
ischemia (within 6 months prior to screening), myocardial infarction
(within 6 months prior to screening), cardiac failure congestive (NYHA
Class ≥II), severe arrhythmia requiring medication, and liver, kidney or
metabolic disease
14)
History of the following diseases within 6 months prior to screening:
gastrointestinal ulcers, gastrointestinal perforation, corrosive esophagitis
or gastritis, inflammatory bowel disease or diverticulitis, abdominal
fistula, or intra-abdominal abscess
15)
Subjects with tracheoesophageal fistula
16)
Clinically significant third spacing (such as ascites or pleural effusion
that are uncontrollable by drainage or other treatments)
17)
Subjects with pulmonary fibrosis history or active pneumonia shown on
CT during screening
18)
History of malignant tumors other than NSCLC within 5 years prior to
randomization, except for adequately treated cervical carcinoma in situ,
basal or squamous cell skin cancer, locoregional prostate cancer after


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radical surgery, ductal carcinoma in situ after radical surgery
19)
Subjects with autoimmune disease
20)
Subjects with positive test result of HBsAg, and peripheral blood HBV
DNA titer ≥1 × 103 copies/L; subjects with positive test result of HBsAg
and peripheral blood HBV DNA titer < 1 × 103 copies/L are eligible if
the investigator determine that the subject's chronic hepatitis B is stable
and participation in the study would add no further risks to the subject
21)
Subjects who are tested positive for HCV antibody, HIV antibody or
syphilis
22)
Subjects with known history of allergic diseases or allergic physique
23)
Received treatment with other investigational drugs or participated in
another interventional study within 30 days prior to screening
24)
History of alcohol or drug abuse
25)
Female subjects who are pregnant or breastfeeding, or expected to be
pregnant or breastfeeding during the study
26)
Known allergies to bevacizumab or any of its excipients, or any
chemotherapeutic agents
27)
Other conditions unsuitable for the inclusion as determined by the investigator
Investigational Drug, Dosage,
and Route of Administration:
IBI305: 15 mg/kg in combination chemotherapy and 7.5 mg/kg monotherapy,
administered via intravenous infusion on D1 of every 3-week treatment cycle
until PD, unacceptable toxicity, withdrawal of informed consent, lost to follow-
up, death, or end of study (whichever comes first)
Control Drug, Dosage, and
Route of Administration:
Bevacizumab: 15 mg/kg in combination chemotherapy and 7.5 mg/kg
monotherapy, administered via intravenous infusion on D1 of every 3-week
treatment cycle until PD, unacceptable toxicity, withdrawal of informed consent,
lost to follow-up, death, or end of study (whichever comes first)
Chemotherapy:
Paclitaxel: 175 mg/m² administered via intravenous infusion on D1 of every
3-week treatment cycle for up to 6 cycles until PD, unacceptable toxicity,
withdrawal of informed consent, loss of follow-up, or death.
Carboplatin: Areas under the concentration-time curve (AUC) = 6.0 administered
via intravenous infusion on D1 of every 3-week treatment cycle for up to 6 cycles
until PD, unacceptable toxicity, withdrawal of informed consent, loss of follow-up,
or death.


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Evaluation criteria:
Efficacy endpoints:
Primary efficacy endpoint:

Objective response rate (ORR)
Secondary efficacy endpoints:

Duration of response (DOR)

Progression-free survival (PFS)

Disease control rate (DCR)

Overall survival (OS)
Safety endpoints:

Vital signs

Physical examination

Laboratory tests (routine blood test, blood chemistry, and urinalysis)

12-Lead ECG

Adverse event (AE, including treatment-emergent AE (TEAE)), AE of special interest (AESI)
(hypertension, proteinuria, gastrointestinal perforation, hemorrhage [cerebral hemorrhage, hematuria and
upper gastrointestinal hemorrhage], cardiotoxicity, and thrombosis), and serious adverse event (SAE)

Immunogenicity: Positive rates of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs)
Statistical methods:
Sample size calculation:
A number of 200 subjects for each group (400 subjects in total) will provide over 80% power to confirm the clinical
equivalence between IBI305 plus paclitaxel/carboplatin and bevacizumab plus paclitaxel/carboplatin. Estimation of
sample size: If the significance level of the two one-sided test is 0.05, the ORR between IBI305 and bevacizumab
group is about 54.4%, with an equivalence margin of (-15%, 15%). Based on the above assumptions, 189 subjects
are required for each group (378 subjects in total). The sample size is expanded to 200 subjects for each group
(400 subjects in total) after taking dropouts into consideration.
Efficacy analysis:
Clinical equivalence will be determined by whether the 90% confidence interval (CI) of the difference in ORR
between the IBI305 and bevacizumab arms falls within the preset margin of (-15% to 15%). The ORR and 95% CI
of two groups, ORR difference and 90% CI, and ORR ratio and 90% CI will be estimated using the generalized
linear model (GLM, including groups and stratification factors).


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Median survival (OS) and survival curves will be estimated using the Kaplan-Meier method. The hazard ratio (HR)
and 95% CI of two groups will be estimated using the Cox model. DORs and PFSs will be analyzed by the same
method as the median survivals. DCR will be analyzed using the same method for primary efficacy endpoints, but
an equivalence test will not be conducted.
Safety analysis:
All adverse events (AE) will be coded using MedDRA and graded according to CTCAE v4.03. All treatment-
emergent adverse events (TEAEs), Grade 3 or greater TEAEs, serious adverse events (SAEs), investigational drug-
related TEAEs, investigational drug-related SAEs, TEAEs leading to treatment discontinuation, TEAEs leading
to study termination, and adverse events of special interest (AESIs) will be listed based on system organ class,
preferred terms, and groups and the numbers of corresponding subjects and percentages will be summarized.
In addition, the severity of TEAEs and the correlation with the study drug will also be summarized by system
organ class, preferred terms, and treatment groups.
Measured values and changes from baseline for vital signs, physical examination, laboratory tests and 12-lead ECG
will be analyzed using descriptive statistics. Baseline results and worst results during the study will be presented in
cross tabulation.
The number and percentage of subjects who developed anti-drug antibodies and neutralizing antibodies during the
study will be summarized by treatment group.


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TABLE OF CONTENTS
SIGNATURE PAGE..................................................................................................................... 2
PROTOCOL SYNOPSIS..............................................................................................................3
TABLE OF CONTENTS............................................................................................................ 10
LIST OF ABBREVIATIONS AND DEFINITIONS................................................................15
1
INTRODUCTION............................................................................................................... 17
1.1 Study Background........................................................................................................... 17
1.1.1 Disease background............................................................................................... 17
1.1.2 Investigational drug................................................................................................19
1.1.2.1 Description of investigational drug..............................................................19
1.1.2.2 Preclinical studies........................................................................................ 20
1.1.2.3 Clinical studies.............................................................................................22
1.2 Study Principles and Risk/Benefit Assessment...............................................................22
1.2.1 Study principles and dose selection....................................................................... 22
1.2.2 Risk/benefit assessment......................................................................................... 23
2
STUDY OBJECTIVES....................................................................................................... 24
2.1 Primary Objective............................................................................................................24
2.2 Secondary Objectives......................................................................................................24
3
STUDY PLAN......................................................................................................................25
3.1 Overview of Study Design.............................................................................................. 25
3.2 Study Design Discussion.................................................................................................26
4
STUDY POPULATION...................................................................................................... 27
4.1 Inclusion Criteria.............................................................................................................27
4.2 Exclusion Criteria............................................................................................................29
4.3 Screening Failure.............................................................................................................31
4.4 Subject Restrictions.........................................................................................................31
4.5 Subject Withdrawal and Replacement............................................................................ 31
5
STUDY TREATMENT.......................................................................................................33
5.1 Therapies by Study Drugs............................................................................................... 33
5.2 Chemotherapy................................................................................................................. 33
5.3 Dose Adjustment of Each Study Drug............................................................................ 33


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5.3.1 General principles.................................................................................................. 33
5.3.2 Dose adjustments of study drugs........................................................................... 36
5.3.3 Dose adjustments of chemotherapy....................................................................... 41
5.4 Study Drug Properties..................................................................................................... 46
5.6 Packaging, Labeling, and Storage................................................................................... 46
5.7 Subjects Allocation..........................................................................................................47
5.8 Blinding...........................................................................................................................47
5.9 Concomitant Medications and Treatments......................................................................47
5.9.1 Prohibited medications...........................................................................................47
5.9.2 Medications allowed.............................................................................................. 48
5.9.3 Treatment after study treatment............................................................................. 48
5.10 Treatment Compliance.................................................................................................. 48
5.11 Study Drug Count..........................................................................................................48
6
STUDY PROCEDURE....................................................................................................... 49
6.1 Screening Visits (D -28 to D -1)..................................................................................... 50
6.2 Baseline Visits (D1 of cycle 1)........................................................................................51
6.3 Cycle 2 (week 4 ± 3 days)...............................................................................................52
6.4 Cycle 3 (week 7 ± 3 days)...............................................................................................52
6.5 Cycle 4 (week 10 ± 3 days).............................................................................................52
6.6 Cycle 5 (week 13 ± 3 days).............................................................................................53
6.7 Cycle 6 (week 16 ± 3 days).............................................................................................53
6.8 Cycle 7 and Subsequent Treatment Cycles (±3 Days)....................................................54
6.9 End-Of-Treatment Visit.................................................................................................. 54
6.10 Disease Progression Visit..............................................................................................56
6.11 Survival Follow-Up.......................................................................................................56
6.12 Study Completion..........................................................................................................56
6.13 Tumor Assessment........................................................................................................ 56
6.14 Clinical Laboratory Evaluations....................................................................................57
6.15 Vital Signs, Physical Examinations, and Other Safety Assessments............................59
6.15.1 Vital signs............................................................................................................ 59
6.15.2 Height and weight................................................................................................ 60


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6.1.5.3 Physical examinations.........................................................................................60
6.15.4 12-Lead ECG....................................................................................................... 62
6.15.5 Immunogenicity assessment.................................................................................62
6.15.6 EGFR testing........................................................................................................62
7
STUDY ASSESSMENTS.................................................................................................... 67
7.1 Efficacy Assessment........................................................................................................67
7.1.1 Primary efficacy endpoint......................................................................................67
7.1.2 Secondary efficacy endpoints................................................................................ 67
7.2 Safety Assessments......................................................................................................... 68
7.2.1 Adverse events....................................................................................................... 68
7.2.1.1 Definition.....................................................................................................68
7.2.1.2 Severity of adverse events........................................................................... 69
7.2.1.3 Relationship between adverse events and the investigational drug.............69
7.2.1.4 Serious adverse event reporting...................................................................70
7.2.1.5 Management and follow-up of adverse events............................................ 70
7.2.1.6 Adverse events of special interest................................................................70
7.2.1.7 Pregnancy.....................................................................................................71
7.2.1.8 Summary of adverse event collection, documentation, and reporting.........71
8
STATISTICS........................................................................................................................72
8.1 Sample Size Determination.............................................................................................72
8.2 Statistical Population.......................................................................................................72
8.3 General Principles for Statistical Analyses..................................................................... 73
8.4 Statistical Methods.......................................................................................................... 73
8.4.1 Adjustments for covariates.....................................................................................73
8.4.2 Managing dropouts and missing data.....................................................................73
8.4.3 Interim analysis......................................................................................................73
8.4.4 Multi-center study..................................................................................................73
8.4.5 Multiple comparisons and adjustments to multiplicity..........................................73
8.5 Statistical Analyses..........................................................................................................73
8.5.1 Subject distribution................................................................................................ 73
8.5.2 Demographics and other baseline characteristics.................................................. 74


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8.5.3 Compliance and drug exposure..............................................................................74
8.5.4 Efficacy.................................................................................................................. 74
8.5.4.1 Primary efficacy endpoint............................................................................74
8.5.4.2 Secondary efficacy endpoints...................................................................... 75
8.5.4.3 Sensitivity analysis...................................................................................... 75
8.5.4.4 Antibody and efficacy analysis....................................................................75
8.5.5 Interim analysis......................................................................................................75
8.5.6 Safety analysis........................................................................................................76
8.5.6.1 Adverse events.............................................................................................76
8.5.6.2 Laboratory tests............................................................................................76
8.5.6.3 ECG examinations.......................................................................................76
8.5.6.4 Vital signs, physical examinations, and other safety examinations.............76
8.5.6.5 Concomitant medications............................................................................ 76
9
QUALITY ASSURANCE AND QUALITY CONTROL.................................................77
9.1 Clinical Monitoring......................................................................................................... 77
9.2 Data Management/Coding...............................................................................................78
9.3 Audits and Inspections.................................................................................................... 79
10
ETHICS................................................................................................................................ 80
10.1 Independent Ethics Committee..................................................................................... 80
10.2 Implementation of Ethical Principles............................................................................80
10.3 Subject Information and Informed Consent.................................................................. 81
10.4 Protection of Subject Data.............................................................................................81
11
STUDY MANAGEMENT...................................................................................................82
11.1 Organizational Structure................................................................................................82
11.1.1 Independent review committee............................................................................ 82
11.2 Archiving of Study Documents.....................................................................................82
11.3 Access to Source Data/Documents................................................................................83
11.4 Protocol Revisions.........................................................................................................83
11.5 Investigator's Responsibilities.......................................................................................83
11.6 Study Termination.........................................................................................................84
11.7 Publishing Policies........................................................................................................ 84


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11.8 Finance and Insurance...................................................................................................84
12
REFERENCES.................................................................................................................... 85
13
APPENDIX...........................................................................................................................86
13.1 Appendix I.....................................................................................................................86
13.2 Appendix II....................................................................................................................87
13.3 APPENDIX 3................................................................................................................ 88
14
INVESTIGATOR SIGNATURE PAGE......................................................................... 102
LIST OF TABLES
Table 1. Dose adjustments of paclitaxel and carboplatin (febrile neutropenia)............................ 42
Table 2. Dose adjustments of paclitaxel and carboplatin (thrombocytopenia)..............................42
Table 3. Dose adjustment of paclitaxel (hepatotoxicity)............................................................... 43
Table 4. Dose adjustment of paclitaxel (neurotoxicity).................................................................44
Table 5. Study drugs......................................................................................................................46
Table 6. Schedule of activities.......................................................................................................63
Table 7. Assessment criteria for causality between an adverse event and the investigational drug....... 69
Table 8. Reporting and follow-up of adverse events.....................................................................71
Table 9. Organizational structure...................................................................................................82
LIST OF FIGURE
Figure 1. Study design schematic.................................................................................................. 29


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LIST OF ABBREVIATIONS AND DEFINITIONS
Abbreviations
Definitions
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AUC
Area under the curve
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
CFDA
China Food and Drug Administration (now National Medical
Products Administration)
CQA
Clinical quality assurance
CR
Complete response
CRA
Clinical research associate
CRO
Contract research organization
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DCR
Disease control rate
DOR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data collection
EGFR
Epithelial growth factor receptor
FAS
Full analysis set
GCP
Good Clinical Practice
HBsAg
Hepatitis B surface antigen
HBV-DNA
Hepatitis B virus deoxyribonucleic acid
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Hazard ratio
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
INR
International normalized ratio
ITT
Intention-to-treat
NCCN
National Comprehensive Cancer Network


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NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PP
Per-protocol
PR
Partial response
RPLS
Reversible posterior leukoencephalopathy syndrome
PTT
Partial thromboplastin time
SAE
Serious adverse event
SD
Stable disease
SOP
Standard operating procedure
SS
Safety set
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
VEGF
Vascular endothelial growth factor


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1 INTRODUCTION
1.1 Study Background
1.1.1 Disease background
Lung cancer has the highest incidence and mortality globally among all cancers. According to
the 2012 Global Cancer Statistics (GLOBOCAN 2012) published by International Agency for
Research on Cancer, there were approximately 1.8 million new lung cancer cases worldwide,
which accounted for 13% of the global newly-diagnosed cancers, and 58% of these cases
occurred in underdeveloped areas1. According to the data released by the National Central
Cancer Registry of China in 2015, lung cancer was the most prevalent malignancy in China in
2011, with about 650,000 new cases every year. Lung cancer was also the leading cause of death,
with about 520,000 deaths per year2. The limited clinical treatment of lung cancer is the main
reason for its poor prognosis. There is a huge demand for new types of lung cancer treatment
drugs.
Approximately 85–90% of lung cancers are non-small cell lung cancer (NSCLC) and patients
with NSCLC are usually in the advanced stages when diagnosed3. According to the Chinese
guidelines for the diagnosis and treatment of primary lung cancer, anatomic pulmonary resection
is the mainstay of treatment for early stage lung cancers4. However, despite surgery, some
patients develop distance metastases that eventually lead to death5. Surgery is not possible for
most patients with clearly diagnosed stage IIIb and IV as well as some patients with stage IIIa
NSCLC4. Comprehensive treatment based on systemic therapy is used to maximize patient
survival, control progressive disease, and improve the quality of life6.
In recent years, anti-tumor therapies have entered a new era with the emergency of targeted
drugs. Some of these targeted drugs have demonstrated satisfactory efficacy in the treatment of
advanced NSCLC. These targeted drugs include monoclonal antibodies and tyrosine kinase
inhibitors (TKIs), mostly targeting epidermal growth factor receptors (EGFRs) and vascular
endothelial growth factor (VEGF), such as bevacizumab, cetuximab, gefitinib, erlotinib, and
icotinib. Monoclonal antibodies have become the drugs of choice in various treatment guidelines
due to the good targeting ability, low drug resistance, and good patient tolerability. Bevacizumab
combination chemotherapy is a first-line therapy of NSCLC recommended by the National
Comprehensive Cancer Network (NCCN)7. Additionally, bevacizumab in combination with
paclitaxel/carboplatin has also been approved as the first-line therapy of unresectable advanced,
metastatic, or relapsed non-squamous NSCLC by China Food and Drug Administration (CFDA)
on Jul. 9, 20156.


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Compared with traditional chemotherapy that directly inhibit or kill tumor cells, anti-angiogenic
drugs have the following unique advantages8:

The targets are genetically stable vascular endothelial cells (VECs) rather than highly
heterogeneous tumor cells, thus leading to lower drug resistance;

The number of tumor-induced VECs is far less than that of tumor cells, and the efficacy
is preferable targeting on VECs and their cytokines;

Normal VECs are quiescent, whereas tumor VECs are active in proliferation. Anti-
angiogenic therapy targets activated cells and avoids damage to normal VECs, thus
leading to better targeting ability;

Anti-angiogenic therapy can normalize the tumor vessels and thereby reduce the
pressure in tumor tissues. This enhances the delivery of chemotherapeutic agents into
tumor tissues, thus increasing the efficacy of chemotherapy.
Angiogenesis is a basic biological characteristic of tumors. The growth of both solid and
hematologic tumors are depended on angiogenesis regardless of the nature of tumor cells.
Therefore, anti-angiogenic therapy is broad-spectrum and applicable to various tumors.
Bevacizumab is a recombinant humanized monoclonal antibody that selectively binds to human
VEGF and blocks its biological activity. Bevacizumab consists of a framework region of a
human antibody and a humanized murine antigen binding region that can inhibit the binding of
VEGF to its receptors on epithelial cells, Flt-1 and KDR. By blocking the activity of VEGF and
reducing tumor angiogenesis, tumor growth is inhibited9.
In a study conducted by the Estern Cooperative Oncology Group (ECOG), compared with
chemotherapy alone (paclitaxel/ carboplatin), bevacizumab in combination with paclitaxel/carboplatin
significantly increased the overall survival (OS) (median: 12.3 vs. 10.3 months), progression-free
survival (PFS) (median: 6.2 vs. 4.5 months), and overall response rate (ORR) (35% vs. 15%) in
patients with advanced, metastatic, or relapsed non-squamous NSCLC10. In another foreign
AVAiL study, different doses of bevacizumab (7 and 15 mg/kg) in combination with
chemotherapy (cisplatin and gemcitabine) and placebo combine with chemotherapy were
compared for the treatment of non-squamous NSCLC. The study found that the two
bevacizumab groups had significantly increased the PFS (median: 6.7 months (7.5 mg/kg
combination chemotherapy group) vs. 6.5 months (15 mg/kg combination chemotherapy group)
vs. 6.1 months (placebo combination chemotherapy group)) and the ORR (37.8% (7.5 mg/kg
combination chemotherapy group) vs. 34.6% (15 mg/kg combination chemotherapy group) vs.
21.6% (placebo combination chemotherapy group)) in patients with locally advanced, metastatic,
or relapsed non-squamous NSCLC11. In a BEYOND study conducted in China, compared with


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placebo in combination with paclitaxel/carboplatin, bevacizumab in combination with
paclitaxel/carboplatin significantly increase the PFS (median: 9.2 vs. 6.5 months), OS (median:
24.3 vs. 17.7 months), and the ORR (54% vs. 26%) in patients with advanced or relapsed non-
squamous NSCLC12.
In China, the antibodies and fusion proteins targeting VEGF are research hotspots. However,
since 2006, the clinical efficacies of various drugs has not been verified and no products have
been marketed. Considering the complexity of macromolecular drugs and the limitations of drug
development capability in China, advanced technologies in antibody development, production,
and quality control is required to develop high-quality VEGF inhibitors that are safe and
effective. IBI305 has showed high similarity to bevacizumab in various pharmaceutical and
nonclinical studies (refer to Investigator's Brochure [IB]). Besides, the efficacy and safety of
bevacizumab for treatment of locally advanced, metastatic or relapsed lung cancer have been
verified. The relevant domestice and external pivotal clinical studies are referable for the
protocol design of IBI305 clinical study. In summary, the clinical study of IBI305 for treatment
of NSCLC has a solid foundation and relatively low risks. The successful development of IBI305
indicates an additional first-line targeted drug for lung cancer in China, providing doctors and
patients with more therapeutic options.
1.1.2 Investigational drug
1.1.2.1 Description of investigational drug
IBI305 is a recombinant humanized anti-VEGF monoclonal antibody injection developed by
Innovent Biologics (Suzhou) Co., Ltd. (hereafter as sponsor) that specifically binds human
VEGF. The molecular weight of IBI305 is 149 KDa. IBI305 specifically binds to VEGF-A,
inhibits the binding of VEGF-A to VEGF-R1 and VEGF-R2, blocks the signaling pathways such
as PI3K/Akt/PKB and Ras-Raf-MEK-ERK. IBI305 also inhibits the growth, proliferation, and
migration of VECs and angiogenesis, decreases the vascular permeability, blocks blood supply to
tumor tissues, inhibits the proliferation and metastasis of tumor cells, and induces the apoptosis
of tumor cells, thereby generates anti-tumor effects. The main active ingredient is recombinant
humanized anti-VEGF monoclonal antibody and excipients include sodium acetate, sorbitol, and
polysorbate 8013. Refer to the Investigator's Brochure for the detailed structure and
physicochemical properties of IBI305.


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1.1.2.2 Preclinical studies
Pharmaceutical studies
The pharmaceutical studies showed that stability, primary structure, higher-order structure,
oligosaccharide distribution, charge variant, and product-related impurities of IBI305 are highly
similar to those of bevacizumab, and the process-related impurities meet the proposed
specification. Therefore, IBI305 is considered to have highly similar protein properties and
product quality to bevacizumab13.
Pharmacodynamic studies
In vitro and in vivo pharmacodynamic (PD) studies of IBI305 showed the following findings:
1)
Target: IBI305 displayed specifically high-affinity binding to recombinant human
VEGF-A with an affinity constant same as that of bevacizumab, indicating that IBI305,
the same as bevacizumab, is a specific human VEGF blocker with a clear target.
2)
Specificity: IBI305 displayed specifically high-affinity binding to recombinant human
VEGF-A, medium-affinity binding to canine VEGF-A, but low-affinity binding to
human VEGF-B, VEGF-C, VEGF-D, PlGF, suggesting that IBI305 recognizes specific
targets and has low off-target toxicity risk; no obvious affinity to mouse VEGF-A164
and rat VEGF-A164, suggesting that IBI305 has high species specificity.
3)
Mechanism of action: IBI305 specifically binds to VEGF-A and inhibits the activation
of VEGFR-2 and ERK1/2, blocks the proliferation and migration of HUVEC, and
inhibits the sprouting from rat aortic ring, suggesting that IBI305 antagonizes VEGF-
A-induced signaling pathway to block the proliferation and migration of VECs and
inhibit angiogenesis, which leads to the reduction of nutritional supply and metastasis
of tumor.
4)
Anti-tumor effects: IBI305 significantly inhibits the growth of human colon cancer
Ls174t and lung cancer NCI-H460 cells in xenografts in nude mice, indicating that
IBI305 has significant anti-tumor effects.
Results from in vitro and in vivo studies of IBI305 showed highly similarity with that of
bevacizumab designed simultaneously, demonstrating that the target, mechanism of action,
and anti-tumor effects of IBI305 are highly similar to bevacizumab13.


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Pharmacokinetic studies
In vitro and in vivo pharmacokinetic (PK) studies of IBI305 showed the following findings:
1)
IBI305 showed no significant cross-reactivity with normal human tissues and
cynomolgus monkey tissues, and only cross-reacted with the positive-control. i.e.
human angiosarcoma tissue, suggesting that IBI305 is highly specific to cancer tissues
rather than normal human tissues and has very low on-target toxicity.
2)
Linearity: With single dose or repeated doses of IBI305 (2-50 mg/kg) vis intravenous
injection in cynomolgus monkeys, the test showed significant PK, thus reducing the
suddenly rising toxicity risks with increased clinical doses.
3)
Immunogenicity: With single dose or repeated doses of IBI305 or bevacizumab via
intravenous injection in cynomolgus monkeys, the test showed abnormal changes of
drug concentration-time curves in several animals. The anti-drug antibody (ADA) test
results showed that IBI305 has a medium immunogenicity.
4)
Accumulation: With repeated doses of IBI305 or bevacizumab via intravenous
injection in cynomolgus monkeys, the test showed that drug exposure of the last
dose was significantly higher than that of the first dose, and the steady-state drug
concentration after repeated doses was higher than that after a single dose, suggesting
that the drug may be accumulated in body.
The results of tissue cross-reactivity and PK/toxicokinetic studies in cynomolgus monkeys
indicated that IBI305 and bevacizumab have similar characteristics in tissue cross-reactivity and
PK/toxicokinetics13.
Toxicological studies
Toxicological studies of IBI305 showed the following findings:
1)
Single dose: With single dose of IBI305 (up to 300 mg/kg) via intravenous injection in
cynomolgus monkeys, the test showed good tolerability without any abnormal clinical
symptoms and toxicity. The dose was about 48 times the proposed clinical dose for
human based on body surface area. In the safety pharmacology test, with single dose of
IBI305 (50 mg/kg) via intravenous injection in cynomolgus monkeys, the test showed
no significant effects on the central nervous system, respiratory system, and
cardiovascular system, suggesting that the single dose of IBI305 via intravenous
injection has a high safety.


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2)
Repeated doses: With repeated doses of IBI305 (up to 50 mg/kg) via intravenous
injection twice weekly for 9 consecutive doses in cynomolgus monkeys, equivalent to
20 times the proposed clinical dose for humans (based on the weight), the test showed
extremely mild to mild linear growth arrest of metaphyseal lines at knee joint and
disordered chondrocyte proliferation, extremely mild increases in macrophage count
in white pulp of spleen, pulmonary (including bronchial) hemorrhage, and deposits of
hemosiderin in lymphoid tissue of bronchial mucosa, indicating that the target organ
toxicities are mainly in the bone, spleen, and lungs.
3)
Immunotoxicity and immunogenicity: With repeated doses of IBI305 via intravenous
injection twice weekly for 9 consecutive in cynomolgus monkeys, the test showed
medium immunotoxicity to the spleen. Different doses of IBI305 may result in the
production of ADAs, a portion of which are neutralizing antibodies (NAbs), indicating
that IBI305 has medium immunotoxicity and immunogenicity.
4)
Local irritation test: With repeated dose of IBI305 via intravenous injection in
cynomolgus monkeys, the test showed no irritation at the injection site, suggesting that
administration of IBI305 via intravenous injection is safe and feasible.
5)
In vitro hemolysis assay: With maximum proposed clinical concentration of IBI305
(9 mg/mL), the assay showed no hemolysis, suggesting that IBI305 is suitable for
intravenous injection.
IBI305 has high similarity with bevacizumab in safety pharmacology, long-term toxicity,
immunotoxicity, immunogenicity, local irritation, and hemolysis13.
1.1.2.3 Clinical studies
This study is the first study of IBI305 in humans.
1.2 Study Principles and Risk/Benefit Assessment
1.2.1 Study principles and dose selection
A biosimilar drug refers to a therapeutic biological product that is similar in quality, safety and
efficacy with an approved reference drug14. IBI305, developed and sold in the market by the
sponsor, is a bevacizumab biosimilar, and has the same administration method and indications
as bevacizumab.


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This study is conducted in accordance with the "Guidelines on Development and Evaluation of
Bosimilars (for Trial Version)" issued by the NMPA (formerly CFDA)14. The doses of IBI305
selected in this study are based on the preclinical studies that showed highly similarity between
IBI305 and bevacizumab in pharmacology, PD, PK and toxicology (refer to the Investigator's
Brochure for details). Besides, the efficacy and safety of bevacizumab for treatment of advanced,
metastatic or relapsed non-squamous NSCLC have been verified, and the indications have also
been approved in China. Therefore, the dose and administration of IBI305 is similar to
bevacizumab in this study, that is, 15 mg/kg intravenously on D1 of every 3-week cycle
when used in combination with chemotherapy (paclitaxel and carboplatin). In the subsequent
monotherapy therapy, IBI305 will be given intravenously at a dose of 7.5 mg/kg on the first day
of every 3-week cycle. This design of this study is to further demonstrate that IBI305 is similar
to bevacizumab in clinical efficacy, safety, and immunogenicity in subjects with advanced,
metastatic or relapsed non-squamous NSCLC.
1.2.2 Risk/benefit assessment
IBI305 is a bevacizumab biosimilar developed by the sponsor. Based on the clinical pharmacology
and toxicology characteristics of IBI305, the risks and benefits of IBI305 are expected to be similar
to bevacizumab.
The treatment-related risks of bevacizumab are detailed in its prescribing information. This study
is the first human study of IBI305 so that unexpected adverse reactions will be possible. The
design of this study ensures the minimized subject risks by close monitoring of the adverse
events (AEs) before, during, and after the infusion of the investigational drugs. Once an adverse
reaction occurs, the investigator will immediately take appropriate action for the subject safety.
The platinum-based therapy is the standard first-line regimen of advanced NSCLC4. This study
uses the combination of paclitaxel/carboplatin, ensuring the basic anti-tumor therapy for subjects.


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2 STUDY OBJECTIVES
2.1 Primary Objective
The primary objective of this study is to compare the objective response rate (ORR) of IBI305
plus paclitaxel/carboplatin versus bevacizumab plus paclitaxel/carboplatin for the treatment of
advanced or relapsed non-squamous NSCLC.
2.2 Secondary Objectives
Secondary objectives include:

To compare the duration of response (DOR), progression-free survival (PFS), disease
control rate (DCR), and overall survival (OS) in subjects with advanced or relapsed
non-squamous NSCLC treated by IBI305 plus paclitaxel/carboplatin versus
bevacizumab plus paclitaxel/carboplatin

To compare the safety and immunogenicity of IBI305 plus paclitaxel/carboplatin
versus bevacizumab plus paclitaxel/carboplatin for the treatment of advanced or
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3 STUDY PLAN
3.1 Overview of Study Design
This is a randomized, double-blind, active-controlled, and multi-center phase III study. A total of
400 subjects across 35 study sites with non-squamous NSCLC will be planned, randomized in a
1:1 ratio into the IBI305 plus paclitaxel/carboplatin group or bevacizumab plus paclitaxel/carboplatin
group, and stratified according to age (< 60 vs. ≥60 years old) and epidermal growth factor
receptor (EGFR) status (wild type vs. mutant). Each treatment cycle is 3 weeks for both groups.
15 mg/kg IBI305 or bevacizumab is administered on D1 of each cycle along with paclitaxel/carboplatin.
Subjects will receive up to 6 treatment cycles of combination therapy until PD, unacceptable
toxicity, withdrawal of informed consent, loss of follow-up, or death (whichever comes first).
Then subjects received monotherapy, that is, discontinuing paclitaxel/carboplatin while
continuing therapy with IBI305 or bevacizumab. The monotherapy continues every 3 weeks.
On D1 of each treatment cycle, subjects will be administered 7.5 mg/kg of either IBI305 or
bevacizumab until PD, unacceptable toxicity, withdrawal of informed consent, lost to follow-up,
death, or end of study (whichever comes first).
After discontinuing the study drug, subjects will return to the study site 28 days (± 7 days) after
the last dose for an end-of-treatment visit. If the subjects discontinue the study treatment for
reasons other than PD, subsequent follow-up will be continued until PD, withdrawal of informed
consent, start of other anti-tumor therapies, loss of follow-up, death, or end of study. If the
subjects discontinue the study treatment for PD, the investigator will make telephone follow-up
every 12 weeks (± 7 days) to collect information of subsequent anti-tumor therapies and survival.
A CT or an MRI will be performed every 6 weeks (± 7 days) until PD, withdrawal of informed
consent, start of other anti-tumor therapies, loss of follow-up, death, or end of study. The method
for subsequent imaging examination should be consistent with that at baseline, and the chest,
abdomen and pelvis of the subject must be scanned. Each assessment must be completed within
7 days from the most recent visit. The investigators then perform the evaluation based on the
RECIST 1.1 criteria to determine whether the subject can continue receiving the next cycle of
treatment. Furthermore, the independent tumor evaluation committee (Section 11.1.1) will also
evaluate tumor response according to the RECIST version 1.1. If the subject discontinue the
study treatment for reasons other than PD, subsequent tumor evaluation should be continued
according to the study procedures until PD, withdrawal of informed consent, start of other anti-
tumor therapies, loss of follow-up, death or, end of study.
The study design is shown in Figure 1.


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Figure 1. Study design schematic
3.2 Study Design Discussion
This is a randomized, double-blind study, and bias in treatment groups is avoided. Furthermore,
the CT/MRI images of each subject will be evaluated by an independent tumor evaluation committee
according to the RECIST 1.1 to ensure consistency in evaluation.
Screening
period
Combination therapy (once every 3 weeks)
IBI305 or bevacizumab plus
Paclitaxel + carboplatin
Follow-
up
Monotherapy
(once every 3 weeks) IBI305 or
Bevacizumab
End-of-treatment visit
(28 days (±7 days) after
last dose)
Cycle n
D-28
to
D-1
Cycle 1
randomiz
ation
(D1)
Cycle 2
Cycle 3
Cycle 6
Cycle 7
Post-treatment follow-up


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4 STUDY POPULATION
4.1 Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be enrolled in the study:
1)
Sign the informed consent form
2)
Male or female ≥18 and ≤70 years old
3)
Histologically or cytologically confirmed unresectable locoregionally advanced (stage
IIIb), metastatic (stage IV), or relapsed non-squamous NSCLC; mixed tumors should
be categorized according to the main cell types
4)
Histologically confirmed EGFR wild type
5)
Histologically confirmed EGFR mutation type, but subjects who have not received
EGFR-TKI treatment due to various reasons
6)
Must have at least one measurable target lesion (as per RECIST 1.1)
7)
Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0–1
8)
Expected survival ≥6 months
9)
Laboratory results during screening:
Routine blood test: WBC ≥3.0 × 109/L, ANC ≥1.5 × 109/L, platelets ≥100 × 109/L,
and hemoglobin ≥90 g/L
Hepatic function: TBIL < 1.5 × ULN; ALT and AST < 2.5 × ULN for subjects
without liver metastasis, or ALT and AST < 5 × ULN for subjects with liver
metastasis
Renal function: SCr ≤1.5 × ULN or CrCl ≥50 mL/min, and urine protein < 2 +
in routine urinalysis. Subjects with urine protein ≥2+ at baseline must have
undergone 24 h urine collection with total protein content <1 g
INR ≤1.5 and PTT or aPTT ≤1.5 × ULN within 7 days prior to the study treatment
10) Able to comply with study protocol
11) Female and male subjects of childbearing age, and partners of these male subjects must
agree to use effective contraceptive measures (such as abstinence, sterilization, oral
contraceptives, medroxyprogesterone injections or contraceptive implants) during the


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study and for 6 months after the infusion of the study drug


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4.2 Exclusion Criteria
Subjects meeting any of the followings are not enrolled in the study:
1)
Prior chemotherapy or targeted therapy (such as monoclonal antibody or tyrosine
kinase inhibitor) for the treatment of the current stage of disease (Stage IIIb not suitable
for multidisciplinary treatment, stage IV or relapsed disease). Prior surgery and
radiotherapy are permitted, provided that the criteria outlined in the study protocol are
met. Subjects who received prior adjuvant therapy and relapsed within 6 months are not
eligible
2)
Mixed non-small cell and small cell carcinoma, or mixed adenosquamous carcinoma
predominantly containing squamous cell carcinoma component
3)
History of hemoptysis within 3 months prior to screening, with a volume of blood
greater than 2.5 mL each time
4)
Radiographic evidence of tumor invasion in great vessels. The investigator or the
radiologist must exclude subjects with tumors that are fully contiguous with,
surrounding, or extending into the lumen of a great vessel (such as pulmonary artery or
superior vena cava)
5)
History of brain metastasis, spinal cord compression, or carcinomatous meningitis, or
brain metastasis confirmed by CT or MRI during screening
6)
Subjects who received radical thoracic radiation therapy within 28 days prior to
enrollment; subjects who received palliative radiation for non-thoracic bone lesions
within 2 weeks prior to the first dose of the study drug
7)
Subjects with severe skin ulcers or fracture, or having major surgery within 28 days
prior to randomization or expecting to have major surgery during the study
8)
Subject who received minor surgery (including catheterization) within 48 h prior to the
first dose of the study drug
9)
Currently or recently (within 10 days prior to the first dose of study drug) used aspirin
(> 325 mg/day) or other nonsteroidal anti-inflammatory drugs known to inhibit platelet
function
10) Currently or recently (within 10 days prior to the first dose of study drug) received
treatment with full dose oral or parenteral anticoagulants or thrombolytic agents.
However, anticoagulants for prophylaxis are accepted.
11) Subjects with inherited hemorrhagic tendency or coagulopathy, or history of thrombosis


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12) Uncontrolled hypertension (systolic greater than 150 mmHg and/or diastolic greater
than 100 mmHg), history of hypertensive crisis or hypertensive encephalopathy
13) Any unstable systemic disease including but not limited to: active infection, unstable
angina, cerebrovascular accident or transient cerebral ischemia (within 6 months prior
to screening), myocardial infarction (within 6 months prior to screening), cardiac
failure congestive (NYHA Class ≥II), severe arrhythmia requiring medication, and
liver, kidney or metabolic disease
14) History of the following diseases within 6 months prior to screening: gastrointestinal
ulcers, gastrointestinal perforation, corrosive esophagitis or gastritis, inflammatory
bowel disease or diverticulitis, abdominal fistula, or intra-abdominal abscess
15) Subjects with tracheoesophageal fistula
16) Clinically significant third spacing (such as ascites or pleural effusion that are
uncontrollable by drainage or other treatments)
17) Subjects with pulmonary fibrosis history or active pneumonia shown on CT during
screening
18) History of malignant tumors other than NSCLC within 5 years prior to randomization,
except for adequately treated cervical carcinoma in situ, basal or squamous cell skin
cancer, locoregional prostate cancer after radical surgery, ductal carcinoma in situ after
radical surgery, or papillary thyroid carcinoma
19) Subjects with autoimmune disease
20) Subjects with positive test result of HBsAg, and peripheral blood HBV DNA titer ≥1 ×
103 copies/L; subjects with positive test result of HBsAg and peripheral blood HBV
DNA titer < 1 × 103 copies/L are eligible if the investigator determined that the subject's
chronic hepatitis B is table and participation in the study would add no further risks to the
subject
21) Subjects who are tested positive for HCV antibody, HIV antibody or syphilis
22) Subjects with known history of allergic diseases or allergic physique
23) Received treatment with other investigational drugs or participated in another
interventional study within 30 days prior to screening
24) History of alcohol or drug abuse
25) Female subjects who are pregnant or breastfeeding, or expected to be pregnant or
breastfeeding during the study


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26) Known allergies to bevacizumab or any of its excipients, or any chemotherapeutic
agents
27) Other conditions unsuitable for the inclusion as determined by the investigator
4.3 Screening Failure
Screening failure is that the subject who has signed the informed consent form fails to meet the
inclusion criteria. Subjects with screening failure will not get a randomization number. The
reasons of screening failure will be documented in the electronic case report forms (eCRFs).
4.4 Subject Restrictions
Female subjects of childbearing age must take effective contraceptive measures during the study
and 6 months after the last dose.
Male subjects must take effective contraceptive measures during the study and 6 months after the
last dose to avoid the pregnancy of their partners.
Restrictions on the use of medication during the study are shown in Section 5.9.
4.5 Subject Withdrawal and Replacement
All subjects may withdraw from this study at any time, with or without a reason. Subjects who
withdraw from the study will not be subjected to discrimination or retaliation, and their medical
treatment will not be affected.
Subjects may discontinue the study treatment or withdraw from the study under the following
circumstances:

Unacceptable toxicity

Progressive disease

Investigator believes that the subject should withdraw from the study. If an unacceptable
adverse event (AE) occurs and the investigator believes that the subject should
withdraw from the study, the study treatment should be discontinued and appropriate
measures should be taken. In addition, the sponsor or personnel designated by the
sponsor should be notified.

Withdrawal of informed consent form by the subject

Serious protocol deviation determined by the investigator and/or sponsor


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
Poor protocol compliance

Study termination by the investigator or sponsor for any reason

Enrollment error* (enrollment of subjects who have violated the inclusion/exclusion
criteria)

Use of prohibited concomitant medications or other medications that the investigator
believes that it may result in toxicities or may affect study results

Subject lost to follow-up

Death of subject
* If the subject is determined by the investigator and the sponsor's doctor to be medically suitable
to continue with the study drugs without any risk or inconvenience, the mistakenly enrolled or
randomized subject will continue with the study treatment and assessments.
In any cases, reasons for withdrawal must be documented in the eCRFs. If the subject withdraws
from the study prematurely for any reason, the investigator should make every effort to persuade
the subject to receive the corresponding assessment, and continue the follow-up of all unresolved
AEs based on the AE reports and follow-up requirements (Table 2):

If the subject withdraws during the study, the series of assessments listed under the End
of Treatment Visit (Section 6.9) should be performed

If the subject withdraws after the end of the treatment visit and has not experienced PD,
the series of assessments listed under the Follow-Up for PD (Section 6.10) should be
performed (tumor assessment is not required to be repeated if it has been performed
within 6 weeks prior to this follow-up)

If the subject withdraws during the follow-up for survival, the information of subsequent
anti-tumor therapies and survival should be collected by telephone follow-up only
Subjects who withdraw their informed consent are not to be contacted again unless they clearly
indicate the willingness to be contacted. The sponsor may use the clinical study data obtained
before the withdrawal of informed consent.
Subjects who have been randomized will not be replaced.


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5 STUDY TREATMENT
5.1 Therapies by Study Drugs
The study drugs of this study are IBI305 and bevacizumab.
In this study, the dose of IBI305 or bevacizumab during combination therapy with chemotherapy
is 15 mg/kg, while the dose during monotherapy is 7.5 mg/kg. The study drugs are administered
intravenously on D1 of each 3-week cycle until PD, unacceptable toxicity, withdrawal of informed
consent, loss to follow-up, death, or end of study (whichever comes first).
The duration of the first dose of IBI305 or bevacizumab should be 90 min (± 15 min). If the
first infusion is well-tolerated by the subject, then the duration of the second infusion can be
shortened to 60 min (± 15 min). If the 60 min infusion is also well-tolerated by the subject, then
the subsequent infusions can be completed within 30 min (± 15 min).
5.2 Chemotherapy
Paclitaxel will be administered after the IBI305 or bevacizumab infusion is completed, then
followed by carboplatin:
Paclitaxel: 175 mg/m² administered via intravenous infusion for 3 h (may be adjusted according
to clinical practice of each study site) on D1 of every 3-week cycle for up to 6 cycles until PD,
unacceptable toxicity, withdrawal of informed consent, loss of follow-up, or death.
Carboplatin: AUC 6.0 administered via intravenous infusion for 15-30 min (may be adjusted
according to clinical practice of each study site) on D1 of every 3-week cycle for up to 6 cycles
until PD, unacceptable toxicity, withdrawal of informed consent, loss of follow-up, or death.
The chemotherapeutic agents are supplied by the sponsor.
Formulas for calculating surface area, creatinine clearance and carboplatin dose are shown in
Section 13.2.
5.3 Dose Adjustment of Each Study Drug
5.3.1 General principles
The reasons for dose adjustments or delayed administration, measures taken, and
results should be documented in the medical records and eCRFs


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If the concomitant symptoms exist at baseline, the investigator will determine whether
the dose should be adjusted according to the change in severity of toxicity. For example,
if the subject has Grade 1 "weakness" at baseline and Grade 2 "weakness" during the
study treatment, the dose should be adjusted based on Grade 1 toxicity since the
severity has increased by one grade
If several toxic reactions of different grades or severity occur simultaneously, the dose
will be adjusted according to the highest observed grade/severity
If a dose adjustment is required solely due to abnormal lab test results, then the dose
should be adjusted based on the measured values obtained prior to the start of the
treatment cycle
If the investigator determines that the toxicity is unlikely to further develop into a
serious or life-threatening event, the current dose will be continued without any
adjustments or treatment interruptions. In addition, dose adjustments or treatment
interruptions will not be performed for non-hemolytic anemia as the symptoms can be
alleviated through blood transfusions.
If the investigator determines that a toxicity is caused by a specific therapeutic drug,
then the dose adjustments of other drugs are not required
Discontinuation of one or two therapeutic drugs before PD will not affect the continued
treatment with other drugs
Dose reductions or adjustments of IBI305 or bevacizumab are not permitted.
Subsequent therapeutic dose will not be adjusted according to weight change, unless
the subject weight has changed by ≥10% from baseline
Once the dose of any chemotherapeutic agents is reduced, the original dose should no
longer be adopted
If any but not all of the therapeutic drug (IBI305, bevacizumab or chemotherapeutic
agents) treatments is interrupted due to toxicity, then this treatment will be considered
as a treatment cycle
If the administration of any one of the chemotherapeutic agents is delayed for more
than 3 weeks, the subject should permanently discontinue that chemotherapeutic agent


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If IBI305/bevacizumab is continued/infused after a delay for more than 3 weeks, the
investigator must discuss with the sponsor


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5.3.2 Dose adjustments of study drugs
Dose adjustments of IBI305 or bevacizumab are not permitted except for the adjustments
(adjusted to 7.5 mg/kg for monotherapy) specified in the study protocol. The dose of IBI305 or
bevacizumab is calculated according to the subject weight at baseline (prior to the first dose), and
remains unchanged throughout the study, unless the subject weight has changed by ≥10% from
baseline.
If an infusion reaction occurs during a 60-minute infusion, the infusion time should be extended
to 90 minutes for all subsequent infusions. Likewise, if an infusion reaction occurs during a 30-
minute infusion, the infusion time should be extended to 60 minutes for all subsequent infusions.
IBI305 or bevacizumab in combination with paclitaxel/carboplatin will be administered every
3-week treatment cycle for 6 cycles. If PD is not observed in subject during treatment, then the
subject will continue to receive IBI305 or bevacizumab as monotherapy every 3-week treatment
cycle until PD, unacceptable toxicity, withdrawal of informed consent, loss of follow-up, death,
or end of study (whichever comes first).
If IBI305 or bevacizumab is permanently discontinued due to unacceptable toxicity or subject
refusal to continue the study drugs during the combination therapy, then the subject will continue
to receive the chemotherapy (paclitaxel/carboplatin) until 6 treatment cycles are completed as
determined by the investigator. If any one of the chemotherapeutic agents (paclitaxel or carboplatin)
is prematurely discontinued due to unacceptable toxicity, the subject can continue to receive
IBI305 or bevacizumab treatment until PD, unacceptable toxicity, withdrawal of informed
consent, loss of follow-up, or death (whichever comes first).
When a Grade 3 or 4 IBI305- or bevacizumab-related toxicity is observed, the investigators
should determine whether to continue or terminate IBI305 or bevacizumab treatment according
to the followings:
First occurrence:
IBI305 or bevacizumab administration should be interrupted until toxicity symptoms return to
baseline level or are at least reduced to the Common Terminology Criteria for Adverse Events
(CTCAE) Grade 1 or lower (except for the special circumstances listed below)
Note that when Grade 4 febrile neutropenia and/or thrombocytopenia occur(s), IBI305
or bevacizumab administration should be interrupted until the symptoms return to
baseline levels or at least reduced to CTCAE Grade 1 or lower, since these events
increase the risk of hemorrhage.


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Re-occurrence in re-administration:
If Grade 3 IBI305- or bevacizumab-related toxicity occurs again, the investigator
should assess the risk/benefit of study drug continuation for the subject. If such toxicity
re-occurs again after re-administration, IBI305 or bevacizumab should be permanently
discontinued
If Grade 4 IBI305- or bevacizumab-related toxicity occurs again, IBI305 or
bevacizumab should be permanently discontinued
Measures should be taken in the following special circumstances (classified based on CTCAE
version 4.03):
Hemorrhage
Subjects with Grade 3 or 4 hemorrhages should be treated accordingly and permanently
discontinue the study treatment
Thrombosis/embolism

Subjects with arterial thrombosis of any severity grades should permanently
discontinue the study treatment

Subjects with Grade 4 venous thrombosis should permanently discontinue the
study treatment

Subjects with Grade 3 venous thrombosis should interrupt the study treatment. If
the anticoagulant therapy at the planned therapeutic dose is < 2 weeks, the study
treatment should be interrupted until the anticoagulant therapy is completed. If
the anticoagulant therapy at the planned therapeutic dose is > 2 weeks, IBI305
or bevacizumab administration should be interrupted for 2 weeks, and the study
treatment can be restarted during the anticoagulant therapy if the following criteria
are met:
- INR is within the target range (usually 2-3) prior to restarting of study treatment
- Subjects must not have experienced Grade 3 or 4 hemorrhage since enrollment
- No signs of great vessel invasion or adjacency to great vessels from previous
tumor assessments
Note: Therapeutic dose of anticoagulant therapy is defined as the escalating dose of
warfarin or other anticogulants until INR is maintained at no less than 1.5 (usually


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2-3). The warfarin dose should be documented in the eCRFs, and the INR of
subjects receiving anticoagulant therapy should be monitored during the treatment.
Hypertension
BP should be measured frequently to monitor the occurrence and exacerbation of hypertension.
Subjects should remain at resting position for at least 5 min before BP measurement.
Grade 1 hypertension: Asymptomatic transient (< 24 h) increase in BP (> 20 mmHg
diastolic blood pressure), or > 150/100 mmHg in this measurement, but previous BP
was within normal range. No interventions are required.
Grade 2 hypertension: Repeated or sustained (> 24 h) or symptomatic BP increase (>
20 mmHg diastolic blood pressure), or > 150/100 mmHg in this measurement, but
previous BP was within normal range. One antihypertensive drug can be used. Once
BP is lowered to < 150/100 mmHg, the subject may continue the study treatment.
Grade 3 hypertension: Requires more than one antihypertensive drugs or more potent
treatment. Study treatment should be interrupted in case of persistent or symptomatic
hypertension; study treatment should be permanently discontinued for uncontrollable
hypertension.
Grade 4 hypertension: Life-threatening (i.e. hypertensive crisis). The study treatment
should be permanently discontinued in case of Grade 4 hypertension. The dose of all
antihypertensive agents used should be documented during each visit.
The dose of antihypertensive agents used should be documented during each visit. If the subject
remains hypertensive despite treatment discontinuation, BP and antihypertensive agents used
should be monitored every 3 months until BP returns to normal or end of study.
Reversible posterior leukoencephalopathy syndrome (RPLS)
There have been a few reports with signs and symptoms consist with RPLS after study treatment.
RPLS is a rare neurological disease and its signs and symptoms include epilepsy, headache,
altered mental status, visual impairment, or cortical blindness, with or without hypertension.
Subjects with RPLS should permanently discontinue the study treatment.
Proteinuria
Urinalysis dipstick test should be performed prior to each IBI305 or bevacizumab infusion unless
24-h proteinuria test has already been performed.


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First occurrence of proteinuria:
The urinalysis dipstick test should be performed if:
Urine protein is < 2+, continue study treatment as scheduled, no additional tests are
required.
Urine protein is ≥2+ (strip test), continue study treatment as scheduled, and a 24-h
urine protein test should be performed within 3 days prior to the next treatment cycle:

If 24-h urine protein is < 2 g, continue study treatment as scheduled, and perform
urinalysis dipstick test before each scheduled dose.

If 24-h urine protein is > 2 g, the current study treatment is interrupted, and a 24-h
urine protein test should be performed within 3 days prior to the next planned dose.
Study treatment is delayed until 24-h urine protein is ≤2 g, and a 24-h urine protein
test prior to each subsequent dose is performed until urine protein is reduced to ≤
1 g/24 h. Interrupt study treatment only when 24-h urine protein is > 2 g.
Second and subsequent occurrence of proteinuria:
< 3+ (strip test): continue study treatment as scheduled, no additional tests are required.
Urine protein is ≥3+ (strip test), continue study treatment as scheduled, and a 24-h
urine protein test should be performed within 3 days prior to the next treatment cycle:

If 24-h urine protein ≤2 g, continue study treatment as scheduled.

If 24-h urine protein is > 2 g, the current study treatment is interrupted, and a 24-h urine
protein test should be performed within 3 days prior to the next planned dose. Study
treatment is delayed until 24-h urine protein is ≤2 g, and a 24-h urine protein test
prior to each subsequent dose is performed until urine protein is reduced to ≤
1 g/24 h. Interrupt study treatment only when 24-h urine protein is > 2 g.
Nephrotic syndrome (Grade 4): Study treatment is permanently discontinued
Gastrointestinal perforation
If gastrointestinal perforation occurs, appropriate measures should be taken and the study
treatment should be permanently discontinued.
Wound healing complications
The study treatment should not begin within 28 d after a major surgery, or before the surgical


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wound is fully healed. If a complication of wound healing occurs during study treatment, the
study treatment should be interrupted until the wound is fully healed. If an elective surgery is
required, the study treatment should be interrupted.
Abdominal abscess or fistula
If abdominal abscess or fistula occurs, the study treatment should be discontinued. However, the
investigator will determine whether study treatment will be continued if the above AE is resolved.


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Infusion-related and allergic reactions:
Infusion-related reactions after first dose of the study drug is uncommon (< 3%), and the incidence
of a severe reaction is only 0.2%.
If a mild (grade 1 or 2) reaction (such as fever, chills, headache, and nausea) occurs, pretreatment
prior to subsequent administration should be performed and infusion time should not be reduced.
If the subject is well-tolerated during infusion after pretreatment, the infusion time can be
reduced by 30 minutes (+10 minutes) for subsequent administration with pretreatment. If an
infusion-related AE occurs during a 60-minute infusion, the subsequent infusion should be
completed within 90 minutes (+15 minutes) with pretreatment. Likewise, if an infusion-related
AE occurs during a 30-minute infusion, the subsequent infusion should be completed in 60 minutes
(+10 minutes) with pretreatment. If a subject has a grade 3 infusion-related reaction, the study
treatment should be interrupted and not be restarted on the same day. However, since there lacks
the dose adjustment method for grade 3 infusion-related reactions, the investigators may decide
to either discontinue the study drug or perform pretreatment, and complete the infusion within
90 minutes (+15 minutes). If an adverse reaction still occurs during a 90-minute infusion, the
infusion should be continued at a slower rate and then gradually returned to a 90-minute infusion.
If the investigator is uncertain about the handling, the study treatment should be discontinued.
When the study treatment is restarted, the subject should be closely monitored based on routine
clinical practice until the possible time of adverse reaction has passed. If a subject has a grade 4
infusion-related reaction, the study treatment should be discontinued.
An allergic reaction is defined as the vascular collapse or shock (systolic BP < 90 mmHg,
unresponsive to rehydration) that occurs within 30 minutes of a study drug infusion caused by
an allergy, with or without respiratory distress. Skin reactions include pruritus, urticaria, and
angioedema. Subjects with allergic reactions should discontinue the study treatment.
5.3.3 Dose adjustments of chemotherapy
Paclitaxel and carboplatin should be administered according to the study site guidelines and local
prescribing information. For the specific information for use, preparation, and storage of
paclitaxel and carboplatin, refer to the prescribing information and local dosing information.
Carboplatin-based chemotherapies have a relatively high incidence of emesis. Therefore,
antiemetics for prophylaxis can be used.
Hematological toxicity:
Absolute neutrophil count (ANC; dose can only be reduced when febrile neutropenia occurs.
ANC must be ≥1.5 × 109/L and platelet count ≥100 × 109/L on D1 of each treatment cycle)


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Table 14. Dose adjustments of paclitaxel and carboplatin (febrile neutropenia)
Dose Adjustments of Paclitaxel/Carboplatin
ANC (D1 of each treatment cycle)
< 1.5 x 109/L
≥1.5 x 109/L
Febrile neutropenia
(regardless of duration)
0
Paclitaxel = 150 mg/m2
Carboplatin = AUC 4.5
Platelet count:
Table 15. Dose adjustments of paclitaxel and carboplatin (thrombocytopenia)
Lowest Level After Last Dose
Dose Adjustments of Paclitaxel/Carboplatin
Platelet count (D1 of each treatment cycle)
< 100 x 109/L
≥100 x 109/L
< 25 × 109/L or
< 50 × 109/L with hemorrhage or
requires blood transfusion
0
Paclitaxel = 150 mg/m2
Carboplatin = AUC 4.5
Once the chemotherapeutic dose is reduced due to febrile neutropenia or thrombocytopenia
(platelet count < 25 × 109/L or < 50 × 109/L with hemorrhage or blood transfusion required), the
original dose should no longer be adopted. If dose reduction is required due to another incident
of febrile neutropenia or thrombocytopenia, the dose of paclitaxel and carboplatin will be
reduced to 100 mg/m2 and AUC 3.0, respectively. If the dose reduction is required for the third
time, the chemotherapy should be immediately discontinued.
If the dose adjustment is required when ANC and thrombocytopenia occur concurrently, the low-
dose chemotherapy should be adopted.
Chemotherapy may be delayed for up to 3 weeks. If after the chemotherapy has been delayed for
3 weeks, ANC does not reach ≥1.5 × 109/L and platelet count does not reach ≥100 × 109/L on
D1 of the scheduled chemotherapy, the chemotherapy should be permanently discontinued. If the
above values have been reached, the next course of chemotherapy should be continued.
The investigator should monitor the subject closely for toxicity with particular attention to early
and evident signs of myelosuppression, infection, or febrile neutropenia to timely and
appropriately treat the complications.
Subjects should be informed to pay attention to these signs and receive treatment as soon as possible.


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If the chemotherapy must be interrupted due to hematological toxicity, the complete blood count
should be performed regularly (including WBC differentials) until all the counts reach the
minimum requirements for treatment continuation. Thereafter the scheduled treatment plan will
be performed.
Dose adjustments are not required for anemia. However, treatment based on guidelines of each
clinic should be performed.
Gastrointestinal toxicity
Antiemetics will be used to control nausea and/or emesis. If grade 3 or 4 nausea and/or emesis
occur(s) despite of antiemetics, the chemotherapeutic dose should be reduced by 20% for the
next treatment cycle. The dose should be returned to the initial level as possible if the subject is
tolerated.
If the subject experiences stomatitis on D1 of any treatment cycle, the chemotherapy should be
interrupted until the symptoms resolve. If the stomatitis has not resolved after 3 weeks, the
chemotherapy should be permanently discontinued (refer to CTCAE version 4.03). If an acute
Grade 3 stomatitis occurs, the chemotherapeutic dose should be reduced to 75% of the proposed
dose when symptoms resolve.
Hepatotoxicity (Paclitaxel)
The paclitaxel dose should be determined based on the lab values measured on D1 of each
treatment cycle.
Table 16. Dose adjustment of paclitaxel (hepatotoxicity)
AST
Bilirubin
Paclitaxel Dose
≤5 x UNL
and
WNL
175 mg/m2
> 5 x UNL
or
> UNL ~ 1.5 x UN
150 mg/m
> 1.5 x UN
0
If paclitaxel is interrupted due to hepatotoxicity, carboplatin should also be interrupted until
paclitaxel is restarted. Paclitaxel will be interrupted for up to 3 weeks. If the subject's hepatic
function does not return to the acceptable ranges in 3 weeks, paclitaxel should be permanently
discontinued. The carboplatin dose will not be adjusted when hepatotoxicity occurs.


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The investigators should avoid PD due to abnormal hepatic enzyme levels as possible. If PD
occurs, all the study drugs should be permanently discontinued, including chemotherapy.
Cardiovascular toxicity (paclitaxel)
The arrhythmia in subjects was infrequent in previous clinical studies. However, most subjects
were asymptomatic and electrocardiographic monitoring was not required. Asymptomatic
transient bradycardia was observed in 29% of subjects, but significant atrioventricular block was
rare. Cardiac events should be treated as follows:
Asymptomatic bradycardia: no intervention indicated
Symptomatic arrhythmia during infusion: Discontinue paclitaxel infusion and perform
routine treatment of arrhythmia. Discontinue subsequent paclitaxel treatment.
Document this AE in the AE Report Form of eCRF.
Chest pain and/or symptomatic hypotension (< 90/60 mmHg or rehydration therapy
required): discontinue the paclitaxel infusion. Perform electrocardiography (ECG). If
hypersensitivity reaction is suspected, administer diphenhydramine and dexamethasone
via intravenous infusion. If the chest pain is not considered as cardiogenic, epinephrine
or bronchodilators will be administered. Document this AE in the AE Report Form of
eCRF. Discontinue subsequent paclitaxel treatment and provide symptomatic treatment.
Consult a cardiologist if needed.
Neurotoxicity (paclitaxel)
The dose of paclitaxel should be adjusted according to Table when neuropathy occurs. The dose
adjustment of carboplatin is not needed when neurotoxicity occurs.
Table 17. Dose adjustment of paclitaxel (neurotoxicity)
Toxicity Grade (CTCAE version 4.03)
Paclitaxel dose adjustment
Grade 1 or below
175 mg/m2
2
Interrupt treatment until return to grade 1, then reduce dose to 140 mg/m2
(20% of reduction) and restart infusion
Grade 3 or above
Interrupt treatment until return to grade 1, then reduce dose to 125 mg/m2
(30% of reduction) and restart infusion.
Once the dose is reduced due to neurotoxicity, the original dose should no longer be adopted.


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If the neurotoxicity does not return to grade 1 after paclitaxel interruption for 3 weeks, paclitaxel
should be permanently discontinued.
Allergic reactions/hypersensitivity reactions (paclitaxel)
Note: Prophylaxis for hypersensitivity reactions (see below) and close monitoring of vital signs
are recommended for subjects with history of mild to moderate hypersensitivity reactions when
hypersensitivity reactions reoccur.
Mild symptoms: complete paclitaxel infusion. Close monitoring; no treatment indicated.
Moderate symptoms: Interrupt paclitaxel infusion, administer diphenhydramine 25–
50 mg and dexamethasone 10 mg via intravenous infusion. Once symptoms have
resolved, resume paclitaxel infusion at a slower rate (20 mL/hour for 15 minutes, then
at 40 mL/hour for 15 minutes, and if no further symptoms develop, continue at original
rate until infusion is complete). Document this AE in the AE Report Form of eCRF. If
symptoms reoccur, interrupt the paclitaxel infusion and permanently discontinue
subsequent paclitaxel infusion.
Severe and life-threatening symptoms: Interrupt paclitaxel infusion, administer
diphenhydramine and dexamethasone via intravenous infusion (as above). Use
epinephrine or bronchodilators if indicated. Document this AE in the AE Report Form
of eCRF. Subsequent courses of paclitaxel infusion should be permanently
discontinued.
Moderate or severe hypersensitivity reactions should be documented as AEs.
Other toxicities
If other unmentioned grade 3–4 toxicities occur, the chemotherapy should be interrupted until
symptoms resolve or return to grade 1. Thereafter restart the infusion at 50% of the original dose
(which should no longer be adopted). If the toxicity does not return to grade 1 after an
interruption for 3 weeks, the chemotherapy should be permanently discontinued. Dose
adjustments are not recommended for grade 1 and 2 toxicities.
Investigator should closely monitor toxicities in subjects during chemotherapy. Before the start
of next chemotherapy cycle, the laboratory test results must be:

ANC ≥1.5 × 109/L

Platelet count ≥100 × 109/L

Serum creatinine < 1.5 × ULN


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
Bilirubin ≤1.5 × ULN

ALT and AST ≤2.5 × ULN; ALT and AST < 5 × ULN in subjects with liver metastasis
5.4 Study Drug Properties
IBI305 is a bevacizumab biosimilar. The active ingredient of both drugs is recombinant humanized
anti-VEGF monoclonal antibody; Bevacizumab is the standard commercially available drug, provided
by the sponsor.
Detailed information on the study drugs is shown in Table .
Table 18. Study drugs
Study Drugs
Dosage Form and
Strength
Excipient
Appearance
Manufacturer
IBI305
4 mL: 100 mg
Sodium acetate,
sorbitol, and
polysorbate 80
Sterile solution for
intravenous injection
pH 5.2
Clear, colorless liquid, no
foreign matters, no floc
or precipitation
Innovent Biologics (Suzhou)
Co., Ltd.
Bevacizumab 4 mL: 100 mg
α,α-trehalose
dihydrate, sodium
dihydrogen phosphate
monohydrate,
disodium hydrogen
phosphate,
polysorbate 20, and
sterile water for
injection
Sterile solution for
intravenous injection
pH 5.9–6.3
Clear to slight
opalescent, colorless to
light brown
Roche Pharma (Schweiz)
Ltd.
5.5 Preparation and Distribution
IBI305 or bevacizumab is diluted in 0.9% sodium chloride solution by the pharmacist or research
nurse before infusion. Check the particles and discoloration prior to administration.
The investigator should ensure that the pharmacist or research nurse administers the study drugs
according to study protocol.
5.6 Packaging, Labeling, and Storage
The sponsor should package and label the study drugs according to appropriate local regulations.
All study drugs (IBI305 and bevacizumab) must be stored at 2–8 °C away from light. The study
drugs should be stored in a safe zone only accessible by authorized staff prior to dispensation to
the subjects.


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5.7 Subjects Allocation
After confirming that the subject meets all of the inclusion and exclusion criteria, the study site
will log in the Interactive Web Response System (IWRS) and enter the subject information into
the IWRS. The IWRS will allocate a random number to the subject and provide a medication
number. Stratified randomization is used in this study. Stratifying factors include age (< 60 vs.
≥60 years old) and EGFR status (wild vs. mutant type).
5.8 Blinding
This is a randomized, double-blind, and active-controlled study, and only relevant study
personnel had access to the randomization numbers. A non-blinded pharmacist or research nurse
will prepare the medications since IBI305 and bevacizumab do not have an identical appearance.
The pharmacist or research nurse who is responsible for preparing the study drugs is not allowed
to disclose any information regarding treatment allocation to the subject, the subject's family
members, or other personnel including the physician and the relevant study staff.
Unblinding: Subject unblinding should only be performed after database locking.
Emergency unblinding: In case of an emergency where the investigator must know the
medication given to a particular subject, the investigator will unblind the subject via the IWRS
and immediately inform the sponsor and CRO. The reasons for unblinding, date, and outcomes
should be documented in the source document and eCRF of the subject.
5.9 Concomitant Medications and Treatments
All medications except for the study drugs, including other chemotherapies not specified in the
study, Chinese herbal medicines, and other non-traditional therapies, are considered concomitant
medications. All concomitant medications used within 30 days prior to screening should be
documented in the eCRFs, including the information of generic name, route of administration,
start date, end date, and indication.
5.9.1 Prohibited medications
No other anti-tumor therapies or medications with anti-tumor indications, including Chinese
herbal medicine, radiotherapy, or other investigational drugs, are allowed during this study other
than IBI305, bevacizumab, paclitaxel, and carboplatin.
Severe myelosuppression is possible after chemotherapy. Granulocyte colony-stimulating factor
or granulocyte-macrophage colony-stimulating factor are not allowed to be used prophylactically
in the first treatment cycle.


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5.9.2 Medications allowed
Prophylactic use of anti-emetics, glucocorticoids, or other treatments targeting toxicities is permitted
during the study. Unconventional treatments (such as acupuncture) and vitamins/microelements are
permitted if their use does not affect the study endpoints as determined by the investigators.
Starting from the 2nd chemotherapy cycle, granulocyte colony-stimulating factor or granulocyte-
macrophage colony-stimulating factor are allowed to be used prophylactically to prevent severe
myelosuppression.
5.9.3 Treatment after study treatment
Subsequent therapy after the end of study treatment should be determined by the subject's
attending doctor.
5.10 Treatment Compliance
The dosage and dosing time of IBI305 or bevacizumab and paclitaxel + carboplatin in each
treatment cycle should be documented in the eCRFs. Reasons for dosing delay, dose reduction or
missed dossing should also be documented in the eCRFs.
Treatment and protocol compliance refers to the subject's voluntary compliance with each aspect
of the protocol, including compliance with blood collection for safety evaluation and imaging
examination for tumor assessment. If a subject does not return for the scheduled follow-up visits,
his/her participation in the study may be terminated based on the opinions of the primary
investigator or sponsor.
5.11 Study Drug Count
The investigator, other relevant stuff, or authorized pharmacists should document the receipt and
distribution of study drugs on the study drug count table and ensure that the table is readily
available for inspection.
The study drugs are only for the use of study subjects. At the end of the trial, all study drugs
should be counted and explanations for deviations should be provided in a written document.
The investigator shall count all unused study drugs and packaging materials, and return them to
the sponsor or the designated third party. Used empty drug bottles/bags will be destroyed on-site
according to the institutional standards.


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6 STUDY PROCEDURE
The detailed procedures of this study are shown in Table 1. Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
.
6.1 Screening Visits (D -28 to D -1)
Complete the screening visits within 28 days prior to study treatment commencement. The
following procedures must be completed during screening to ensure that subject meets the
requirements for participating in this study:

Sign the ICF

Record the demographics, including age, ethnicity, and gender

Record the past medical history, including smoking history

Record the history of anti-tumor therapies

Record the concomitant medications (within 30 days prior to screening)

Record the vital signs

Measure the height and weight (including BMI)

ECOG score

Physical examination

12-Lead ECG

Hepatitis B panel, anti-HCV, anti-HIV, and syphilis tests

Clinical laboratory tests (routine blood test, coagulation test, blood chemistry, and
urinalysis)


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
Blood pregnancy test (for female subjects of childbearing age only)

Imaging examinations (CT or MRI: Head, chest, abdomen, and pelvis cavity)*

EGFR test#

Review the inclusion/exclusion criteria

Record the AEs
* Retests are not required if the tests have been performed within 28 days prior to the first dose,
unless the investigators suspect changes in tumor burden. Imaging results during screening will
be used as the baseline data. The same method of imaging test is used at baseline and during
follow-up. Imaging evaluations of the chest, abdomen, and pelvis are required.
# If the subject has been tested for EGFR of tumor sample at the study site with documentation,
the subject will not be required for retest.
6.2 Baseline Visits (D1 of cycle 1)
D1 refers to the day of receiving the first dose of the study drugs. Eligible subjects meeting the
inclusion criteria will return to the study site and complete the following procedures:

Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests * (routine blood test, blood chemistry, and urinalysis)

Immunogenicity test (ADAs and neutralizing antibodies)

Confirm the inclusion/exclusion criteria

Record the AEs and concomitant medications
* If clinical laboratory screening tests (routine blood test, blood chemistry, urinalysis) are
performed within 7 days prior to the first dose, then the results of the screening test can be
used as baseline.
If the subject meets the inclusion criteria, the following procedures should be complete:

Randomization and grouping

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)


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
Record the AEs and concomitant medications
6.3 Cycle 2 (week 4 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
6.4 Cycle 3 (week 7 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
Imaging tests (CT or MRI) should be done every 6 weeks (±7 days), and tumor assessment
should be completed within 7 days prior to this visit to determine whether the study treatment
should be continued.
6.5 Cycle 4 (week 10 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.


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Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Immunogenicity test

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
6.6 Cycle 5 (week 13 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
Imaging tests (CT or MRI) should be done every 6 weeks (±7 days), and tumor assessment
should be completed within 7 days prior to this visit to determine whether the study treatment
should be continued.
6.7 Cycle 6 (week 16 ± 3 days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Subjects should complete the following procedures during this visit:

Record the vital signs


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
Measure the weight

Physical examination

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Study drug infusion (IBI305 or bevacizumab)

Chemotherapeutic drug infusion (paclitaxel + carboplatin)

Record the AEs and concomitant medications
6.8 Cycle 7 and Subsequent Treatment Cycles (±3 Days)
Subjects should return to the study site 3 weeks (±3 days) after the last infusion of the study drug.
Monotherapy will start from week 7 and the dose of study drug will be adjusted to 7.5 mg/kg.
Subjects should complete the following procedures during each visit:

Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Study drug infusion (IBI305 or bevacizumab)

Record the AEs and concomitant medications
Imaging tests (CT or MRI) should be done every 6 weeks (±7 days), and tumor assessment
should be completed within 7 days prior to this visit to determine whether the study treatment
should be continued.
6.9 End-Of-Treatment Visit
The end of treatment visit in study sites will be conducted in 28 days (±7 days) after the last dose
of study drug. Subjects should complete the following procedures during this visit:

Record the vital signs

Measure the weight

Physical examination

Clinical laboratory tests (routine blood test, blood chemistry, and urinalysis)

Immunogenicity test


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
Blood pregnancy test (for female subjects of childbearing age only)

Tumor assessment (CT or MRI, completed within 7 days prior to this visit; not required
to be repeated if it has been performed within 6 weeks prior to this visit)

Subsequent anti-tumor therapy

Record the AEs and concomitant medications
If the subject has not experienced PD, the subsequent follow-up for PD will be performed
(Section 6.10). If the subject has experienced PD, the subsequent follow-up for survival will be
performed (Section 6.11).


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6.10 Disease Progression Visit
If the study drugs are discontinued for reasons other than PD, the end of treatment visit in study
sites will be conducted in 28 days after the last dose of study drug, and tumor assessments should
be conducted every 6 weeks (±7 days) until PD if possible (after which, follow-up for survival
will be conducted [Section 6.11]), withdraw of informed consent, loss to follow-up, death,
start of other anti-tumor therapies, or end of study. During the visit, vital signs and weight
measurements will be performed, and any subsequent anti-tumor therapies will be documented.
6.11 Survival Follow-Up
The investigator will make telephone follow-up every 12 weeks (±7 days) to collect the
information of subsequent anti-tumor therapies and survival until withdrawal of informed
consent, loss to follow-up, death, or end of study.
6.12 Study Completion
Completion of this clinical study is defined as 18 months after the enrollment of the last subject.
If the subjects continue to receive the study drug treatment before this cut-off time, the treatment
should be discontinued and the end of treatment visit should be completed (Section 6.9).
6.13 Tumor Assessment
Imaging tests (CT or MRI) of the brain, chest, abdomen, and pelvis are required at baseline. If
these tests are performed within 28 days prior to the first dose of the study drug, they do not need
to be repeated unless the investigator believes that there have been changes in the subject's tumor
burden. After the start of treatment, imaging tests are performed once every 6 weeks (±7 days)
and have to be completed within 7 days prior to the scheduled visits, until progressive disease,
start of other treatment, withdrawal of informed consent, loss to follow-up, death, or study
completion. The same method of imaging test was used at baseline and during follow-up.
Imaging evaluations of the chest, abdomen, and pelvis are required.
The investigator should perform a tumor assessment based on RECIST v1.1 (Section 13.3) prior
to each dose to determine whether the subject should continue with the next round of treatment.
An independent review committee will also assess the tumor response (Section 11.1.1). Imaging
tests will not be rescheduled if the study drugs or chemotherapeutic agents are interrupted due to
toxicities. Every effort should be made to continue the schedule for imaging tests even for
subjects who discontinue one or two study treatment(s) due to drug-related toxicities.
If subject experience PD according to the RECIST v 1.1 criteria, the attending doctor should
discuss with the subject regarding subsequent routine cancer therapies.


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6.14 Clinical Laboratory Evaluations
Clinical laboratory tests will be conducted at the laboratories of each study site. Sample collection
and analysis should be performed according to the requirements of each laboratory.
The following laboratory tests should be conducted according to the study procedures (Table 1.
Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
x
x
x
x
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
carboplatin) k
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
):
Routine blood test: hemoglobin, hematocrit, WBC and differentials (including
absolute neutrophil and lymphocyte counts), platelets, and RBC
Routine coagulation test (baseline test): INR, aPTT, and PTT
➢
Blood chemistry: Creatinine, blood urea nitrogen, total protein, albumin, total
bilirubin, alkaline phosphatase, aspartate aminotransferase (AST), alanine
aminotransferase (ALT), fasting blood glucose, sodium, potassium, chloride,
calcium, phosphorus, and magnesium
➢
Urinalysis: Specific gravity, pH, glucose, protein, occult blood, and leukocytes
➢
Pregnancy test: Serum pregnancy tests are performed on women of childbearing age
during screening and the end-of-treatment visit.
These tests are carried out at the laboratory of each trial site.
For subsequent visits, all laboratory tests need to be completed within 3 days prior to the
administration. During the study, the frequency of these laboratory tests will be increased if
safety is a concern. The investigator should review the laboratory test results throughout the
study to determine whether the results are clinically significant. The investigator should assess
the changes in laboratory test results. If the investigator considers a laboratory test result to be
abnormal and of clinical significance, it is considered as an AE.


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6.15 Vital Signs, Physical Examinations, and Other Safety Assessments
6.15.1 Vital signs
Vital signs include pulse, BP, temperature, and respiratory rate. The subject must rest for at least
5 minutes prior to each vital sign assessment.
Vital signs will be assessed according to the Schedule of Activities (Table 1. Schedule of follow-
up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
(including smoking
history)
x
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
x
x
x
x
x
x
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
bevacizumab) j
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
). During the study, the investigator may increase the frequency of vital sign measurement if
safety is a concern.
6.15.2 Height and weight
Height is only measured during screening. Weight is measure during each visit.
6.1.5.3 Physical examinations
The following organs/systems will be examined according to the Schedule of Activities (Table 1.
Schedule of follow-up visits
Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
Informed consent
x
Inclusion/exclusion
criteria assessment
x
x
Demographics
x
Medical history
x


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Stage
Screening
period
Treatment period (21-day cycles)
After treatment
Combination treatment period
Maintenance
therapy
End-of-
treatment
visit (28
days after
last dose)
PD
follow-
upa
Survival
follow-
upb
(Once
every 12
weeks
after
PD)
Cycle (C) and day
(D)
D-28 to
D1
C1D1 C2D1 C3D1 C4D1 C5D1 C6D1
Cycle 7 to
end-of-
treatment
Time window (day)
-
-
±3
±3
±3
±3
±3
±3
±7
-
±7
Visit
1
2
3
4
5
6
7
8-N
(including smoking
history)
NSCLC treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
x
x
x
x
x
x
Routine blood test d
x
x
x
x
x
x
x
x
x
Coagulation test
x
Blood chemistry d
x
x
x
x
x
x
x
x
x
Urinalysis d
x
xe
xe
xe
xe
xe
xe
xe
xe
Pregnancy test f
x
x
Immunogenicity g
x
x
x
HBV, HCV, HIV,
and syphilis testing
x
Imaging assessment
(CT or MRI) h
x
x
x
x
x
x
Tumor specimen
collection for EGFR
testing i
x
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab) j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin) k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
Aes
x
x
x
x
x
x
x
x
x
Subsequent anti-
tumor therapy
x
x
x
Survival follow-up
x
x
x
Pharmacokinetic
(PK)
x
x
x
x
x
VEGF testing
x
x
x
x
): general condition, head (eyes, ears, nose, and throat), neck and thyroid, respiratory system,
cardiovascular system, abdomen, nervous system, skeletal muscles and limbs, as well as


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lymphatic system and skin.
6.15.4 12-Lead ECG
The subject will undergo a 12-lead ECG during screening, and also during the course of the
study if deemed necessary by the investigator.
The following ECG parameters should be documented: HR, PR-interval, QRS-complex, QT-
interval, and QTc-interval. The subject must be in the supine position for at least 5 minutes prior
to undergoing the 12-lead ECG. All ECG are evaluated by qualified physicians. All clinically
significant abnormal findings should be reported as AEs.
6.15.5 Immunogenicity assessment
Blood samples are collected before the first dose, on D1 of Cycle 4, and during the end-of-treatment
visit for immunogenicity assessment including testing of anti-drug antibodies and neutralizing
antibodies. Immunogenicity testing will be carried out at the relevant central laboratory. Details
regarding sample collection, processing, labeling, storage, transport, and analysis are provided in
the Central Laboratory Manual.
6.15.6 EGFR testing
All subjects should undergo tumor tissue EGFR testing during screening at the laboratory of each
trial site (The test does not need to be repeated if it can be confirmed with relevant reports that
the test has already been completed at the trial site).


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Table 19. Schedule of follow-up visits
Item
Screening
period
Combination treatment period
Monotherapy
period
After treatment
Time point
D-28 to
D-1
Cycle 1
(D1)
Cycle 2
(±3 days)
Cycle 3
(±3 days)
Cycle 4
(±3 days)
Cycle 5
(±3 days)
Cycle 6
(±3 days)
Cycle 7 to
end-of-treatment
(3 weeks/cycle
[±3 days])
End-of-
treatment
visit
(28 ± 7 days)
PD
follow-
upa
Survival
follow-upb
(Once every
12 weeks
[±7 days] after
PD)
Informed
consent
x
Inclusion/exclus
ion criteria
assessment
x
x
Demographics
x
Medical history
(including
smoking
history)
x
NSCLC
treatment
history
x
Vital signs
x
x
x
x
x
x
x
x
x
x
Height and
weight
x
xc
xc
xc
xc
xc
xc
xc
xc
xc
ECOG score
x


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Item
Screening
period
Combination treatment period
Monotherapy
period
After treatment
Time point
D-28 to
D-1
Cycle 1
(D1)
Cycle 2
(±3 days)
Cycle 3
(±3 days)
Cycle 4
(±3 days)
Cycle 5
(±3 days)
Cycle 6
(±3 days)
Cycle 7 to
end-of-treatment
(3 weeks/cycle
[±3 days])
End-of-
treatment
visit
(28 ± 7 days)
PD
follow-
upa
Survival
follow-upb
(Once every
12 weeks
[±7 days] after
PD)
Physical
examination
x
x
x
x
x
x
x
x
x
12-Lead ECG
x
If clinically indicated
Routine blood
test
x
xd
x
x
x
x
x
x
x
Coagulation
test
x
Blood chemistry
x
xd
x
x
x
x
x
x
x
Urinalysis
x
xd,e
xe
xe
xe
xe
xe
xe
xe
Pregnancy testf
x
x
Immunogenicityg
x
x
x
HBV, HCV,
HIV, and
syphilis testing
x
Imaging
assessment
(CT or MRI)h
x
x
x
x
x
x
Tumor specimen
collection for
EGFR testingi
x


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Item
Screening
period
Combination treatment period
Monotherapy
period
After treatment
Time point
D-28 to
D-1
Cycle 1
(D1)
Cycle 2
(±3 days)
Cycle 3
(±3 days)
Cycle 4
(±3 days)
Cycle 5
(±3 days)
Cycle 6
(±3 days)
Cycle 7 to
end-of-treatment
(3 weeks/cycle
[±3 days])
End-of-
treatment
visit
(28 ± 7 days)
PD
follow-
upa
Survival
follow-upb
(Once every
12 weeks
[±7 days] after
PD)
Randomization
x
Study drug
administration
(IBI305 or
bevacizumab)j
x
x
x
x
x
x
x
Chemotherapy
(paclitaxel +
carboplatin)k
x
x
x
x
x
x
Concomitant
medications
x
x
x
x
x
x
x
x
x
AEs
x
x
x
x
x
x
x
x
x
Subsequent
anti-tumor
therapy
x
x
x
Survival
follow-up
x
x
x
a.
After completing the on-site end-of-treatment visit 28 days after the last dose, subjects who discontinue the investigational drug treatment due to reasons
other than PD should continue to undergo tumor assessments once every 6 weeks (±7 days) until PD (and begin post-PD follow-up thereafter), withdrawal
of consent, start of another antineoplastic treatment, loss to follow-up, death, or study completion.
b.
For subjects with PD, collect survival information once every 12 weeks (84 days, ±7 days) by phone until death, loss to follow-up, withdrawal of informed
consent, or study completion. Subsequent antineoplastic treatments should be documented in the eCRF.


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c.
Only measure weight.
d.
Clinical laboratory tests are carried out at the laboratory of each hospital. If screening laboratory tests (routine blood test, blood chemistry, and urinalysis)
are performed within 7 days prior to the first dose, the screening results may be used as baseline data. For subsequent visits, all laboratory tests have to be
completed within 3 days prior to the dose administration.
e.
Prior to each IBI305/bevacizumab infusion, test paper should be used to examine urinary protein.
f.
Women of childbearing age should undergo serum pregnancy tests.
g.
Immunogenicity testing (for anti-drug antibodies and neutralizing antibodies) is performed at the central laboratory.
h.
Image assessments (CT or MRI) of the brain, chest, abdomen, and pelvis should be completed at baseline. If these tests are performed within 28 days prior
to the first dose of the study drug, they do not need to be repeated unless the investigator believes that there have been changes in the subject's tumor burden.
After the start of treatment, imaging tests are performed once every 6 weeks (±7 days) and have to be completed within 7 days prior to the scheduled visits,
until progressive disease, start of other treatment, withdrawal of informed consent, loss to follow-up, death, or study completion. The same method of
imaging test is used at baseline and during follow-up. Imaging evaluations of the chest, abdomen, and pelvis are required.
i.
All subjects should undergo tumor tissue EGFR testing, but the test does not need to be repeated if it can be confirmed with relevant reports that the test has
already been completed at the trial site. EGFR testing will be carried out at the laboratory of each trial site.
j.
Each treatment cycle for the investigational drug is 3 weeks long. IBI305 or bevacizumab is administered on D1 of each cycle, at 15 mg/kg during
combination treatment with chemotherapy and 7.5 mg/kg during monotherapy, until disease progression (PD), unacceptable toxicity, withdrawal of
informed consent, loss to follow-up, death, or study completion, whichever occurs first. After all assessments are completed, the study drug is administered
followed by chemotherapy.
k.
Each treatment cycle is 3 weeks long. Chemotherapy (paclitaxel + carboplatin) is administered on D1 of each cycle for up to 6 cycles, or until disease
progression (PD), unacceptable toxicity, withdrawal of informed consent, loss to follow-up, or death. Paclitaxel is administered after the infusion of study
drug is completed, followed by carboplatin.


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7 STUDY ASSESSMENTS
7.1 Efficacy Assessment
7.1.1 Primary efficacy endpoint

Objective response rate (ORR)
ORR will be assessed using RECIST v1.1. ORR is defined as the proportion of subjects whose
tumor volume has reduced to a predetermined value for a minimum time limit, including patients
who achieved complete response (CR) and partial response (PR). The cutoff date for the primary
efficacy endpoint analysis of this study is 6 months after subject randomization.
7.1.2 Secondary efficacy endpoints

Duration of response (DOR)

Progression-free survival (PFS)

Disease control rate (DCR)

Overall survival (OS)
Each endpoint will be assessed using RECIST v1.1.
DOR is defined as the time from initial tumor response (CR or PR) to PD or death before PD;
Subjects with CR or PR who do not progress or die will be censored on the date of the last tumor
assessment.
PFS is defined as the time from the date of randomization to the date of PD or death; Subjects
who do not progress or die will be censored on the date of the last tumor assessment.
DCR is defined as the proportion of patients whose tumor volume has reduced to a
predetermined value for a minimum time limit, including patients who achieved CR, PR, and SD.
OS is defined as the time from the date of randomization to the date of death of any cause. For
subjects that are alive on the date of study completion or are lost to follow-up, their survival time
will be censored at the date of last contact.


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7.2 Safety Assessments
7.2.1 Adverse events
7.2.1.1 Definition
AEs
An adverse event is defined as any untoward medical occurrence suffered by the subject of the
clinical research, which does not necessarily have a causal relationship with the treatment.
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal
laboratory finding), symptom, or disease temporally associated with the use of the investigational
drug, whether or not considered related to the investigational drug.
Serious adverse event
A serious adverse event does not necessarily have a causal relationship with the investigational
drug. It refers to any untoward medical occurrence that (at any dose of the investigational drug):
(1)
Results in death.
(2)
Is life-threatening (The term "life-threatening" refers to an event in which the subject is
at risk of death at the time of the event; it does not refer to an event which hypothetically
might have caused death if it is more severe).
(3)
Requires inpatient hospitalization or prolongation of existing hospitalization: This does
not include hospitalization and/or surgical procedures scheduled to be conducted prior
to or during the study for a disease or disorder that exists prior to study enrollment and
has not worsened during the course of the study.
(4)
Results in permanent or severe disability/incapacity.
(5)
Results in congenital anomalies/birth defects.
(6)
Other important medical events: Medical events that do not necessarily result in death,
are not life-threatening, and do not require hospitalization, but may jeopardize the
subject and may require medical or surgical intervention to prevent one of the aboves
outcomes, are also considered SAEs.
Note: Hospitalization as a result of PD is not considered an SAE.
Other Definitions
An adverse drug reaction (ADR) refers to any untoward response related to the investigational
drug after receiving any dose.


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An unexpected adverse drug reaction is any adverse reaction that is not consistent with
information known about the investigational drug.
7.2.1.2 Severity of adverse events
The severity of AEs will be assessed by CTCAE 4.03. The classifications are as follows:

Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations
only; intervention not indicated.

Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL (e.g. preparing meals, shopping for groceries or clothes,
using the telephone, managing money, etc.)

Grade 3 Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care
ADL (e.g. bathing, dressing and undressing, feeding oneself, using the toilet, taking
medications, and not bedridden)

Grade 4
Life-threatening; urgent intervention indicated

Grade 5
Death related to AE
7.2.1.3 Relationship between adverse events and the investigational drug
The relationship between the investigational drug and AE can be classified into five categories:
definitely related, probably related, possibly related, unlikely related, and definitely unrelated.
Specific assessment criteria are as follows:
Table 20. Assessment criteria for causality between an adverse event and the investigational drug
Parameters
Definitely
related
Probably related
Possibly
related
Unlikely
related*
Definitely
not related
Reasonable temporal relationship
Yes
Yes
Yes
Yes
No
Recognized pharmacological
phenomenon
Yes
Yes
Yes
No
No
Positive dechallenge
Yes
Yes
Yes or No
Yes or No
No
Positive rechallenge
Yes
?**
?**
?**
No
Other alternative explanations
No
No
Yes
Yes
Yes
* Unlikely related = further observations required to make an assessment;
? ** Rechallenge not permitted due to ethical reasons.


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7.2.1.4 Serious adverse event reporting
Any SAE that occurs during the trial should be reported in accordance with SAE reporting
procedures of regulatory authorities or the ethics committee, regardless of whether the event is
related to treatment.
The investigator should take the following measures:

If necessary, take appropriate treatment measures immediately;

Immediately (within 24 hours after becoming aware of the event or obtaining new
information about the event) report the event to the sponsor's authorized representative
responsible for relevant safety information using a method approved by the sponsor;

Document the SAE in the AE and SAE section of the eCRF as well as in the source
documents;

The investigator must immediately (within 24 hours) submit the signed and dated SAE
Report to the independent ethics committee, NMPA (formerly CFDA), health
administration department, and local drug administration authorities;

Follow and document the course of the event, until the event resolves or returns to
baselines levels, or becomes clinically stable.
In addition, the sponsor or its representative (such as CRO) should report the SAE to the
corresponding regulatory agencies and other investigators in accordance with the requirements of
regulatory agencies and local regulations.
7.2.1.5 Management and follow-up of adverse events
The investigator is responsible for providing appropriate medical treatment for all AEs (Indicate
the actions taken, such as suspension/termination of the investigational drug, dose modification,
drug therapy, etc.). When an AE occurs, the investigator should actively take appropriate
measures to ensure the safety of the subject. All AEs observed from the signing of the ICF
to the time specified in the protocol (Table 2) must be followed. Refer to Section 7.2.1.8 for
the specific follow-up time.
The investigator should report any AE that occurs after the time specified in the protocol (Table 2)
and is suspected of being related to the investigational drug to the sponsor.
7.2.1.6 Adverse events of special interest
The AESI for this study include:

Hypertension


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
Proteinuria

Gastrointestinal perforation

Hemorrhage (cerebral hemorrhage, hematuria, and upper gastrointestinal hemorrhage)

Cardiotoxicity

Thrombus
An AESI should also be reported as an SAE if the definition of SAE is met.
7.2.1.7 Pregnancy
Any pregnancy during the study, though not an SAE, must be reported using the Clinical Trial
Pregnancy Report. To ensure subject safety, the investigator must submit the report to the sponsor
or the sponsor's representative within 24 hours after becoming aware of the event. Pregnancies
must be followed to determine the outcome (including early termination) and the condition of the
mother and the baby. Complications and termination of pregnancy due to medical reasons should
be reported as AE or SAE. A spontaneous abortion should be reported as an SAE.
The investigator should pay attention to any pregnancy-related SAE that occurs after study
completion. Any SAE that the investigator believes may be related to the study treatment should
be reported immediately to the sponsor.
7.2.1.8 Summary of adverse event collection, documentation, and reporting
All adverse events that occur from the signing of the ICF to the time specified in the protocol
(Table 2) must be collected and documented in the AE page of the eCRF regardless of severity
(all SAEs and non-serious AEs).
The investigator must fill out all the required information, including the description of the AE,
start date, end date, severity, measures taken, outcome, seriousness, and causality with the
investigational drug. Each AE should be documented separately.
Table 21. Reporting and follow-up of adverse events
Reporting time limit
Visit time limit
AEs
From the signing of the ICF until 28 days after the
last dose of the study treatment
Until resolution or 28 days after the
last dose of the study treatment
Adverse events of
special interest (AESIs)
From the signing of the ICF until 6 months after the
last dose of the study treatment
Until resolution or 6 months after the
last dose of the study treatment
Serious adverse event
From the signing of the ICF until 6 months after the
last dose of the study treatment
Until resolution (treatment-related) or
6 months after the last dose of the
study treatment (not treatment-related)
Pregnancy
From the first dose until 6 months after the last dose
of the study treatment
Until the end of the event


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8 STATISTICS
8.1 Sample Size Determination
It will require 200 subjects in each treatment group (400 in total) to demonstrate clinical
equivalence between IBI305 + paclitaxel/carboplatin and bevacizumab + paclitaxel/carboplatin
with more than 80% power.
The sample size is estimated based on the following assumptions:

The actual difference in ORR between subjects in the IBI305 and bevacizumab arms is 0

The ORR of subjects in the bevacizumab arm is about 54.4%

The equivalence margin is (-15%, 15%)

The significance level of the two one-side test is 0.05

1:1 randomization
Based on the above assumptions, 189 subjects are required for each treatment group (378 in total).
The sample size is expanded to 200 subjects for each treatment group (400 in total) after taking
dropouts into consideration. The sample size was estimated using PASS 2013.
8.2 Statistical Population
Intention-to-Treat (ITT): All randomized subjects who received the study treatment.
Full Analysis Set (FAS): All randomized subjects who received at least one dose of the study
treatment. This dataset is used as the primary analysis set for efficacy assessment.
Per-Protocol (PP): Based on the FAS, subjects with the predetermined minimum drug exposure
and without any predetermined major protocol deviations. This dataset is used as the secondary
analysis set for efficacy assessment.
Safety set (SS): Includes all randomized subjects who received at least one dose of the study
treatment and have safety evaluation data. This data set is used for the safety evaluation of this
study.
Intention-to-Treat (ITT): All randomized subjects.


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8.3 General Principles for Statistical Analyses
For continuous variables, descriptive statistics should include the count, mean, standard
deviation, median, maximum, and minimum. For categorical variables, descriptive statistics will
include the frequency as well as the absolute or relative percentage. Statistical analyses will be
carried out using SAS 9.4.
8.4 Statistical Methods
8.4.1 Adjustments for covariates
Not applicable.
8.4.2 Managing dropouts and missing data
The analyses of primary and secondary endpoints will include data from dropouts. The management
of missing data is described in the Statistical Analysis Plan.
8.4.3 Interim analysis
There is no interim analysis planned for this study.
8.4.4 Multi-center study
Since this is a multicenter study, the primary endpoint (ORR) will be listed according to study
sites and treatment groups. However, individual equivalence analysis will not be conducted.
Trial sites with fewer than 5 ITT subjects per treatment group will need to be combined for
analysis. Details will be discussed in the data review meeting.
8.4.5 Multiple comparisons and adjustments to multiplicity
Not applicable.
8.5 Statistical Analyses
8.5.1 Subject distribution
Refer to Figure 1: Study design schematic for the schedule of activities. The number and
percentage of patients who have completed or dropped out of the study (including the reason for
dropouts such as loss to follow-up, AEs, and poor compliance) are summarized based on
treatment groups.


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The number and percentage of subjects in each analysis set are calculated based on treatment groups.
The number and percentage of protocol deviations are calculated based on treatment groups.
8.5.2 Demographics and other baseline characteristics
Demographic information such as age, height, sex, and weight, and other baseline characteristics
such as disease history (including NSCLC diagnosis, staging, previous cancer treatment, and
target and nontarget lesions) are summarized using descriptive statistics.
8.5.3 Compliance and drug exposure
The required dose and the actual dose must be documented in the eCRF. Subject compliance is
calculated based on the ratio of the actual dose (number of doses) to the required dose (number
of doses). Subject compliance is classified into the following categories: < 80%, 80–120%, and >
120%. The number and percentage of subjects in each category will be summarized.
8.5.4 Efficacy
The efficacy analysis will be based on the FAS. Results of the PP set will also be presented.
8.5.4.1 Primary efficacy endpoint
The primary objective of this study is to determine the clinical equivalence between IBI305 +
paclitaxel/carboplatin and bevacizumab + paclitaxel/carboplatin for the treatment of advanced or
relapsed non-squamous non-small cell lung cancer (NSCLC). The primary endpoint is objective
response rate (ORR). ORR is defined as the incidence of patients with confirmed complete
response (CR) or partial response (PR), when a validated imaging method and RECIST v1.1
are used to evaluate target and non-target lesions. Subjects without tumor assessments beyond
baseline will be considered unresponsive to treatment. Subjects qualified for the evaluation of
CR or PR must have at least one measurable lesion according to RECIST v1.1. The evaluation
of clinical equivalence will be based on the ORR provided by the independent review committee
(IRC). Results provided by the investigator will be used for sensitivity analysis.
Clinical equivalence will be declared if the 90% confidence interval of the difference in ORR
between IBI305 and bevacizumab groups falls within the preset margin of (-15%, 15%).
The ORR and corresponding 95% confidence interval of the two treatment groups, the ORR
difference and the 90% confidence interval, as well as the ORR ratio between the two groups and
the 90% confidence interval will be estimated using the generalized linear model (GLM, which
includes treatment groups and stratification factors).


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8.5.4.2 Secondary efficacy endpoints
The secondary endpoints for this study include DOR, DCR, progress-free survival (PFS), and
overall survival (OS).
DCR is defined as the incidence of patients with confirmed complete response (CR), partial
response (PR), and stable disease (SD), when a validated imaging method and RECIST v1.1 are
used to evaluate target and non-target lesions.
DOR is defined as the time from initial tumor response (CR or PR) to PD or death; Subjects with
CR or PR who do not progress or die will be censored on the date of the last tumor assessment.
OS refers to the time from the date of randomization to the date of death (of any cause). For
subjects who are still alive at the time of the analysis, their survival time is censored on the last
known alive date. PFS refers to the time from the date of randomization to the date of first
documented PD or death, whichever occurs first. The investigator will assess PD using RECIST
v1.1. Subjects who do not progress or die will be censored on the date of the last tumor
assessment. Subjects without tumor assessments after baseline are censored on their date of
randomization.
Median OS and its 95% CI will be estimated using the Kaplan-Meier method. The survival curve
will be plotted. The hazard ratio (HR) between the two groups and its 95% CI will be estimated
using a Cox model. The Cox model includes treatment groups and stratification factors. DOR
and PFS will be analyzed using the same method as for OS. DCR will be analyzed using the
same method for primary efficacy endpoints, but an equivalence test will not be conducted.
8.5.4.3 Sensitivity analysis
The center effect (fixed or random) will be considered in the primary and secondary endpoints
analysis models (GLM or Cox).
8.5.4.4 Antibody and efficacy analysis
Subjects who develop antibodies during the clinical study will be summarized in detail. The
difference in efficacy between subjects with and without antibodies will be compared if
necessary.
8.5.5 Interim analysis
No interim analysis is planned for this study.


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8.5.6 Safety analysis
The safety analysis is based on the safety analysis set.
8.5.6.1 Adverse events
All adverse events (AE) will be coded using MedDRA and graded using CTCAE v4.03. All
TEAEs, TEAEs ≥grade 3, SAEs, drug-related TEAEs, drug-related SAEs, TEAEs resulting in
the termination of study drugs, TEAEs resulting in the termination of study, and AESIs will be
listed based on system organ class, preferred terms, and groups and the corresponding numbers
and percentages of subjects will be summarized. In addition, the severity of TEAEs and
relevance to the study drugs will also be summarized system organ class, preferred terms, and
treatment groups.
8.5.6.2 Laboratory tests
All laboratory test results and changes relative to baseline will be summarized by scheduled time
point and treatment group using descriptive statistics. Laboratory abnormalities will be listed.
8.5.6.3 ECG examinations
Results of ECG and changes relative to baseline will be summarized using descriptive statistics.
8.5.6.4 Vital signs, physical examinations, and other safety examinations
Descriptive statistics of vital signs and relative changes from baseline are shown.
Results of physical examinations are listed by treatment groups.
8.5.6.5 Concomitant medications
Concomitant medications are non-study medications that meet one of the followings:
(1)
Any drug therapy started during or after the first dose of the study treatment;
(2)
Any drug therapy started before the first dose of the study treatment and continued after
the first dose of the study treatment. Concomitant medications are listed by treatment
groups.


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9 QUALITY ASSURANCE AND QUALITY CONTROL
According to GCP principles, the sponsor is responsible for implementing and maintaining
quality assurance and quality control systems based on standard operating procedures (SOP),
to ensure that the implementation of the clinical trial and the collection, documentation, and
reporting of trial data is in accordance with the protocol, GCP, and applicable regulatory
requirements.
To ensure that the data is reliable and processed correctly, there should be quality control for
every step during the data processing.
In addition, the Clinical Quality Assurance (CQA) Department of the sponsor and/or CRO may
conduct regular audits of the study process, including but not limited to auditing the study site,
on-site visits, central laboratory, suppliers, clinical database, and the final clinical study report.
Regulatory authorities may also conduct inspections during the trial or at any time after the trial
is completed. The investigator and the research institution must allow the sponsor's representative
and regulatory authorities to review source data.
9.1 Clinical Monitoring
The sponsor has authorized Wuxi Clinical Co., Ltd. to conduct clinical monitoring for this study.
The clinical research associate (CRA) should follow the SOPs of Wuxi Clinical Co., Ltd. when
carrying out monitoring, and has the same rights and responsibilities as the sponsor's monitor.
The CRA should maintain regular communication with the investigator and the sponsor.
Before the start of the study, the associate monitor assess the qualifications of each study site,
and report issues related to facilities, technical equipment, or medical staff to the sponsor. During
the study, the CRA will be responsible for confirming whether written informed consent is
obtained from all subjects, and whether data documentation is accurate and complete. At the
same time, the CRA will compare data entered in to the eCRF with source data, and notify the
investigator of any errors or omissions. The CRA will also verify protocol compliance of the
study site, as well as the dispensing and storage of investigational drugs to ensure protocol
requirements are met.
The monitoring visit will be conducted in accordance with applicable statutes and regulations.
Each site receives regular monitoring visits from the time the subjects are enrolled. The CRA
should submit a written report to the sponsor after each monitoring visit to the study site.


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9.2 Data Management/Coding
The Data Management and Biostatistics Department of Wuxi Clinical Co., Ltd will process data
generated from this study in accordance with relevant SOPs.
This study will use an electronic data capture (EDC) system. Trial data will be entered into the
eCRF by the investigator or authorized study personnel. Prior to launching of the study site or
data entry, the investigator and authorized study personnel will receive appropriate training, and
appropriate safety measures will be taken.
All data are input in Chinese. The eCRF should be completed during or soon after each visit, and
should be constantly updated to ensure that it reflects the latest status of the subject. To avoid
discrepancies in outcome assessments between different evaluators, ensure that baseline and all
subsequent efficacy and safety assessments for the same subject are performed by the same
person. The investigator must review trial data to ensure the accuracy and correctness of all data
entered into the eCRF. During the study, the investigator should document any evaluations that
are not conducted, or any information that is not available, applicable, or known. The
investigator need to sign all verified data electronically.
The CRA will review the eCRF, and evaluate its completeness and consistency. The CRA will
also compare the eCRF with the source documents to ensure the consistency of critical data. Data
entry, corrections, or modifications are completed by the investigator or designated staff. The
CRA do not have access to data entry. The data in eCRF is submitted to the data server, and any
changes to the data will be documented in the audit trail, including the reason for the change, the
name of the operator, as well as the time and date of the change. The roles and permissions of
study personnel responsible for data entry will be predetermined. The CRA or data manager will
submit data queries in the EDC system, and study personnel shall respond to the queries. The
EDC system will record the audit trail of each query, including the name of the investigator, as
well as the time and date.
Unless otherwise specified, the eCRF should be considered simply as a form for data collection
and not a source document. A source file is used by the investigator or hospital, relevant to the
subject, and can prove the existence of the subject, inclusion criteria, and all records of
participation in the study, including laboratory records, ECG results, memorandum, pharmacy
dispensing records, and subject folders.


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The investigators are required to maintain all source documents and to offer the documents to the
CRA for review during each visit. In addition, the investigator must submit a complete eCRF for
each subject, regardless of the duration of the subject's participation in the study. The study
number and subject number in all supporting documents (such as laboratory records or hospital
records) submitted along with the eCRF should be carefully verified. All personal privacy
information (including the name of the subject) should be deleted or be made indecipherable in
order to protect subject privacy.
The investigator could be automatically added to the eCRF with his/her user ID. The investigators
verify that the record have been reviewed and that the data are accurate with an electronic
signature. The electronic signature is completed with the investigator's user ID and password.
The system automatically attaches the date and time of the signature. The investigator could not
share the user ID and password with other personnel. If data in the eCRF need to be modified,
the procedures defined by the EDC system have to be followed. All modifications and reasons
for the changes are recorded in the audit trail.
Training on the EDC system will be provided to study personnel at the study site.
Adverse events, and concurrent diseases/medical history will be coded. The medical dictionary
used for coding will be described in the Clinical Study Report (CSR).
9.3 Audits and Inspections
The sponsor or its representative (WuXi Clinical Co., Ltd) may conduct quality assurance audits
on the study site, database, and relevant study-related documents. Also, regulatory authorities
may also decide to inspect the study site, database, and relevant study-related documents at its
own discretion. The aim of audits and inspections is to systematically and independently check
all study-related procedures and documents to ensure that the clinical study is being carried out
in accordance with requirements of the trial protocol, GCP, Declaration of Helsinki, and
applicable regulations. The investigator must inform the sponsor immediately when an
inspection notice is received from the regulatory authorities.


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10 ETHICS
10.1 Independent Ethics Committee
The sponsor and its designated personnel will prepare all documents to be submitted to the
independent ethics committee (IEC) of each study site. The trial protocol, informed consent form
(ICF), investigators brochure, subject recruitment material or advertisements (if applicable), as
well as other documents required by regulations must be submitted to the IEC for approval. Prior
to the start of the study, written approval from the IEC must be obtained and provided to the
sponsor. The IEC approval must clearly state the title, number, and version of the study protocol
as well as the version of other documents (e.g. ICF) and the date of approval. The investigator
must notify the sponsor of the IEC's written comments concerning delays, suspension and re-
approval.
The study site must follow the requirements of the IEC. IEC requirements may include
submitting the revised protocol, ICF, or subject recruitment material to the IEC for approval,
local regulatory requirements for safety reports, and regular reports, updates, and submitting the
final report as per IEC requirements. The above documents as well as the IEC approval must be
provided to the sponsor or its designated personnel.
10.2 Implementation of Ethical Principles
The study process and the acquisition of informed consent should comply with the Declaration of
Helsinki, relevant GCP requirements (CPMP/ICH/135/95), and applicable statutes and
regulations related to drugs and data protection in the country in which the study is conducted.
The GCP is an international ethical and scientific quality standard for designing, conducting,
recording and reporting clinical trials that involve the participation of human subjects. To protect
the rights, safety, and healthy of subjects, this study will be carried out in accordance with GCP
and applicable national regulations, as well as ethical principles outlined in the Declaration of
Helsinki.
The investigator is required to follow the procedures specified in this protocol and must not
change the procedures without the permission from the sponsor. Protocol deviations will be
reported in accordance with the requirements of each ethics committee.


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10.3 Subject Information and Informed Consent
Prior to undergoing any study procedure, the ICF should be used to explain to potential participants
the potential risks and benefits of this study. The informed consent form should be in a language
that is simple and be easy to understand. The ICF should state that informed consent is voluntary,
emphasize the potential risks and benefits of participating in this study, and that the subject may
withdraw from the study at any time. The investigator may only enroll a subject after fully
explaining the details of the study, answering questions to the subject's satisfaction, giving
the subject sufficient time for consideration, and obtaining written consent from the subject or
his/her legal representative. All signed ICF must be retained in the investigator's documents or
the subject's folder.
The investigator is responsible for explaining the contents of the ICF and obtaining the ICF
signed and dated by the subject or his/her legal representative prior to starting the study. The
investigator should provide the subject with a copy of the signed ICF. The investigator must
document the informed consent process in the source document of the trial.
10.4 Protection of Subject Data
Information about data protection and privacy protection will be included in the ICF (or in some
cases, in a separate document).
Study personnel must ensure that the privacy of clinical trial subjects are protected. In all
documents submitted to the sponsor, the clinical trial subjects must only be identified with
subject number and not with the full name.
Additional precautions should be taken to ensure the confidentiality of the documents and
to prevent the identification of subjects based on genetic data. However, under special
circumstances, some personnel may be permitted to see the genetic data and personal
identification number of a subject. For example, in the event of a medical emergency, the
sponsor, designated physician, or investigator will have access to the subject identification code
and the subject's genetic data. In addition, regulatory agencies may request access to relevant
documents.


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11 STUDY MANAGEMENT
11.1 Organizational Structure
Refer to Table 3 for relevant collaborating parties.
Table 22. Organizational structure
Sponsor
Innovent Biologics (Suzhou) Co., Ltd.
No. 168 Dongping Street, Suzhou Industrial Park, Jiangsu, China
Telephone: (+86) 0512-69566088
Contract research
organization
WuXi Clinical Development Services (Shanghai) Co., Ltd.
19F, Building A, SOHO Fuxing Plaza, 388 Madang Road, Shanghai
Tel: (+86) 21-23158000
Data management and
biostatistics
WuXi Clinical Development Services (Shanghai) Co., Ltd.
19F, Building A, SOHO Fuxing Plaza, 388 Madang Road, Shanghai
Tel: (+86) 21-23158000
11.1.1 Independent review committee
Central imaging evaluation will be performed by Parexel China Co., Ltd. The CT/MRI images of
each subject will be evaluated using RECIST v1.1.
11.2 Archiving of Study Documents
Clinical trial documents (protocol and amendments, completed eCRFs, signed ICFs, etc.) must
be retained and managed as per GCP requirements. The study site must retain these documents
for 5 years after the completion of the study. The sponsor should retain clinical trial data for
5 years after the investigational drug is approved for marketing.
Study documents should be retained properly for future access or data traceability. Safety and
environmental risks should be considered when retaining documents.
The documents associated with the study may only be destroyed with the written consent of the
sponsor and the investigator. Study documents may be transferred to other parties that comply
with or other locations that meet retention requirements only after the sponsor is notified and
written consent thereof is obtained.


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11.3 Access to Source Data/Documents
Source data refers to source records of subject data obtained from a clinical study. These source
records are source documents, which include but are not limited to medical records (hospital
records, nursing records, pharmacy dispensing records, etc.), electronic data, screening logs,
laboratory test results, as well as medical device test results (ECG, CT/MRI, etc.). All source
documents associated with the trial are retained by the study site and the investigator. The
original ICFs will be retained according to standard practices developed by the clinical trial
institution.
The investigator will prepare sufficient and accurate source documents for each randomized
subject in order to document all examination results and other relevant data, and retain these
documents properly.
During the study, the CRA will conduct on-site visits to verify protocol compliance, EDC data
entry, documentation of subjects' medical history, drug inventory, and whether the study is
carried out in accordance with applicable regulations. In addition, regulatory authorities, IRB,
IEC, and/or the quality assurance department of the sponsor will verify source data and/or
conduct on-site audits or inspections. The investigator should allow direct access to documents
associated with the study, including medical records of subjects.
11.4 Protocol Revisions
The sponsor and the investigator must both agree on any appropriate protocol revisions during
the course of the study. The sponsor shall ensure that the protocol revision is submitted to the
regulatory authority in a timely manner.
All protocol revisions must be submitted to the IEC, and if needed, to regulatory authorities for
approval. Revisions may only be implemented after approval from the IEC and regulatory
authorities (if needed) is obtained (except for changes to eliminate immediate risks to subjects).
11.5 Investigator's Responsibilities
The investigator will conduct this study in accordance with the protocol, ethical principles of the
Declaration of Helsinki, Chinese GCP, and applicable regulations. Details of the investigator's
responsibilities are list in Chapter 5 (Investigator's Responsibilities) of the Chinese GCP (NMPA
order No. 3).


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11.6 Study Termination
The study may be terminated after a discussion between relevant parties if the investigator or the
sponsor becomes aware of circumstances or events that could jeopardize the subjects if the study
is continued. The sponsor may also decide to terminate the study even without such findings.
Reasons for study termination include but are not limited to:

Unexpected, serious, or unacceptable risks to enrolled subjects

Slow recruitment

The sponsor decides to suspend or discontinue the development of the drug
11.7 Publishing Policies
All the data generated in this study is the confidential information owned by the sponsor. The
sponsor has the right to publish study results. The investigator shall not publish any data relevant
to this study (posters, abstracts, papers, etc.) without prior communication with the sponsor.
Information on the publishing policies of the sponsor and investigator will be described in the
clinical trial agreement.
11.8 Finance and Insurance
The sponsor will purchase insurance for subjects participating in the study in accordance with
local regulations, and bear the cost of treatment and corresponding financial compensation for
the subjects who suffer injury during the study due to the investigational drug or the study
process. Insurance related terms shall be saved in the study folder.


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12 REFERENCES
1.
GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. Apr.
11, 2016: http://globocan.iarc.fr/Default.aspx
2.
陈万青，郑荣寿，曾红梅，等. 2011 年中国恶性肿瘤发病和死亡分析. 中国肿瘤.
2015;24(1):1-10.
3.
GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. Apr.
11, 2016: http://www.cancer.org/acs/groups/cid/documents/webcontent/003115-pdf.pdf
4.
支修益，石远凯，于今明. 中国原发性肺癌诊疗规范（2015 年版）. 中华肿瘤杂志.
2015;37(1):67-78.
5.
Pisters KMW and Chevalier TL. Adjuvant Chemotherapy in Completely Resected Non–
Small-Cell Lung Cancer. J Clin Oncol. 2005;23:3270-3278.
6.
石远凯，孙燕，于今明，等. 中国晚期原发性肺癌诊治专家共识（2016 年版）. 中国
肺癌杂志. 2016;19(1):1-15.
7.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN
Guidelines®) Non-Small Cell Lung Cancer (Version 4. 2016). Apr. 11, 2016:
http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
8.
郝希山，魏于全. 肿瘤学（第二版）. 北京: 人民卫生出版社. 108; 2010.
9.
Package insert of bevacizumab (Nov. 25, 2015). Apr. 11, 2016:
http://www.roche.com.cn/content/dam/roche_china/zh_CN/pdf/product/Avastin_20151125_
IM %20PI%20CDS32.0-33.0.pdf
10. Sandler A., Gray R., Perry MC., et al. Paclitaxel-carboplatin alone or with bevacizumab for
non-small-cell lung cancer. N Engl J Med. 2006;355:2542-2550.
11. Reck M., von Pawel J., Zatloukal P., et al. Overall survival with cisplatin-gemcitabine and
bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer:
results from a randomized phase III trial (AVAiL). Annals of Ocology. 2010;21:1804-1809.
12. Zhou CC., Wu YL., C GY., et al. BEYOND: A randomized, double-blind, placebo-
controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab
or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung
cancer. J Clin Oncol. 2015;33:2197-2204.
13. IBI305 研究者手册. 信达生物制药（苏州）有限公司. 2016 年5 月11 日.
14. Technical Guidelines for Development and Evaluation of Biosimilars by NMPA (Trial). Apr. 21,
2016: http://www.sda.gov.cn/WS01/CL1616/115104.html


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13 APPENDIX
13.1 Appendix I
Eastern Cooperative Oncology Group (ECOG) Performance Status Score
Score
Performance Status
0
Fully active, and able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activities but able to move around easily and carry out work of
a light or sedentary nature, e.g. light house work or office work
2
Capable of moving around easily and self-care but unable to carry out any work activities; up and
about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or wheelchair more than 50% of waking hours
4
Bedridden and incapable of self-care
5
Death
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative
Oncology Group. Am J Clin Oncol. 1982;5:649-655.


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13.2 Appendix II
Calculation of body surface area
Creatinine Clearance (Cockroft-Gault Equation)
Ccr (mL/min) = [(140 - age) x weight (kg)]/[72 x Scr (mg/dL)]
Female subjects: results × 0.85
1 mg/dL = 88.41 µmol/L
Carboplatin Dose (Calvert Equation)
Carboplatin dose (mg) = target AUC (mg/mL/min) × [creatinine clearance rate (mL/min) + 25]


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13.3 APPENDIX 3
RECIST v1.1
1
MEASURABILITY OF TUMOR AT BASELINE
1.1
Definitions
At baseline, tumor lesions/lymph nodes will be categorized as measurable or not measurable as
follows:
1.1.1
Measurable
Tumor lesions: must be accurately measured in at least one dimension (longest diameter in the
plane of measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm)

10 mm caliper measurement by clinical exam (lesions which cannot be accurately
measured with calipers should be documented as not measurable).

20 mm by chest X-ray.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will
be measured and followed.
1.1.2
Not measurable
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes
with a short axis ≥10 and <15 mm) as well as truly not measurable lesions. Lesions considered
truly not measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion,
inflammatory breast disease, lymphangitis involving the skin or lungs, abdominal masses/
abdominal organomegaly identified by physical exam but not measurable by reproducible
imaging techniques.
1.1.3
Special considerations regarding measurable bone lesions, cystic lesions, and lesions
with prior locoregional treatment:
Bone lesions:

Bone scan, PET scan or plain films are not considered adequate imaging
techniques to measure bone lesions. However, these techniques can be used to
confirm the presence or disappearance of bone lesions.


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
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue
components, that can be evaluated by cross sectional imaging techniques (such as
CT or MRI) can be considered as measurable lesions if the soft tissue
components meet the definition of measurability described above.

Blastic bone lesions are not measurable.
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not
be considered as malignant lesions (neither measurable nor not measurable) since
they are, by definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as
measurable lesions, if they meet the definition of measurability described above.
However, if noncystic lesions are present in the same patient, these noncystic
lesions are preferred for selection as target lesions.
Lesions with prior locoregional treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to
other locoregional therapy are usually not considered measurable, unless there
has been demonstrated progression in the lesion. The study protocol should detail
the conditions under which such lesions would be considered measurable.
1.2
Specifications by Methods of Measurements
1.2.1
Measurement of lesions
All measurements should be documented with metric symbols. Calipers should be used if clinical
assessments are required. All baseline evaluations should be performed as close as possible to
the beginning of the treatment but never more than 4 weeks before the beginning of the treatment.
1.2.2
Method of assessment
The same method of assessment and the same technique should be used to characterize each
identified and reported lesion at baseline and during follow-up. Imaging evaluation should
always be done rather than clinical examination unless the lesion(s) being followed cannot be
imaged but are assessable by clinical examination.
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial
and its diameter is ≥10 mm as assessed using calipers (e.g. skin nodules). For skin lesions,
documentation by color photography including a plotting scale to estimate the size of the lesion
is recommended. As noted above, when lesions can be evaluated by both clinical examination
and imaging evaluation, the latter should be undertaken since it is more objective and may also


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be reviewed at the end of the study.
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.
However, lesions on chest X-ray may be considered measurable if they have clear boundaries
and are surrounded by aerated lung tissues.
CT and MRI: CT is the best currently available and reproducible method to measure lesions
selected for response assessment. This guideline has defined measurability of lesions on CT scan
based on the assumption that CT slice thickness is 5 mm or less. When CT scans have a slice
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice
thickness. MRI is also acceptable in certain situations (e.g. for body scans).
Ultrasound: Ultrasound should not be used for measuring lesion size and should not be used as
a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for
independent review at a later date and, because they are operator dependent, it cannot be
guaranteed that the same technique and measurements will be taken from one assessment to the
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT
or MRI is recommended. If there is concern about radiation exposure at CT, MRI may be used
instead of CT in selected instances.
Endoscopy and laparoscopy: The utilization of these techniques is not recommended for
objective tumor evaluation. However, they can be used to confirm complete pathological
response when biopsies are obtained or to determine relapse in trials where recurrence following
complete response or surgical resection is an endpoint.
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If
markers are initially above the upper limit of normal, however, they must normalize for a patient
to be considered in complete response. Because tumor markers are disease specific, instructions
for their measurement should be incorporated into the protocol on a disease specific basis.
Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response
(in recurrent prostate cancer) have been published. In addition, the Gynecologic Cancer
Intergroup has developed CA125 progression criteria which are to be integrated with objective
tumor assessment for use in first-line trials in ovarian cancer.
Cytology and histology: These techniques can be used to differentiate between PR and CR in rare
cases if required by the protocol (for example, residual lesions in tumor types such as seminoma,
where known residual benign tumors can remain). When effusions are known to be a potential
adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors),
cytological confirmation of the neoplastic origin of any effusion that appears or worsens during


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treatment can be considered if the measurable tumor has met criteria for response or stable
disease in order to differentiate between response (or stable disease) and progressive disease.
2.
TUMOR RESPONSE EVALUATION
2.1
Assessment of Overall Tumor Burden and Measurable Disease
To assess objective response or future progression, it is necessary to estimate the overall tumor
burden at baseline and use this as a comparator for subsequent measurements. Only patients with
measurable disease at baseline should be included in regimens where objective tumor response is
the primary endpoint. Measurable disease is defined by the presence of at least one measurable
lesion. In studies where the primary endpoint is tumor progression (either time to progression or
proportion with progression at a fixed date), the protocol must specify if entry is restricted to
those with measurable disease or whether patients having non-measurable disease only are also
eligible.
2.2
Baseline Documentation of "Target" and "Non-Target" Lesions
When more than one measurable lesion is present at baseline, all lesions (five lesions at most,
and two lesions per organ at most) representative of all involved organs should be identified as
target lesions and will be recorded and measured at baseline (This means in instances where
patients have only one or two organ sites involved, a maximum of two and four lesions
respectively will be recorded).
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be
representative of all involved organs, and should be those with reproducible repeated
measurements. It may be the case that, the largest lesion does not have reproducible
measurements, in which circumstance the next largest lesion with reproducible measurements
should be selected.
Lymph nodes merit special mention since their normal anatomical structures may be visible by
imaging even if not involved by tumor. Pathological nodes which are defined as measurable and
may be identified as target lesions must have a short axis of ≥15 mm by CT scan. Only the short
axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter
normally used by radiologists to judge if a node is invaded by solid tumor. Nodal size is
normally reported as two dimensions in the plane in which the image is obtained (for CT scan
this is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal or
coronal). The smaller of these measures is the short axis. For example, an abdominal node which
is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies as a malignant
measurable node. In this example, 20 mm should be reported as the node measurement. All other
pathological nodes (those with a short axis ≥10 mm but < 15 mm) should be considered non-


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target lesions. Lymph nodes that have a short axis < 10 mm are considered non-pathological and
should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions; short axis for nodal lesions) for all target
lesions will be calculated and reported as the baseline sum of diameters. If lymph nodes are to be
included in the sum, then as noted above, only the short axis is added into the sum. The baseline
sum of diameters will be used as reference to further characterize any objective tumor regression
in the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as
non-target lesions and should also be recorded at baseline. Measurements are not required and
these lesions should be recorded as "present", "absent", or in rare cases "unequivocal
progression". In addition, it is possible to record multiple target lesions involving the same organ
as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple
liver metastases’).
2.3
Response Criteria
2.3.1
Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes
(whether target or non-target) must have a reduced short axis of <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions vs. the
baseline sum of diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions vs.
the smallest sum during the study (this includes the baseline sum if that is the smallest). In
addition to the relative increase of 20%, the sum must also have an absolute increase of at least
5 mm. (Note: The appearance of one or more new lesions is also considered progression).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to
qualify for PD, using the smallest sum of diameters during the study as reference.
2.3.2
Special notes on the assessment of lymph nodes which are target lesions
Lymph nodes identified as target lesions should always have the actual short axis measurement
recorded (measured in the same anatomical plane as during the baseline examination), even if the
nodes regress to below 10 mm at the time of the study. This means that when lymph nodes are
included as target lesions, the "sum" of lesions may not be zero even if complete response
criteria are met, since a normal lymph node is defined as having a short axis of <10 mm. Case
report forms or other data collection methods may therefore be designed to have target nodal
lesions recorded in a separate section where, in order to qualify for CR, each node must have a


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short axis of <10 mm. For PR, SD, and PD, the actual short axis measurement of the nodes is to
be included in the sum of target lesions.
Target lesions that are "too small to measure". During the study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent
evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or lymph nodes
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist
may not feel comfortable assigning an exact measurement and may report them as being "too
small to measure". When this occurs it is important that a value be recorded on the case report
form. If it is the opinion of the radiologist that the lesion has probably disappeared, the
measurement should be recorded as 0 mm. If the lesion is believed to be present and is faintly
seen but too small to measure, a default value of 5 mm should be assigned (Note: It is less likely
that this rule will be used for lymph nodes since they usually have a definable size when normal
and are frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is
believed to be present and is faintly seen but too small to measure, a default value of 5 mm
should be assigned in this circumstance as well). This default value is derived from the 5 mm CT
slice thickness (but should not be changed with varying CT slice thickness). The measurements
of these lesions are potentially non-reproducible, therefore providing this default value will
prevent false responses or progressions caused by measurement errors. To reiterate, however, if
the radiologist is able to provide an actual measurement, that value should be recorded, even if it
is below 5 mm.
Lesions that split or coalesced at the time of treatment. When non-nodal lesions fragment, the
longest diameters of the fragmented portions should be added together to calculate the target lesion sum.
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such that
they are no longer separable, the vector of the longest diameter in this instance should be the maximal
longest diameter for the "coalesced lesion".
2.3.3
Evaluation of non-target lesions
This section provides the definitions of the criteria used to determine the tumor response for the
group of non-target lesions. While some non-target lesions may actually be measurable, they do
not need to be measured and instead should be assessed only qualitatively at the time points
specified in the protocol.
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor
marker level. All lymph nodes must be non-pathological in size (short axis <10 mm).
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor
marker level above the normal limits.


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Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: The
appearance of one or more new lesions is also considered progression).
2.3.4
Special notes on the assessment of progression of non-target lesions
The concept of progression of non-target disease requires additional explanation as follows: When
the patient also has measurable lesions. In this setting, to achieve ‘unequivocal progression’ on the
basis of the non-target lesion, there must be an overall level of substantial worsening in non-target
disease such that, even in the presence of SD or PR of the target disease, the overall tumor burden
has increased sufficiently to merit discontinuation of therapy. A minimal increase in the size of one
or more non-target lesions is usually not sufficient to quality for unequivocal progression status.
The designation of overall progression solely on the basis of change in non-target lesions in the
face of SD or PR of target disease will therefore be extremely rare.
When the patient has only lesions that are not measurable. This circumstance arises in some
phase III trials when the presence of measurable lesions is not a criterion for study enrollment.
The same general concepts apply here as well. However, in this instance there are no measurable
lesions to factor into the interpretation of an increase in non-measurable lesion burden. Because
worsening in non-target lesion cannot be easily quantified (by definition: if all lesions are truly
not measurable), a useful test that can be applied when assessing patients for unequivocal
progression is to consider if the increase in overall lesion burden based on the change in non-
measurable disease is comparable in magnitude to the increase that would be required to declare
PD for measurable disease: i.e. an increase in tumor burden representing an additional 73%
increase in volume (which is equivalent to a 20% increase of diameter in a measurable lesion).
Examples include an increase in pleural effusion from "trace" to "large amount", an increase in
lymphangitic lesion from localized to widespread, or a description in the protocol such as
"sufficient to require a change in therapy". If ‘unequivocal progression’ is seen, the patient
should be considered to have had overall PD at that point. While it would be ideal to have
objective criteria to apply to diseases that are not measurable, the very nature of these diseases
makes it impossible to do so, therefore the increase must be substantial.
2.3.5
New lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on the detection of new lesions are important. There are no specific criteria for the
identification of new radiographic lesions; however, the finding of a new lesion should be
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging
modality or findings thought to represent something other than tumors (for example, some new
bone lesions which may be simply healed or flare of pre-existing lesions). This is particularly


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important when the patient’s baseline lesions show partial or complete response. For example,
necrosis of a liver lesion may be reported by a CT scan as a "new" cystic lesion, while it is
actually not.
A lesion identified during a follow-up in an anatomical location that is not discovered during the
baseline scan is considered a new lesion and will indicate disease progression. For example, a
patient with a visceral disease at baseline has a brain CT or MRI which reveals metastases. The
patient's brain metastases are considered evidence of PD even if he/she does not have brain
imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents a truly new lesion. If repeat scans confirm there is
definitely a new lesion, then progression should be declared using the date of the initial scan.
While FDG-PET response assessments need additional studies, it is sometimes reasonable to
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of
progression (particularly possible "new" lesions). New lesions on the basis of FDG-PET imaging
can be identified as follows:
a.
A negative FDG-PET at baseline and a positive FDG-PET at follow-up is a sign of PD
based on a new lesion.
b.
No FDG-PET at baseline and a positive FDG-PET at follow-up:
If the positive FDG-PET at follow-up corresponds to a new lesion site confirmed by
CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new lesion
site on CT, additional follow-up CT scans are needed to determine if there is truly
progression at that site (if so, the date of PD will be the date of the initial abnormal
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing
lesion site on CT that is not progressing according to the anatomic images, this is not PD.
2.4
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until
the end of treatment, taking into account any requirement for confirmation. On occasion a
response may not be documented until after the end of therapy, so the study protocol should
clearly state if post-treatment assessments are to be considered when determining best overall
response. The study protocol must specify how any new therapy introduced before progression
will affect best response designation. Assignment of best overall response for the patient will
depend on the findings of both target and non-target lesions and will also take into consideration
the appearance of new lesions. Furthermore, depending on the nature of the study and the


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protocol requirements, confirmatory measurement may also be required. Specifically, in non-
randomized trials where response is the primary endpoint, confirmation of PR or CR is needed to
determine which one is the "best overall response".
2.4.1
Time point response
It is assumed that at each time point specified by the study protocol, a response assessment
occurs. Table 1 on the next page provides a summary of the overall response status calculation at
each time point for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used.
2.4.2
Missing assessments and non-evaluable targets
When no imaging/measurement is done at a particular time point, the patient is not evaluable
(NE) at that time point. If only a subset of lesion measurements are made at an assessment,
usually the case is also considered NE at that time point, unless a convincing argument can be
made that the missing lesion(s) would not change the response at the assigned time point. This
would be most likely to happen in the case of PD. For example, if a patient have a baseline sum
of 50 mm with three measured lesions and at follow-up only two lesions are assessed and with
a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution of the
missing lesion.
2.4.3
Best overall response: all time points
The best response is determined once all the data for the patient is obtained.
Best response determination in trials where confirmation of complete or partial response is not
required: Best response in these trials is defined as the best response across all time points (for
example, the best overall response of a patient who has SD at the first assessment, PR at the
second, and PD at the last is PR). When SD is believed to be best response, it must also meet the
minimum time from baseline specified by the protocol. If the minimum time is not met,
otherwise SD is the best time point response, the patient’s best response depends on subsequent
assessments. For example, if a patient has SD at the first assessment, PD at the second and does
not meet the minimum duration for SD, his/her best response is PD. The same patient lost to
follow-up after the first SD assessment would be considered not evaluable.
Best response determination in trials where confirmation of complete or partial response is
required: Complete or partial responses may be claimed only if the criteria for each are met at a
subsequent time point specified in the protocol (generally 4 weeks later). In this circumstance,
the best overall response can be interpreted as in Table 3.


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2.4.4
Special notes on response assessment
When nodal lesions are included in the sum of target lesions and the nodes decrease to "normal"
size (<10 mm), they may still have a measurement reported on scans. This measurement should
be recorded even if the nodes are normal in size in order not to overstate progression should it be
based on the increase in size of the nodes. As noted earlier, this means that patients with CR may
not have a total sum of "zero" on the case report form (CRF).
In trials where confirmation of response is required, repeated "NE" time point assessments may
complicate best response determination. The analysis plan for the trial must explain how missing
data/assessments will be addressed in the determination of response and progression. For
example, in most trials it is reasonable to consider a patient with time point responses of PR-NE-
PR as a confirmed response.
Patients with a global deterioration of health status requiring discontinuation of treatment without
objective evidence of disease progression at that time should be reported as "symptomatic
deterioration". Every effort should be made to document objective progression even after
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective
response. Instead, it is a reason for stopping the study treatment. The objective response status of
this type of patients is to be determined by evaluation of target and non-target lesions as shown
in Table 1–3.
Conditions that define "early progression, early death, and non-evaluability" are study specific
and should be clearly described in each study protocol (depending on treatment duration and
treatment periodicity).
In some circumstances it may be difficult to distinguish a residual lesion from normal tissues.
When the evaluation of complete response depends upon this determination, it is recommended
that the residual lesion be investigated (by fine needle aspirate/biopsy) before assigning a status
of complete response.
Like a biopsy, FDG-PET may also be used to upgrade a response to a CR in cases where a
residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-
PET in this circumstance should be pre-defined in the protocol and supported by disease specific
medical literature for the indication. However, it must be acknowledged that both approaches
may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.


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Table 1. Time point response: patients with target (+/– non-target) disease.
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or
No
PR
Not all were evaluated
SD
Non-PD or
No
SD
Not all were evaluated
Not all were
evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not evaluable
Table 2. Time point response: patients with non-target disease only.
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PDa
Not all were evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease, and NE = not evaluable.
a "Non-CR/non-PD" is preferred over "stable disease" for non-target disease, since SD is increasingly used as an
endpoint for assessment of efficacy in some trials, thus assigning this category in the absence of measurable
lesions is not advised.
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at
the next scheduled assessment, progression is confirmed, the date of progression should be the
earlier date when progression is suspected.


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Table 3. Best overall response when confirmation of CR and PR required.
Overall response
First time point
Overall response
Subsequent time
point
Best overall response
CR
CR
CR
CR
PR
SD, PD, or PRa
CR
SD
SD provided that the minimum duration for SD is met, otherwise PD
CR
PD
SD provided that the minimum duration for SD is met, otherwise PD
CR
NE
SD provided that the minimum duration for SD is met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided that the minimum duration for SD is met, otherwise PD
PR
NE
SD provided that the minimum duration for SD is met, otherwise NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not
evaluable.
a If CR is truly achieved at the first time point, then any lesions seen at a subsequent time point, even those meeting
PR criteria relative to baseline, make the disease PD at that time point (since lesions must have reappeared after
CR). Best response would depend on whether the minimum duration for SD is met. However, sometimes CR may
be claimed and subsequent scans suggest small lesions are likely still present, while in fact the patient have PR
instead of CR at the first time point. Under these circumstances, CR should be changed to PR and the best response
is PR.
2.5 Frequency of Tumor Re-Evaluation
Frequency of tumor re-evaluation during treatment should be protocol specific and adapted to the
type and schedule of treatment. However, for phase II studies where the beneficial effect of the
treatment is not known, follow-up every 6–8 weeks (timed to coincide with the end of a cycle) is
reasonable. Smaller or greater time intervals may be justified for certain regimens or circumstances.
The study protocol should specify which organ sites are to be evaluated at baseline (usually those
most likely to be involved with metastatic disease for the tumor type under study) and how
often evaluations are repeated. Normally, all target and non-target sites are evaluated at each
assessment. Under certain circumstances, some non-target organs may be evaluated less frequently.
For example, bone scans may need to be repeated only when complete response is identified in
the target lesion or when progression is suspected.


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After the end of the treatment, the need for repeated tumor evaluations depends on whether the
trial has a goal such as a certain response rate or a certain time to an event (progression/death).
If ‘time to an event’ (e.g. time to progression, disease-free survival, progression-free survival) is
the main endpoint of the study, then routine scheduled re-evaluation of lesion sites specified by
the protocol must be carried out. In randomized comparative trials in particular, the scheduled
assessments should be performed on time (for example: every 6–8 weeks during the treatment or
every 3–4 months after the treatment) and should not be affected by treatment delays, holidays or
any other events that might lead to imbalance in the timing of disease assessment between
treatment arms.
2.6 Confirmation of Measurements/Duration of Response
2.6.1 Confirmation
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is
required to ensure responses identified are not the result of measurement errors. This will also
permit appropriate interpretation of results in the context of historical data. Response
confirmation has been traditionally required in such trials. However, in all other circumstances,
i.e. in randomized trials (phase II or III) or studies where stable disease or progression are the
primary endpoints, confirmation of response is not required since it will not add value to the
interpretation of trial results. However, elimination of the requirement for response confirmation
may increase the importance of central review to protect against bias, in particular in studies
which are not blinded.
In the case of SD, measurements after study entry must have met the minimum interval for SD
(generally not shorter than 6–8 weeks) defined in the study protocol at least once.
2.6.2 Duration of overall response
The duration of overall response is measured from the time CR/PR measurement criteria are first
met CR/PR (whichever is first documented) until the date when recurrent or progressive disease
is objectively documented for the first time (using the shortest time to progressive disease
documented during the study as reference).
The duration of overall complete response is measured from the time CR measurement criteria
are first met until the date when recurrent disease is objectively documented for the first time.
2.6.3 Duration of stable disease
Stable disease is measured from the start of the treatment (in randomized trials, from the date
of randomization) until the criteria for progression are met, using the smallest sum during the
study as reference (if the baseline sum is the smallest, then it is used as the reference for the
calculation of PD).


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The clinical relevance of the duration of stable disease varies with different studies and diseases.
If the proportion of patients achieving stable disease for a minimum period of time is an endpoint
of importance in a particular trial, the protocol should specify the minimal time interval required
between two measurements for the determination of stable disease.
Note: The duration of response and stable disease as well as the progression-free survival are
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of th
guidelines to define a standard follow-up frequency. The frequency should take into account
many parameters including disease types and stages, treatment periodicity, and standard practice.
However, limitations of the precision of the measured endpoint should be taken into account if
comparisons between trials are to be made.


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14 INVESTIGATOR SIGNATURE PAGE
Protocol Title: A randomized, double-blind, multi-center phase III study comparing the efficacy
and safety of IBI305 plus paclitaxel/carboplatin vs. bevacizumab plus paclitaxel/carboplatin in
treatment-naive patients with advanced or relapsed non-squamous NSCLC.
Protocol No.: CIBI305A301
This protocol is a trade secret owned by Innovent Biologics (Suzhou) Co., Ltd. I have read and
fully understood this protocol, and agree to conduct this study in accordance with the
requirements found in this protocol and the Good Clinical Practice, and in compliance with
relevant laws and regulations and the Declaration of Helsinki. At the same time, I promise not to
disclose any confidential information associated with this study to any third party without the
written consent of Innovent Biologics (Suzhou) Co., Ltd.
Instructions for the Investigator: Please sign and date this signature page, type the investigator's name and job
title, as well as the name of the study site, and return this document to Innovent Biologics (Suzhou) Co., Ltd.
I have read the entire contents of this study protocol and shall perform the study as required:
Investigator's signature:
Date:
Name (in Print):
Job Title:
Name and Address of Study Site:

SAP_000.pdf: 
Protocol No.: CIBI305A301 
Statistical Analysis Plan Confidential  
Version: V1.0 
Version Date: November 14, 2018 
 
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Statistical Analysis Plan 
 
 
A Randomized, Double-blind, Multicenter, Phase III Study to Evaluate 
the Efficacy and Safety of IBI305 Plus Paclitaxel/Carboplatin 
Compared to Bevacizumab Plus Paclitaxel/Carboplatin in Treatment-
naive Subjects with Advanced or Recurrent Non-squamous Non-small 
Cell Lung Cancer 
 
 
 
Generic Name of the 
Investigational Drug: 
Recombinant Humanized Anti-VEGF Monoclonal Antibody for Injection 
(IBI305) 
Sponsor: 
Innovent Biologics (Suzhou) Co., Ltd. 
Statistical Analysis 
Institution: 
WuXi Clinical Development Services (Shanghai) Co., Ltd. 
Version No.: 
V1.0 
Version Date: 
November 14, 2018 
NCT Number： 
 
   NCT02954172 
Confidentiality Statement 
The information contained in this statistical analysis plan is confidential. These documents 
are property of Innovent Biologics (Suzhou) Inc. Without permission, the data should not be 
disclosed, published, or made public in any other manner. 
 
 
 


Protocol No.: CIBI305A301 
Statistical Analysis Plan Confidential  
Version: V1.0 
Version Date: November 14, 2018 
 
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Signature Page for Approval 
The following signers approved the Statistical Analysis Plan: 
Signature 
Date 
Name: Zeng Huaxi 
Department/Title: Clinical Information/Senior Biostatistician 
Institution: WuXi Clinical Development Services (Shanghai) Co., Ltd. 
 
Signature 
Date 
Name: Luo Zhaoyu 
Department/Position: Clinical Information Department/Senior Biostatistics Director 
Institution: WuXi Clinical Development Services (Shanghai) Co., Ltd. 
 
Signature 
Date 
Name: Yanyan Zhang 
Department/Title: Clinical Operation/Project Manager 
Institution: WuXi Clinical Development Services (Shanghai) Co., Ltd. 
 
Signature 
Date 
Name: Xing Sun 
Department/Title: Senior Director, Biostatistics 
Institution: Innovent Biotechnology (Suzhou) Co., Ltd. 
 


Protocol No.: CIBI305A301 
Statistical Analysis Plan Confidential  
Version: V1.0 
Version Date: November 14, 2018 
 
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Contents 
1. Introduction ..................................................................................................................... 5 
1.1 Changes of Planned Statistical Analysis for the Study ............................................. 5 
2. Objective of the Trial ...................................................................................................... 5 
3. Design of the Trial .......................................................................................................... 6 
3.1 Estimation of Sample Size ........................................................................................ 7 
3.2 Randomization .......................................................................................................... 7 
4. Study Endpoints .............................................................................................................. 8 
4.1 Efficacy Endpoints .................................................................................................... 8 
4.2 Safety Endpoints ....................................................................................................... 9 
4.3 PK/PD Endpoints ...................................................................................................... 9 
5. Definition ...................................................................................................................... 10 
5.1 Baseline ................................................................................................................... 10 
5.2 Change Since Baseline ............................................................................................ 10 
5.3 Number of Research Days ...................................................................................... 10 
6. Analysis Dataset............................................................................................................ 10 
7. Interim Analysis ............................................................................................................ 11 
8. Data Management and Review ..................................................................................... 11 
8.1 Data Processing and Transfer .................................................................................. 11 
9. Statistical Method ......................................................................................................... 12 
9.1 General Considerations for Statistical Analysis ...................................................... 12 
9.1.1 General Rules ................................................................................................... 12 
9.1.2 Hypothesis testing: ........................................................................................... 12 
9.1.3 Handling of Missing Data................................................................................. 13 
9.1.4 Export of Statistical Results ............................................................................. 15 
9.1.5 Multicenter Study ............................................................................................. 15 
9.2 Disposition of Subjects ........................................................................................... 15 
9.2.1 Protocol Deviations .......................................................................................... 16 
9.3 Demographics and Other Baseline Characteristics ................................................. 16 
9.3.1 Demographics ................................................................................................... 16 
9.3.2 Past history, surgical history and prior treatment ............................................. 17 
9.3.3 Prior and Concurrent Medications .................................................................... 17 
9.3.4 Other Baseline Tests ......................................................................................... 18 
9.4 Efficacy Analysis .................................................................................................... 18 
9.4.1 Primary Efficacy Analysis ................................................................................ 18 
9.4.2 Secondary Efficacy Analysis ............................................................................ 19 
9.4.2.1 Disease Control Rate (DCR) ...................................................................... 19 
9.4.2.2 Duration of Response (DOR)..................................................................... 19 
9.4.2.3 Progression-free Survival (PFS) ................................................................ 19 
9.4.2.4 Overall Survival (OS) ................................................................................ 20 
9.4.3 Sensitivity Analysis .......................................................................................... 20 
9.4.4 Subgroup Analysis ............................................................................................ 20 
9.5 Subsequent Anti-tumor Therapy ............................................................................. 21 
9.6 Safety Analysis ........................................................................................................ 21 
9.6.1 Drug Exposure and Compliance Analysis ........................................................ 21 
9.6.2 Adverse Events ................................................................................................. 22 


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9.6.3 Clinical laboratory Test Value .......................................................................... 26 
9.6.4 Vital Signs ........................................................................................................ 26 
9.6.5 12-Lead ECG .................................................................................................... 27 
9.6.6 Physical Examination ....................................................................................... 27 
9.6.7 Immunogenicity ................................................................................................ 27 
9.6.8 Other Tests ........................................................................................................ 28 
9.7 Pharmacokinetic Analysis ....................................................................................... 28 
9.8 Pharmacodynamic Analysis .................................................................................... 28 
10. Quality Control ........................................................................................................... 28 
Appendix 1. Abbreviations ............................................................................................... 29 
Appendix 2. Tables, Figures, and Lists............................................................................. 30 
 


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1. Introduction 
This statistical analysis plan (SAP) is intended to describe the statistical analysis methods 
employed in the clinical trial, protocol number CIBI305A301. The clinical trial is proposed 
to evaluate the efficacy and safety of IBI305 plus paclitaxel/carboplatin compared to 
bevacizumab plus paclitaxel/carboplatin in the treatment of advanced or recurrent non-
squamous NSCLC. 
The Statistical Analysis Plan is based on the Clinical Study Protocol version 3.2 (date: 
November 5, 2018), and Case Report form (CRF) version 1.0 (date: Oct 24, 2016). Any 
revision of the trial protocol or CRF would result in update of the Statistical Analysis Plan 
as required. 
This SAP must be finalized prior to the final data lock upon approval of the sponsor. 
1.1 Changes of Planned Statistical Analysis for the Study 
The immunogenicity analysis set (ADA-AS) was added to this SAP, defined as subjects in 
the SS population who have at least one valid anti-drug antibody assay after the use of 
study drug. The definition of pharmacokinetic analysis set (PKAS) was changed to subjects 
in the SS population with at least one PK value. Pharmacodynamic analysis set (PDAS) 
was changed to subjects in the SS population with at least one PD value. 
2. Objective of the Trial 
Primary Objective: To compare the objective response rate (ORR) of IBI305 plus 
paclitaxel/carboplatin compared to bevacizumab plus paclitaxel/carboplatin in the 
treatment of advanced or recurrent non-squamous NSCLC. 
Secondary Objectives: 
 
To compare the duration of response (DOR), progression-free survival (PFS), disease 
control rate (DCR) and overall survival (OS) of IBI305 plus paclitaxel/carboplatin 
compared to bevacizumab plus paclitaxel/carboplatin in the treatment of advanced or 
recurrent non-squamous NSCLC 
 
To compare the safety and immunogenicity of IBI305 plus paclitaxel/carboplatin 
compared to bevacizumab plus paclitaxel/carboplatin in the treatment of advanced or 
recurrent non-squamous NSCLC 
Exploratory Objectives: 
 
To compare the population pharmacokinetics (PPK) of IBI305 and bevacizumab in 


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subjects with advanced or recurrent non-squamous NSCLC 
 
To compare the Pharmacodynamic (PD) of IBI305 and bevacizumab in subjects with 
advanced or recurrent non-squamous NSCLC 
3. Design of the Trial 
This is a randomized, double-blind, multicenter Phase 3 study. It is planned to enroll 436 
subjects with non-squamous NSCLC and randomize them in a 1:1 ratio, to IBI305 plus 
paclitaxel/carboplatin arm or bevacizumab plus paclitaxel/carboplatin arm with 
stratification factors including age (< 60 years vs. ≥ 60 years) and EGFR status (wild-type 
vs. unknown type). 
With every 3 weeks as a treatment cycle, both arms are given 15 mg/kg of IBI305 or 
bevacizumab plus paclitaxel/carboplatin on Day 1 of each cycle. A maximum of 6 cycles 
of combination therapy may be given in the absence of progressive disease (PD), 
intolerable toxicity, withdrawal of consent, loss to follow-up or death (whichever occurs 
first). Subsequently the subjects will receive single-agent maintenance therapy, i.e., stop 
paclitaxel/carboplatin and continue treatment with IBI305 or bevacizumab. The single-
agent maintenance therapy continues in a 3-week cycle, administered 7.5 mg/kg on Day 1 
of each cycle until PD, intolerable toxicity, withdrawal of consent, end of study, loss to 
follow-up or death, whichever occurs first. 
During the study, subjects will undergo CT or MRI examination every 6 weeks (± 7 days) 
for tumor assessment by the investigator at each site to confirm whether to continue the 
study treatment until PD, withdrawal of consent, loss to follow-up, death, other anti-tumor 
treatment or end of study. If the study treatment is terminated for reasons other than PD, 
tumor assessment should be continued for the subject until PD, withdrawal of consent, loss 
to follow-up, death, other anti-tumor treatment or end of study. If the treatment is 
terminated due to PD, the investigator will perform telephone visits for the subject every 
12 weeks (± 7 days) to collect subsequent anti -tumor treatment and survival information 
of the subject until death, withdrawal of consent, loss to follow-up or end of study. 
Flowchart: 


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Figure 1. Principle for Study Design 
3.1 Estimation of Sample Size 
Two hundred and eighteen (218) subjects in each arm (436 subjects in total) achieving a 
80% 
power 
can 
confirm 
the 
clinical 
equivalence 
between 
IBI305 
plus 
paclitaxel/carboplatin and bevacizumab plus paclitaxel/carboplatin. 
This sample size is estimated based on the following assumptions: 
 
ORR is equal between IBI305 and bevacizumab arms 
 
ORR of bevacizumab arm is set as 50.0% 
 
The equivalence cutoff of ORR ratio is assumed (0.75, 1/0.75) 
 
The significance level for two one-sided tests is 0.05 (one-sided) 
 
The randomization ratio is 1:1 
Based on the above assumptions, each group needs 218 subjects (436 subjects in total). 
The sample size is estimated using software PASS2013. 
3.2 Randomization 
Subject random number: This study is a randomized, double-blind, active-controlled 
multicenter Phase 3 study. It is planned to enroll 436 subjects with non-squamous NSCLC 
at about 35 site across the nation and randomize them, in a 1:1 ratio, to IBI305 plus 
paclitaxel/carboplatin arm or bevacizumab plus paclitaxel/carboplatin arm with 
stratification factors including age (< 60 years vs. ≥ 60 years) and EGFR status (wild-type 
vs. unknown type), a total of four combinations. The randomization list and labels will be 
Screening Stage 
Combination Therapy (every 3 
weeks) IBI305 or Bevacizumab 
Paclitaxel + Carboplatin 
Single-agent Maintenance 
Therapy (every 3 weeks) 
IBI305 or Bevacizumab 
EOT Visit (28 
days (± 7 days) 
after the last dose) 
Subsequent 
Follow-Up 
Cycle 2 
Cycle 1 
Randomizatio
n (D1)
D-28 to D-1 
Cycle 3 
Cycle 6 
Cycle 7 
Cycle n 
Post-Treatment 
Follow-Up 


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prepared 4 times the total number of subjects enrolled (in case of accidental drug loss or 
unbalanced enrollment in stratified subgroups), i.e., randomization list and labels for 436 
subjects are prepared in each stratified subgroup (1: < 60 years, wild-type EGFR; 2: < 60 
years, EGFR unknown; 3: ≥ 60 years, wild-type EGFR; 4: ≥ 60 years, EGFR unknown). 
The block randomization will be used, and subjects in each block will be randomized in a 
1:1 ratio to receive IBI305 and bevacizumab. 
Drug random number: IBI305 or bevacizumab plus paclitaxel/carboplatin will be 
administered at 15 mg/kg on Day 1 of each 3-week treatment cycle. A maximum of 6 
cycles of combination therapy may be given in the absence of PD, intolerable toxicity, 
withdrawal of consent, loss to follow-up or death (whichever occurs first). The study drug 
(IBI305 or bevacizumab) for injection is available in strength of 100 mg/vial. It is estimated 
that each subject (e.g., 60 kg) requires an average of 9 vials in each cycle and approximately 
54 vials for 6 cycles. For a total of 436 subjects with non-squamous NSCLC to be enrolled, 
about 23,544 vials will be needed, and 6 significant digits are taken as the drug random 
number (XXXXXX). The Statistical Analysis Institution must produce drug randomization 
no. and grouping information, based on the random number for drugs, required for blinding, 
validity term of the drugs, and corresponding quantity of the drugs, provided by the 
Sponsor. 
4. Study Endpoints 
4.1 Efficacy Endpoints 
1) Primary efficacy endpoint 
 
Objective response rate (ORR) 
ORR is evaluated according to RECIST v1.1, which is defined as the proportion of subjects 
who achieve a reduction of tumor volume to the pre-specified value maintaining for the 
minimum time limit, including those with complete response (CR) and partial response 
(PR). The analysis data cutoff date for assessing primary efficacy endpoint is 18 weeks 
after randomization of the last subject. 
ORR = 
Number of CR + PR subjects 
x 100% 
Total number of analysis population 
2) Secondary efficacy endpoints 


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 
Duration of response (DOR) 
 
Progression-free survival (PFS) 
 
Disease control rate (DCR) 
 
Overall survival (OS) 
All indices, except for OS, are evaluated according to RECIST v1.1. 
DOR is defined, for CR or PR subjects, as the duration from first tumor assessment as CR 
or PR to PD or death before PD; if the CR or PR subject does not have PD or death before 
PD, the date of last imaging assessment is censored date. 
PFS is defined as the duration from randomization to PD or death before PD; if no PD or 
death before PD occurs, the date of last imaging assessment is censored date. 
DCR is defined as the proportion of subjects whose tumor is reduced or stabilized 
maintaining for a certain period of time, including subjects with CR, PR, and stable disease 
(SD). The analysis data cutoff date for assessing DCR is 18 weeks after randomization of 
the last subject. 
DCR = 
Number of CR+PR+SD subjects 
x 100% 
Total number of analysis population 
OS is defined as the duration from randomization to patient death for various reasons. If 
the subject is surviving or lost to follow-up as of the end of study, the censored date will 
be the date of their last contact. 
4.2 Safety Endpoints 
 
Vital signs 
 
Physical examination 
 
Laboratory tests (Hematology Test, blood biochemistry, and urine test) 
 
12-Lead ECG 
 
Adverse events (AE, including treatment-emergent adverse event [TEAE]), adverse 
events of special interest (hypertension, proteinuria, gastrointestinal perforation, 
hemorrhages [cerebral hemorrhage, hematuria, and upper gastrointestinal hemorrhage], 
cardiotoxicity and thrombosis), and serious adverse events (SAE) 
 
Immunogenicity: ADA-positive rate and neutralizing antibody positive rate 
4.3 PK/PD Endpoints 


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 
Population PK including trough steady-state concentration after multiple dose 
 
Changes of serum vascular endothelial growth factor (VEGF) at different time points 
5. Definition 
5.1 Baseline 
Trial baseline value: For safety endpoints, it is defined as the last non-missing measurement 
before first dose of study drug; for efficacy endpoints, it is defined as the last non-missing 
measurement before randomization. If the last non-missing measurement cannot be judged 
by time and corresponding scheduled visit measurement is non-missing, corresponding 
scheduled visit measurement is used. 
5.2 Change Since Baseline 
Change from baseline: Defined as the difference of measured value from baseline value 
 
Change since Baseline = Measured Value at Visit X - Baseline Value 
The percentage since baseline is calculated as: 
 
Percent of change from baseline = (Measurement at visit X - Baseline value)/Baseline 
value × 100%  
5.3 Number of Research Days 
Study day: Calculated from the day the subject takes study drug, the day of using the study 
drug is regarded as Day1, indicating the time from the first dose of study drug to the 
start/end of test or occurrence of event (e.g., progressive disease, death). 
If the event occurs on or after the day of using study drug: Study day = Date of event - Date 
of using study drug + 1; 
If the event occurs before the day of using study drug: Study day = Date of event - Date of 
using study drug. 
6. Analysis Dataset 
Intention-To-Treat (ITT): 
Includes all randomized subjects. 
The data set will be used to summarize major protocol violations and disposition of subjects 
and populations. 
Full analysis set (FullAnalysisSet, FAS): 
Includes all evaluable subjects who are randomized and have received at least one dose of 


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study drug. The data set is the primary analysis set for efficacy evaluation and will be 
additionally used to summarize demographics and other baseline characteristics, including 
medical history and treatment history. 
After discussion at blind data review meeting, the following three categories of subjects 
will be excluded from full analysis set: 
1. Subjects who experience allergy on the first dose, do not receive a full combination dose, 
and are immediately withdrawn from the study. 
2. Second-line patients who are wrongly enrolled. 
3. Subjects whose baseline lesions are not measurable as determined by central imaging. 
Per Protocol (PP): 
On the basis of FAS, the subjects who have completed the pre-specified minimum exposure 
to study drug without pre-specified major protocol violation. The data set is the secondary 
analysis set for efficacy evaluation. 
Safety dataset (SafetySet, SS): 
All subjects who have received at least one dose of any study drug after randomization and 
have post-medication data for safety evaluation. The data set is used to evaluate the safety 
in this study. 
Pharmacokinetic Analysis Set (PKAS): 
Subjects in the SS population who have at least one PK value. 
Pharmacodynamic analysis set (PDAS): 
Subjects in the SS population who have at least one PD value. 
Immunogenicity Analysis Set (ADA-AS): 
Subjects in the SS population who have at least one valid anti-drug antibody assay after 
the use of study drug. 
7. Interim Analysis 
No interim analysis is planned for this study. 
8. Data Management and Review 
The data used for final data are cleaned data. 
8.1 Data Processing and Transfer 
Electronic case report form (eCRF) data will be exported from Electronic Data Capture 
(EDC) system by data management team and transmitted as SAS datasets to statistical 


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programming team. 
In addition to data screening based on data management protocol, the programmer 
programming to generate analysis datasets and graphs provides additional data screening 
for the data collected. The expected data problems will be exported and confirmed as 
“problems” by the SAS Log, and picked out by SAS Macro and transferred to the Data 
Management Department. 
Prior to database lock, a further data screening will be provided for review of charts 
produced, based on the cleaned subset of the subjects. Prior to database lock, those charts 
will be discussed in the data review conference with the Sponsor, to confirm any data 
problem and seek for correction. 
A final blind data review meeting will be held prior to final data locking. At the final blind 
data review meeting, the criteria for major protocol violations will be reviewed, especially 
those for major protocol violations to be excluded from PP set, and final decision will be 
made. 
9. Statistical Method 
9.1 General Considerations for Statistical Analysis 
9.1.1 General Rules 
For continuous variables, descriptive statistics will include count, mean, standard deviation, 
median, minimum and maximum; for categorical variables, descriptive statistics will 
include the number and percentage of each category. 
Unless otherwise specified, the default significance level is 5%; all tests are two-sided. 
9.1.2 Hypothesis testing: 
This is a clinical equivalence study between IBI305 and bevacizumab, with objective 
response rate (ORR) as the primary endpoint. The equivalence hypothesis testing is: 
H0: π test arm/π control arm ≤0.75 
H0: π test arm/π control arm≥1/0.75 
H1: π test arm/π control arm>0.75 
H1: π test arm/π control arm  
α = 0.05 (one-sided) 
α = 0.05 (one-sided) 
The confidence interval method is used to judge the equivalence: If 90%CI of between-
group ORR ratio (test arm to control arm) is within (0.75, 1/0.75), it is considered that the 


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clinical equivalence of test arm with control arm is established. The between-group ORR 
ratio and 90% confidence interval are estimated using a generalized linear model (GLM): 
Group and stratification factors, age (< 60 years vs. ≥ 60 years) and EGFR status (wild-
type vs. unknown type) are included in the model. 
9.1.3 Handling of Missing Data 
Safety data: Missing data are not imputed. Missing data are imputed only when time is 
divided for summary analysis. 
For categorical variables, subjects with missing data will not be included in the percentage 
calculation unless otherwise specified. The number of subjects with missing data will be 
presented. 
Calculation of treatment duration when the date of last dose of study drug is missing 
For the calculation of treatment duration, the date of last study drug infusion should be 
consistent with that of last dose on the dosing page of CRF. If date of last dose on the 
dosing page is missing on CRF, the treatment duration should be counted as missing. 
The last infusion should be clearly recorded on CRF and not be estimated by the date of 
returning remaining medicinal product. 
Handling of missing and partially missing dosing time for concomitant medication 
Dose start and end times will not be imputed. If the date or time of a dose is missing or 
partially missing, and it cannot determine whether the dose is administered before or after 
the first dose of study drug, the dose will be considered as prior concomitant medication. 
Handling of missing and partially missing onset date and time of adverse event 
Missing and partially missing onset date and time of adverse event will be imputed in case 
that the adverse event will be classified as treatment-emergent adverse event when the 
information does not indicate that the adverse event starts earlier than the first dose of study 
drug or later than treatment-emergent adverse event. The completely missing end date and 
time of adverse event will not be imputed, and partially missing end date and time of 
adverse event will be imputed. The above mentioned data imputation is only used for the 
division of adverse events and will not be presented in listings. The date and time of adverse 
event outcome will not be imputed except for analyses involving calculation of duration of 
adverse event. 
Imputation rules for AE onset date missing: 


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 
If year and month are known and earlier than month and year of the first dose of study 
drug, the last day of known month will be used for imputation. 
 
If the year and month are known and exactly the same month and year of the first dose 
of study drug, the start date of AE is the date of first dose of study drug (date refers to 
"mm-dd"). 
 
If year and month are known and later than month and year of the first dose of study 
drug, the first day of known month will be used for imputation. 
 
If only the year is known and earlier than year of the first dose of study, it is imputed 
as "December 31”. 
 
If only the year is known and exactly the same year of the first dose of study drug, the 
start date of AE is the date of first dose of study drug (date refers to "mm-dd"). 
 
If only the year is known and later than year of the first dose of study, it is imputed as 
"January 1”. 
 
If the day, month, and year are all missing, the date of first dose of study drug is taken 
as the corresponding start date. 
 
If the imputed start date is after the end date, the end date will be taken as the 
corresponding start date. 
 
It is considered as missing in other cases. 
Missing of AE end date 
 
If year and month are known, the last day of known month will be used for imputation. 
 
If only the year is known, it is imputed as "December 31”. 
 
For AE of subjects who died eventually, the AE end date should be an earlier date 
between date of death and imputed end date. 
 
It is considered as missing in other cases. 
Handling of adverse events with missing date and time of first dose 
When both date and time of the first dose of study drug are missing, all adverse events 
occurring on or after the day of randomization should be regarded as treatment-emergent 
adverse events. The treatment duration is counted as missing. If the subject's first dose date 
is complete but time is missing, whether it is a treatment-emergent adverse event is 
determined according to the date. 
Handling of adverse events with missing relationship to study drug 


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If relationship to study drug is missing, the relationship of adverse event to study drug will 
be considered as possible in the relationship table, but missing data will not be imputed. 
Handling of potentially clinically significant abnormalities 
Subjects with missing baseline data will be classified in "normal/missing baseline” 
category. 
Measurements marked as invalid by the laboratory will not be included in the analysis. 
Efficacy data: Except for censoring rules specified in Section 9.4, any missing values will 
not be imputed for primary and secondary efficacy analyses. For ORR and DCR in FAS 
and PP sets, subjects without tumor assessment after baseline period will be considered as 
non-evaluable (NE) according to RECIST criteria. 
9.1.4 Export of Statistical Results 
All statistical results will be exported directly by SAS. See separate documents for samples 
of the figures, tables, and listings. The export template is used to standardize the 
programmer’s work. In this Plan, it is not required to revise and review any non-substantial 
or modificatory adjustment to the export template that does not influence the Plan. 
Unless otherwise specified, in the description P-values are presented to 4 decimal places, 
mean, median, Q1, Q3 to +1 decimal place in the original data format, minimum and 
maximum to the same decimal places as original data recorded in the database, and SD to 
+2 decimal places in the original data format. Percent ( %) is presented to 1 decimal place, 
rate ratio to 2 decimal places, hazard ratio to 2 decimal places, and confidence interval to 
3 decimal places. 
9.1.5 Multicenter Study 
As this study is a multicenter study, the primary endpoint (ORR) will also be tabulated by 
site and group, but no separate equivalence analysis will be performed by site. Sites with 
< 5 ITT subjects per treatment group will be combined for analysis and specific site 
combined analysis will be discussed at the data review meeting. 
9.2 Disposition of Subjects 
The disposition of subjects is summarized for all subjects. The number and percentage of 
subjects with screen failure, reasons for screen failure, number and percentage of subjects 
enrolled, still receiving study drug, stopping study drug, completing the study as planned, 
withdrawing from the study prematurely and not completing the study will be calculated 


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by arm and site. Subjects withdraw early will be summarized by the main causes for 
withdrawal from the trial. Number and percentage of subjects will be calculated by group, 
according to disposition of subjects in the analysis populations. 
A listing of subject disposition by arm and subject number will be provided. 
9.2.1 Protocol Deviations 
A listing of protocol violations by trial arm and subject number will be provided. 
In case of any other protocol violation, case discussion meeting should be held as needed 
or based on the opinions of principal investigator or statistician at the final blind data 
review meeting to decide corresponding treatment (classified as major protocol violation, 
whether it affects efficacy analysis, and minor protocol violation) 
9.3 Demographics and Other Baseline Characteristics 
Analyses of demographics and other baseline characteristics are based on FAS. 
Randomized but not included patient information will be listed separately for FAS set. 
Between-group differences in demographics and other baseline characteristics will not be 
statistically tested. If significant difference is observed in a specific variable, for continuous 
variables, t-test is used to calculate the statistics and P value for differences; for categorical 
variables, chi-square test or Fisher's exact test is used to calculate P values for differences. 
9.3.1 Demographics 
Descriptive statistical analysis will be performed for demographic variables by trial arm. 
The following information will be tabulated and summarized. 
 
Age (years) = Integer [(Date of Signature of the Informed Consent - Date of Birth + 
1)/365.25]. 
 
Sex: male, female 
 
Nationality: Han Nationality, Other 
 
Height (cm) 
 
Body Weight (kg) 
 
Body Mass Index BMI (kg/m2) 
 
Body surface area (m2) = 0.00616 height (cm) + 0.01286 weight (kg) - 0.1529 
 
Smoking history 
 
Baseline ECOG (Eastern Cooperative Oncology Group) performance status 
The demographics list is provided by trial group and subject serial no. 


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9.3.2 Past history, surgical history and prior treatment 
Past history and surgical history will be coded using Medical Dictionary for Regulatory 
Affairs (MedDRA) V19.1 and tabulated by preferred term and group. 
The primary tumor history will be summarized in this study, including the following 
information: 
 
Time interval from diagnosis date to randomization date (months) = (Date of 
randomization - Date of diagnosing primary disease + 1)/30.25, rounded to one 
decimal place 
 
Disease stage: Locally advanced, metastatic, local advanced and metastatic 
 
Diagnostic method: Histology, cytology 
 
Tissue type 
 
Differentiation: Well differentiated (G1), moderately differentiated (G2), poorly 
differentiated (G3), undifferentiated (G4), grade cannot be assessed (GX) 
 
Malignant pleural effusion: Yes, no 
 
TNM staging 
 
Clinical staging 
 
Relapse: yes, no 
 
EGFR status: wild-type, unknown 
The number of subjects receiving at least one prior tumor therapy (chemotherapy, 
radiotherapy and surgery) will be summarized separately, and the treatment information 
will be pooled. For chemotherapy regimens and radiotherapy sites, coded data will be 
categorized by clinical team to determine the specific categories presented in the form. 
All past history, surgical history, primary tumor history and prior tumor therapy will be 
listed. 
9.3.3 Prior and Concurrent Medications 
Prior and concomitant drug name will be coded using WHO-Drug (version date: June 1, 
2016 or later) and ATC, and summarized by ATC code and trial arm. 
“Prior” medications are drugs that are used and stopped prior to the first dose of the 
investigational drug. 
“Concurrent” medications are drugs of which: 
 
All medications started on or after the first dose of study drug; 


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 
All concomitant medications starting before the first dose of study drug and continued 
after the first dose of study drug are tabulated by treatment group. 
A listing of all prior and concomitant medications will be provided. 
9.3.4 Other Baseline Tests 
Baseline ECOG scores are pooled and listings are provided. 
9.4 Efficacy Analysis 
Efficacy analysis is primarily based on FAS, and PP set will serve as sensitivity analysis 
dataset for efficacy analysis. 
9.4.1 Primary Efficacy Analysis 
The primary study objective is to examine the clinical equivalence of IBI305 plus 
paclitaxel/carboplatin compared to bevacizumab plus paclitaxel/carboplatin in the 
treatment of advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) 
with objective response rate (ORR) as primary endpoint. ORR is defined as the rate of 
confirmed complete response (CR) or partial response (PR), assessed by validated 
radiological methods for target lesions and non-target lesions, and judged according to 
RECIST v1.1. Subjects who have no tumor assessment after baseline period will be 
considered as non-evaluable according to RECIST criteria. Subjects eligible for complete 
or partial response assessment must have at least one available lesion measured by 
RECISTv1.1. 
The assessment of ORR in clinical equivalence evaluation is the results based on 
independent tumor assessment committee (refer to Protocol Appendix III: RECIST V1.1 
for the assessment criteria and process of independent tumor assessment committee), and 
the investigator's assessment result will be used for sensitivity analysis. 
The clinical equivalence will be determined by whether the 90%CI of ORR ratio of IBI305 
to bevacizumab is within the equivalence cutoff (0.75, 1/0.75) of ORR ratio. Generalized 
linear model (GLM, including group and stratification factors, age (< 60 years vs. ≥ 60 
years) and EGFR status (wild-type vs. unknown)) is used to estimate the ORR and 
corresponding 95%CI of two groups, ORR ratio between two groups and corresponding 
90% and 95%CI. The difference in ORR between two groups and corresponding 90% and 
95%CI are also estimated by the GLM model. In the analysis of actual data, too less 
subjects in the subgroup according to baseline EGFR will cause the GLM not converging, 


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then the baseline EGFR will not be included in the GLM. 
9.4.2 Secondary Efficacy Analysis 
The secondary efficacy analysis will be based on the results assessed by independent tumor 
assessment committee, and the investigator's assessment will be used for sensitivity 
analysis. 
9.4.2.1 Disease Control Rate (DCR) 
DCR is defined as the rate of confirmed complete response (CR), partial response (PR) and 
stable disease (SD) assessed by validated imaging methods for target lesions and non-target 
lesions, and judged according to RECIST v1.1. The analysis of DCR is the same as that for 
primary efficacy endpoint, but equivalence test is not performed. 
9.4.2.2 Duration of Response (DOR) 
DOR is defined, for CR or PR subjects, as the duration from first tumor assessment as CR 
or PR to PD or death before PD; if the CR or PR subject does not have PD or death before 
PD, the date of last imaging assessment is censored date. If the subject experiences 
progression or death missing two or more consecutive tumor assessments, the time of last 
evaluable tumor data is taken as censored date. If the subject receives other anti-tumor 
therapy prior to PD, the date of last imaging examination for other anti-tumor therapy is 
taken as censored date. 
Duration of response (months) = (Date of PD or death before PD or censored date - Date 
of first tumor assessment as CR or PR + 1)/30.25, rounded to two decimal places 
Kaplan-Meier method is used to estimate median DOR and its 95% confidence interval, 
and the survival curve is plotted. Hazard ratio (HR) of two groups, 90% and 95% 
confidence intervals are estimated from a Cox model, which includes group and 
stratification factors. 
9.4.2.3 Progression-free Survival (PFS) 
PFS is defined as the duration from the date of randomization to the date of first 
documented PD or death before PD, whichever occurs first. For subjects who have no 
progression or death before PD, the date of last tumor assessment will be taken as censored 
date. For subjects who have no tumor assessment after baseline period, the date of 
randomization will be taken as censored date. If the subject experiences progression or 
death missing two or more consecutive tumor assessments, the time of last evaluable tumor 


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data is taken as censored date. If the subject receives other anti-tumor therapy prior to PD, 
the date of last imaging examination for other anti-tumor therapy is taken as censored date. 
Progression-free survival (months) = (Date of event - Date of randomization + 1)/30.25, 
rounded to two decimal places 
Kaplan-Meier method is used to estimate median PFS and its 95% confidence interval, and 
the survival curve is plotted. Hazard ratio (HR) of two groups, 90% and 95% confidence 
intervals are estimated from a Cox model, which includes group and stratification factors. 
9.4.2.4 Overall Survival (OS) 
OS is defined as the duration from the date of randomization to date of death (from any 
causes). For subjects who have not been reported dead at the time of analysis, their last 
known surviving date will be taken as censored date. 
Overall survival (months) = (Date of event - Date of randomization + 1)/30.25, rounded to 
two decimal places 
Kaplan-Meier method is used to estimate median OS and its 95% confidence interval, and 
the survival curve is plotted. Hazard ratio (HR) of two groups, 90% and 95% confidence 
intervals are estimated from a Cox model, which includes group and stratification factors. 
9.4.3 Sensitivity Analysis 
The analyses of primary and secondary efficacy endpoints will be repeated based on 
investigator assessment. 
Based on the assessment of independent tumor assessment committee, center effect (fixed 
or random) is included in the model (GLM or Cox) analysis of primary efficacy endpoint 
and secondary efficacy endpoints, and the significance of center effect is tested. 
Analysis of primary and secondary efficacy based on central imaging and investigator 
assessment will be performed on PP set. 
9.4.4 Subgroup Analysis 
Subgroup analysis will be performed for ORR by stratification factors, presented with a 
forest plot, and the analysis of ORR for treatment group is provided. Subgroups include: 
 
Age (< 60 years vs. ≥ 60 years) 
 
Gender (male vs female) 
 
EGFR status (wild type vs. unknown) 
 
ECOG score (0 vs 1) 


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 
Smoking (yes vs no vs ex-smoking) 
 
Tumor staging (stage IIIB vs stage IV) 
 
Relapse (yes vs no) 
9.5 Subsequent Anti-tumor Therapy 
Subsequent anti-tumor therapy will be tabulated by subject group and summarized by 
treatment session and type (chemotherapy, radiotherapy and surgery). For chemotherapy 
regimens and radiotherapy sites, coded data will be categorized by clinical team to 
determine the specific categories presented in the form. 
A listing of all subsequent anti-tumor therapies will be provided. 
9.6 Safety Analysis 
The safety analysis is based on the safety analysis set. 
Safety observation period starts from the patient signing the informed consent and is 
divided into the following 3 periods: 
 Pre-treatment period: From signing of informed consent to the first dose of study drug. 
 Treatment period: From the first dose of study drug to 30 days after the last dose of 
study drug. 
 Post-treatment period: From 31 days after the last dose of study drug to the end of 
follow-up period. A listing of all AEs in three observation periods will be provided. 
Tabular summary of AEs in treatment period will be provided. 
9.6.1 Drug Exposure and Compliance Analysis 
The total exposure to medications (combination therapy and separately administered 
IBI305/bevacizumab) is calculated, and P value of the difference is calculated using t-test. 
The following summaries will be provided for combination therapy period (first 6 cycles), 
single-agent maintenance period (continuous treatment) and overall: 
 
Number of cycles 
 
Duration of treatment (weeks) 
 
Cumulative exposure (mg) 
 
Actual number of injections 
 
Number of dose delays or adjustments 
 
Relative injected dose intensity (%) 
 
Compliance with number of injections (%) 


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Duration of treatment (weeks) in this study is defined as: 
Duration of treatment = (Date of last injection - Date of first injection + 1)/7 
Treatment compliance is defined as: 
Relative injected dose intensity = (Cumulative actual total dose/Cumulative planned total 
dose) × 100  
Compliance with number of injections = (Cumulative actual total injections/Cumulative 
planned total injections) × 100  
The actual number of injections is the planned number of injections when combination 
therapy period continues for 4 to 6 cycles. For medication with monoclonal antibody less 
than 4 cycles, the planned number of injections is 4. Treatment compliance is summarized 
only for combination therapy period. 
Subjects are further classified by compliance: <80%; ≥80% and ≤20%; >120%. 
9.6.2 Adverse Events 
All adverse events (AEs) will be classified in accordance with the System Organ Class 
(SOC) and preferred terms of the ICH Medical Dictionary for Regulatory Activities 
(MedDRA). 
Severity 
Severity of each TEAE will be classified as one of 5 grades (Grades 1-5) in accordance 
with the National Cancer Institute - Common Terminology Criteria for Adverse Events 
(NCICTCAE) V4.03, and the incidence (frequency and percentage) will be provided by 
SOC and PT. 
TEAEs with missing CTCAE grade in severity after first dose of study drug are classified 
as severe. If a subject reports one TEAE more than once in SOC/PT, then AE with the 
maximum severity will be used in the summary of corresponding severities. 
Relationship with the Investigational Drug 
The investigator will indicate the relationship with the investigational drug, classified as 
“Related”, “Possibly Related”, “Unlikely Related”, “Unrelated”, and “Cannot be Judged”. 
TEAE with missing relationship with the investigational drug would be considered as 
“Possibly Related” with the investigational drug. If a subject reports the same one AE more 
than once in SOC/PT, then AE with the maximum severity will be used in the summary of 
corresponding relationships. Relevant TEAEs in the summary table include TEAEs which 


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are “Related”, “Possibly related”, and “Cannot be judged” with the investigational drug. 
Observation period of adverse events 
All AEs, regardless of severity and relationship to study treatment, from signing of 
informed consent to the end of follow-up period should be recorded on the corresponding 
page or interface of CRF. 
Adverse events are classified as follows: 
 Pre-treatment AE: Any AE reported during pre-treatment period, 
 Treatment-emergent adverse event (TEAE): AE reported during treatment period as 
defined above, 
 Post-treatment AE: AE reported during post-treatment period. 
Adverse event analysis mainly focuses on TEAE. A listing of all AEs will be provided. 
Analysis of treatment-emergent adverse events 
The following summary of TEAE is generated for the treated population: 
 An overview of TEAE outlines the number (%) of patients who experience any of the 
following events 
- TEAE 
- Grade 3 and above TEAE 
- Serious TEAE 
- TEAE leading to trial discontinuation 
- TEAE resulting in dose reduction 
- TEAE leading to death 
- TEAE leading to permanent discontinuation of treatment 
- Adverse event of special interest 
 All TEAEs are coded by primary SOC and PT, and the number (%) of patients 
experiencing at least 1 TEAE is presented. TEAEs are sorted by internationally 
recognized (ICH recommended) SOC order in decreasing incidence of PT within each 
SOC by IBI305 group. This ranking applies to all other tables unless otherwise 
specified. 
 All TEAEs related to study drug are coded by primary SOC and PT, and the number 
(%) of patients experiencing at least 1 TEAE is presented; SOCs are sorted by 
internationally recognized order, and PTs in each IBI305 group within SOC are sorted 


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by decreasing incidence. 
A listing of TEAEs in all patients will be provided. 
Analysis of all serious treatment-emergent adverse events 
The following summaries of serious TEAEs are given for the treated population: 
 All serious TEAEs are coded by primary SOC, PT, and most serious grade. The 
number (%) of patients experiencing at least 1 TEAE is presented and sorted by 
internationally recognized order of SOC and decreasing incidence of PT within each 
SOC by IBI305 group. 
 All serious TEAEs related to study drug are coded by primary SOC, PT, and most 
serious grade. The number (%) of patients experiencing at least 1 TEAE is presented 
and sorted by internationally recognized order of SOC and decreasing incidence of PT 
within each SOC by IBI305 group. 
 A listing of all SAEs is provided. 
Analysis of all treatment-emergent adverse events leading to dose modification 
The following summaries of TEAEs leading to dose modification are given to the treated 
population: 
 All treatment-emergent adverse events leading to dose reduction, dose interruption, 
dose omission and cycle delay will be categorized by primary SOC, PT and the most 
serious grade. The number (%) of patients will be given and sorted by internationally 
recognized order of SOCs and decreasing incidence of PT within each SOC. 
 A listing of all TEAEs leading to dose modification will be provided. 
Analysis of all treatment-emergent adverse events leading to treatment discontinuation 
The following summaries of TEAEs leading to treatment discontinuation are given to the 
treated population. 
 All treatment-emergent adverse events leading to treatment discontinuation will be 
categorized by primary SOC, PT and the most serious grade. The number (%) of 
patients will be given and sorted by internationally recognized order of SOCs and 
decreasing incidence of PT within each SOC. 
 A listing of all TEAEs leading to treatment discontinuation will be provided. 
In the table for overall incidences of adverse events, patients with the same AE once but 
with different severities will be only counted once in the frequency table; its maximum 


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severity will be used, applicable for SOC and PT. 
A listing of all adverse events (including"non-treatment-emergent adverse events") will be 
provided. 
Adverse Events of Special Interest (AESI) 
Adverse events of special interest (AESIs) will be summarized and listed by incidence 
(frequency and percentage). Including the following adverse events: 
 
Gastrointestinal perforation 
 
Surgical and wound healing complications 
 
Hemorrhage 
 
Fistula 
 
Hypertension 
 
Thrombotic event 
 
Posterior reversible encephalopathy syndrome (PRES) 
 
Proteinuria 
 
Infusion reactions 
 
Ovarian failure 
 
Congestive heart failure 
For infusion reaction, duration of TEAE, and the interval form the injection time of the 
drug will be summarized, which are calculated as follows: 
 
Duration of infusion reaction ( min) = End date/time of infusion reaction - Start 
date/time of infusion reaction 
 
Interval (min) from the Injection Time of the Drug = Start Date and Time of the 
Infusion Reaction - Date and Time of the Last Infusion prior to Start of the Infusion 
Reaction 
Major Adverse Events 
A significant adverse event is any adverse event, other than serious adverse event, that 
requires corrective medical action (discontinuation, dose reduction, and symptomatic 
treatment). Tabulated analysis will be made. 
Death 
The observation period for death is the observation period defined above. 
 On-study death: Death occurred during the study 


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 On-treatment death: Death occurred during the treatment 
The following summaries of deaths are given for the treated population: 
 The number (%) of patients who died is statistically analyzed by study period (on-
study and on-treatment), and the cause of death should be indicated if it is available on 
the death report form. 
 Treatment-emergent adverse events leading to death, regardless of relationship to 
study medication, are categorized by primary SOC and PT, number (%) of patients 
will be given; SOC is sorted by internationally recognized order and PT is sorted by 
alphabetical order within each SOC and the most serious NCI grade. 
9.6.3 Clinical laboratory Test Value 
Only safety laboratory tests specified in the protocol will be analyzed. 
For continuous trial data, summary statistics (number, mean, standard deviation, median, 
minimum and maximum) of measured values and changes from baseline will be presented 
by cycle and trial arm. 
The frequency of patients with each grade of laboratory abnormality during on-treatment 
period is summarized for each cycle. For patients with multiple abnormalities in the same 
laboratory variable during on-treatment period, the maximum grade (most serious) for each 
patient is used. 
A listing of all laboratory parameters will be presented. 
The last non-missing measurement before the use of study drug is referred to as baseline 
measurement. The treatment period for all laboratory parameters starts from day 1 of study 
medication. 
For the last cycle, evaluations performed between day 2 of the cycle and 30 days after last 
dose (whichever occurs later) are assigned to the last cycle. 
For a given parameter, a patient is considered evaluable if he/she has at least one 
measurement for the parameter during treatment. The baseline laboratory evaluation results, 
and the worst results during the trial will be summarized in cross table. 
A listing of all laboratory values and abnormal values will be provided. 
9.6.4 Vital Signs 
For parameters of vital signs, measured values and changes since baseline will be 
summarized by planned time point and trial group. Abnormal values of vital signs will be 


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summarized. 
See the table below for abnormal values of vital signs: 
Parameter 
Unit 
Low 
High 
Systolic 
blood 
pressure 
mmHg 
<=90 mmHg, or change <= -20 
mmHg since baseline 
≥140 mmHg, and change ≥20mmHg 
since baseline 
Diastolic 
blood 
pressure 
mmHg 
<=50 mmHg, and change <= -15 
mmHg since baseline 
≥90 mmHg, and change ≥15mmHg 
since baseline 
Pulse 
Bpm 
<=50 bpm, and change <= -15 
bpm since baseline 
≥120 bpm, and change ≥ 15bpm since 
baseline 
Body 
temperature 
℃ 
NA 
≥37.5℃, and change ≥1.1℃ since 
baseline 
Body weight 
Kg 
Percentage change <= -10.0% 
since baseline 
Percentage change ≥ 10.0% since 
baseline 
A list for all parameter values of vital signs, and for abnormal values will be provided 
Trend charts for changes in systolic and diastolic blood pressures are presented by 
scheduled time point and trial arm. 
9.6.5 12-Lead ECG 
For parameters of 12-lead ECG, measured values and changes since baseline will be 
summarized by planned time point and trial group. The baseline laboratory evaluation 
results of 12-lead ECG, and the worst results during the trial will be summarized in cross 
table. 
Refer to the following definitions for summary of abnormal QTc intervals: 
Absolute values of QTc intervals will be classified as: 
 
>450 msec 
 
>480 msec 
 
>500 msec 
Changes of QTc intervals since baseline will be classified as: 
 
Prolongation > 30 msec 
 
Prolongation > 60 msec 
A list of all parameter values and prolonged QTc intervals will be provided. 
9.6.6 Physical Examination 
Physical examination results will not be summarized. A list of all physical examination 
results will be provided and abnormal values will be indicated. 
9.6.7 Immunogenicity 
The positive rates of anti-drug antibody (ADA) and neutralizing antibody (Nab) in patients 


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who have at least one valid anti-drug antibody assay after study medication will be 
summarized by scheduled time point and trial arm, and post-baseline positive rates will 
also be summarized. A listing of all immunogenicity test values will be provided. 
9.6.8 Other Tests 
The following additional safety tests will be only presented as listings. 
 
Blood pregnancy test 
9.7 Pharmacokinetic Analysis 
Population pharmacokinetic analysis is not included in this statistical analysis plan. 
Descriptive statistics and coefficient of variation (CV) of plasma concentration at each time 
point are summarized by trial arm and a listing will be provided. For the calculation of 
descriptive statistics, if the plasma concentration is below the lower limit of quantification, 
it will be set as 0. The mean concentration-time profiles will be presented graphically by 
trial arm. 
9.8 Pharmacodynamic Analysis 
The pharmacodynamic analysis set is used for analysis. 
The measured levels of serum VEGF will be summarized by scheduled time point and trial 
arm, and a listing will be provided. 
10. Quality Control 
To ensure that TFL results are delivered each time at high quality level, the quality control 
procedure of TFL will be defined detailedly in the Quality Control Plan Document. 


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Appendix 1. Abbreviations 
AE 
Adverse Events 
AESI 
Adverse Event of Special Interest 
ATC 
Anatomic Therapeutic Chemical Classification 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DOR 
Duration of Response 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EGFR 
Epidermal Growth Factor Receptor 
FAS 
Full Analysis Set 
GLM 
Generalized Linear Model 
HR 
Hazard Ratio 
ICH 
International Conference of Harmonization 
ITT 
Intent-To-Treat 
MedDRA 
ICH Medical Dictionary for Regulatory Activities 
NSCLC 
Non-small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PDAS 
Pharmacodynamic Analysis Set 
PFS 
Progression-free Survival 
PK 
Pharmacokinetics 
PKAS 
Pharmacokinetic Analysis Set 
PP 
Per Protocol 
PR 
Partial Response 
PRES 
Posterior Reversible Encephalopathy Syndrome 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
Organ System 
SD 
Stable Disease 
SS 
Safety Dataset 
TEAE 
Treatment-Emergent Adverse Event 
TFL 
Table, Figure, and List 
VEGF 
Vascular Endothelial Growth Factor 
WHO-DD 
World Health Organization Drug Dictionaries 
 


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Appendix 2. Tables, Figures, and Lists 
14.1 Demographics and Other Baseline Characteristics 
Table 14.1.1. Summary of Subjects Disposition - All Subjects 
Table 14.1.2 Major Protocol Violations - Intent-To-Treat 
Table 14.1.3 Disposition of Analysis Population - All Subjects 
Table 14.1.4.1 Summary of Randomized Subjects by Site - All Subjects 
Table 14.1.4.2 Disposition of Statistical Analysis Population - Intent-to-Treat 
Table 14.1.5 Summary of Demographics and Other Baseline Characteristics - Full Analysis Set 
Table 14.1.6 Summary of Smoking History - Full Analysis Set 
Table 14.1.7.1 Summary of Past History by System Organ Class and Preferred Term - Full Analysis Set 
Table 14.1.7.2 Summary of Surgical History by System Organ Class and Preferred Term - Full Analysis 
Set 
Table 14.1.7.3 Summary of Hemoptysis History - Full Analysis Set 
Table 14.1.7.1. Summary of Prior Medications by the 3-Level ATC Code - Safety Analysis Set 
Table 14.1.7.2. Summary of Concomitant Medications coded by 3-Level ATC Code - Safety Analysis 
Set 
Table 14.1.9 Summary of Medical History - Full Analysis Set 
Table 14.1.10.1 Summary of Prior Chemotherapy - Full Analysis Set 
Table 14.1.10.2 Summary of Prior Radiotherapy - Full Analysis Set 
Table 14.1.10.3 Summary of Prior Surgery - Full Analysis Set 
Table 14.1.11 Summary of Viral Testing Results at Screening - Safety Analysis Set 
 
14.2 Tables for Efficacy Data 
Table 14.2.1 Summary of Target Lesions at Screening - Full Analysis Set 
Table 14.2.2 Summary of Non-Target Lesions at Screening - Full Analysis Set 
Table 14.2.3 Summary of Objective Response Rate by Site - Full Analysis Set 
Table 14.2.3.1 Analysis of Objective Response Rate (IRC-assessed) - Full Analysis Set 
Table 14.2.3.2 Sensitivity Analysis of Objective Response Rate (IRC-assessed) - Per Protocol Set 
Table 14.2.3.3 Sensitivity Analysis of Objective Response Rate (IRC-assessed) - Full Analysis Set 
Table 14.2.3.4 Sensitivity Analysis of Objective Response Rate (investigator-assessed) - Per Protocol 
Set 
Table 14.2.4.1 Analysis of Disease Control Rate (IRC-assessed) - Full Analysis Set 
Table 14.2.4.2 Sensitivity Analyses of Disease Control Rate (IRC-assessed) - Per Protocol Set 
Table 14.2.4.3 Sensitivity Analysis of Disease Control Rate (investigator-assessed) - Full Analysis Set 
Table 14.2.4.4 Sensitivity Analysis of Disease Control Rate (investigator-assessed) - Per Protocol Set 
Table 14.2.3.5 Subgroup Analysis of Objective Response Rate (IRC-assessed) - Full Analysis Set 
Table 14.2.5.1 Analysis of Duration of Response (IRC-assessed) - Full Analysis Set 
Table 14.2.5.2 Sensitivity Analysis of Duration of Response (IRC-assessed) - Per Protocol Set 
Table 14.2.5.3 Sensitivity Analysis of Duration of Response (investigator-assessed) - Full Analysis Set 
Table 14.2.5.4 Sensitivity Analysis of Duration of Response (Investigator Assessment) - Per Protocol 
Set 
Table 14.2.6.1 Analysis of Progression-Free Survival (IRC-assessed) - Full Analysis Set 
Table 14.2.6.2 Sensitivity Analysis of Progression-Free Survival (IRC-assessed) - Per Protocol Set 
Table 14.2.6.3 Sensitivity Analysis of Progression-Free Survival (investigator-assessed) - Full Analysis 
Set 
Table 14.2.6.3 Sensitivity Analysis of Progression-Free Survival (investigator-assessed) - Per Protocol 
Set 
Table 14.2.7.1 Analysis of Overall Survival - Full Analysis Set 
Table 14.2.7.2 Sensitivity Analysis of Overall Survival - Per Protocol Set 
 
Table 14.2.8.1 Summary of Subsequent Anti-tumor Chemotherapy - Full Analysis Set 
Table 14.2.8.2 Summary of Subsequent Anti-tumor Radiotherapy - Full Analysis Set 


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14.3. Tables for Safety Data 
Table 14.3.1 Summary of Treatment Cycles - Safety Analysis Set 
Table 14.3.2 Summary of Drug Exposure - Safety Analysis Set 
Table 14.3.3 Summary of Drug Compliance - Safety Analysis Set 
Table 14.3.2.1. Summary of Adverse Events - Safety Analysis Set 
Table 14.3.3.2 Summary of Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term - Safety Analysis Set 
Table 14.3.3.3.1 Summary of Treatment-Emergent Adverse Events Related to Monoclonal Antibody by 
System Organ Class and Preferred Term - Safety Analysis Set 
Table 14.3.3.3.2 Summary of Treatment-Emergent Adverse Events Related to Chemotherapy Agents 
by System Organ Class and Preferred Term - Safety Analysis Set 
Table 14.3.3.3.3 Summary of Bleeding Events by System Organ Class and Preferred Term - Safety 
Analysis Set 
Table 14.3.3.3.4 Summary of Thrombotic Events by System Organ Class and Preferred Term - Safety 
Analysis Set 
Table 14.3.2.4. Summary of Serious Adverse Events by System Organ Class and Preferred Term - 
Safety Analysis Set 
Table 14.3.3.5 Summary of Grade 3 and Higher Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term - Safety Analysis Set 
Table 14.3.3.6.1 Summary of Treatment-Emergent Adverse Events Leading to Discontinuation of 
Monoclonal Antibody by System Organ Class and Preferred Term - Safety Analysis Set 
Table 14.3.3.6.2 Summary of Treatment-Emergent Adverse Events Leading to Discontinuation of 
Chemotherapy Agent by System Organ Class and Preferred Term - Safety Analysis Set 
Table 14.3.3.7 Summary of Treatment-Emergent Adverse Events Leading to Study Discontinuation by 
System Organ Class and Preferred Term - Safety Analysis Set 
Table 14.3.2.7. Summary of Adverse Events of Special Interest by System Organ Class and Preferred 
Term - Safety Analysis Set 
Table 14.3.2.8. Summary of Important Adverse Events by System Organ Class and Preferred Term - 
Safety Analysis Set 
Table 14.3.3.10.1 Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and Maximum Severity - Safety Analysis Set 
Table 14.3.3.10.2 Summary of Treatment-Emergent Adverse Events Related to Monoclonal Antibody 
by System Organ Class, Preferred Term, and Maximum Severity - Safety Analysis Set 
Table 14.3.3.10.3 Summary of Treatment-Emergent Adverse Events Related to Chemotherapy Agents 
by System Organ Class, Preferred Term, and Maximum Severity - Safety Analysis Set 
Table 14.3.3.10.4 Summary of Significant Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, and Maximum Severity - Safety Analysis Set 
Table 14.3.3.10.5 Summary of Significant Treatment-Emergent Adverse Events Related to Monoclonal 
Antibody by System Organ Class, Preferred Term, and Maximum Severity - Safety Analysis Set 
Table 14.3.3.10.6 Summary of Significant Treatment-Emergent Adverse Events Related to 
Chemotherapy Agents by System Organ Class, Preferred Term, and Maximum Severity - Safety 
Analysis Set 
Table 14.3.3.10.7 Summary of Significant Adverse Events of Special Interest (AESI) by System Organ 
Class, Preferred Term, and Maximum Severity - Safety Analysis Set 
Table 14.3.3.11 Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and Relationship to Study Drug - Safety Analysis Set 
Table 14.3.2.14. Summary of Infusion Reactions - Safety Analysis Set 
Table 14.3.4.1.1 Cross Table of Before and After Hematology - Safety Analysis Set 
Table 14.3.4.1.2 Listing of Abnormal Hematology Results - Safety Analysis Set 
Table 14.3.4.2.1 Cross Table of Before and After Blood Chemistry - Safety Analysis Set 
Table 14.3.4.2.2 Listing of Abnormal Blood Chemistry Results - Safety Analysis Set 
Table 14.3.4.3.1 Summary of Urinalysis - Safety Analysis Set 
Table 14.3.4.3.2 Cross Table of Before and After Urinalysis - Safety Analysis Set 


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Table 14.3.4.3.3 Listing of Abnormal Urinalysis Results - Safety Analysis Set 
Table 14.3.4.4.1 Summary of Coagulation - Safety Analysis Set 
Table 14.3.4.4.2 Cross Table of Before and After Coagulation - Safety Analysis Set 
Table 14.3.4.4.3 Listing of Abnormal Coagulation Results - Safety Analysis Set 
Table 14.3.4.5 Summary of Immunogenicity Assay Results - Immunogenicity Analysis Set 
Table 14.3.4.1. Summary of Vital Signs - Safety Analysis Set 
Table 14.3.4.2. Summary of Abnormal Vital Signs - Safety Analysis Set 
Table 14.3.5.1. Summary of 12-Lead ECG - Safety Analysis Set 
Table 14.3.5.2. Cross table prior to and after 12-Lead ECG Overall Evaluation - Safety Analysis Set 
Table 14.3.5.3. Summary of Abnormal QTc Intervals - Safety Analysis Set 
14.4 Pharmacodynamic Tables 
Table 14.4.1 Summary of Serum VEGF - PK Analysis Set 
14.5 Pharmacokinetic tables 
Table 14.5.1 Summary of Plasma Drug Concentrations - PK Analysis Set 
14.6 Figure 
Figure. 14.6.1.1 Sum of Longest Axis of Target Lesions (mm) - Best Value (%) Changed from Baseline 
- Full Analysis Set 
Figure. 14.6.1.2 Kaplan-Meier Plot of Time to Sustained Response by Treatment Arm - Full Analysis 
Set 
Figure. 14.6.1.3 Kaplan-Meier Plot of Progression-Free Survival by Treatment Arm - Full Analysis Set 
Figure. 14.6.1.4 Kaplan-Meier Plot of Overall Survival by Treatment Arm - Full Analysis Set 
Figure. 14.6.1.5 Forest Plot of ORR Subgroup Analysis - Full Analysis Set 
Figure. 14.6.1.6 Mean Measured Systolic and Diastolic Blood Pressure by Visit - Safety Analysis Set 
Figure. 14.6.1.7 Mean Measured Serum VEGF by Visit - Safety Analysis Set 
Figure. 14.6.1.8 Mean Plasma Concentration-Time Profile (±SD) - Linear Scale - PK Analysis Set 
16. Lists of Trial Data 
List 16.1.1.1 Disposition of Subjects - All Subjects 
List 16.1.1.2.1 Subjects Who Prematurely Withdrawn from the Study - All Subjects 
List 16.1.1.2.2 Subjects Who Prematurely Discontinued Treatment - All Subjects 
List 16.1.1.2.3 Subjects Who Were Randomized but Did Not Receive Study Drug - All Subjects 
List 16.1.1.3 Subjects Eliminated from Analysis Datasets - All Subjects 
List 16.1.2. Protocol Deviations - Full Analysis Set 
List 16.1.3. Demographics - Full Analysis Set 
List 16.1.4 Smoking History - Full Analysis Set 
List 16.1.5. Prior Medical History and Surgical History - Full Analysis Set 
List 16.1.6 Medical History - Full Analysis Set 
List 16.1.7 EGFR Status - Full Analysis Set 
List 16.1.8.1 Prior Chemotherapy - Full Analysis Set 
List 16.1.8.2 Prior Radiotherapy - Full Analysis Set 
List 16.1.8.3 Prior Surgery - Full Analysis Set 
List 16.1.9 Dosing Records - Safety Analysis Set 
List 16.1.10 Prior and Concomitant Medications - Safety Analysis Set 
List 16.2.1 Tumor Assessment - Target Lesions (investigator-assessed) - Full Analysis Set 
List 16.2.2 Tumor Assessment - Non-Target Lesions (investigator-assessed) - Full Analysis Set 
List 16.2.3 Tumor Assessment - New Lesions (investigator-assessed) - Full Analysis Set 
List 16.2.4.1 Tumor Response Assessment (investigator-assessed) - Full Analysis Set 
List 16.2.4.1 Tumor Response Assessment (IRC-assessed) - Full Analysis Set 
List 16.2.5.1 Best Overall Response and Duration of Response (investigator-assessed) - Full Analysis 
Set 
List 16.2.5.2 Best Overall Response and Duration of Response (IRC-assessed) - Full Analysis Set 
List 16.2.6 Progression-Free Survival and Overall Survival (investigator-assessed) 
List 16.2.7 Subsequent Anti-tumor Therapies - Full Analysis Set 
List 16.3.1.1. All Adverse Events - Safety Analysis Set 


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Version: V1.0 
Version Date: November 14, 2018 
 
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List 16.3.1.2. Serious Adverse Events - Safety Analysis Set 
List 16.3.1.3. Adverse Events leading to Death - Safety Analysis Set 
List 16.3.1.4. Adverse Events leading to Discontinuation of the Study - Safety Analysis Set 
List 16.3.1.5. Adverse Events of Special Interest - Safety Analysis Set 
List 16.3.1.6. Important Adverse Events - Safety Analysis Set 
List 16.3.1.7 Death Events - Safety Analysis Set 
List 16.3.2.1. Hematology Test Results - Safety Analysis Set 
List 16.3.2.2. Blood Biochemistry Results - Safety Analysis Set 
List 16.3.2.3. Urine Test Results - Safety Analysis Set 
List 16.3.2.4. Coagulation Test Results - Safety Analysis Set 
List 16.3.2.5. Virological Test Results - Safety Analysis Set 
List 16.3.2.6. Immunogenicity Test Results - Immunogenicity Analysis Set 
List 16.3.3.1 Physical Examination - Safety Analysis Set 
List 16.3.3.2 List of Abnormal Physical Examination Values - Safety Analysis Set 
List 16.3.4 Vital Signs - Safety Analysis Set 
List 16.3.5.1 12-Lead ECG - Safety Analysis Set 
List 16.3.5.2 List of Abnormal 12-Lead ECG Values - Safety Analysis Set 
List 16.3.3. ECOG Score - Safety Analysis Set 
List 16.3.7 Blood Pregnancy Test - Safety Analysis Set 
List 16.4.1 Serum VEGF Test - PD Analysis Set 
List 16.5.1 Serum Concentrations (ng/mL) - PK Analysis Set