Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: Cancer Bevacizumab Carboplatin Paclitaxel
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 731
Healthy volunteers: no

Brief summary:
The purpose of this research study is to compare the effectiveness and safety of FKB238 against Avastin® in men and women with advanced/recurrent non squamous non-small cell lung cancer

Detailed description:

Arms:
arm 1: Drug: FKB238:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

Area Under Curve (AUC) = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles. arm 2: Drug: Avastin:

15 mg/kg IV infusion on Day 1 of each 21-day cycle.

Drug: Paclitaxel:

200 mg/m2 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Drug: Carboplatin:

AUC = 6.0 IV infusion on Day 1 of each 21-day cycle for at least 4 and no more than 6 cycles.

Interventions: intervention 1: FKB238 (bevacizumab) intervention 2: Avastin (bevacizumab) intervention 3: Paclitaxel intervention 4: Carboplatin
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
Prot_000.pdf: 
 
 
Official Title: 
A Randomised, Parallel, Double Blinded Study to Compare the 
Efficacy and Safety of FKB238 to Avastin® In 1st Line Treatment 
for Patients with Advanced/Recurrent Non-Squamous Non-Small 
Cell Lung Cancer in Combination of Paclitaxel and Carboplatin 
AVANA 
 
 
NCT Number: 
NCT02810457 
 
 
Document Date: 
Protocol Version 5: 22 May 2018 
 


CONFIDENTIAL AND PROPRIETARY
Information described herein is confidential and may be disclosed
only with the express written permission of Centus Biotherapeutics Limited.
This study will be performed in compliance with Good Clinical Practices.
Title:
Protocol Number:
IND Number:
EudraCT Number: 
Investigational Product: 
Phase:
Sponsor:
Sponsor Contact:
Coordinating 
Investigator:
Contract Research 
Organization:
Date of Protocol: 
Version
A Randomised, Parallel, Double Blinded Study to Compare the 
Efficacy and Safety of FKB238 to Avastin® In 1st Line Treatment
for Patients with Advanced/Recurrent Non-Squamous Non-Small 
Cell Lung Cancer in Combination of Paclitaxel and Carboplatin
AVANA
FKB238-002
122990
2015-004104-33
FKB238
III
Centus Biotherapeutics Limited
1 Francis Crick Avenue
Cambridge Biomedical Campus
Cambridge
CB2 0AA
United Kingdom
PAREXEL International (IRL) Limited
70 Sir John Rogerson’s Quay
Dublin 2
Ireland
22 May 2018
5


Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
PROTOCOL SYNOPSIS
Study Number:
FKB238-002
Title of Study:
A Randomised, Parallel, Double Blinded Study to Compare the 
Efficacy and Safety of FKB238 to Avastin® In 1st Line Treatment
for Patients with Advanced/Recurrent Non-Squamous Non-Small 
Cell Lung Cancer in Combination of Paclitaxel and Carboplatin
Short Title: AVANA
Indication:
Non-squamous non-small cell lung cancer (NS-NSCLC)
Number of
Study Centres:
Approximately 200 sites in 31 countries
Development
Phase:
III
Study Period
Estimated date of first patient enrolled: June, 2016
Estimated date of last patient last visit: February, 2022
Objectives:
Primary
• 
To demonstrate the efficacy equivalence of FKB238 and
EU approved-Avastin 
(EU-Avastin) 
when 
used 
in
combination with paclitaxel/carboplatin as measured by 
overall response rate (ORR)
Secondary
• 
To compare FKB238 and EU-Avastin through:
o ORR at week 19
o Progression-free survival (PFS)
o Overall survival (OS)
o Duration of response (DOR)
o Disease control rate (DCR)
• 
To compare the safety of FKB238 and EU-Avastin
• 
To compare the antidrug antibodies (ADAs) produced by
FKB238 and EU-Avastin
• 
To compare the serum trough concentration (Ctrough) of
FKB238 and EU-Avastin
Methodology/
Study Design:
This is a global multi-centre, double-blind, parallel, Phase 3 study
designed to compare the efficacy and safety of FKB238 and
EU-Avastin when used in combination with paclitaxel and 
carboplatin in the 1st line treatment of advanced or recurrent
NS-NSCLC.
Patients aged 18 years or older who have advanced or recurrent 
NS-NSCLC will be screened for participation up to 28 days before 
randomisation. Approximately 730 eligible patients will be 
randomly assigned in a 1:1 ratio to 1 of 2 treatment groups. 
Randomisation will be stratified according to epidermal growth
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
factor receptor (EGFR) mutation and anaplastic lymphoma
receptor tyrosine kinase (ALK) gene arrangement status (both are 
tested and known negative versus status unknown for either), 
geographical region, prior weight loss over the previous 6 months 
(< 5% yes versus no), and disease stage (advanced or recurrent). 
The following treatment groups will be included in this study:
• 
FKB238 group: paclitaxel + carboplatin (combination
drugs) + FKB238 (investigational product [IP])
• 
Avastin group: paclitaxel + carboplatin (combination
drugs) + EU-Avastin (IP)
Upon randomisation, patients will enter the Study Treatment 
Period. Following start of study treatment, patients will attend for
study visits every 3 weeks as long as they are receiving study
treatment. The combination drugs (paclitaxel + carboplatin) will 
be administered on Day 1 of each 21-day cycle for at least 4, and 
no more than 6 cycles. The number of cycles is determined by 
patients’ need and the investigator’s assessment. FKB238 or 
EU-Avastin (IP) will also be administrated on Day 1 of each 
21-day cycle until objective disease progression (PD) or other 
criteria for treatment discontinuation are met. Radiological 
assessment using Response Evaluation Criteria in Solid Tumours 
(RECIST) v1.1 will be performed at screening and every 6 weeks 
(± 1 week) for 24 weeks, then every 9 weeks (± 1 week) for the 
remainder of the treatment period, and then every 12 weeks 
(± 1 week) after the completion of study treatment. Patients who 
develop toxicity may delay study treatment for up to 3 weeks. In 
most cases, patients who require the combination drugs and/or IP 
to be held for more than 3 weeks will discontinue the study 
treatment. In some cases, should re-start of the study treatment 
after a delay of more than 3 weeks be required, a discussion 
should occur between the medical monitor and the investigator. 
All such decisions need to be appropriately documented. Patients 
who discontinue study treatment for reasons other than PD will 
continue to undergo RECIST v1.1 tumour assessments until PD, 
until death, or until data cut-off (whichever occurs first).
Data cut-off is defined as 12 months from randomisation of the 
last patient enrolled in the study and is expected in January 2019 
for the purpose of the primary and secondary endpoint analyses. 
After discontinuation of the study treatment, further care and 
treatment will be at the discretion of the investigator. Up to the 
time of data cut-off, any systemic anti-cancer treatment, 
radiotherapy or cancer surgery conducted after discontinuation of 
study treatment will be collected until death, loss to follow-up,
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
withdrawal of consent or until end of study. Assessments for
survival should be made every 8 weeks (± 1 week) following 
objective PD. At data cut-off all patients previously discontinued 
from study treatment and continuing in follow-up will complete 
the study and no further study assessments will be performed.
The Extended Treatment Period is the time after data cut-off to 
end of study in which patients may continue receiving IP if they 
are considered by the treating investigator to be gaining clinical 
benefit.
Number of
Patients 
(planned and 
analysed):
Assuming a dropout rate of 10%, it is anticipated that
approximately 730 patients will be randomised into the study in a 
1:1 ratio (365 patients in the FKB238 group and 365 patients in 
the Avastin group) in order to have a total of 656 patients who 
complete study treatment. Sample size was determined to meet 
both the European Medicines Agency (EMA) and Food and Drug 
Administration (FDA) requirements, which differ in several 
aspects.
To fulfil the EMA requirements, a meta-analysis of available 
randomised clinical studies of Avastin demonstrated that the
risk-difference for the ORR for the control arm compared to the
Avastin treatment arm was calculated to be 0.1938 (80% 
confidence interval [CI]: [0.1564,0.2312]). Based on the result of 
the meta-analysis, an equivalence margin for the risk-difference 
was determined to be 0.1221, which preserves over 22% of the 
treatment effect characterised by the lower 80% CI for the
risk-difference of ORR.
The NCSS PASS 2005 statistical software was used for the sample
size 
calculation. 
With 
the 
equivalence 
margin 
for 
the
risk-difference of 0.1221, an expected response rate of 35% in 
both treatment arms, the study design employing a two one-sided 
test (TOST) procedure, and an overall Type I error rate of 2.5%, a 
sample size of 656 patients (328 per group) was calculated to 
provide 80% power to demonstrate that the 95% CI about the
risk-difference 
comparing 
FKB238 
and 
EU-Avastin 
falls
completely within ± 0.1221. A total of approximately 730 
NS-NSCLC patients (allowing for a dropout rate of 10%) will be 
randomised either to the FKB238 group or Avastin group in a 1:1 
ratio in a parallel group study.
Per the FDA requirements, a meta-analysis was performed on data 
from relevant clinical trials of Avastin, resulting in an estimate of 
the risk-ratio of 0.5212 along with a 70% CI, (0.4775, 0.5689). 
With lower and upper equivalence margins of 0.73 and 1.38, 
which preserve 50% treatment effects determined by the lower and
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
upper limits respectively of the 70% CI, an expected response rate
of 35% in both treatment arms, a TOST procedure for equivalence, 
and an overall Type I error rate at 5%, a sample size of 
656 patients (328 per group) provides 80% power to demonstrate 
that the 90% CI for the risk-ratio comparing FKB238 and 
EU-Avastin is entirely enclosed within 0.73 and 1.38. Accounting 
for potential 10% dropouts, approximately 730 patients will be 
randomised.
Diagnosis and
Main Criteria 
for Inclusion:
The following are the inclusion criteria:
1. Patients aged 18 years or older
2. Newly diagnosed advanced (stage IV) /recurrent NS-NSCLC for 
which they had not received any systemic anti-cancer therapy for 
metastatic disease, including chemotherapy, biologic therapy, 
immunotherapy, or any investigational drug
3. Histologically or cytologically confirmed diagnosis of
predominantly NS-NSCLC
4. Be eligible to receive study treatment of bevacizumab, 
paclitaxel, and carboplatin for the treatment of advanced or 
recurrent NS-NSCLC
5. Existence of at least 1 measurable lesion by response
evaluation criteria (RECIST v1.1), defined as; at least one lesion, 
not previously irradiated, that can be accurately measured at 
baseline as  10 mm in the longest diameter (except lymph 
nodes which must have short axis  15 mm) with computed 
tomography (CT) or magnetic resonance imaging (MRI) which 
is suitable for accurate repeated measurements.
6. Eastern Collaborative Oncology Group Performance Status
(ECOG PS) 0 or 1
7. Life expectancy longer than 6 months
8. Adequate haematological function: absolute neutrophil count 
1.5 × 109/L; platelets 100 × 109/L; haemoglobin 9 g/dL
9. International normalised ratio (INR)  1.5 and partial 
thromboplastin time  1.5 × the upper limit of normal (ULN) 
within 7 days prior to starting study treatment
10. Adequate liver function: Serum bilirubin  1.5 × ULN (and in
case of documented Gilbert’s Syndrome [unconjugated 
hyperbilirubinaemia]  3 x ULN); transaminases  2.5 × ULN 
(and in case of liver metastases < 5 × ULN)
11. Adequate renal function:
a.
Creatinine clearance, measured and/or calculated 
according to the formula of Cockroft and Gault  60 mL/
min AND
b. Urine dipstick or urinalysis for proteinuria < 2+. If the
urine dipstick or urinalysis is  2+, 24-hour urine must
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
demonstrate  1 g of protein in 24 hours
12. Negative serum/urine pregnancy test within 7 days of starting 
study treatment in premenopausal women and women
< 2 years after the onset of menopause
13. Signed informed consent
14. Able to comply with the protocol
Exclusion
Criteria:
The following are the exclusion criteria:
1. Small cell lung cancer (SCLC) or combination SCLC and 
NSCLC. Squamous-cell tumours and mixed adenosquamous 
carcinomas of predominantly squamous nature
2. Recurrence occurred within 12 months from the last dose of
neoadjuvant/adjuvant therapy
3. Any unresolved toxicities from prior systemic therapy (eg, 
adjuvant chemotherapy) greater than Common Terminology 
Criteria for Adverse Events (CTCAE) grade 1 at the time of 
starting study drug with the exception of alopecia
4. Evidence of a tumour that compresses or invades major blood
vessels or tumour cavitation that in the opinion of the 
investigator is likely to bleed
5. Known sensitising EGFR mutations (eg, deletion 19 or
L858R) or EML4-ALK translocation positive mutations
6. Previous dosing with vascular endothelial growth factor 
(VEGF) inhibitor
7. Brain metastasis or spinal cord compression (computed
tomography or magnetic resonance imaging of the head is 
required within 4 weeks prior to randomisation)
8. Malignancy other than NS-NSCLC within 5 years before
randomisation, except for adequately treated carcinoma in situ of 
the cervix, basal or squamous cell skin cancer, localised prostate 
cancer treated surgically with curative intent, or ductal 
carcinoma in situ of the breast treated surgically with curative 
intent
9. Known hypersensitivity to active ingredients or any excipients
of the IPs and combination chemotherapy
10. Use of aspirin (> 325 mg/day) or treatment with dipyridamole,
ticlopidine, clopidogrel, prasugrel, or cilostazol within 14 days 
before the first dose of IP
11. Use of full-dose oral or parenteral anticoagulants or
thrombolytic agents within 6 months before the first dose of IP 
(use of low dose anticoagulants for venous access device 
maintenance or prophylactic use of anticoagulants will be 
allowed)
12. Known Hepatitis B, Hepatitis C, or human immunodeficiency
virus (HIV) infection
13. Major surgery, significant traumatic injury, or radiotherapy
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
(except for palliative intention which requires 14 days wash
out period for bone lesions outside the thoracic region) within 
28 days before the first dose of IP or anticipation of the need 
for major surgery during study treatment
14. Fine needle aspirations, indwelling catheter placement, or core
biopsy within 7 days of randomisation
15. Non-healing wound, ulcer, or bone fracture
16. Uncontrolled 
hypertension 
or 
systolic 
blood 
pressure
> 140 mmHg or diastolic blood pressure > 90 mmHg
17. Patients with unstable angina, myocardial infarction, coronary 
artery bypass graft, angioplasty, vascular stenting, or 
cardiovascular event within 6 months before the first dose of
IP; coagulopathy, any bleeding disorders, poorly controlled
diabetes, or active gastrointestinal inflammation such as gastric 
or duodenal ulcer, diverticulitis, inflammatory bowel disease, 
or cholecystitis
18. History of fistulas or abdominal perforations
19. History of arterial or venous thromboembolic or ischemic 
events, or congestive heart failure (New York Heart 
Association class  2) within 6 months before the first dose of
IP
20. History of haemoptysis of  ½ teaspoon of red blood within
28 days before the first dose of IP
21. Fertile men or women of childbearing potential not using 
adequate contraception. Patients of child bearing potential and 
their partners, who are sexually active, must agree to the use of
at least one highly effective form of contraception throughout
their participation in the study and for 6 months after last dose 
of study treatment
22. Breastfeeding women (unless the patient is willing to
discontinue breastfeeding throughout their participation in the 
study and for 6 months after last dose of study treatment)
23. Treatment with any other investigational agent for any reason
within 28 days before the first dose of IP
24. Presence of any other disease, metabolic dysfunction, physical 
examination finding, or laboratory finding that, in the opinion
of the investigator, puts the patient at high risk for
treatment-related complications in this study
Study
Treatment:
Concomitant Chemotherapy (Combination Drugs), Dose, and
Mode of Administration:
Paclitaxel, 200 mg/m2, intravenous (IV) infusion over 3 hours
should be immediately followed by carboplatin, area under the 
time curve 6.0, IV infusion over 15 to 60 minutes on Day 1. 
Paclitaxel and carboplatin will be administered once every 21 days 
(± 3 days) for at least 4, and no more than 6 cycles. The number of 
cycles is determined by patients’ need and the investigator’s
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
assessment.
Test Product (IP), Dose, Dosage Form, and Mode of 
Administration:
FKB238,
carboplatin, to be administered once every 21 days (± 3 days) until
objective PD or other criteria for treatment discontinuation are met 
the initial dose should be delivered over 90 minutes as an IV 
infusion. If the first infusion is well tolerated, the second infusion 
may be administered over 60 minutes. If the 60-minute infusion is 
well tolerated, all subsequent infusions may be administered over 
30 minutes.
Reference therapy (IP), Dose, and Mode of Administration: EU-
Avastin (bevacizumab), 15 mg/kg, IV infusion immediately 
following carboplatin, to be administered once every 21 days 
(± 3 days) until objective PD or other criteria for treatment 
discontinuation are met. The initial dose should be delivered over 
90 minutes as an IV infusion. If the first infusion is well tolerated, 
the second infusion may be administered over 60 minutes. If the 
60-minute infusion is well tolerated, all subsequent infusions may 
be administered over 30 minutes.
Duration of
Treatment:
Concomitant chemotherapy will be administered once every
21 days (± 3 days) for at least 4, and no more than 6 cycles. 
IP treatment will be given until PD or other criteria for treatment 
discontinuation are met.
Duration of
Patient 
Participation in 
Study:
This study consists of a Screening Period (up to 28 days), a Study
Treatment Period, a study treatment discontinuation visit, a 
Follow-up Period (up to the data cut-off which occurs with a 
minimum of 12 months after randomisation of the last patient 
enrolled), and an Extended Treatment Period.
Patients may remain on IP treatment until PD or other criteria for 
treatment discontinuation are met. Patients who are withdrawn 
from treatment will continue to be followed in the Follow-up 
Period until formal withdrawal of consent, until death, or until the 
data cut-off (whichever occurs first). At data cut-off all patients 
previously discontinued from study treatment and continuing in 
follow-up will complete the study and no further study 
assessments will be performed.
Following data cut-off, patients on treatment at that time may 
continue receiving IP during an Extended Treatment Period if the 
investigator believes they are gaining clinical benefit from the 
treatment.
Study
Populations:
The Intent-to-Treat (ITT) Population includes all patients
randomised to treatment. All efficacy analyses will be performed 
on the ITT population. These analyses will be treated as the 
primary analysis for the FDA requirement and as sensitivity
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CONFIDENTIAL
15
mg/kg,
IV
infusion
immediately
following


Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
analysis otherwise.
The Per-Protocol Set (PPS) includes all ITT patients who received 
at least 1 dose of IP with no important protocol violations or 
deviations. All efficacy analyses will be performed on the PPS 
population. These analyses will be treated as the primary analysis 
for the EMA requirement and as sensitivity analysis otherwise.
The Safety Population includes all ITT patients who received at 
least 1 dose of IP. All safety analyses will be performed on the 
Safety Population.
The Pharmacokinetic (PK) Population includes all PPS patients 
who have at least 1 serum drug concentration data, which is 
defined in the study protocol, after IP administration.
Evaluation: 
Efficacy
Primary Endpoints:
• 
ORR (by RECIST v1.1) assessed as the rate of the best
response (complete response [CR] or partial response [PR]).
Primary efficacy assessment will be presented based on the
investigators’ assessment results as well as the independent central
radiological assessment results, but primary efficacy assessment 
based on the independent central radiological assessment results 
will be used as a pivotal result of the study.
Secondary Endpoints:
• 
ORR (by RECIST v1.1) at week 19, defined as the rate of the
best response of CR or PR assessed at week 19
• 
PFS, defined as the time from randomisation to the first
documented PD or death, whichever occurs first
• 
OS, defined as the time from randomisation to death from any
cause
• 
DOR, defined as the time from the first documented PR or CR
(by RECIST v1.1) to the first documented PD or death,
whichever occurs first
• 
DCR, defined as the rate of CR, PR, SD ( 6 weeks)
Data from efficacy assessments during the Extended Access 
Period will not be collected.
Evaluation: 
Safety
Safety will be evaluated through adverse events (AEs), vital signs,
haematology, clinical chemistry, urinalysis, electrocardiogram, 
ECOG PS, and physical examination.
Only serious adverse events, pregnancies, overdoses, and AEs that 
lead to treatment discontinuation or death will be collected during 
the Extended Treatment Period.
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
Evaluation:
Other
• 
Pharmacokinetics: Ctrough
• 
Immunogenicity: presence of ADAs
Samples for pharmacokinetics and immunogenicity will not be 
collected during the Extended Treatment Period.
Statistical 
Methods:
The TOST procedure will be used for testing the null hypothesis
of non-equivalence against the alternative hypothesis of
equivalence. To fulfil the EMA’s requirement, the TOST 
procedure will be carried out using PPS by comparing a 95% 
confidence interval (CI) for the ORR difference between FKB238 
and EU-Avastin to the margin [± 0.1221], which is deemed to 
represent a clinically acceptable difference with respect to ORR. If 
the true CI is within the interval [± 0.1221], an equivalence 
between FKB238 and EU-Avastin, with respect to the ORR, is 
confirmed. To meet the FDA’s requirements, the TOST procedure 
will be performed based on ITT population by comparing a 90% 
CI for the ORR ratio between FKB238 and EU-Avastin to the 
margin [0.73, 1.38], which is deemed to represent a clinically 
acceptable difference with respect to ORR. If the CI is within the 
interval [0.73, 1.38], an equivalence between FKB238 and
EU-Avastin, with respect to the ORR, is confirmed.
The logistic regression model will be fitted for the overall 
response and treatment adjusted for the covariates. The adjusted 
odds ratio and corresponding 95% CI will be presented.
Kaplan-Meier curves for PFS, OS, and DOR, medians, and 
corresponding 95% CI based on Kaplan-Meier estimator per 
treatment arm will be presented.
The multiple Cox proportional hazards model will be fitted for all 
time to event endpoints, including treatment group adjusted for the 
covariates. The hazard ratios and corresponding 95% CI for 
treatment effect and the covariates will be presented.
PFS and OS will be compared between treatment groups and 
descriptive statistics will be provided.
DCR and ORR at week 19 will be estimated and compared 
between treatment groups, using descriptive statistics.
Ctrough will be compared between treatment groups and descriptive 
statistics will be provided.
The ADA rates of FKB238 and EU-Avastin at each time point will 
be summarised.
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
Sponsor
Sponsor Contact
LIST OF STUDY PERSONNEL
Centus Biotherapeutics Limited
1 Francis Crick Avenue
Cambridge Biomedical Campus 
Cambridge
CB2 0AA
United Kingdom
 
Coordinating Investigator
Contract Research 
Organization
 
PAREXEL International (IRL) Limited
70 Sir John Rogerson’s Quay
Dublin 2
Ireland
Phone: +35 314 739500
Fax: +35 314 739501
Contact details of other study participants (eg, central laboratory, medical monitor for 
safety reporting, study drug logistics) are provided in the study manual.
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
TABLE OF CONTENTS
1.
SPONSOR SIGNATURE PAGE ......................... .................... ............................................................. 21
2.
INVESTIGATOR AGREEMENT......................................................................................................... 22
2.1
Coordinating Investigator .....................................
............................................................... 22
2.2
Investigator Agreement ............................ ....................
........................................................ 23
3.
LIST OF ABBREVIATIONS AND DEFINITIONS ............................................................................. 24
4.
ETHICAL AND REGULATORY REQUIREMENTS ......................................................................... 27
4.1
Ethical Conduct of the Study .......................................
........................................................ 27
4.2
Patient Data Protection ................................................
........................................................ 27
4.3
Ethics and Regulatory Review ................................................................................................... 27
4.4
Informed Consent .................................... .............
............................................................... 27
4.5
Changes to the Protocol and Informed Consent Form ............................................................... 28
4.6
Audits and Inspections ............................. ....................
........................................................ 28
5.
INTRODUCTION .................................................................................................................................. 29
5.1
Summary of Nonclinical and Clinical Studies ........................................................................... 29
5.1.1 
Nonclinical Studies ....................................
........................................................ 29
5.1.2 
Clinical Studies ..........................................
........................................................ 30
5.2
Potential Risks and Benefits .................................
............................................................... 32
5.3
Study Rationale ........................................ .............
............................................................... 33
6.
STUDY OBJECTIVES......................................... ................................................................................. 35
6.1
Primary Objective .................................................
............................................................... 35
6.2
Secondary Objectives...................................................
........................................................ 35
6.3
Study Endpoints ....................................... .............
............................................................... 36
7.
INVESTIGATION PLAN .................................... ................................................................................. 36
7.1
Overall Study Design and Plan Description ............................................................................... 36
7.2
Discussion of Study Design, Including the Choice of Control Groups .................................... 39
7.3
Selection of Study Population ......................................
........................................................ 40
7.3.1 
Inclusion Criteria .......................................
........................................................ 40
7.3.2 
Exclusion Criteria ......................................
........................................................ 41
7.4
Patient Enrolment .................................................
............................................................... 43
7.4.1 
Procedures for Handling Patients Incorrectly Enrolled or Initiated on Study
Treatment ................................................... ............................................................. 43
7.4.2 
Discontinuation of Study Treatment ....................................................................... 44
7.4.3 
Replacement of Patients ........................... ............................................................... 45
7.4.4 
Follow-up of Patients Discontinued from the Study Treatment Regimen ............. 45
7.4.5 
Withdrawal from the Study ...................... ............................................................... 45
7.4.6 
Screening Failures ......................................
........................................................ 46
7.5
Data Monitoring Committee .................................
............................................................... 46
7.6
Treatment of Patients ............................... ....................
........................................................ 46
7.6.1 
Treatments Administered ......................... ............................................................... 46
7.6.2 
Identity of Investigational Product .................. ........................................................ 47
7.6.3 
Investigational Product Accountability, Reconciliation, and Return ..................... 49
7.6.4 
Study Drug Handling and Disposal .......... ............................................................... 49
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
7.6.5 
Method of Assigning Patients to Treatment Groups and Measures to
Minimise/Avoid Bias ............ ................................................................................. 49
7.6.5.1 
Patient Identification ....... ................................................................................. 49
7.6.5.2 
Randomisation ...................................... ............................................................. 49
7.6.5.3 
Blinding ................................................ ............................................................. 50
7.6.5.4 
Breaking the Blind ............................. ............................................................... 50
7.6.5.5 
Scheduled Unblinding ....................................................................................... 51
7.6.6 
Selection of Doses in the Study ............................................................................... 51
7.6.7 
Criteria for Schedule Adjustment, Dose Modifications, and Discontinuation of
Study Treatment ...................................................................................................... 51
7.6.7.1 
FKB238/EU-Avastin ....... ................................................................................. 51
7.6.7.2 
Paclitaxel and Carboplatin ......................... ........................................................ 55
7.6.8 
Pre-study and Concomitant Medications ........ ........................................................ 61
7.6.8.1 
Restrictions ........................................................................................................ 62
7.6.8.2 
Premedication ....................................... ............................................................. 63
7.6.8.3 
Prohibited Medications....................... ............................................................... 63
7.6.8.4 
Other Concomitant Medications................ ........................................................ 63
7.6.9 
Treatment Compliance ............................. ............................................................... 65
7.7
Study Procedures ..................................... .............
............................................................... 65
7.7.1 
Schedule of Assessments ......................... ............................................................... 65
7.7.2 
Screening Procedures .................................
........................................................ 70
7.7.3 
Study Treatment Period Procedures Prior to Data Cut-Off .................................... 71
7.7.3.1 
Cycle 1 ................................................. ............................................................. 71
7.7.3.2 
Cycle 2 to Cycle 6 ............................................................................................. 72
7.7.3.3 
Cycle 7 and Subsequent Cycles ......................................................................... 73
7.7.3.4 
Study Treatment Discontinuation Visit ............................................................ 73
7.7.3.5 
Follow-up 30 Days After Last Dose of Study Treatment ................................. 74
7.7.4 
Follow-up Period .......................................
........................................................ 74
7.7.5 
Patient Management Post Data Cut-Off (Extended Treatment Period).................. 75
7.8
Efficacy and Safety Variables ......................................
........................................................ 76
7.8.1 
Efficacy Assessments .................................
........................................................ 76
7.8.1.1 
Primary Efficacy Assessment .................... ........................................................ 77
7.8.1.2 
Secondary Efficacy Assessments .............. ........................................................ 77
7.8.1.3 
Tumour Assessments by Imaging Techniques Using RECIST ........................ 77
7.8.2 
Safety Assessments ....................................
........................................................ 79
7.8.2.1 
Adverse Events ................................... ............................................................... 79
7.8.2.1.1 
Definition of Adverse Events ................................................................................... 79
7.8.2.1.2 
Definition of Serious Adverse Events ...... ............................................................... 79
7.8.2.1.3 
Recording of Adverse Events................................................................................... 79
7.8.2.1.4 
Variables ................................ ....................
........................................................ 80
7.8.2.1.5 
Severity of AEs ..........................................
........................................................ 81
7.8.2.1.6 
Causality Collection ...................................
........................................................ 81
7.8.2.1.7 
Adverse Events Based on Signs and Symptoms .................................................... 82
7.8.2.1.8 
Adverse Events Based on Examinations and Tests ................................................ 82
7.8.2.1.9 
Disease Progression ...................................
........................................................ 82
7.8.2.1.10 
New Cancers .......................... ....................
........................................................ 83
7.8.2.1.11 
Lack of Efficacy ..................... ....................
........................................................ 83
7.8.2.1.12 
Deaths .................................... ....................
........................................................ 83
7.8.2.1.13 
Reporting of Serious Adverse Events ...... ............................................................... 83
7.8.2.2 
Overdose .............................................. ............................................................. 84
7.8.2.3 
Pregnancy ............................................. ............................................................. 85
7.8.2.4 
Safety Laboratory Determinations .................................................................... 85
7.8.2.5 
Vital Signs, Physical Examination, and Other Safety Evaluations ................... 87
7.8.2.5.1 
Vital Signs .............................. ....................
........................................................ 87
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
7.8.2.5.2 
Weight and Height ................................................................................................... 88
7.8.2.5.3 
Physical Examination .................................
........................................................ 88
7.8.2.5.4 
12-lead Electrocardiogram ....................................................................................... 88
7.8.2.5.5 
ECOG PS ...................................................
........................................................ 88
7.8.3 
Other Assessments ................................... ............................................................... 88
7.8.3.1 
Immunogenicity Assessment ..................... ........................................................ 88
7.8.3.2 
Pharmacokinetics Measurement ................ ........................................................ 89
7.9
Statistical Methods ................................... .............
............................................................... 89
7.9.1 
Determination of Sample Size ........................ ........................................................ 89
7.9.2 
Patient Populations Analysed ................... ............................................................... 90
7.9.3 
General Considerations ..............................
........................................................ 90
7.9.4 
Important Protocol Violations ......................... ........................................................ 91
7.9.5 
Efficacy Analysis .......................................
........................................................ 91
7.9.5.1 
Primary Efficacy Outcome Measures ................................................................ 91
7.9.5.2 
Secondary Efficacy Outcome Measures ........................................................... 91
7.9.6 
Safety Analysis ..........................................
........................................................ 92
7.9.7 
Other Outcome Measures ......................... ............................................................... 92
7.9.7.1 
Immunogenicity Outcome Measures ................................................................ 92
7.9.7.2 
Pharmacokinetics Outcome Measures .............................................................. 92
7.9.8 
Interim Analysis .........................................
........................................................ 93
8.
STUDY MANAGEMENT BY PAREXEL ........................................................................................... 93
8.1
Pre-study Activities ...............................................
............................................................... 93
8.2
Training of Study Site Personnel ..........................
............................................................... 93
8.3
Monitoring of the Study ........................... ....................
........................................................ 93
8.4
Source Data .............................................. .............
............................................................... 93
8.5
Study Agreements .................................... .............
............................................................... 93
8.6
Archiving of Study Documents.............................
............................................................... 93
9.
DATA MANAGEMENT AND QUALITY CONTROL BY PAREXEL ............................................ 94
9.1
Electronic Data Capture ........................... ....................
........................................................ 94
9.2
Monitoring ............................................... .............
............................................................... 94
9.3
Data Quality Assurance ...............................................
........................................................ 95
9.4
Records Retention .................................... .............
............................................................... 95
9.5
Confidentiality ......................................... .............
............................................................... 95
10.
REFERENCES ....................................................................................................................................... 96
11.
APPENDICES ........................................................................................................................................ 97
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
LIST OF TABLES
Table 1 
Summary of Similarity Analysis of Primary Endpoints ........................................................... 31
Table 2
Summary of Similarity Analysis of Secondary Endpoints.......................................................31
Table 3
Phase 3 Results of Avastin in 1st Line NS-NSCLC and 1st Line mCRC..................................34
Table 4 
Chemotherapy Dose Level Modifications for Defined Toxicities ........................................... 55
Table 5 
Chemotherapy Dose Modification at the Start of the Subsequent Cycle ................................. 56
Table 6 
Dose Adjustments for Hepatic Toxicities .................................................................................. 56
Table 7 
Dose Modifications for Cardiac Toxicity .................................................................................. 57
Table 8 
Dose Modification for Neurologic Toxicity .............................................................................. 58
Table 9 
Dose Modifications for Gastrointestinal Toxicity at the Start of the Subsequent Cycle .......... 59
Table 10 
Dose Adjustments Related to Infusion Reactions and Hypersensitivity .................................. 60
Table 11 
Dose Modifications for Nonhaematologic Toxicity ................................................................... 61
Table 12 
Highly Effective Methods of Contraception .............................................................................. 63
Table 13 
Schedule of Assessments Prior to Data Cut-Off ........................................................................ 66
Table 14 
Schedule of Assessments After Data Cut-Off ............................................................................ 76
Table 15 
Contact Information for Submitting All Paper Forms After Data Cut-Off .............................. 76
Table 16 
Laboratory Variables ............................... .................... ............................................................. 86
Table 17 
Volume of Blood to be Collected ............ ................................................................................. 86
Table 18 
Schedule of Pharmacokinetic and Antidrug Antibody Sampling............................................. 89
LIST OF FIGURES
Figure 1: 
Study Design .............................................................................................................................. 39
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
2.
INVESTIGATOR AGREEMENT
2.1 
Coordinating Investigator
A Randomised, Parallel, Double Blinded Study to Compare the Efficacy and Safety of 
FKB238 to Avastin® In 1st Line Treatment for Patients with Advanced/Recurrent Non-
Squamous Non-Small Cell Lung Cancer in Combination of Paclitaxel and Carboplatin
I understand that all information concerning FKB238 supplied to me by Centus 
Biotherapeutics Limited (hereafter referred to as Centus) and the Contract Research 
Organization, in connection with this study and not previously published is confidential 
and should not be disclosed, other than to those directly involved in the execution or 
ethical review of this study. This information includes the Investigator’s Brochure, 
protocol, case report forms, assay methods, technical methodology, and basic scientific 
data.
As the Coordinating Investigator I agree to act as a signatory to the Clinical Study Report 
(CSR) for the referenced clinical study, thereby acknowledging that to the best of my 
knowledge the CSR accurately describes the conduct and results of the study. In reporting 
the results of this multi-centre study, I am expressing an opinion on the safety and 
efficacy of the investigational medicinal product on behalf of all centres.
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
2.2 
Investigator Agreement
I understand that all information concerning FKB238 supplied to me by Centus and the 
Contract Research Organization, in connection with this study and not previously 
published is confidential and should not be disclosed, other than to those directly 
involved in the execution or ethical review of this study. This information includes the 
Investigator’s Brochure, protocol, case report forms, assay methods, technical 
methodology, and basic scientific data.
I agree to conduct this study according to this protocol and in keeping with the principles
of the Declaration of Helsinki, Good Clinical Practice, and the laws and regulations of the 
country where the study is to be conducted. I understand that any substantial changes to 
the protocol must be approved in writing by Centus, Regulatory Authorities, and the 
Institutional Review Board/Independent Ethics Committee before implementation as 
applicable, except where necessary to eliminate apparent immediate hazards to the 
patients.
I am aware of my responsibilities as a Principal Investigator as provided by the Sponsor 
and as described in the guidelines for Good Clinical Practice.
I confirm that I will report all adverse events following the regulations laid down in the 
protocol.
I agree to make available to Centus personnel, their representatives, and relevant 
regulatory authorities, my patients’ study records in order to verify the data that I have 
entered into the case report forms. I confirm that I am informed of the need for record 
retention and that no data can be destroyed without the written consent of Centus.
I understand that Centus may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the study, I will communicate 
my intention immediately in writing to Centus.
By my signature below, I hereby attest that I have read, understood, and agree to abide by 
all conditions, instructions, and restrictions contained in this version of the protocol.
Investigator’s Signature 
Date
Investigator’s Name (printed)
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
4.
ETHICAL AND REGULATORY REQUIREMENTS
4.1 
Ethical Conduct of the Study
The study will be performed in accordance with ethical principles that have their origin in 
the Declaration of Helsinki and are consistent with International Council for 
Harmonisation (ICH)/Good Clinical Practice (GCP), and applicable regulatory 
requirements.
4.2 
Patient Data Protection
The informed consent forms (ICFs) will incorporate (or, in some cases, be accompanied 
by a separate document incorporating) wording that complies with relevant data 
protection and privacy legislation. Pursuant to this wording, patients will authorise the 
collection, use and disclosure of their study data by the investigator and by those persons 
who need that information for the purposes of the study. The ICF will explain that study 
data will be stored in a computer database, maintaining confidentiality in accordance with 
national data legislation. All data computer processed by the Sponsor will be identified 
by an “individual treatment code” and study code. The Sponsor will not provide 
individual genotype results to patients, any insurance company, any employer, their 
family members, general physician or any other third party, unless required to do so by 
the law.
4.3 
Ethics and Regulatory Review
An Independent Ethics Committee (IEC) or Institutional Review Board (IRB) should 
approve the final study protocol, including the final version of the ICFs and any other 
written information and/or materials to be provided to the patients. The investigator or 
Contract Research Organization (CRO) will ensure the distribution of these documents to 
the applicable IEC/IRB, and to the study site staff. The opinion of the IEC/IRB should be 
given in writing. The investigator or CRO should submit the written approval to the
Sponsor before enrolment of any patient into the study. The IEC/IRB should approve all
advertising used to recruit patients for the study. The Sponsor should approve any 
modifications to the ICF that are needed to meet local requirements. If required by local 
regulations, the protocol should be re-approved by the IEC/IRB.
Before enrolment of any patient into the study, the final study protocol is approved by the 
national regulatory authority or a notification to the national regulatory authority is done, 
according to local regulations. The Sponsor or its representative will handle the 
distribution of any of these documents to the national regulatory authorities. The Sponsor 
or its representative will provide regulatory authorities, IECs/IRBs, and investigators with 
safety updates/reports according to local requirements, including suspected unexpected 
serious adverse reactions (SUSARs), where relevant.
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
4.4 
Informed Consent
The investigator at each centre will:
• 
Ensure each patient is given full and adequate oral and written information about
the nature, purpose, possible risk and benefit of the study
• 
Ensure each patient is notified that they are free to discontinue from the study at
any time
• 
Ensure that each patient is given the opportunity to ask questions and allowed
time to consider the information provided
• 
Ensure each patient provides signed and dated informed consent before
conducting any procedure specifically for the study, including the following: 
collection of study blood samples and biopsies, specifically to fulfil study 
inclusion requirements
• 
Ensure the original, signed ICF(s) is/are stored in the investigator's study file
• 
Ensure a copy of the signed ICF is given to the patient
• 
Ensure that any incentives for patients who participate in the study as well as any
provisions for patients harmed as a consequence of study participation are
described in the informed consent form that is approved by an IEC/IRB
4.5 
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the Coordinating 
Investigator and the Sponsor. If there are any substantial changes to the study protocol,
then these changes will be documented in a study protocol amendment and where
required in a new version of the study protocol (revised clinical study protocol). The 
amendment is to be approved by the relevant IEC/IRB and, if applicable, also the national 
regulatory authority before implementation. Local requirements are to be followed for 
revised protocols. The Sponsor or its representative will distribute any subsequent 
amendments and new versions of the protocol to each investigator. For distribution to 
IECs/IRBs see Section 4.3.
If a protocol amendment requires a change to a centre's ICF, the Sponsor (or its 
representative) and the centre's IEC/IRB are to approve the revised ICF before the revised 
form is used. If local regulations require, any administrative change will be 
communicated to or approved by each IEC/IRB.
4.6 
Audits and Inspections
Authorised representatives of the Sponsor, a regulatory authority, or an IEC/IRB may 
perform audits or inspections at the centre, including source data verification. The 
purpose of an audit or inspection is to systematically and independently examine all study
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
related activities and documents, to determine whether these activities were conducted, 
and data were recorded, analysed, and accurately reported according to the protocol, 
GCP, guidelines of the ICH, and any applicable regulatory requirements. The investigator 
will contact the Sponsor immediately if contacted by a regulatory agency about an 
inspection at the centre.
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
5.
INTRODUCTION
Bevacizumab is a recombinant humanised monoclonal antibody (mAb) expressed in 
Chinese Hamster Ovary (CHO) cells. Bevacizumab binds vascular endothelial growth 
factor (VEGF)-A and prevents the interaction of VEGF-A with its receptors, Fms-like 
tyrosine kinase-1 (Flt-1; vascular endothelial growth factor receptor-1 [VEGFR-1]) and 
kinase insert domain receptor (KDR; VEGFR-2), which are present in varying degrees on 
endothelial cells. VEGF-A is overexpressed in a variety of tumours and is known to be a 
cytokine involved in tumour growth. This is mediated by interaction of VEGF-A with its 
receptors (primarily KDR), which has been observed to cause endothelial cell 
proliferation and new blood vessel formation in in vitro models of angiogenesis, a key 
factor in the growth of many tumour types. Bevacizumab was first approved for the 
treatment of metastatic carcinoma of the colon or rectum (mCRC) in February 2004 in 
the United States (US) and in January 2005 in the European Union (EU), and was
subsequently launched globally under the brand name Avastin®. Avastin is currently
indicated for the treatment of mCRC and non-small cell lung cancer (NSCLC) in the EU, 
US, and Japan, ovarian cancer in the EU and Japan, metastatic renal cell cancer (mRCC) 
in the EU and US, metastatic breast cancer (mBC) in the EU and Japan, glioblastoma in 
the US and Japan, and persistent, recurrent, or metastatic carcinoma of the cervix in the 
US. Approved doses and treatment regimens are tumour- and region-specific and 
generally range between 5 and 15 mg/kg. Avastin is a solution for intravenous (IV) 
infusion and is presented as 100 mg in a 4 mL or 400 mg in a 16 mL vial.1
FKB238 is being developed as a proposed biosimilar biological product to Avastin. 
FKB238 is a recombinant humanised mAb expressed in the CHO cell line. The similarity 
between FKB238 and Avastin has been assessed in a range of initial characterisation 
studies and no significant differences have been observed. In addition, preliminary 
nonclinical studies demonstrate similarity between FKB238 and EU-Avastin in terms of 
pharmacological activity.
5.1 
Summary of Nonclinical and Clinical Studies
5.1.1 Nonclinical Studies
With respect to nonclinical development, the EU and US guidance documents 
recommend a risk-based approach to evaluation of biosimilar mAbs and in determining 
the choice and extent of in vitro and in vivo studies to be conducted.
Fujifilm Kyowa Kirin Biologics Co., Ltd. has conducted in vitro and in vivo studies to 
evaluate the following:
• 
Binding to the target antigen
• 
Binding to the Fc receptors and FcRn
• 
Fab-associated functions (neutralisation activity)
• 
Fc-associated functions (binding to C1q)
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
• 
Pharmacological effects on xenograft model mice
• 
Single dose pharmacokinetic (PK) study in rats
• 
2-week repeated dose toxicology study in rats
In vitro studies have shown that FKB238 and Avastin are similar in terms of binding to 
the target antigen (recombinant human VEGF isoforms), binding to Fc receptors and 
FcRn, neutralisation of VEGF mediated activities, and binding to C1q. An in vivo study 
using a severe combined immunodeficient mouse model bearing human colorectal 
adenocarcinoma DLD-1 cells showed that the mean increase in tumour volume observed 
for the study was suppressed to a similar extent by FKB238 and Avastin. A PK study in 
Crl:CD(SD) rats revealed that the PK concentration-time curves for FKB238 and Avastin 
were similar. A Good Laboratory Practice-compliant, repeat-dose, nonspecific toxicity 
study in 20 Crl:CD(SD) rats was conducted to evaluate the toxicity of FKB238 15 mg/kg 
or 75 mg/kg when repeatedly administered by IV twice weekly for 2 weeks. No animals 
died or were euthanized due to moribundity in the FKB238 group. No toxic changes were 
observed in clinical signs, body weight, food consumption, water consumption, 
ophthalmology, urinalysis, haematology, blood chemistry, bone marrow examination, 
organ weights, gross pathology, and histopathology in the FKB238 group. Toxicokinetics 
showed no differences in systemic exposure between male and female groups. It was 
concluded from these results that under the conditions of this study, there were no 
toxicities seen with the FKB238 treatments.
Additional details on nonclinical studies can be found in the FKB238 Investigator’s 
Brochure.1
5.1.2 Clinical Studies
Avastin has been studied in over 5200 patients with various malignancies, predominantly 
treated with Avastin in combination with chemotherapy in clinical trials. The most 
frequently observed adverse reactions across clinical trials in patients receiving Avastin, 
according to the Summary of Product Characteristics (SmPC), were hypertension, fatigue 
or asthenia, diarrhoea, and abdominal pain. The occurrence of hypertension and 
proteinuria with Avastin therapy appears to be dose-dependent. According to the Avastin 
US Product Label, the most common adverse reactions (> 10% and at least twice the 
control arm rate) were epistaxis, headache, hypertension, rhinitis, proteinuria, taste 
alteration, dry skin, rectal haemorrhage, lacrimation disorder, back pain, and exfoliative 
dermatitis.
The first human study of FKB238, a randomised, double-blind, active-control study to 
compare the safety and PK of FKB238 and Avastin after single doses, by IV infusion, in 
healthy male volunteers has completed study enrolment in March 2015. Initially, a total 
of 120 healthy male subjects were expected to be enrolled in the study. But after a
pre-planned interim analysis conducted at the time when PK data from 46 subjects
became available, study enrolment was terminated following the pre-specified criteria. As 
a result, a total of 99 subjects were randomly assigned to receive a single 5 mg/kg IV
Protocol V5.0 (22 May 2018) 
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
infusion of EU-approved Avastin (EU-Avastin), US-licensed Avastin (US-Avastin), or 
FKB238, in a 1:1:1 ratio. Similarity between FKB238 and EU-Avastin, FKB238 and US-
Avastin, EU-Avastin and US-Avastin was all confirmed in all 2 primary PK 
parameters analysed (AUC0-, AUC0-t). Two secondary PK parameters (Cmax and t1/2)
also met pre-specified equivalence criteria. A summary of similarity analysis is shown in
Table 1 and Table 2.
Table 1 
Summary of Similarity Analysis of Primary Endpoints
1 Similarity is achieved if the 90% CI falls within pre-specified acceptance range (0.80, 1.25)
Table 2 
Summary of Similarity Analysis of Secondary Endpoints
1 Similarity is achieved if the 90% CI falls within pre-specified acceptance range (0.80, 1.25)
There were no deaths nor serious adverse events (SAEs) observed in the PK comparison 
study. Numerically, a greater percentage of subjects on FKB238 arm had treatment-
emergent adverse events (TEAEs) when compared to either EU-Avastin or
US-Avastin (97%, 76%, 72% respectively). Similarly, treatment-emergent adverse drug
reactions were experienced by a greater numerical percentage of subjects receiving 
FKB238 compared to either EU-Avastin or US-Avastin (45%, 32%, 38%, respectively).
Protocol V5.0 (22 May 2018) 
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CONFIDENTIAL
Geometric Least Square (LS) Mean 1
FKB238
EU-Avastin
US-Avastin
AUC0-(h*µg/mL)
52,300
49,400
53,500
AUC0-t (h*µg/mL)
50,800
49,300
51,800
Ratio of Geometric LS Means (90% Confidence Interval [CI])
FKB238 / EU-
Avastin
FKB238 / US-
Avastin
EU-Avastin /
US-Avastin
AUC0-(h*µg/mL)
1.06 (0.99, 1.13)
0.98 (0.92, 1.04)
0.92 (0.87, 0.98)
AUC0-t (h*µg/mL)
1.03 (0.97, 1.09)
0.98 (0.93, 1.04)
0.95 (0.90, 1.01)
Geometric Least Square (LS) Mean 1
FKB238
EU-Avastin
US-Avastin
Cmax (µg/mL)
139
142
138
t1/2 (h)
439
412
463
Ratio of Geometric LS Means (90% Confidence Interval [CI])
FKB238 /
EU-Avastin
FKB238 /
US-Avastin
EU-Avastin /
US-Avastin
Cmax (µg/mL)
0.97 (0.91, 1.04)
1.01 (0.94, 1.07)
1.03 (0.97, 1.10)
t1/2 (h)
1.06 (0.98, 1.16)
0.95 (0.87, 1.03)
0.89 (0.82, 0.97)


Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
All the observed treatment-emergent adverse drug reactions were mild or moderate. A 
single subject had a TEAE which was a grade 3 or above (grade 3 tooth infection) but 
causality to study drug was assessed as not related. The most common adverse event 
(AE) was headache, experienced in 48.5% of the subjects who received FKB238. 
Similarly the most common adverse drug reaction was headache.
Four out of overall 99 enrolled subjects were positive for antidrug antibody (ADA). ADA 
positive subjects were equally distributed in 3 arms (1 in FKB238 arm, 2 in EU-Avastin 
arm, and 1 in US-Avastin arm).
Additional details on clinical studies can be found in the FKB238 Investigator’s 
Brochure.1
5.2 
Potential Risks and Benefits
5.2.1 Established Safety Profile for Avastin
The safety and immunogenicity data for Avastin are mostly from clinical studies and 
postmarketing experience in patients with cancers such as mCRC, NS-NSCLC, mBC, 
glioblastoma, or mRCC, treated at the recommended dose and schedule for a median of 
8 to 23 doses of Avastin. Many of the adverse effects observed are considered to be 
influenced by the underlying disease state of the patients; eg, as described in the SmPC 
for Avastin, in clinical studies, the incidence of gastrointestinal perforation/fistula in each 
cancer type was different, suggesting that these events are related to underlying disease 
related conditions such as tumour necrosis, chemotherapy related colitis, bowel surgery, 
and peritoneal metastasis. Also, as SmPC suggested, haemorrhagic reactions observed in 
clinical studies of Avastin were predominantly tumour-associated haemorrhage and 
minor mucocutaneous haemorrhage (eg, epistaxis).
While bevacizumab is not a cytotoxic agent, its use is associated with a number of 
mechanism based AEs. Gastrointestinal perforations, haemorrhage, and arterial 
thromboembolism are specified as the most serious adverse reactions of the drug. In 
addition, fistulas, wound-healing complications, hypertension, congestive heart failure,
posterior 
reversible 
encephalopathy 
syndrome, 
proteinuria, 
hypersensitivity
reactions/infusion reactions, and laboratory test abnormalities are also listed as serious 
adverse reactions. Of these, as described in the SmPC for Avastin, hypertension and 
proteinuria have been noted to be likely dose-dependent.
5.2.1 Potential Safety Profile for FKB238
From the first in human clinical study of FKB238, no SAEs were observed. All the 
observed treatment-emergent adverse drug reactions were mild or moderate. FKB238 is 
intended to be developed as a biosimilar product to bevacizumab. Data obtained during a 
range of initial characterisation and nonclinical studies with FKB238 to date do not 
indicate an additional potential impact on patient safety. Therefore, it could be expected 
that similar class effects and a safety profile to Avastin (bevacizumab) will be observed. 
However, due to the very limited patient exposure to FKB238, it should be noted that 
unexpected safety issues may arise during clinical development.
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
Additional details are available in the Investigator’s Brochure.1
5.3 
Study Rationale
The FKB238-002 study is designed to confirm equivalence of efficacy for FKB238 and
EU-Avastin.
The current European Medicines Agency (EMA) “Guideline on similar biological 
medicinal products containing biotechnology-derived proteins as active substance: 
nonclinical and clinical issues (EMEA/CHMP/BMWP/42832/2005 Rev1)” describes that 
“in the absence of surrogate markers for efficacy, it is usually necessary to demonstrate
comparable clinical efficacy of the biosimilar and the reference medicinal product in
adequately powered, randomised, parallel group comparative clinical trial(s), preferably 
double-blind, by using efficacy endpoints.” Due to the lack of a validated surrogate 
serum biomarker for the evaluation of efficacy of bevacizumab in any indications 
approved, the current study will directly compare the efficacy of FKB238 to EU-Avastin.
Choice of Patient Population
The development program for FKB238 is designed to obtain the data necessary to 
support the approval of FKB238 as a biosimilar to Avastin in the EU, US, and Japan. 
Among the approved indications of Avastin, NSCLC and mCRC are the only 2 that are 
common to all 3 regions. On this basis, patients with these conditions were considered to 
represent the most appropriate populations for inclusion in this study.
In the scientific literature, there are 2 randomised Phase 3 studies of Avastin in 
combination with chemotherapy that have been conducted in 1st line NS-NSCLC and 
2 Phase 3 studies in 1st line mCRC (Table 3). In each of the 2 randomised studies in 
1st line NS-NSCLC, there was a statistically significant treatment benefit of Avastin as 
assessed by overall response rate (ORR) and progression-free survival (PFS).2,3,4 In 1 of 
the 2 studies in 1st line mCRC, a statistically significant treatment effect was also noted in 
both ORR and PFS,5 while in the other, the effect was only observed in relation to PFS.6 
A statistically significant overall survival (OS) benefit was observed in 1 of 2 studies 
conducted in each population. Thus, based on the available data, while Avastin was 
clearly effective in both cancer types, the efficacy was more consistently observed across 
the study endpoints in patients with NS-NSCLC. Therefore, NS-NSCLC was considered 
as the most sensitive population to assess clinical efficacy of bevacizumab. During the 
health authority meetings with FDA and EMA, both agencies agreed that the proposed
patient population is considered to be most sensitive for the proposed study.
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
Table 3 
Phase 3 Results of Avastin in 1st Line NS-NSCLC and 1st Line mCRC
Abbreviations:  NS-NSCLC = non-squamous non-small cell lung cancer; mCRC = metastatic colorectal 
cancer; ORR = overall response rate; PFS = progression-free survival; OS = overall survival; CBDCA = 
carboplatin; CDDP = cisplatin; GEM = gemcitabine; FOLFOX = fluorouracil + leucovorin + oxaliplatin; 
IFL = irinotecan + fluorouracil + leucovorin; PTX = paclitaxel; XELOX = capecitabine + oxaliplatin.
Choice of Dose Regime
Patients will receive either FKB238 or EU-Avastin 15 mg/kg every 3 weeks 
(investigational products [IPs]) in combination with paclitaxel and carboplatin 
(combination drugs) in line with the approved regiment for Avastin outlined in the 
Package Insert and the SmPC.
Choice of Primary Endpoint
Among the conventional clinical efficacy endpoints in oncology studies, ORR is 
considered as the most sensitive parameter for evaluation of the similarity of efficacy of 
FKB238 versus EU-Avastin. In the draft FDA guidance “Scientific Considerations in 
Demonstrating Biosimilarity to a Reference Product February 2012,” the FDA 
recommends that a Sponsor use endpoints that are clinically relevant and sufficiently 
sensitive to detect clinically meaningful differences in safety and effectiveness between 
the proposed product and the reference product. In addition, the draft guidance states that 
a Sponsor can use endpoints that are different from those used in the pivotal trial for the 
reference product. A similar position was given in the “EMA Guideline on similar 
biological medicinal products containing monoclonal antibodies - nonclinical and clinical 
issues (EMA/CHMP/BMWP/403543/2010).” This guideline suggests that conventional 
clinical efficacy endpoints other than ORR, such as PFS and OS, may not be feasible or 
sensitive enough for establishing similarity of an anti-cancer biosimilar mAb to a 
reference mAb. This perspective comes from one of the core concepts of biosimilarity 
which is that the focus of the similarity exercise is to demonstrate similar efficacy and 
safety and not patient benefit per se. In fact, PFS and OS will be influenced by factors not 
attributable to efficacy differences between the products, but by factors such as tumour
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Study
Target
Treatment Arm
N
ORR
(%)
PFS
(months)
OS
(months)
Sandler et al.,
20062
1st line
NS-
NSCLC
PTX + CBDCA
433
15
4.5
10.3
PTX + CBDCA +
Avastin 15 mg/kg
417
35
(p<0.001)
6.2
(p<0.001)
12.3
(p=0.003)
Reck et al.,
2009,3
Reck et al.,
20104
1st line
NS-
NSCLC
GEM + CDDP
347
21.6
6.1
13.1
GEM + CDDP +
Avastin 7.5 mg/kg
345
37.8
(p=0.0001)
6.7
(p=0.003)
13.6
(p=0.42)
GEM + CDDP +
Avastin 15 mg/kg
351
34.6
(p=0.0002)
6.5
(p=0.03)
13.4
(p=0.76)
Hurwitz et al.,
20045
1st line
mCRC
IFL
411
34.8
6.2
15.6
IFL + Avastin
402
44.8
(p=0.004)
10.6
(p<0.001)
20.3
(p<0.001)
Saltz et al.,
20086
1st line
mCRC
FOLFOX4/XELOX
701
38
8
19.9
FOLFOX4/XELOX +
Avastin
699
38
(p=0.99)
9.4
(p=0.0023)
21.3
(p=0.77)


Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
burden, performance status, previous lines of treatment, underlying clinical conditions, 
and subsequent lines of treatment (for OS). Given the above considerations, ORR was 
considered as the most appropriate primary endpoint for this efficacy equivalence study. 
However, ORR at week 19, PFS, OS, DOR, and DCR data representing patient benefit 
will also be collected and evaluated as secondary endpoints.
The results of this efficacy equivalence study, together with completed PK comparison 
study, will fully support the global biosimilar product applications and that the planned 
trials are consistent with the US biosimilar guidance as well as EU guidelines for 
biosimilars.
Choice of PK Endpoint
Sparse PK sampling (8 samples per subject) will be gathered during the study. A single 
dose PK study in healthy subjects has already established the PK similarity of FKB238 
and EU-Avastin. The sparse sampling in this study will further help evaluate the multiple 
dose PK comparison of the two compounds in the target patient population. Samples will 
also be drawn for ADA assessment of the two compounds.
6.
STUDY OBJECTIVES
6.1 
Primary Objective
The primary objective of this study is:
• 
To demonstrate the efficacy equivalence of FKB238 and EU-Avastin when used
in combination with paclitaxel/carboplatin as measured by ORR
6.2 
Secondary Objectives
Secondary objectives of this study are:
• 
To compare FKB238 and EU-Avastin through:
o ORR at week 19
o PFS
o OS
o Duration of response (DOR)
o Disease control rate (DCR)
• 
To compare the safety of FKB238 and EU-Avastin
• 
To compare the ADAs produced by FKB238 and EU-Avastin
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
• 
To compare the serum trough concentration (Ctrough) of FKB238 and EU-Avastin
6.3 
Study Endpoints
The primary endpoint is:
• 
ORR (by Response Evaluation Criteria [RECIST] v1.1) assessed as the rate of the
best response (complete response [CR] or partial response [PR])
The secondary efficacy endpoints are:
• 
ORR (by RECIST v1.1) at week 19, defined as the rate of the best response of CR
or PR assessed at week 19
• 
PFS, defined as the time from randomisation to the first documented disease
progression (PD) or death, whichever occurs first
• 
OS, defined as the time from randomisation to death from any cause
• 
DOR, defined as the time from the first documented PR or CR (by RECIST v1.1)
to the first documented objective PD or death, whichever occurs first
• 
DCR, defined as the rate of CR, PR, SD ( 6 weeks)
Other endpoints are:
• 
Safety as evaluated through AEs, vital signs, haematology, clinical chemistry,
urinalysis, electrocardiogram (ECG), Eastern Collaborative Oncology Group
Performance Status (ECOG PS), and physical examination
• 
Immunogenicity (presence of ADAs)
• 
Pharmacokinetics (Ctrough)
7.
INVESTIGATION PLAN
7.1 
Overall Study Design and Plan Description
This is a global multi-centre, double-blind, parallel comparative, Phase 3 study designed 
to compare the efficacy and safety of FKB238 and EU-Avastin when used in
combination with paclitaxel and carboplatin in the 1st line treatment of advanced or
recurrent NS-NSCLC.
Patients aged 18 years or older who have advanced or recurrent NS-NSCLC will be 
screened for participation up to 28 days before randomisation. Approximately 
730 eligible patients will be randomly assigned in a 1:1 ratio to 1 of 2 treatment groups. 
Randomisation will be stratified according to epidermal growth factor receptor (EGFR) 
mutation and anaplastic lymphoma receptor tyrosine kinase (ALK) gene arrangement
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
status (both are tested and known negative versus status unknown for either), 
geographical region, prior weight loss over the previous 6 months (< 5% yes versus no), 
and disease stage (advanced or recurrent). The following treatment groups will be 
included in this study:
• 
FKB238 group: paclitaxel + carboplatin (combination drugs) + FKB238 (IP)
• 
Avastin group: paclitaxel + carboplatin (combination drugs) + EU-Avastin (IP)
Upon randomisation, patients will enter the Study Treatment Period. Following start of 
study treatment, patients will attend for study visits every 3 weeks as long as they are 
receiving study treatment. The combination drugs (paclitaxel + carboplatin) will be 
administered on Day 1 of each 21-day cycle for at least 4, and no more than 6 cycles. The 
number of cycles is determined by patients’ need and the investigator’s assessment. 
FKB238 or EU-Avastin (IP) will also be administrated on Day 1 of each 21-day cycle 
until objective PD or other criteria for treatment discontinuation are met.
Radiological assessment using RECIST v1.1 will be performed at screening until PD and 
every 6 weeks (± 1 week) for 24 weeks, then every 9 weeks (± 1 week) for the treatment 
period up to data cut-off, and then every 12 weeks (± 1 week) after the completion of 
study treatment up to data cut-off. Following data cut-off, study-specific radiological 
assessments will not be performed for patients in the Extended Treatment Period. The 
investigator may elect to perform radiological assessments according to locally defined 
standard of care practices. However, no efficacy data will be collected by the sponsor 
during the Extended Treatment Period.
Patients who develop toxicity may delay study treatment for up to 3 weeks. In most 
cases, patients who require the combination drugs and/or IP to be held for more than 3 
weeks will discontinue the study treatment. In some cases, should re-start of the study 
treatment after a delay of more than 3 weeks be required, a discussion should occur 
between the medical monitor and the investigator. All such decisions need to be 
appropriately documented. Patients who discontinue IP treatment for reasons other than 
PD will continue to undergo RECIST v1.1 tumour assessments until PD, until death, or 
until data cut-off (whichever occurs first).
After the discontinuation of the study treatment, further care and treatment will be at the 
discretion of the investigator. Any systemic anti-cancer treatment, radiotherapy or cancer 
surgery conducted after discontinuation of study treatment will be collected until death, 
loss to follow-up, withdrawal of consent or until end of study. Assessments for survival 
should be made every 8 weeks (± 1 week) following objective PD until data cut-off.
At data cut-off, all patients previously discontinued from study treatment and continuing 
in follow-up will complete the study and no further study assessments will be performed.
The end of the study is defined as the last patient last visit. The endpoint analyses occur 
after data cut-off, which is a minimum of 12 months after randomisation of the last 
patient enrolled. The Extended Treatment Period is the time after data cut-off to end of
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
study in which patients may continue receiving IP if they are considered to be gaining 
clinical benefit. These patients may receive treatment until withdrawal, PD, or death. See 
Section 7.7.5 for information regarding patient management and reporting after data cut- 
off.
Prior to data cut-off, AEs will be collected from time of signature of informed consent, 
throughout the treatment period and up to and including 30 calendar days after the last 
study treatment. All ongoing and any new AEs/SAEs identified at data cut-off and during 
the 30 calendar days after last dose of study treatment must be followed to resolution 
unless the event is considered by the investigator to be unlikely to resolve, or the patient 
is lost to follow-up.
The Schedule of Assessments prior to Data Cut-Off (Table 13) indicates the timing of the 
planned visits including visit window for the study visits. The investigator/sub- 
investigator should adhere to the Schedule of Assessment procedures and perform
tests/observations according to the protocol. Assessments after start of Study Treatment
should be performed within a window of ± 3 days of the scheduled visit date. Computed 
tomography (CT) or magnetic resonance imaging (MRI) assessments should be done 
within a window of ± 7 days of the scheduled date according to the RECIST v1.1 criteria, 
but every effort should be made to adhere as closely as possible to the original schedule 
of scans.
Baseline RECIST v1.1 assessment will be performed using CT (or MRI scans where CT 
is clinically contra-indicated) at screening no more than 28 days prior to start of study 
treatment (Cycle 1 Day 1) and ideally should be performed as close as possible to the 
start of the study treatment. Baseline radiological assessments should cover the chest and 
the upper abdomen (including liver and the adrenal glands). Brain CT/MRI is required 
within 4 weeks prior to randomization. Any other areas of the disease involvement should 
be additionally investigated based on signs and symptoms of individual patients.
After start of study treatment, RECIST v1.1 assessment using CT (or MRI scans where 
CT is clinically contra-indicated) will be performed every 6 weeks (± 1 week) for 
24 weeks, then every 9 weeks (± 1 week) for the remainder of the treatment period, until 
objective PD or data cut-off. The methods of assessment of tumour burden used at 
baseline CT or MRI scans of chest and upper abdomen (including liver and adrenal 
glands) must be used at each subsequent follow-up assessment. Any other sites at which 
new disease is suspected should also be appropriately imaged. If an unscheduled 
assessment was performed and the patient has not progressed, every attempt should be 
made to perform the subsequent assessments at their scheduled visits.
No further radiological tumour assessments will be done after objective PD is 
documented. Patients who discontinue study treatment for reasons other than PD will 
continue to undergo RECIST v1.1 tumour assessments every 12 weeks (± 1 week) until 
PD, death or the data cut-off (whichever occurs first).
Every effort should be made to adhere to the original schedule of RECIST v1.1 scans.
Protocol V5.0 (22 May 2018) 
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
Figure 1 presents a graphic description of the study design.
Protocol V5.0 (22 May 2018) 
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
1st line
non-squamous 
NSCLC
• 
Measurable 
• 
PS 0-1
FKB238 15 mg/kg every 
3 weeks + PTX/CBDCA 
(4-6 cycles)
Avastin 15 mg/kg every 
3 weeks + PTX/CBDCA 
(4-6 cycles)
Until
progression 
or death (or 
other 
discontinuat 
ion criteria 
are met)
Overall
Survival
Follow
up until
DCO
Extended 
Treatment 
Period
Post DCO
Abbreviations: CBDCA=carboplatin; NSCLC=non-small cell lung cancer; PS=performance status; 
PTX=paclitaxel; DCO=data cut-off.
Figure 1: 
Study Design
7.2 
Discussion of Study Design, Including the Choice of Control Groups
FKB238 is a recombinant humanised mAb expressed in CHO cell line to be developed as 
a proposed biosimilar product to the Avastin (bevacizumab) product currently marketed 
and available to the public in the EU, US, and Japan. This efficacy equivalence study is 
designed to compare the efficacy and safety of FKB238 to EU-Avastin. Similarity 
between FKB238 and EU-Avastin, FKB238 and US-Avastin, EU-Avastin and US-
Avastin were all confirmed in all 2 primary PK parameters analysed (AUC0-,
AUC0-t) in the first human study of FKB238, a randomised, double-blind, parallel study
to compare PK and safety of FKB238 and Avastin after single dose IV infusion, in
healthy male volunteers. Two secondary PK parameters (Cmax and t1/2) also met pre-
specified equivalence criteria. As such, EU-Avastin has been selected as the active 
comparator in a randomised, double-blind study.
Paclitaxel and carboplatin were selected as the concomitant chemotherapy for both 
treatment groups as a widely accepted and approved standard regimen, where the efficacy 
and drug-drug interaction of these chemotherapy agents with Avastin have been well 
established.
Efficacy equivalence will be evaluated based on ORR. In the draft FDA guidance 
“Scientific Considerations in Demonstrating Biosimilarity to a Reference Product 
February 2012,” the FDA recommends that a Sponsor use endpoints that are clinically 
relevant and sufficiently sensitive to detect clinically meaningful differences in safety and 
effectiveness between the proposed product and the reference product. In addition, the 
draft guidance states that a Sponsor can use endpoints that are different from those used 
in the pivotal trial for the reference product. A similar position was given in the “EMA 
Guideline 
on 
similar 
biological 
medicinal 
products 
containing 
monoclonal 
antibodies - nonclinical and clinical issues (EMA/CHMP/BMWP/403543/2010).” This 
guideline suggests that conventional clinical efficacy endpoints other than ORR, such as 
PFS and OS, may not be feasible or sensitive enough for establishing similarity of an anti-
cancer biosimilar mAb to a reference mAb. This perspective comes from one of the core 
concepts of biosimilarity which is that the focus of the similarity exercise is to
Protocol V5.0 (22 May 2018) 
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
demonstrate similar efficacy and safety and not patient benefit per se. PFS and OS will be 
influenced by factors not attributable to efficacy differences between the products, but by 
factors such as tumour burden, performance status, previous lines of treatment, 
underlying clinical conditions, and subsequent lines of treatment (for OS). Given the 
above considerations and further discussions with health authorities, ORR was 
considered and agreed to be the most appropriate primary endpoint for this study.
Safety will be compared based on the frequency/severity of all AEs, clinical laboratory 
assessments, ECG, ECOG PS, and physical examination results. Immunogenicity will be 
determined by the presence of ADAs.
7.3 
Selection of Study Population
7.3.1 Inclusion Criteria
To be eligible to participate in the study, patients must meet all of the following criteria:
1. Patients aged 18 years or older
2. Newly diagnosed advanced (stage IV) /recurrent NS-NSCLC for which they had not 
received any systemic anti-cancer therapy for metastatic disease, including 
chemotherapy, biologic therapy, immunotherapy, or any investigational drug
3. Histologically or cytologically confirmed diagnosis of predominantly NS-NSCLC
4. Be eligible to receive study treatment of bevacizumab, paclitaxel, and carboplatin for 
the treatment of advanced or recurrent NS-NSCLC
5. Existence of at least 1 measurable lesion by response evaluation criteria 
(RECIST v1.1; APPENDIX C) defined as; at least one lesion, not previously 
irradiated, that can be accurately measured at baseline as  10 mm in the longest
diameter (except lymph nodes which must have short axis  15 mm) with computed
tomography (CT) or magnetic resonance imaging (MRI) which is suitable for 
accurate repeated measurements. For additional information, refer to Section 7.8.1.3.
6. ECOG PS 0 or 1 (APPENDIX B – Eastern Collective Oncology Group Performance 
Status)
7. Life expectancy longer than 6 months
8. Adequate haematological function: absolute neutrophil count (ANC)  1.5 × 109/L; 
platelets  100 × 109/L; haemoglobin  9 g/dL
9. International normalised ratio (INR)  1.5 and partial thromboplastin time (PTT) 
 1.5 × the upper limit of normal (ULN) within 7 days prior to starting study 
treatment
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
10. Adequate liver function: Serum bilirubin  1.5 × ULN (and in case of documented
Gilbert’s Syndrome [unconjugated hyperbilirubinaemia]  3 x ULN); transaminases 
 2.5 × ULN (and in case of liver metastases < 5 × ULN)
11. Adequate renal function:
a.
Creatinine clearance, measured and/or calculated according to the formula 
of Cockroft and Gault  60 mL/min AND
b. Urine dipstick or urinalysis for proteinuria < 2+. If the urine dipstick or 
urinalysis is  2+, 24-hour urine must demonstrate  1 g of protein in 24 
hours.
12. Negative serum/urine pregnancy test within 7 days of starting study treatment in
premenopausal women and women < 2 years after the onset of menopause
13. Signed informed consent
14. Able to comply with the protocol
7.3.2 Exclusion Criteria
Patients who meet any of the following criteria will not be eligible to participate in the 
study:
1. Small cell lung cancer (SCLC) or combination SCLC and NSCLC. Squamous-cell 
tumours and mixed adenosquamous carcinomas of predominantly squamous nature
2. Recurrence occurred within 12 months from the last dose of neoadjuvant/adjuvant 
therapy
3. Any unresolved toxicities from prior systemic therapy (eg, adjuvant chemotherapy) 
greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at 
the time of starting study drug with the exception of alopecia
4. Evidence of a tumour that compresses or invades major blood vessels or tumour 
cavitation that in the opinion of the investigator is likely to bleed
5. Known sensitising EGFR mutations (eg, deletion 19 or L858R) or EML4-ALK 
translocation positive mutations
6. Previous dosing with VEGF inhibitor
7. Brain metastasis or spinal cord compression (computed tomography [CT] or magnetic 
resonance imaging [MRI] of the head is required within 4 weeks prior to 
randomisation)
8. Malignancy other than NS-NSCLC within 5 years before randomisation, except for
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, 
localised prostate cancer treated surgically with curative intent, or ductal carcinoma in 
situ of the breast treated surgically with curative intent
9. Known hypersensitivity to active ingredients or any excipients of the IPs 
(APPENDIX D – Excipients of the IPs) and combination chemotherapy
10. Use of aspirin (> 325 mg/day) or treatment with dipyridamole, ticlopidine,
clopidogrel, prasugrel, or cilostazol within 14 days before the first dose of IP
11. Use of full-dose oral or parenteral anticoagulants or thrombolytic agents within 
6 months before the first dose of IP (use of low dose anticoagulants for venous access
device maintenance or prophylactic use of anticoagulants will be allowed)
12. Known Hepatitis B, Hepatitis C, or human immunodeficiency virus (HIV) infection
13. Major surgery, significant traumatic injury, or radiotherapy (except for palliative 
intention which requires 14 days wash out period for bone lesions outside the thoracic 
region) within 28 days before the first dose of IP or anticipation of the need for major
surgery during study treatment
14. Fine needle aspirations, indwelling catheter placement, or core biopsy within 7 days
of randomisation
15. Non-healing wound, ulcer, or bone fracture
16. Uncontrolled hypertension or systolic blood pressure > 140 mmHg or diastolic blood
pressure > 90 mmHg
17. Patients with unstable angina, myocardial infarction, coronary artery bypass graft, 
angioplasty, vascular stenting, or cardiovascular event within 6 months before the 
first dose of IP; coagulopathy, any bleeding disorders, poorly controlled diabetes, or 
active gastrointestinal inflammation such as gastric or duodenal ulcer, diverticulitis,
inflammatory bowel disease, or cholecystitis
18. History of fistulas or abdominal perforations
19. History of arterial or venous thromboembolic or ischemic events, or congestive heart 
failure (New York Heart Association class  2) within 6 months before the first dose
of IP
20. History of haemoptysis of  ½ teaspoon of red blood within 28 days before the first
dose of IP
21. Fertile men or women of childbearing potential not using adequate contraception. 
Patients of child bearing potential and their partners, who are sexually active, must 
agree to the use of at least one highly effective form of contraception throughout their
participation in the study and for 6 months after last dose of study treatment
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
22. Breastfeeding women (unless the patient is willing to discontinue breastfeeding 
throughout their participation in the study and for 6 months after last dose of study
treatment)
23. Treatment with any other investigational agent for any reason within 28 days before
the first dose of IP
24. Presence of any other disease, metabolic dysfunction, physical examination finding, 
or laboratory finding that, in the opinion of the investigator, puts the patient at high
risk for treatment-related complications in this study
7.4 
Patient Enrolment
Investigators should keep a record, the patient screening log, of patients who entered
pre-study screening. The investigators will:
1.
Obtain signed informed consent from the potential patient before any study
specific procedures are performed
2.
Assign potential patient a unique 7-digit enrolment number obtained through the
interactive voice response system (IVRS) in the following format ECCNNXXX: 
CC being the country code, NN being the centre number and XXX being the 
patient enrolment code at the centre
3.
Determine patient eligibility (see Section 7.3)
At Cycle 1 Day 1, once the patient is confirmed to be eligible, the investigator or suitably 
trained delegate will:
4.
Perform a drug dispensing call in IVRS
If a patient withdraws from participation in the study, then his/her enrolment code cannot 
be reused.
7.4.1 Procedures for Handling Patients Incorrectly Enrolled or Initiated on Study
Treatment
Patients who fail to meet the inclusion/exclusion criteria should not, under any 
circumstances, be enrolled in this clinical study. There can be no exceptions to this rule. 
Patients who are enrolled, but subsequently found not to meet all the eligibility criteria 
must not be initiated on treatment, and must be withdrawn from the study.
Where patients who do not meet the selection criteria are started on treatment in error, the
investigator should inform the medical monitor immediately, and a discussion should 
occur between the medical monitor and the investigator regarding whether to continue or 
discontinue the patient from treatment. The medical monitor is to ensure that all such 
decisions are appropriately documented.
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
7.4.2 Discontinuation of Study Treatment
Patients may voluntarily withdraw from study treatment at any time and for any reason. 
At the time of withdrawal from study treatment, patients will be asked to provide a 
primary reason for discontinuation. Reasons for withdrawal from study treatment may 
include:
• 
Objective PD assessed by RECIST v1.1
• 
Intolerable AE
• 
Unable to initiate a new cycle of study treatment with a delay of more than
3 weeks. Should re-start of the study treatment after a delay of more than 3 weeks
be required, a discussion should occur between the medical monitor and the 
investigator. All such decisions are to be appropriately documented.
• 
Pregnancy
• 
Use of illicit drugs or other substances that may, in the opinion of the investigator,
have a reasonable chance of contributing to toxicity or otherwise skewing the
study data
• 
Development of an intercurrent illness or situation which would, in the opinion of
the investigator, affect assessments of clinical status and study endpoints to a
significant degree
• 
The patient is unwilling or unable to adhere to the protocol
• 
Patient withdrawal of consent
• 
Patient is lost to follow-up. A patient should be considered lost to follow-up only
after multiple efforts have been made to contact the patient to assess his/her health
status. If after 2 documented phone calls the study site is still unable to contact the 
patient, a certified letter should be sent to his/her home for immediate response. If 
there is still no response, the patient is to be considered lost to follow-up. A 
record of the patient being lost to follow-up should be noted in the source 
documents along with the phone contacts and the returned certified mail (if sent 
back)
• 
Investigator discretion
• 
Sponsor terminates the study
Withdrawal from study treatment does not constitute withdrawal from study. All patients 
who discontinue study treatment prior to data cut-off, regardless of reason for 
discontinuation, should complete the study treatment discontinuation visit and should be 
encouraged to remain on the study for follow-up of primary and secondary endpoints,
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Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
according to Table 13. In all cases, the reason for withdrawal from the study treatment 
must be recorded in the eCRF and in the patient's medical records. After data cut-off, 
once the patient withdraws from treatment, they will also withdraw from the study and 
the investigator will be required to submit a paper Subject Disposition Form to Sponsor 
confirming patient withdrawal, PD or death.
7.4.3 Replacement of Patients
Patients who withdraw from the study will not be replaced.
7.4.4 Follow-up of Patients Discontinued from the Study Treatment Regimen
A patient who decides to discontinue study treatment will always be asked about the 
reason(s) and the presence of any AEs. If possible, the patient will be seen and assessed 
by the investigator.
Following discontinuation of study treatment, patients may receive any subsequent 
therapy for NS-NSCLC at the discretion of the investigator. After discontinuation of 
study treatment, all systemic anti-cancer treatment, radiotherapy or cancer surgery will be 
collected until death, loss to follow-up, withdrawal of consent or until the data cut-off 
(whichever occurs first).
Patients who discontinue study treatment prior to data cut-off will be followed up for 
progression in line with the Schedule of Assessment (Table 13), unless objective PD is 
documented or the patient has withdrawn consent to both study treatment and study 
assessments, or had died. At data cut-off all patients previously discontinued from study 
treatment and continuing in follow-up will complete the study. After data cut-off, there 
will be no follow-up required for patients discontinued from study treatment. The 
investigator will provide locally defined standard of patient care.
All ongoing and any new AEs/SAEs identified during the 30 calendar days after the last 
dose of study medication must be followed to resolution unless the event is considered by 
the investigator to be unlikely to resolve, or the patient is lost to follow-up. New AEs 
including SAEs will be recorded into the eCRF.
SAEs occurring more than 30 days after the discontinuation of the study treatment should 
be reported if they are considered to be related to the study treatment by the investigator. 
These SAEs will be not entered into the study database but should be reported to the 
Sponsor within the requested timeframe.
Treatment discontinuation should be reported via Randomisation and Trial Supply 
Management (ClinPhone®RTSM) by the investigator.
7.4.5 Withdrawal from the Study
Patients are free to withdraw from the study at any time (study treatment and 
assessments), without prejudice to further treatment. A patient who withdraws consent 
will always be asked about the reason(s) and the presence of any AEs.
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
The term withdrawal from the study refers to both discontinuation from study treatment 
and study assessments.
Patients may be withdrawn from the study for the following reasons:
• 
Screening failure
• 
Death
• 
Withdrawal of consent
If a patient wishes to withdraw their consent to both study treatment and study 
assessments, they should be asked if they are willing to continue in a Follow-up Period 
(which can be conducted by telephone – see Section 7.7.4). If a patient wishes to 
withdraw their consent to further participation in the study entirely, including follow-up, 
this should be clearly documented in the patient notes and in the clinical study database.
7.4.6 Screening Failures
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not receive study treatment. These patients should have the reason for 
study withdrawal recorded as “Ineligible” (i.e., patient does not meet the required inclusion/
exclusion criteria). This reason for study withdrawal is only valid for screening failures 
(not patients who have received study treatment).
Patients who initially fail screening due to out of range laboratory values will be allowed 
to repeat the laboratory assessment within the Screening Period, and if the repeat 
laboratory values are within normal range, the patient may be randomized into the study 
and receive study treatment. For patients who experience a temporary acute medical 
event that would prohibit randomisation of the patient within the normal duration of the 
Screening Period, discussion of an extension of the Screening Period with the medical 
monitor may occur. Otherwise, patients will not be rescreened and the patient 
identification number for screen failures will not be used. Patients who discontinue from 
study treatment will not be replaced.
7.5 
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be involved in the conduct of this study. The 
DMC has the responsibility for monitoring the progress of the clinical study and the 
safety of the study participants. The DMC will perform review of safety data and study 
conduct during the course of the clinical trial, as defined in the DMC Charter for this 
clinical trial. The DMC will not stop the trial for efficacy. The memberships of the DMC 
and reporting structure are defined in the DMC Charter.
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
7.6 
Treatment of Patients
7.6.1 Treatments Administered
During the Study Treatment Period, paclitaxel + carboplatin (combination drugs) will be 
administered on Day 1 of each 21-day cycle for at least 4, and no more than 6 cycles. 
Carboplatin AUC should be calculated by the Calvert formula and creatinine clearance 
calculated by the Cockcroft-Gault formula (APPENDIX E). The number of cycles is 
determined by patients’ need and the investigator’s assessment. FKB238 or EU-Avastin 
(IP) will also be administrated on Day 1 of each 21-day cycle until objective PD or other 
criteria for treatment discontinuation met. Paclitaxel, 200 mg/m2, IV infusion over 
3 hours should be immediately followed by carboplatin, area under the time curve 6.0, IV 
infusion over 15 to 60 minutes. FKB238 or EU-Avastin, 15 mg/kg, IV infusion should be 
administered immediately following carboplatin. The initial dose should be delivered
over 90 minutes as an IV infusion. If the first infusion is well tolerated, the second
infusion may be administered over 60 minutes. If the 60-minute infusion is well tolerated, 
all subsequent infusions may be administered over 30 minutes. Patient weight will be 
assessed at Day 1 of every cycle during the Study Treatment Period.
If a patient’s body weight changes by  10% from baseline, combination drug and IP 
doses should be recalculated. Baseline weight is initially defined as the weight collected 
during the Cycle 1 Day 1 visit. On any occasion if a patient’s body weight changes 
±10% from baseline (Cycle 1 Day 1), the combination drug and IP doses will be 
recalculated. Upon recalculation, that weight and combination drug and IP dose 
adjustment will become the new baseline. Each time a new baseline is established, it will 
be used to calculate a subsequent dose adjustment if a patient’s body weight changes 
±10% again.
FKB238 group:
• 
Paclitaxel 200 mg/m2 on Day 1 for at least 4, and no more than 6 cycles
• 
Carboplatin area under the curve (AUC) 6.0 on Day 1 for at least 4, and no more
than 6 cycles
• 
FKB238 15 mg/kg on Day 1 until objective PD or other criteria for treatment
discontinuation are met
Avastin group:
• 
Paclitaxel 200 mg/m2 on Day 1 for at least 4, and no more than 6 cycles
• 
Carboplatin AUC 6.0 on Day 1 for at least 4, and no more than 6 cycles
• 
EU-Avastin 15 mg/kg on Day 1 until objective PD or other criteria for treatment
discontinuation are met
7.6.2 Identity of Investigational Product
The Sponsor will supply the following IPs:
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
FKB238
FKB238 is supplied as a concentrate for solution for infusion in 100 mg/4 mL preservative-
free, single-use vials to deliver FKB238 (25 mg/mL). FKB238 is a clear to slightly 
opalescent, colourless to pale brown, sterile, pH 5.5 solution for IV infusion.
FKB238 should be diluted in a total volume of 100 mL of 0.9% sodium chloride in the 
majority of the occasions. DO NOT ADMINISTER OR MIX WITH DEXTROSE
SOLUTION.
EU-Avastin
EU-Avastin is supplied as a concentrate for solution for infusion in 100 mg/4 mL 
preservative-free, single-use vials to deliver EU-Avastin (25 mg/ml). EU-Avastin is a 
clear to slightly opalescent, colourless to pale brown, sterile, pH 6.2 solution for IV 
infusion.
EU-Avastin should be diluted in a total volume of 100 mL of 0.9% sodium chloride in 
the majority of the occasions. DO NOT ADMINISTER OR MIX WITH DEXTROSE
SOLUTION.
The investigative site might be responsible for supplying additional medications 
identified in the protocol including, but not limited to, the chemotherapeutic agents 
paclitaxel and carboplatin, and supportive care products such as chemotherapy
pre-medications and permitted haematopoietic growth factors, antibiotics, transfusions,
etc., as well as the IV admixture solutions needed for the reconstitution of investigational 
and concomitant products.
7.6.2.1 Packaging and Labelling
IP vial will be re-packaged in a blinding carton containing 1 IP vial in a blinded manner 
with uniquely numbered kits of FKB238/EU-Avastin (IP kit). IP kit will be packaged, 
and labelled in accordance with Good Manufacturing Practice and distributed under 
Good distribution Practice. The labels will include all the information required by each 
country’s regulatory requirements.
The quantity of IP kits in the initial shipment will depend on the recruitment expectations 
of the site, resupply of IP kits will be made automatically according to 
ClinPhone®RTSM.
TO MAINTAIN STUDY BLIND, THE BLINDING CARTON SHOULD NEVER 
BE OPENED.
7.6.2.2 Storage and Stability
FKB238/EU-Avastin
IP kits should be stored refrigerated at 2°C to 8°C (do not freeze), protect from light. Do
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
not shake. IP kits should be kept in their original package carton that should never be 
opened.
After dilution with 100 mL of 0.9% sodium chloride, the solutions may be stored in IV 
bags for up to 8 hours at temperature of 2-8°C, protected from light. The product must 
not be frozen or shaken.
HOWEVER, FROM A MICROBIOLOGICAL POINT OF VIEW, THE 
PRODUCT SHOULD BE USED IMMEDIATELY AFTER DILUTION.
The investigator should ensure that the IP, as well as other drug products used in the trial, 
is stored in accordance with the environmental conditions (temperature, light, and 
humidity) as determined by the Sponsor and defined in the Pharmacy Manual.
7.6.3 Investigational Product Accountability, Reconciliation, and Return
All IP will be administered at the study site by study personnel. Receipt, accountability 
and return of IP kits will be recorded in ClinPhone®RTSM.
A CRO study monitor will review the IP receipt, accountability and check all IP kit 
returns (both unused and used IP kits) in the ClinPhone®RTSM system prior to making 
arrangements for their return to the CRO depots or local contracted depots, in exceptional 
cases (eg, if required by local regulations) local destruction upon Sponsor authorization.
7.6.4 Study Drug Handling and Disposal
The study site has to ensure that the IP kits are accessible to authorized personnel only. 
Used, partially used and unused IP kits should be retained in a separate location from the 
unused IP kits until the study monitor has been able to complete drug accountability and 
reconciliation.
All IP kits used and/or unused are to be returned to the CRO depots or local contracted 
depots, these returns must be accompanied with the ClinPhone®RTSM accountability log 
and be clearly identified on the outermost shipping box. All returned IP kits should not 
have been removed from the original IP carton. It is the investigator’s responsibility to 
arrange for disposal of all other non-IP, provided that procedures for proper disposal have 
been established according to applicable local, national and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept and a certificate of 
destruction is provided to the Sponsor or designated CRO.
TO MAINTAIN STUDY BLIND, THE BLINDING CARTON SHOULD NEVER 
BE OPENED.
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
7.6.5 Method of Assigning Patients to Treatment Groups and Measures to
Minimise/Avoid Bias
7.6.5.1 
Patient Identification
After signing the ICF, patients will be assigned a unique patient identification number 
using ClinPhone®RTSM. The patient identification number will be used to identify the 
patient on the eCRF and on all source documents.
7.6.5.2 
Randomisation
Patients who qualify for participation will be randomly assigned to 1 of 2 blinded 
treatment groups in a 1:1 ratio using ClinPhone®RTSM. Randomisation will be stratified 
(using a dynamic allocation model) according to EGFR mutation and ALK gene 
arrangement status (both are tested and known negative versus status unknown for 
either), geographical region (North America, Western Europe, East Asia, All Other 
Regions), prior weight loss over the previous 6 months (< 5% yes versus no), and disease 
stage (advanced or recurrent). The following treatment groups will be included in this 
study:
FKB238 group: paclitaxel + carboplatin + FKB238
Avastin group: paclitaxel + carboplatin + EU-Avastin
The randomisation schedule will be developed by ClinPhone®RTSM. Details of the 
randomisation schedule are provided in the ClinPhone®RTSM specifications document.
7.6.5.3 
Blinding
Investigators, site staff including pharmacy staff, patients, CRO personnel, and Sponsor
personnel (except for a specified IP distribution manager) will be blinded to individual 
patient treatment assignment during the course of the study until data cut-off. 
ClinPhone®RTSM will develop the randomisation schedule.
The IP will be packaged and labelled in such a way that visual inspection of the IP or 
packaging will not reveal the treatment assignment; however, each individual kit of IP 
will be numbered so that, if necessary, the number can be used to break the treatment 
blind if this becomes necessary to protect the safety of the patient.
TO MAINTAIN STUDY BLIND, THE BLINDING CARTON SHOULD NEVER 
BE OPENED.
7.6.5.4 
Breaking the Blind
This study will be conducted in a manner consistent with the protection of the blinded 
treatment assignment for all study participants. Treatment assignments should not be 
prematurely unblinded by the investigator unless there is an immediate and material
medical need to know the patient’s treatment assignment in order to protect patient
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
safety. In most situations, lacking treatment-specific antidotes, the investigator should 
have time to discuss the reason for unblinding with the medical monitor/Sponsor before 
proceeding to unblinding. However, should it become necessary to break the treatment
blind to protect the safety of the patient, the investigator may contact ClinPhone®RTSM
to obtain the treatment assignment, as detailed in the Pharmacy Manual. If possible, the 
investigator should contact the medical monitor before breaking the treatment blind to 
obtain approval. If it is not possible to contact the medical monitor before breaking the 
blind, the medical monitor should be notified as soon as possible of this action after the 
blind is broken. At all times, the number of study participants who become unblinded to 
the patient’s treatment assignment should be minimised. The Sponsor and medical 
monitor will determine whether the patient will remain under study treatment after 
breaking the blind or whether the patient will be withdrawn from study treatment and 
enter follow-up.
7.6.5.5 
Scheduled Unblinding
After data cut-off and database lock, all patients will be unblinded.
7.6.6 Selection of Doses in the Study
Patients will receive 15 mg/kg of either FKB238 or EU-Avastin in combination with 
paclitaxel and carboplatin in line with the approved regiment for EU-Avastin outlined in 
the Package Insert and the SmPC.
7.6.7 Criteria for Schedule Adjustment, Dose Modifications, and Discontinuation of
Study Treatment
If during treatment, a severe or intolerable AE occurs or the patient develops toxicity, 
study treatment should be temporarily withheld. If combination drugs are delayed, IP 
administration must also be delayed. The National Cancer Institute (NCI) CTCAE 
version 4.0 will be used to evaluate toxicity.
If the start of the cycle is delayed, the interval of 3 weeks must be kept for subsequent 
cycles. In most cases, patients who require combination therapy and/or IP to be held for 
more than 3 weeks will discontinue study treatment. In some cases, should re-start of 
study treatment after a delay of more than 3 weeks be required, a discussion should occur 
with the medical monitor. All such decisions need to be appropriately documented.
If IP treatment is discontinued due to toxicity, combination drugs will continue. If 
combination drugs are discontinued due to toxicity, IP treatment will continue. Missed 
doses of combination drugs and IP should not be administered later.
Guidelines for treatment of combination drug or IP-related toxicities are provided 
below.
7.6.7.1 
FKB238/EU-Avastin
The dose of IP will not be reduced; dose modifications for IP toxicity will be limited to
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
dose delay or discontinuation only. Any IP-related AEs of hypertension, proteinuria, 
thromboembolism, or haemorrhage should be managed as described below:
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
Hypertension
CTCAE grade 1
Prehypertension (systolic BP 120 –
139 mmHg
or
diastolic
BP
Give IP
89 mmHg)
CTCAE grade 2
Stage 1 hypertension (systolic BP 140 -
159 mmHg or diastolic BP 90 –
99 mmHg); 
medical 
intervention
indicated; 
recurrent 
or 
persistent
( 24 hours); symptomatic increase by
> 20 mmHg 
(diastolic) 
or 
to
> 140/90 mmHg if previously within 
normal limits; monotherapy indicated
Give IP;
Start anti-hypertensive therapy
CTCAE grade 3
Stage 2 hypertension (systolic BP
 160 
mmHg 
or 
diastolic 
BP
 100 mmHg); medical intervention 
indicated; more than 1 drug or more 
intensive therapy than previously used 
indicated
Hold IP;
Start or intensify anti-hypertensive therapy;
Resume IP when BP returns to pre-treatment 
level or to < 160/100 mmHg, and continue 
to monitor BP
CTCAE grade 4
Life-threatening 
consequences 
(eg,
malignant hypertension, transient or
permanent 
neurologic 
deficit,
hypertensive 
crisis); 
hypertension
encephalopathy, urgent intervention
indicated
Permanently discontinue IP
Proteinuria
Proteinuria by urinalysis or dipstick should be assessed before each IP administration. 
Manage proteinuria as follows:
• 
 1+ proteinuria (dipstick or urinalysis): administer IP as planned
• 
2 to 3+ proteinuria (dipstick or urinalysis): administer IP as planned and collect
24-hour urine for determination of total protein within 3 days before the next
scheduled IP administration
o 24-hour proteinuria  2 g: administer next IP dose as scheduled. Continue 
to follow 24-hour urinary protein before each cycle. If urinary protein falls
to < 1 g, resume monitoring by dipstick method.
o 24-hour proteinuria > 2 g: omit next scheduled IP dose and do 24-hour 
urine collection for determination of total protein within 3 days before the 
subsequently scheduled cycle. Delay IP treatment until proteinuria has 
decreased to  2 g. Do 24-hour urine before each scheduled dose until
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80
–


Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
proteinuria has improved to 1 g/24 hours, but omit IP only if > 2 g 
protein/24 hours.
• 
4+ proteinuria (dipstick or urinalysis): hold IP and collect 24-hour urine for
determination of total protein within 3 days before the next scheduled IP
administration
o Restart IP when 24-hour urinary protein falls to  2 g
• 
Nephrotic syndrome: permanently discontinue IP treatment
Thrombosis/Embolism
Arterial thromboembolism:
• 
Any CTCAE grade: permanently discontinue IP treatment
Venous thromboembolism (including pulmonary embolism):
• 
CTCAE grade 2 or 3: hold IP treatment for at least 2 weeks until the patient is
medically stabilized. Anticoagulation therapy should be initiated. The IP may be 
resumed after initiation of therapeutic-dose anticoagulant therapy if the patient is 
on a stable dose of anticoagulant and, if on warfarin, has an INR within the target 
range (usually between 2 and 3) prior to restarting IP treatment.
• 
CTCAE grade 4: permanently discontinue IP treatment. Anticoagulation therapy
should be initiated.
Haemorrhage
• 
Haemoptysis of  1/2 teaspoon: permanently discontinue IP treatment
• 
CTCAE grade 2 bronchopulmonary haemorrhage (moderate symptoms; medical
intervention indicated): permanently discontinue IP treatment
• 
CTCAE grade 3 or 4 bleeding of any kind: permanently discontinue IP treatment
• 
Mild epistaxis/gingival bleeding is common with bevacizumab. Treatment does
not need to be held if bleeding responds to usual first aid measures for epistaxis
Gastrointestinal Perforation/Fistulae
• 
Any CTCAE grade: permanently discontinue IP treatment
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
Wound-healing complications
• 
Wound dehiscence, fistulae, infection: permanently discontinue IP treatment
Posterior Reversible Encephalopathy Syndrome
• 
Permanently discontinue IP treatment
Left ventricular systolic dysfunction
• 
CTCAE grade 3 or 4: permanently discontinue IP treatment
Infusion reactions
• 
Severe infusion reaction (CTCAE grade 3 or 4): permanently discontinue IP
treatment, and administer appropriate medical therapy
Haematological toxicity
• 
Asymptomatic decreases in levels of haematologic parameters, including
neutrophils, leucocytes, platelets and haemoglobin:
o CTCAE grade 3 or above: treat according to institutional guidelines
o
The ANC must be  1.5 x 109/L and platelet count  100 x 109/L prior to 
the
next
scheduled
dose.
If
ANC
< 1.5 x 109/L
and/or
platelets
< 100 x 109/L the dose should be delayed to allow recovery.
o Erythropoietic growth factors and granulocyte-colony stimulating factor
(G-CSF) may be used in accordance with institutional guidelines and the
individual product information
• 
Febrile neutropenia:
o Treat according to institutional guidelines
o
Hold further dosing until the patient is fully recovered (apyrexial for
2 days and ANC 1.5 x 109/L)
• 
See also Section 7.6.7.2 for guidance on carboplatin and paclitaxel dosing
• 
If G-CSF is used in the treatment of neutropaenia consider prophylactic use for
subsequent cycles
Any Other CTCAE grade 3 or 4 FKB238/EU-Avastin -related Event
• 
First occurrence: hold IP until toxicity has improved to CTCAE grade  1
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
• 
Second occurrence: permanently discontinue IP treatment
7.6.7.2 
Paclitaxel and Carboplatin
The chemotherapy dose level modifications to be followed for defined toxicities are 
displayed in the Table 4.
Table 4 
Chemotherapy Dose Level Modifications for Defined Toxicities
* Carboplatin AUC should be calculated by Calvert formula and creatinine clearance calculated by Cockcroft-
Gault formula (APPENDIX E).
A maximum of 2 dose reductions (to dose level -2) for chemotherapy are permitted. 
Patients who require more than 2 chemotherapy dose reductions to doses lower than dose 
level -2 as described in Table 4 will be discontinued from chemotherapy treatment in this 
study.
Except as discussed below for hepatic dysfunction/toxicity, for nausea and vomiting, and 
for haematologic toxicities, all dose reductions are permanent with no dose re-escalation 
permitted.
If multiple toxicities occur, the most stringent dose reduction modification will be 
followed. Dose reductions are not additive (ie, investigators should choose the most 
stringent dose reduction dictated by any toxicity and that will cover all the toxicities).
Haematologic Toxicity Dose Modification
The ANC must be 1.5 × 109/L and platelet count 100 × 109/L on the first day of each 
cycle. 
If 
chemotherapy 
must 
be 
withheld 
due 
to 
haematologic 
toxicity 
(ANC < 1.5 × 109/L and/or platelets < 100 × 109/L), a complete blood count and platelet 
count should be obtained weekly until the counts reach the lower limits for treatment as 
stated. Do not re-treat until the ANC is 1.5 × 109/L and platelet count 100 × 109/L. 
The doses of paclitaxel and/or carboplatin will be modified based on the worst toxicity 
observed during the preceding cycle.
Patients and investigators need to be attentive to the possibility of fever and infection so 
that these complications can be promptly and appropriately managed. When a dose 
reduction in paclitaxel/carboplatin is made for decreased ANC, and/or decreased platelet 
count, or febrile neutropenia and the reduced dosage results in no toxicity in a subsequent 
chemotherapy cycle, re-escalation of the chemotherapy doses may occur in subsequent 
cycles based on the investigator’s discretion.
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Dose Level
Paclitaxel Dose
Carboplatin Dose*
0 (starting dose)
200 mg/m2
AUC 6
-1
175 mg/m2
AUC 5
-2
150 mg/m2
AUC 4


Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
Toxicities will be graded according to CTCAE. There will be no dose reductions for 
anaemia, which may be managed according to institutional guidelines. Erythropoietic 
growth factors may be used in accordance with local health authority stated indication 
criteria. No IP dose reductions should be implemented for haematologic toxicity.
Table 5 
Chemotherapy Dose Modification at the Start of the Subsequent Cycle
Note: First episode of febrile neutropenia will be managed with dose reduction. For a second episode of 
febrile neutropenia, prophylaxis with granulocyte colony-stimulating factor treatment may be instituted in 
lieu of a second dose reduction. Further febrile neutropenia despite granulocyte colony-stimulating factor 
treatment must be managed with a second dose reduction.
Hepatic Dysfunction/Toxicity Dose Modification
The dose of combination drugs will be adjusted for increased alanine transaminase (ALT) 
or aspartate transaminase (AST) or total bilirubin as indicated in Table 6:
Table 6 
Dose Adjustments for Hepatic Toxicities
*If paclitaxel is withheld due to hepatic dysfunction/toxicity, carboplatin should also be withheld and 
administered when paclitaxel is resumed. If paclitaxel is withheld and hepatic values have not recovered
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Haematologic
Paclitaxel
Carboplatin
Worst Toxicity in Preceding Cycle
Febrile neutropenia* for any duration OR
ANC < 1000/mm3 for 5 days OR ANC
< 500/mm3 for any duration
* ANC < 1000/mm3 with a single temperature of
> 38.3°C
decrease 1 dose level
decrease 1 dose level
CTCAE grade 4 thrombocytopenia, or
CTCAE grade 3 thrombocytopenia with 
bleeding or requiring transfusion
decrease 1 dose level
decrease 1 dose level
Hepatic
Transaminases
Total Bilirubin
Paclitaxel
Carboplatin
Laboratory values at time of treatment should be used in determining paclitaxel dose.
ALT and AST  5 x
ULN
AND
 1.25 x ULN
No change
No change
ALT or AST > 5, but 
10 x ULN
OR
> 1.25, but  2 x ULN
Reduce to
175 mg/m2
No change
ALT and AST  10 x
ULN
AND
> 2, but  3 x ULN
Reduce to
150 mg/m2
No change
ALT or AST > 10 x
ULN
OR
> 3 x ULN
Withhold*
Withhold*


Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
within 3 weeks, patients must be discontinued from study chemotherapy.
After any dose reduction of paclitaxel for hepatic clinical laboratory abnormalities, the 
dose of paclitaxel will not be re-escalated unless the hepatic abnormalities have:
• 
Resolved to ALT and AST  5 x ULN and to total bilirubin  1.25 x ULN;
• 
The cause of the hepatic clinical laboratory abnormalities is identified as other
than paclitaxel induced; and
• 
Re-escalation is approved by the medical monitor.
All 3 conditions must be met to permit re-escalation of the paclitaxel dose.
Cardiac Toxicity (Paclitaxel) Dose Modification
Cardiac rhythm disturbances occur infrequently in patients given paclitaxel. Most are 
asymptomatic and cardiac monitoring is not required. Transient asymptomatic 
bradycardia has been reported but clinically significant atrioventricular block is rare. 
Cardiac toxicity should be managed according to Table 7 and follow local institutional 
guidelines if required.
Table 7 
Dose Modifications for Cardiac Toxicity
Event
Management
Asymptomatic bradycardia
No intervention
Symptomatic arrhythmia during infusion
Discontinue study treatment; manage arrhythmia
according to standard local practice
Chest 
pain 
and/or 
symptomatic 
hypotension
(< 90/60 mmHg or requires fluid replacement)
Discontinue study treatment; obtain ECG; decide
between cardiac pain vs non-cardiac infusion 
reaction and manage latter with H1 blocker (eg, 
chlorphenamine 10 mg IV or diphenhydramine 25 
to 50 mg IV) and corticosteroid (eg, dexamethasone
10 mg 
IV). 
Also, 
consider 
epinephrine 
or
bronchodilators if chest pain is not thought to be 
cardiac.
Neurologic Toxicity (Paclitaxel) Dose Modification
Peripheral neuropathy may occur in patients receiving paclitaxel, and should be graded 
according to CTCAE. Dose modification for paclitaxel is described in Table 8. No dose 
adjustment is necessary for carboplatin.
Protocol V5.0 (22 May 2018) 
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
Table 8 
Dose Modification for Neurologic Toxicity
Toxicity
CTCAE grade
Paclitaxel Dose Modification
0
None
1
None
2
Hold chemotherapy until toxicity recovers to CTCAEgrade 1, then resume 
chemotherapy with paclitaxel reduced to 175 mg/m2
3
Hold chemotherapy until toxicity recovers to CTCAEgrade 1, then resume 
chemotherapy with paclitaxel reduced to 150 mg/m2
4
Permanently discontinue chemotherapy
Gastrointestinal Toxicity Dose Modification
Chemotherapy dose modifications will be made based on the worst toxicity in the 
preceding cycle as per Table 9. Nausea and/or vomiting in association with paclitaxel and 
carboplatin should be controlled with adequate antiemetics before administration, and for 
up to 48 hours following administration. If CTCAE grade 3 or 4 nausea/vomiting occurs 
in temporal association with paclitaxel/carboplatin administration in spite of aggressive 
anticipatory and/or follow-up antiemetics therapy, the dose of paclitaxel/carboplatin 
should be reduced as specified in Table 9 below for the next cycle. A second dose 
reduction is at the investigator’s discretion. If tolerated, increase paclitaxel/carboplatin 
back to 100% dose as soon as possible. If CTCAE grade 3 or 4 nausea/vomiting persist, 
study treatment should be permanently discontinued.
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
Table 9 
Dose Modifications for Gastrointestinal Toxicity at the Start of the
Subsequent Cycle
*Doses may be re-escalated 1 dose level per future chemotherapy cycle if nausea and vomiting are 
recovered to < CTCAE grade 3 by any current dose reduction.
Renal Toxicity (Carboplatin)
Recommendations are based on the NCI CTCAE scale for creatinine clearance values 
(chronic kidney disease). For creatinine clearance values corresponding to CTCAE grade 
3 or 4 toxicity, carboplatin should be withheld until the patient recovers completely or to 
CTCAE grade 1 toxicity. The treatment should then be resumed at AUC 4. If recovery to 
CTCAE grade 1 toxicity does not occur within 3 weeks, the patient’s chemotherapy will 
be discontinued. For CTCAE grade 1 and 2 toxicities, no special dose reductions will be 
made because application of the Calvert formula will accommodate the necessary dose 
adjustments.
Paclitaxel and Carboplatin Infusion Related Reactions (Hypersensitivity)
Anaphylaxis and severe hypersensitivity reactions characterised by dyspnoea and 
hypotension requiring treatment; angioedema; and generalized urticaria have occurred in 
2% to 4% of patients receiving paclitaxel in clinical trials. Fatal reactions have occurred 
in patients despite premedication. Hypersensitivity to carboplatin has been reported in 2% 
of patients. These allergic reactions may include rash, urticaria, erythema, pruritus, and, 
rarely, bronchospasm and hypotension. Anaphylactic reactions have been reported as part 
of postmarketing surveillance. These reactions have been successfully managed with 
standard epinephrine, corticosteroid, and antihistamine therapy.
Management of infusion related reactions/hypersensitivity to paclitaxel and carboplatin is 
outlined in Table 10.
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4
GASTROINTESTINAL
Paclitaxel
Carboplatin
Worst Toxicity in Preceding Cycle
CTCAE grade 3 or 4 nausea or
vomiting 
despite 
maximal
antiemetic 
prophylaxis 
and
therapy*
decrease 1 dose level
decrease 1 dose level
CTCAE grade 3 stomatitis
decrease 1 dose level
decrease 1 dose level
CTCAE grade 4 stomatitis
Reduce to lowest dose level,
150 mg/m2; 
or 
discontinue
chemotherapy if lowest dose 
level caused the CTCAE grade 4 
stomatitis
Reduce to lowest dose level,
AUC 
4; 
or 
discontinue
chemotherapy if lowest dose level
caused
the
CTCAE grade
stomatitis


Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
Table 10 
Dose Adjustments Related to Infusion Reactions and Hypersensitivity
Abbreviations:  IV=intravenous.
Hypersensitivity prophylaxis and rate of administration of paclitaxel/carboplatin for 
subsequent cycles in patients who have previously experienced CTCAE grade 1 or 2 
hypersensitivity reactions should be determined according to standard local clinical 
practice.
Other Chemotherapy Nonhaematologic Toxicity Dose Modification
Other chemotherapy nonhaematologic toxicities not addressed above will be managed 
according to Table 11.
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CONFIDENTIAL
2
Paclitaxel
Carboplatin
CTCAE
grade 1
Monitor patient; no treatment or change
to infusion required.
Monitor patient; no treatment or change to
infusion required.
CTCAE
grade 2
Stop paclitaxel infusion; administer H1
blocker (eg, chlorphenamine 10 mg IV or 
diphenhydramine 25 to 50 mg IV) and 
corticosteroid (eg, dexamethasone 10 mg 
IV); after recovery, resume paclitaxel
infusion at reduced rate (1/4th original
infusion rate) for 15 minutes, then ½ the 
original infusion rate for 15 minutes, and, 
if no symptoms, then at full-dose rate 
until infusion is complete. If symptoms 
recur at CTCAE grade 1 intensity, stop 
paclitaxel infusion and patient may be re-
challenged 
at 
next 
scheduled
chemotherapy. If symptoms recur at 
grade 2 intensity, stop infusion and 
discontinue patient from chemotherapy.
Stop carboplatin infusion; administer H1
blocker (eg, chlorphenamine 10 mg IV or 
diphenhydramine 25 to 50 mg IV) and 
corticosteroid (eg, dexamethasone 10 mg IV); 
after recovery, resume carboplatin infusion at
reduced rate (1/4th original infusion rate) for
15 minutes, then ½ the original infusion rate 
for 15 minutes, and, if no symptoms, then at 
full-dose rate until infusion is complete. If 
symptoms recur at CTCAE grade 1 intensity, 
stop carboplatin infusion and patient may be 
re-challenged at next scheduled chemotherapy.
If
symptoms
recur
at
CTCAE grade
intensity, stop infusion and discontinue patient
from chemotherapy.
CTCAE
grade 3 or 4
Stop paclitaxel infusion; administer H1
blocker (eg, chlorphenamine 10 mg IV or 
diphenhydramine 25 to 50 mg IV) and 
corticosteroid (eg, dexamethasone 10 mg
IV) 
and 
manage 
additionally 
with
epinephrine, bronchodilators, and/or O2, 
as necessary. Discontinue patient from 
chemotherapy.
Stop carboplatin infusion; administer H1
blocker (eg, chlorphenamine 10 mg IV or 
diphenhydramine 25 to 50 mg IV) and 
corticosteroid (eg, dexamethasone 10 mg IV) 
and manage additionally with epinephrine, 
bronchodilators, and/or O2, as necessary. 
Discontinue patient from chemotherapy.


Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
Table 11 
Dose Modifications for Nonhaematologic Toxicity
Toxicity Grade
(CTCAE)
Paclitaxel and/or Carboplatin Dose Modification
Baseline or
CTCAE grade 1
No dose reduction
CTCAE grade 2
Identify whether the toxicity is attributable to paclitaxel, carboplatin, or both:
• 
If Day 1 of a cycle: delay chemotherapy until toxicity resolves to
 CTCAE grade 1
• 
If toxicity occurred during preceding cycle but has already resolved
to  CTCAE grade 1, then decrease suspected chemotherapy drug(s) 
1 dose level
• 
If toxicity occurred during preceding cycle but has not resolved to
 CTCAE grade 1, then suspend suspected chemotherapy drug(s) 
until the toxicity resolves to  CTCAE grade 1 for maximum of 
3 weeks. Decrease suspected chemotherapy drug(s) 1 dose level. If 
the toxicity doesn’t resolve to  CTCAE grade 1 within 3 weeks, 
then discontinue patient from suspected chemotherapy drug(s)
CTCAE grade 3 or 4
Identify whether the toxicity is attributable to paclitaxel, carboplatin, or both:
• 
If Day 1 of a cycle: delay chemotherapy until toxicity resolves to
 CTCAE grade 1 or baseline
• 
If toxicity occurred during preceding cycle but has already resolved
to  CTCAE grade 1 or baseline, decrease suspected chemotherapy 
drug(s) to lowest dose level per Table 4; if already at lowest dose 
level per Table 4, then discontinue patient from chemotherapy
• 
If toxicity occurred during preceding cycle but has not resolved to
 CTCAE grade 1 or baseline, then suspend suspected chemotherapy 
drug(s) until the toxicity resolves to  CTCAE grade 1 or baseline 
for maximum of 3 weeks. Decrease suspected chemotherapy drug(s) 
to lowest dose level per Table 4; if already at lowest dose level per 
Table 4, then discontinue patient from chemotherapy. If the toxicity 
doesn’t resolve to  CTCAE grade 1 or baseline within 3 weeks, then 
discontinue patient from chemotherapy
7.6.8 Pre-study and Concomitant Medications
Prior to data cut-off, all concomitant medication(s) must be recorded on the eCRF. Any 
diagnostic, therapeutic, or surgical procedure performed during the study period should 
also be recorded. Patients should receive full supportive care, including transfusions of 
blood and blood products, antibiotics, and antiemetics, where applicable. The reason(s) 
for treatment and treatment dates should also be recorded.
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
After data cut-off (during the Extended Treatment Period), concomitant medications will 
only be reported in the event of an SAE, using the paper SAE form. See Section 7.7.5 for 
information regarding patient management and reporting after data cut-off (during 
Extended Treatment Period).
7.6.8.1 
Restrictions
Female patients of childbearing potential who are sexually active with a non-sterilized 
male partner must use at least one highly effective method of contraception (Table 12) 
from the time of screening and must agree to continue using such precautions for 
6 months after the last dose of study treatment. Male partners of a female patient must 
use male condom plus spermicide throughout this period. Cessation of birth control after 
this point should be discussed with a responsible physician. Not engaging in sexual 
activity for the total duration of the study and the drug washout period is an acceptable 
practice; however, occasional abstinence, the rhythm method, and the withdrawal method 
are not acceptable methods of contraception.
Non-sterilized male patients who are sexually active with a female partner of 
childbearing potential must use male condom plus spermicide from screening through 
6 months after the last dose of study treatment. Not engaging in sexual activity for the 
total duration of the study and the drug washout period is an acceptable practice; 
however, occasional abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. Male patients should refrain from sperm donation 
throughout this period. Female partners of a male patient must use a highly effective 
method of contraception throughout this period.
Females of childbearing potential are defined as those who are not surgically sterile (ie, 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or
post-menopausal (defined as 12 months with no menses without an alternative medical
cause).
Highly effective methods of contraception are described in Table 12. A highly effective 
method of contraception is defined as one that results in a low failure rate (ie, less than 
1% per year) when used consistently and correctly. Note that some contraception 
methods are not considered highly effective (eg, male or female condom with or without 
spermicide; female cap, diaphragm, or sponge with or without spermicide; non-copper 
containing intrauterine device; progestogen-only oral hormonal contraceptive pills where 
inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel 
which is considered highly effective]; and triphasic combined oral contraceptive pills).
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
Table 12 
Highly Effective Methods of Contraception
Note: a highly effective method has a failure rate of <1% per year
Breastfeeding women are to be excluded from the study unless the patient is willing to 
discontinue breastfeeding throughout their participation in the study and for 6 months 
after the last dose of study treatment.
7.6.8.2 
Premedication
Premedication for carboplatin/paclitaxel chemotherapy with corticosteroids (such as 
dexamethasone), diphenhydramine, H2 antagonist (such as cimetidine or ranitidine) and 
antiemetic medication should be given according to institutional standards.
7.6.8.3 
Prohibited Medications
No additional systemic anti-cancer treatment including other chemotherapies, 
radiotherapy, anti-cancer agents, and investigational agents is allowed to be used prior to 
discontinuation of study treatment. Palliative radiotherapy for painful bone metastases 
(except for thoracic region) are allowed during the study treatment. Herbal medications 
intended for anti-cancer use are prohibited.
7.6.8.4 
Other Concomitant Medications
Special warnings and precautions for the use of paclitaxel and carboplatin should be 
observed according to each drug’s label.
The metabolism of paclitaxel is catalysed by cytochrome P450 (CYP) isoenzymes 
CYP2C8 and CYP3A4. Caution should be exercised when administering paclitaxel 
concomitantly with known substrates or inhibitors of the CYP isoenzymes CYP2C8 and 
CYP3A4. Caution should be exercised when paclitaxel is concomitantly administered 
with known substrates (eg, midazolam, buspirone, felodipine, lovastatin, eletriptan, 
sildenafil, simvastatin, and triazolam), inhibitors (eg, atazanavir, clarithromycin, 
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and 
telithromycin), and inducers (eg, rifampin and carbamazepine) of CYP3A4. Caution 
should also be exercised when paclitaxel is concomitantly administered with known 
substrates (eg, repaglinide and rosiglitazone), inhibitors (eg, gemfibrozil), and inducers
Protocol V5.0 (22 May 2018) 
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CONFIDENTIAL
Barrier/Intrauterine Methods
Hormonal Methods
• 
Copper T intrauterine device
• 
Levonorgestrel-releasing intrauterine system
(eg, Mirena®) (This is also considered a
hormonal method)
• 
Etonogestrel implants: eg, Implanon or Norplan
• 
Intravaginal device: eg, ethinylestradiol and
etonogestrel
• 
Medroxyprogesterone injection: eg,
Depo-Provera
• 
Normal and low dose combined oral
contraceptive pill
• 
Norelgestromin/ethinylestradiol transdermal
system
• 
Cerazette (desogestrel)


Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
(eg, rifampin) of CYP2C8.
Other warnings mentioned in the carboplatin label include: Carboplatin has limited 
nephrotoxic potential, but concomitant treatment with aminoglycosides has resulted in 
increased renal and/or audiologic toxicity, and caution must be excised when a patient 
received both drugs.
For the details, please see each drug’s label.
Supportive care therapies including but not limited to analgesics, antipyretics, anti-
infectives, other medical therapies, blood product transfusions, and other supportive and 
palliative therapies are permitted per investigator judgment and local standards of practice 
provided they are not otherwise explicitly prohibited by this protocol.
Low dose of anticoagulation for maintenance of patency of permanent indwelling IV 
catheters is permitted. Prophylactic use of anticoagulants after enrolment and while 
participating in the study (eg, during periods of hospital confinement) is permitted. 
However, the patients should be treated with caution.
Patients who develop CTCAE grades 2 to 3 venous thromboembolism (VTE) (or 
CTCAE grade 1 venous thrombosis where treatment is to include full-dose therapeutic 
anticoagulation) after enrolling and while participating in the study should have IP 
temporarily held while they are medically stabilized and started on full-dose therapeutic 
anticoagulation, either low molecular weight heparin or oral. Please see Section 7.6.7.1 
for more detail.
Plasma levels of anticonvulsant agents may become sub-therapeutic during platinum 
therapy. Concomitant use of drugs with a potential ototoxic or nephrotoxic effect (eg, 
aminoglycosides, cefalotine, furosemide, amphotericin B) should be avoided or 
adequately monitored.
Before, during, and after combination drug administration, adequate hydration and 
diuresis should be ascertained and should be performed according to each centre’s 
practice. Appropriate antiemetic medication should be given.
Concomitant haematopoietic growth factor and prophylactic or therapeutic use of 
granulocyte colony-stimulating factor is permitted according to the American Society of
Clinical Oncology or local regulatory authority guidelines and should be recorded on the
eCRF.
Therapy with bisphosphonates or denosumab is permitted in accordance with local health 
authority product labels.
If surgery is required during study treatment, the IP should be interrupted for a washout 
period of at least 28 days between the last dose of IP and the performance of surgery 
when possible. If a shorter washout period is required on the basis of the investigator’s 
medical judgement, the investigator should discuss the reduction of the washout duration 
with the study medical monitor, and the discussion should be documented appropriately.
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
Re-initiation of IP following surgery should be discussed with the study medical monitor 
and requires documented approval from the investigator.
7.6.9 Treatment Compliance
All doses of IP will be administered to patients at the study site by study site personnel. 
Investigational product accountability will be captured as described in Section 7.6.3, and 
IP compliance will be reported in by-patient listings.
7.7 
Study Procedures
7.7.1 Schedule of Assessments
The schedule of study assessments is provided in Table 13.  See Section 7.7.5 for 
information regarding patient management and reporting after data cut-off (during 
Extended Treatment Period).
Protocol V5.0 (22 May 2018) 
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Centus Biotherapeutics
Clinical Protocol
Protocol No.: FKB238-002
Study Drug Name: FKB238
Table 13
Schedule of Assessments Prior to Data Cut-Off
Day
Screening/
baselinea
Study Treatment Period (all visits within ± 3 days of schedule)
Study
treatment
disconti-
nuation
(± 7 days)
30 days
follow-up
after last
dose of
study
treatment
(± 7 days)
Follow-
up
Cycle 1
Cycle 2
Day 1
Cycle 3
Day 1
Cycle 4
Day 1
Cycles 5
Day 1
Cycle 6
Day 1
Cycle 7
and sub-
sequent
cycles
Day 1
1
8
15
Visit
1
2
3
4
5
6
7
8
9
Visit 10
onwards
Informed consent
X
Inclusion/exclusion criteriab
X
EGFR/ALK statusc
X
Demographics
X
Medical history
X
Physical examination
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (blood pressure, pulse
rate, and body temperature)
Xd
X
X
X
X
X
X
X
X
X
X
X
Heighte, weight
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
X
X
a Within 28 days before randomisation.
b Hepatitis B or C and HIV status should be included as part of the medical history.
c Testing for EGFR activating mutation and ALK gene rearrangement is not required for this study; however, the status EGFR and ALK testing results collected before or during
Screening OR the status of EGFR and ALK mutation as ‘unknown’ should be recorded.
d Blood pressure needs to be assessed 3 times with at least 5 minute intervals for each assessment.
e Height completed at baseline only.
Protocol V5.0 (22 May 2018)
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CONFIDENTIAL


Centus Biotherapeutics
Clinical Protocol
Protocol No.: FKB238-002
Study Drug Name: FKB238
Day
Screening/
baselinea
Study Treatment Period (all visits within ± 3 days of schedule)
Study
treatment
disconti-
nuation
(± 7 days)
30 days
follow-up
after last
dose of
study
treatment
(± 7 days)
Follow-
up
Cycle 1
Cycle 2
Day 1
Cycle 3
Day 1
Cycle 4
Day 1
Cycles 5
Day 1
Cycle 6
Day 1
Cycle 7
and sub-
sequent
cycles
Day 1
1
8
15
Visit
1
2
3
4
5
6
7
8
9
Visit 10
onwards
Radiological evaluation (CT/MRI
scan) of tumour lesions
Xf
Xg
Xg
Xg
Xf,g,h
12-lead ECG
X
Xi
X
X
LVEF by cardiac ultrasound or
MUGA scanj
X
X
Haematology, biochemistry
X
X
X
X
X
X
X
X
X
X
X
Urinalysis or urine dipstickk
X
X
X
X
X
X
X
X
X
X
X
f The chest and the upper abdomen (including liver and the adrenal glands). Brain CT/MRI is required within 4 weeks prior to randomization. Any other areas of the disease 
involvement should be additionally investigated based on signs and symptoms of individual patients.
g Tumour assessments of all regions where tumour lesions have been identified will be performed every 6 weeks (± 1 week) for 24 weeks, then every 9 weeks (± 1 week) for the
remainder of the treatment period. The methods of assessment of tumour burden used at baseline CT or MRI scans of chest and upper abdomen (including liver and adrenal glands)
must be used at each subsequent follow-up assessment. Any other sites at which new disease is suspected should also be appropriately imaged. To be performed within ± 7 days
until PD.
h Patients who discontinue study treatment for reasons other than PD will continue to undergo tumour assessments every 12 weeks (± 1 week) until PD, until death or until the data
cut-off.
i ECG will be performed Day 1 predose and postdose.
j The modality of the cardiac function assessments needs to be consistent throughout the study, i. e., if a MUGA scan is used for LVEF at screening, then a
MUGA scan should also be used for subsequent visits such as the visit of study treatment discontinuation. The patients should also be examined using the same 
machine and operator whenever possible.
k To be performed predose on Day 1 of each cycle. In the event that the urine dipstick or urinalysis shows 2 + proteinuria, a 24-hour urine should be collected.
Protocol V5.0 (22 May 2018)
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Centus Biotherapeutics
Clinical Protocol
Protocol No.: FKB238-002
Study Drug Name: FKB238
Day
Screening/
baselinea
Study Treatment Period (all visits within ± 3 days of schedule)
Study
treatment
disconti-
nuation
(± 7 days)
30 days
follow-up
after last
dose of
study
treatment
(± 7 days)
Follow-
up
Cycle 1
Cycle 2
Day 1
Cycle 3
Day 1
Cycle 4
Day 1
Cycles 5
Day 1
Cycle 6
Day 1
Cycle 7
and sub-
sequent
cycles
Day 1
1
8
15
Visit
1
2
3
4
5
6
7
8
9
Visit 10
onwards
Coagulation
X
X
X
X
X
X
X
X
X
ADA samplingl, m
X
X
X
X
X
Xm
Sampling for serum drug
concentrationm, n, o
Xo
X
Xo
X
X
Xm
Serum/urine pregnancy test – for 
women of childbearing potentialp
X
Randomisation
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
Combination drugs
administrations q
X
X
X
X
X
X
l To be performed at predose at Cycles 1, 2, and 4, Cycle 6 predose, study treatment discontinuation visit, and Follow-up period.
m Follow-up samples will be taken every 12 weeks (up to 1 year [± 14 days] after randomisation) until death, or the patient is lost to follow up, whichever occurs first.
n To be performed at predose at Cycles 1, 2, and 4, Cycle 6 predose, study treatment discontinuation visit, and Follow-up period. Additional samples at immediately after
completion of IP infusion on Cycles 1 and 4 are required.
o Additional samples at immediately after completion of IP infusion on Cycles 1 and 4 are required.
p A negative serum/urine pregnancy test within 7 days of starting study treatment in premenopausal women and women < 2 years after the end of menopause is required for
inclusion in this study.
q At least 4, and no more than 6 cycles. The number of cycles is determined by patients’ need and the investigator‘s assessment.
Protocol V5.0 (22 May 2018)
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Centus Biotherapeutics
Clinical Protocol
Protocol No.: FKB238-002
Study Drug Name: FKB238
Day
Screening/
baselinea
Study Treatment Period (all visits within ± 3 days of schedule)
Study
treatment
disconti-
nuation
(± 7 days)
30 days
follow-up
after last
dose of
study
treatment
(± 7 days)
Follow-
up
Cycle 1
Cycle 2
Day 1
Cycle 3
Day 1
Cycle 4
Day 1
Cycles 5
Day 1
Cycle 6
Day 1
Cycle 7
and sub-
sequent
cycles
Day 1
1
8
15
Visit
1
2
3
4
5
6
7
8
9
Visit 10
onwards
Study drug (IP) administration
X
X
X
X
X
X
X
Subject disposition notification
X
Survival status
Xr
Post Study Treatment therapy s
X
X
X
r Assessments for survival should be made every 8 weeks (± 1 week) following objective PD up to the data cut-off. In addition, patients should be contacted in the week following 
the data cut-off for the final survival analyses to provide complete survival data.
s Any systemic anti-cancer treatment, radiotherapy or cancer surgery conducted after discontinuation of study treatment will be collected until death, loss to follow-up, withdrawal
of consent or until the data cut-off (whichever occurs first).
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
7.7.2 Screening Procedures
All screening activities must be performed within 28 days before randomisation. The 
following lists the preferred sequence of screening activities:
• 
Informed consent
• 
Inclusion and exclusion criteria
• 
Demographics
• 
EGFR mutation and ALK gene rearrangement status. No tests are required.
Results available from standard of care testing and obtained prior to collection of 
informed consent will be acceptable. If the EGFR or ALK status is unknown, that 
should be recorded
• 
Medical history: medical history, surgery history, and prior chemo/radiation
treatment history
• 
Physical examination. For additional information, refer to Section 7.8.2.5.3
• 
Vital signs: blood pressure (mm Hg), pulse rate (bpm), and body temperature (°C).
Blood pressure needs to be assessed 3 times with at least 5 minute intervals for
each assessment. For additional information, refer to Section 7.8.2.5.1
• 
Height (cm) and weight (kg)
• 
ECOG PS. For additional information, refer to Section 7.8.2.5.5 and
APPENDIX B
• 
Baseline RECIST v1.1 assessment will be performed using CT (or MRI scans
where CT is clinically contra-indicated) at screening no more than 28 days prior 
to start of Study Treatment (Cycle 1 Day 1) and ideally should be performed as 
close as possible to the start of the study treatment. Baseline radiological 
assessments should cover the chest and the upper abdomen (including liver and 
the adrenal glands). Brain CT/MRI is required within 4 weeks prior to 
randomisation
• 
Any other areas of the disease involvement should be additionally investigated
based on signs and symptoms of individual patients. For additional information,
refer to Section 7.8.1.3
• 
12-lead ECG. For additional information, refer to Section 7.8.2.5.4
• 
Left ventricular ejection fraction (LVEF) by cardiac ultrasound or multiple-gated
acquisition (MUGA) scan
Protocol V5.0 (22 May 2018) 
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
• 
Laboratory assessments: haematology, biochemistry, urinalysis or urine dipstick
(if proteinuria  2+, 24-hour urine should be collected), and coagulation. For
additional information, refer to Section 7.8.2.4
• 
Pregnancy test - if applicable: serum or urine human chorionic gonadotropin
(hCG) test will be performed for women of childbearing potential. For additional
information, refer to Section 7.8.2.3.
• 
AEs
• 
Concomitant medications
7.7.3 Study Treatment Period Procedures Prior to Data Cut-Off
7.7.3.1 
Cycle 1
Days 1, 8, and 15
• 
On Day 1 only, eligible patients will be randomised in a ratio of 1:1 to either the
FKB238 group (paclitaxel and carboplatin plus FKB238) or the Avastin group
(paclitaxel and carboplatin plus EU-Avastin)
• 
Physical examination
• 
Vital signs: blood pressure, pulse rate, and body temperature
• 
ECOG PS
• 
On Day 1 only, weight
• 
On Day 1 only, 12-lead ECG, 2 hours within predose and postdose
• 
Laboratory assessments: haematology and biochemistry
• 
Coagulation (Day 1 only)
• 
Urinalysis or urine dipstick performed predose. If urinalysis or urine dipstick
shows  2 + proteinuria, 24-hour urine should be collected
• 
Antidrug antibody sampling at Day 1 predose
• 
Sampling for serum drug concentration at Day 1 predose and immediately after
completion of IP infusion
• 
AEs
• 
Concomitant medications
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
• 
On Day 1 only, combination drug administration (paclitaxel + carboplatin)
• 
On Day 1 only, IP administration (FKB238 or EU-Avastin, depending on
treatment assignment)
7.7.3.2 
Cycle 2 to Cycle 6
Day 1
• 
Physical examination
• 
Vital signs: blood pressure, pulse rate, and body temperature
• 
Weight
• 
ECOG PS
• 
Laboratory assessments: haematology and biochemistry
• 
Coagulation
• 
Urinalysis or urine dipstick. If urinalysis or urine dipstick shows  2 +
proteinuria, 24-hour urine should be collected
• 
Antidrug antibody sampling (predose at Day 1 of Cycles 2, 4, and 6)
• 
Sampling for serum drug concentration (predose at Cycles 2, 4, and 6). Additional
samples at immediately after completion of IP infusion on Cycle 4 are required)
• 
RECIST v1.1 assessment using CT (or MRI scans where CT is clinically
contra-indicated) will be performed every 6 weeks (± 1 week) until objective PD. 
The methods of assessment of tumour burden used at baseline CT or MRI scans 
of chest and upper abdomen (including liver and adrenal glands) must be used at 
each subsequent follow-up assessment. Any other sites at which new disease is 
suspected should also be appropriately imaged. If an unscheduled assessment was 
performed and the patient has not progressed, every attempt should be made to 
perform the subsequent assessments at their scheduled visits. No further 
radiological tumour assessments will be done after objective PD is documented. 
Every effort should be made to adhere to the original schedule of RECIST v1.1 
scans
• 
AEs
• 
Concomitant medications
• 
Combination drug administration (paclitaxel + carboplatin). The number of cycles
is determined by patients’ need and the investigator’s assessment
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
• 
IP administration (FKB238 or EU-Avastin, depending on treatment assignment).
Treatment will be continued until objective PD or other criteria for treatment
discontinuation are met
7.7.3.3 
Cycle 7 and Subsequent Cycles
Day 1
• 
Physical examination
• 
Vital signs: blood pressure, pulse rate, and body temperature
• 
Weight
• 
ECOG PS
• 
Laboratory assessments: haematology and biochemistry
• 
Coagulation
• 
Urinalysis or urine dipstick. If urinalysis or urine dipstick shows  2 +
proteinuria, 24-hour urine should be collected
• 
RECIST v1.1 assessment using CT (or MRI scans where CT is clinically
contra-indicated) will be performed every 6 weeks (± 1 week) for 24 weeks, then
every 9 weeks (± 1 week) for the remainder of the treatment period, until 
objective PD. The methods of assessment of tumour burden used at baseline CT 
or MRI scans of chest and upper abdomen (including liver and adrenal glands) 
must be used at each subsequent follow-up assessment. Any other sites at which 
new disease is suspected should also be appropriately imaged. If an unscheduled 
assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits. 
No further radiological tumour assessments will be done after objective PD is 
documented. Every effort should be made to adhere to the original schedule of 
RECIST v1.1 scans
• 
AEs
• 
Concomitant medications
• 
IP administration (FKB238 or EU-Avastin, depending on treatment assignment).
Treatment will be continued until objective PD or other criteria for treatment
discontinuation met
7.7.3.4 
Study Treatment Discontinuation Visit
• 
Physical examination
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
• 
Vital signs: blood pressure, pulse rate, and body temperature
• 
Weight
• 
ECOG PS
• 
12-lead ECG
• 
Laboratory: haematology, biochemistry, and urinalysis or urine dipstick
• 
Antidrug antibody sampling
• 
Sampling for serum drug concentration
• 
LVEF by cardiac ultrasound or MUGA
• 
Coagulation
• 
AEs
• 
Concomitant medications
• 
Post Study Treatment therapy
7.7.3.5 
Follow-up 30 Days After Last Dose of Study Treatment
A follow-up visit should be conducted 30 days after the last dose of study treatment.
• 
Physical examination
• 
Vital signs: blood pressure, pulse rate, and body temperature
• 
12-lead ECG
• 
AEs
• 
Concomitant medications
• 
Post Study Treatment therapy
7.7.4 Follow-up Period
Assessments for survival should be made every 8 weeks (± 1 week) following objective 
PD. Survival information may be obtained via telephone contact with the patient, 
patient’s family or by contact with the patient’s current physician. The details of first and 
subsequent therapies for cancer, after discontinuation of treatment, will be collected. 
Survival data will be collected up to the time of data cut-off. In addition, patients should 
be contacted in the week following the data cut-off for the final survival analyses to
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
provide complete survival data. In the event that the patient has actively withdrawn 
consent to the processing of their personal data the vital status of the patient can be 
obtained by site personnel from publicly available resources where it is possible to do so 
under applicable local laws.
Patients who discontinue study treatment for reasons other than PD will continue to 
undergo RECIST v1.1 tumour assessments every 12 weeks (± 1 week) until PD, until 
death, or until the data cut-off (whichever occurs first).
Follow-up antidrug antibody and serum drug concentration samples will be taken every 
12 weeks (up to 1 year [± 14 days] after randomisation) until death, or the patient is lost 
to follow-up, whichever occurs first.
At data cut-off all patients previously discontinued from study treatment and continuing 
in follow-up will complete the study and no further study assessments will be performed.
All ongoing and any new AEs/SAEs identified during the 30 calendar days after last dose 
of study treatment must be followed to resolution unless the event is considered by the 
investigator to be unlikely to resolve, or the patient is lost to follow-up.
7.7.5 Patient Management Post Data Cut-Off (Extended Treatment Period)
Patients receiving IP at the time of data cut-off will be offered the option of 
continuing IP in an Extended Treatment Period if the investigator believes the patient 
is gaining clinical benefit. See Table 14 for a schedule of assessments during the 
Extended Treatment Period.
The IP provided during the Extended Treatment Period will be consistent with the 
patient’s treatment allocation at the time of randomisation. IP vials will continue to be 
packaged in a blinding carton containing 1 IP vial in a blinded manner with uniquely 
numbered kit of FKB238/EU-Avastin (IP kit). The IP kit will be packaged, and labelled 
in accordance with Good Manufacturing Practice and distributed under Good Distribution 
Practice. The labels will include all the information required by each country’s regulatory 
requirements. The IP kits will continue to be allocated automatically according to
ClinPhone®RTSM.
Sponsor will continue to supply FKB238 after the data cut-off until either it is licensed in 
and commercial and reimbursement routes become available in that country, or it is 
determined that the benefit to risk profile does not support continued development of 
FKB238, or the national health authority has deemed the drug not approvable.
Patients receiving Avastin, where the investigator believes patients are gaining clinical 
benefit, will be provided the drug continuously until it is licensed in and commercial and 
reimbursement routes become available in that country.
In the Extended Treatment Period, patients will have vital signs, physical examinations, 
laboratory analyses, and radiological assessments performed by the investigator 
according to local standard of care practices. Complete assessments for safety, efficacy, 
pharmacokinetics, and immunology will not be collected by Sponsor during this period.
Protocol V5.0 (22 May 2018) 
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
The investigator will perform patient assessments according to locally defined standard 
of care practices. Investigators will be required to report to the Sponsor any SAEs, 
pregnancies, overdoses, and AEs that lead to discontinuation of treatment or death. 
Discontinuation from treatment will be considered discontinuation from the study.
SAEs, including any associated concomitant medications, will continue to be reported to 
the Sponsor for any patients who continue on FKB238/EU-Avastin until 30 days after 
study treatment is discontinued, in accordance with Section 7.8.2.1.13. Additionally, any 
SAE or non-SAE that is ongoing at the end of the study must be followed up to resolution 
unless the event is considered by the investigator to be unlikely to be resolved, or the 
patient is lost to follow-up.
Table 14 
Schedule of Assessments After Data Cut-Off
a
SAE-related treatments and concomitant medications needed to assess the SAE will be collected and
reported on the SAE form.
The investigator will be required to submit a paper Subject Disposition Form to the 
Sponsor or Sponsor’s delegate confirming patient withdrawal or death.
All paper forms should be submitted to the Sponsor via Fax. See Table 15 for contact 
information for submitting paper forms after data cut-off.
Table 15 
Contact Information for Submitting All Paper Forms After Data Cut-
Off
Fax
Email
North America
All other countries
Protocol V5.0 (22 May 2018) 
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CONFIDENTIAL
Day
Prior to entry into Extended
Treatment Period
Extended 
Treatment
Period cycles
Day 1
Treatment 
discontinuation
Informed Consent
X
Study drug (IP) administration
X
Collection and follow-upa for SAEs 
and AEs leading to withdrawal and 
death
X
X
Subject disposition notification
X


Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
7.8 
Efficacy and Safety Variables
7.8.1 Efficacy Assessments
Radiological imaging will be assessed by investigators as well as an independent central 
radiological committee based on RECIST v1.1 criteria. Primary efficacy assessment will 
be presented based on the investigators’ assessment results as well as the independent 
central radiological assessment results, but primary efficacy assessment based on the 
independent central radiological assessment results will be used as a pivotal result of the 
study. As per protocol requirement, efficacy assessments will only be performed prior to 
data cut-off. See Section 7.7.5 for information regarding patient management and 
reporting after data cut-off (during Extended Treatment Period).
7.8.1.1 
Primary Efficacy Assessment
The primary variable in this study is the best overall response (BOR) that is either CR or 
PR (by RECIST v1.1). A BOR is defined as the best response (in the order of CR, PR, 
SD, PD, and not evaluable) among all post-baseline disease assessments that occur until 
progression, or last evaluable assessment in the absence of progression prior to the 
initiation of subsequent anti-cancer therapy, irrespective of whether or not subjects 
discontinued the study treatment. Overall response rate (ORR) is defined as the 
proportion of subjects with BOR of either CR or PR according to RECIST v1.1.
7.8.1.2 
Secondary Efficacy Assessments
The secondary variables of this study are: ORR at week 19, PFS, OS, DOR, and DCR as 
assessed in both treatment arms.
7.8.1.3 
Tumour Assessments by Imaging Techniques Using RECIST
RECIST v1.1 criteria will be used to assess patient response to treatment by determining 
ORR, DOR, PFS, and DCR. The RECIST v1.1 Guidelines for measurable,
non-measurable, target and non-target lesions and the objective tumour response criteria
(CR, PR, SD or PD) are presented in APPENDIX C. Chest X-ray must not be used for 
the assessment of target lesions. The methods of assessment of tumour burden used at 
baseline (CT or MRI scans where CT is clinically contra-indicated of chest and upper 
abdomen including adrenal glands) must be used at each subsequent follow-up 
assessment unless this is medically contra-indicated (eg, the development of an allergy to 
contrast medium).
Baseline RECIST v1.1 assessment will be performed using CT (or MRI scans where CT 
is clinically contra-indicated) at screening no more than 28 days prior to start of study 
treatment (Cycle 1 Day 1) and ideally should be performed as close as possible to the 
start of the study treatment. Baseline radiological assessments should cover the chest and 
the upper abdomen (including liver and the adrenal glands). Any other areas of the 
disease involvement should be additionally investigated based on signs and symptoms of 
individual patients. Brain CT/MRI is required within 4 weeks prior to the randomisation.
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
After start of study treatment, RECIST v1.1 assessment using CT (or MRI scans where 
CT is clinically contra-indicated) will be performed every 6 weeks (± 1 week) for 
24 weeks, then every 9 weeks (± 1 week) for the remainder of the treatment period, until 
objective PD. The methods of assessment of tumour burden used at baseline CT or MRI 
scans of chest and upper abdomen (including liver and adrenal glands) must be used at 
each subsequent follow-up assessment. Any other sites at which new disease is suspected 
should also be appropriately imaged. If an unscheduled assessment was performed and 
the patient has not progressed, every attempt should be made to perform the subsequent 
assessments at their scheduled visits.
Categorisation of objective tumour response assessment will be based on the 
RECIST v1.1 criteria of response: CR, PR, SD, and PD. Target lesion (TL) progression 
will be calculated in comparison to when the tumour burden was at a minimum (ie, 
smallest sum of diameters previously recorded on study). In the absence of progression, 
tumour response (CR, PR, SD) will be calculated in comparison to the baseline tumour 
measurements obtained before starting treatment.
If the investigator is in doubt as to whether progression has occurred, particularly with 
response to NTL (non-target lesion) or the appearance of a new lesion, it is advisable to 
continue treatment until the next scheduled assessment, or sooner if clinically indicated, 
and re-assess the patient’s status. If repeat scans confirm progression, then the date of the 
initial scan should be declared as the date of progression.
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of 
SD or PR in target disease, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more NTLs is 
usually not sufficient to quality for unequivocal progression status.
No further radiological tumour assessments will be done after objective PD is 
documented. Patients who discontinue study treatment for reasons other than PD will 
continue to undergo RECIST v1.1 tumour assessments every 12 weeks (± 1 week) until 
PD, until death, or until the data cut-off (whichever occurs first).
Every effort should be made to adhere to the original schedule of RECIST v1.1 scans.
Please 
consider 
the 
following 
recommendations 
upon 
determining
measurable/non-measurable lesions, and target/non-target lesions:
• 
Previously irradiated lesions should be accessed as NTLs
• 
Brain lesions should be selected as non-measurable lesions
• 
Osteoblastic should be selected as non-measurable lesions
• 
Osteolytic bone lesions or mixed bone metastasis with measurable soft tissue
component should only be selected as TLs, if the soft tissue component meets the
criteria of measurability
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
• 
Skin lesions documented by colour photography should be selected as NTLs due
to significant variability and suboptimal reproducibility of lesion measurements
Central Reading of Scans
An independent central review of all scans used in the assessment of tumours using 
RECIST v1.1 will be conducted. All imaging assessments including unscheduled visit 
scans will be collected on an ongoing basis and sent to a Sponsor appointed CRO for 
central analysis. Results of this independent review will not be communicated to 
investigators, and the management of patients will be based solely upon the results of the 
RECIST v1.1 assessment conducted by the investigator.
7.8.2 Safety Assessments
Safety will be monitored throughout the study for all patients. The analysis of the safety 
data will be performed using the Safety Population. Limited safety reporting will be 
performed during the Extended Treatment Period as detailed in Section 7.7.5.
7.8.2.1 
Adverse Events
7.8.2.1.1 
Definition of Adverse Events
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical 
condition can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged 
liver) or the abnormal results of an investigation (eg, laboratory findings, 
electrocardiogram). In clinical studies, an AE can include an undesirable medical 
condition occurring at any time, including run-in or washout periods, even if no study 
treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
7.8.2.1.2 
Definition of Serious Adverse Events
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-
up), that fulfils one or more of the following criteria:
• 
Results in death
• 
Is immediately life-threatening
• 
Requires in-patient hospitalisation or prolongation of existing hospitalisation
• 
Results in persistent or significant disability/incapacity or substantial disruption of
the ability to conduct normal life functions
• 
Is a congenital abnormality or birth defect
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
• 
Is an important medical event that may jeopardise the patient or may require
medical intervention to prevent one of the outcomes listed above
7.8.2.1.3 
Recording of Adverse Events
Time period for collection of adverse events
AEs will be collected from time of signature of informed consent, throughout the 
treatment period and up to and including the 30-days after the last dose of study 
treatment. Prior to data cut-off, all ongoing and any new AEs/SAEs identified during the 
30 calendar days after last dose of study treatment must be followed to resolution unless 
the event is considered by the investigator to be unlikely to resolve, or the patient is lost 
to follow-up. See Section 7.7.5 for information regarding patient management and 
reporting after data cut-off (during Extended Treatment Period).
SAEs will be recorded from the time of informed consent.
Follow-up of unresolved adverse events
Any SAE or non-serious AE that is ongoing at the time of the 30 day follow-up, must be 
followed up to resolution unless the event is considered by the investigator to be unlikely 
to resolve, or the patient is lost to follow-up.
The Sponsor retains the right to request additional information for any patient with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Post Follow-up adverse events
After study treatment completion (ie, after any scheduled post treatment follow-up period 
has ended) there is no obligation to actively report information on new AEs or SAEs 
occurring in former study patients. This includes new AEs/SAEs in patients still being 
followed up for survival but who have completed the post treatment follow-up period 
(30 days). If an investigator learns of any SAEs, including death, at any time after a 
patient has completed the study, and he/she considers there is a reasonable possibility that 
the event is causally related to the investigational product, the investigator should notify 
the Sponsor.
If patients who are gaining clinical benefit are allowed to continue study treatment post 
data cut-off and / or post study completion then as a minimum all SAEs must continue to 
be collected and reported to the Sponsor within the usual timeframe.
7.8.2.1.4 
Variables
The following variables will be collect for each AE:
• 
AE (verbatim)
• 
The date when the AE started and stopped
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
• 
Changes in CTCAE grade
• 
Whether the AE is serious or not
• 
Investigator causality rating against the Investigational Product (yes or no)
• 
Action taken with regard to investigational product
• 
Outcome
In addition, the following variables will be collected for SAEs:
• 
Date AE met criteria for serious AE
• 
Date investigator became aware of serious AE
• 
Reason that AE is serious ("due to")
• 
Date of hospitalisation
• 
Date of discharge
• 
Probable cause of death
• 
Date of death
• 
Autopsy performed
• 
Causality assessment in relation to Study procedure(s)
• 
Causality assessment in relation to Other medication
• 
Description of AE
7.8.2.1.5 
Severity of AEs
For each episode on an AE, all changes to the CTCAE grade attained as well as the 
highest attained CTCAE grade should be reported.
It is important to distinguish between serious and severe AEs. Severity is a measure of
intensity whereas seriousness is defined by the criteria in Section 7.8.2.1.2. An AE of
severe intensity need not necessarily be considered serious. For example, nausea that 
persists for several hours may be considered severe nausea, but not an SAE. On the other 
hand, a stroke that results in only a limited degree of disability may be considered a mild 
stroke but would be an SAE.
The grading scales found in the National Cancer Institute (NCI) CTCAE version 4.0 will 
be utilised for all events with an assigned CTCAE grading. For those events without
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
assigned CTCAE grades the recommendation is that the CTCAE criteria that convert 
mild, moderate and severe events into CTCAE grades should be used.
7.8.2.1.6 
Causality Collection
The investigator will assess causal relationship between IP and each AE, and answer 'yes' 
or 'no' to the question 'Do you consider that there is a reasonable possibility that the event 
may have been caused by the investigational product?'
For SAEs causal relationship will also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the 
causal relationship is implied as 'yes'.
7.8.2.1.7 
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the patient or reported in response to the open 
question from the study personnel: 'Have you had any health problems since the previous 
visit/you were last asked?', or revealed by observation will be collected and recorded in 
the eCRF. When collecting AEs, the recording of diagnoses is preferred (when possible) 
to recording a list of signs and symptoms. However, if a diagnosis is known and there are 
other signs or symptoms that are not generally part of the diagnosis, the diagnosis and 
each sign or symptom will be recorded separately.
7.8.2.1.8 
Adverse Events Based on Examinations and Tests
The results from protocol-mandated laboratory tests and vital signs will be summarised in 
the CSR. Deterioration as compared to baseline in protocol-mandated laboratory values 
or vital signs should therefore only be reported if they fulfil any of the SAE criteria. If 
these data are the reason for discontinuation of treatment with the IP, then this must be 
recorded as an AE and a description included whether this is temporary or permanent.
If deterioration in a laboratory value/vital sign/ECG is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory 
result/vital sign/ECG will be considered as additional information. Wherever possible the 
reporting investigator uses the clinical, rather than the laboratory term (eg, anaemia 
versus low haemoglobin value). In the absence of clinical signs or symptoms, clinically 
relevant deteriorations in non-mandated parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, 
should not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical 
examination as compared with the baseline assessment will be reported as an AE.
NB. Cases where a patient shows an AST or ALT  3 x ULN together with total bilirubin 
 2 x ULN may need to be reported as SAEs (for details, refer to APPENDIX A).
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
7.8.2.1.9 
Disease Progression
Disease progression can be considered as a worsening of a patient's condition attributable 
to the disease for which the investigational product is being studied. It may be an increase 
in the severity of the disease under study and/or increases in the signs and symptoms of 
the cancer. The development of new, or progression of existing metastasis to the primary 
cancer under study should be considered as disease progression and not an AE. Events, 
which are unequivocally due to disease progression, should not be reported as an AE 
during the study.
7.8.2.1.10 New Cancers
The development of a new primary cancer (including skin cancer) should be regarded as 
an AE and will generally meet at least one of the serious criteria (see Section 7.8.2.1.2). 
New primary cancers are those that are not the primary reason for the administration of 
the study treatment and have developed after the inclusion of the patient into the study. 
They do not include metastases of the original cancer. Symptoms of metastasis or the 
metastasis itself should not be reported as an AE/SAE, as they are considered to be 
disease progression.
7.8.2.1.11 Lack of Efficacy
When there is deterioration in the lung cancer, for which the study treatment(s) is being 
used, there may be uncertainty as to whether this is lack of efficacy or an AE. In such 
cases, unless the Sponsor or the reporting physician considers that the study treatment 
contributed to the deterioration of the condition, or local regulations state to the contrary, 
the deterioration should be considered to be a lack of efficacy and not an AE.
7.8.2.1.12 Deaths
All deaths that occur prior to data cut-off, or within the protocol-defined 30-day post 
study follow-up period after the administration of the last dose of study treatment, must 
be reported as follows:
Death clearly the result of disease progression should be reported to the study monitor at 
the next monitoring visit and should be documented in the DEATH eCRF but should not 
be reported as an SAE.
Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported to the study monitor as a SAE within 24 hours. 
The report should contain a comment regarding the co-involvement of progression of 
disease, if appropriate, and should assign main and contributory causes of death. This 
information can be captured in the DEATH eCRF.
Deaths with an unknown cause should always be reported as a SAE. A post-mortem 
maybe helpful in the assessment of the cause of death, and if performed a copy of the
post-mortem results should be forwarded to the Sponsor within the usual timeframes.
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
After data cut-off, patient deaths will be reported using a paper Patient Disposition Form. 
See Section 7.7.5 for information regarding patient management and reporting after data 
cut-off (during Extended Treatment Period). Death not due (or not clearly due) to 
progression of the disease under study or death with an unknown cause must continue to 
be reported as an SAE using the paper SAE Form.
7.8.2.1.13 Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the 
investigational product, or to the study procedure(s). All SAEs will be recorded in the 
eCRF prior to data cut-off. After data cut-off, SAEs will be reported on a paper SAE 
form. See Section 7.7.5 for information regarding patient management and reporting after 
data cut-off (during Extended Treatment Period).
If any SAE occurs in the course of the study, then investigators or other site personnel 
should complete the eCRF (prior to data cut-off) or paper SAE form (after data cut-off) 
immediately, or no later than 24 hours of when he or she becomes aware of it.
Once the investigators or other site personnel indicate an AE is serious in the eCRF, an 
automated e-mail alert is sent to the designated PAREXEL representative. If the eCRF is 
not available, the investigator or other study site personnel reports a SAE by sending a 
SAE form by fax / e-mail to the designated PAREXEL representative. The PAREXEL 
representative will advise the investigator/study site personnel how to proceed.
The designated PAREXEL representative works with the investigator to ensure that all 
the necessary information is provided .
For fatal or life-threatening AEs where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigators or other site personnel inform 
PAREXEL representatives of any follow-up information on a previously reported SAE 
immediately, or no later than 24 hours of when he or she becomes aware of it.
7.8.2.2 
Overdose
Investigators are advised that any patient, who receives a higher dose than intended 
should be monitored closely, managed with appropriate supportive care and followed up 
expectantly.
Prior to data cut-off, such overdoses should be recorded as follows:
• 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on
the relevant AE modules in the CRF and on the Overdose eCRF module
• 
An overdose without associated symptoms is only reported on the Overdose
eCRF module
After data cut-off, overdoses should be reported using the paper Overdose form. See 
Section 7.7.5 for information regarding patient management and reporting after data cut-
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Study Drug Name: FKB238
off (during Extended Treatment Period).
If an overdose on FKB238/Avastin occurs in the course of the study, then the investigator 
or other site personnel must report the event (using the Overdose eCRF prior to data cut- 
off or paper Overdose form after data cut-off) no later than 24 hours of when he or she 
becomes aware of it.
The designated PAREXEL representative works with the investigator to ensure that all 
relevant information is provided to the safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see 
Section 7.8.2.1.13. For other overdoses, reporting must occur within 30 days.
7.8.2.3 
Pregnancy
7.8.2.3.1 
Maternal exposure
All pregnancies and outcomes of pregnancy should be reported during the course of the 
study and within 30 days of the last dose of study treatment.
A serum/urine pregnancy hCG test will be performed for women of childbearing 
potential at screening. If a patient becomes pregnant during the course of the study, study 
treatment should be discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the IP 
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported 
and handled as SAEs. Elective abortions without complications should not be handled as 
AEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, 
ectopic pregnancy, normal birth or congenital abnormality) should be followed up and 
documented even if the patient was discontinued from the study.
Any pregnancy that occurs in the course of the study or within 30 days of the final dose 
of the investigational product must be reported by the investigator or other site personnel 
within 1 day ie, immediately but no later than 24 hours of when he or she becomes 
aware of it. Before data cut-off, an eCRF must be completed. After data cut-off, 
pregnancies will be reported via a paper pregnancy form. See Section 7.7.5 for 
information regarding patient management and reporting after data cut-off, during 
Extended Treatment Period.
The designated PAREXEL representative works with the investigator to ensure that all 
relevant information is provided to the safety data entry site within 5 calendar days for 
SAEs.
7.8.2.3.2 Paternal exposure
Pregnancy of the patient’s partners is not considered to be an AE. However, the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy,
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Study Drug Name: FKB238
normal birth or congenital abnormality) should if possible be followed up and 
documented. To capture information about a pregnancy from the partner of a male 
patient, the male patient’s partner consent must be obtained to collect information related 
to the pregnancy and outcome; the male patient should not be asked to provide this 
information. A consent form specific to this situation must be used. The outcome of any 
conception occurring from the date of the first dose until 6 months after dosing should be 
followed up and documented.
7.8.2.4 
Safety Laboratory Determinations
Blood and urine samples for determination of clinical chemistry, haematology and 
urinalysis will be taken predose at the times indicated in the schedule in Table 13. If 
clinical chemistry, haematology and urinalysis screening assessments have been 
performed within 14 days prior to staring study treatment, they do not need to be repeated 
on Cycle 1 Day 1 if the patient's condition has not changed (no new treatment during this 
period of time, no new complication or aggravation).
Additional safety laboratory samples may be collected if clinically indicated at the 
discretion of the investigator. The date and results (values, units and reference ranges) 
will be recorded on the appropriate eCRF.
The laboratory variables to be measured are summarised in Table 16.
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Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
Table 16 
Laboratory Variables
Chemistry 
Haematology (whole blood)
Serum (S) / plasma (P)-Albumin 
Haematocrit
S/P-ALP 
Haemoglobin
S/P-ALT 
Platelet count
S/P-AST 
Red blood cell count
S/P-BUN or Urea 
Reticulocytes
S/P-Calcium total 
White blood cell count
S/P-Chloride 
White blood cell differential (% or absolute):
S/P-Creatinine and creatinine clearance 
Basophils
S/P-GGT 
Eosinophils
S/P-Glucose 
Lymphocytes
S/P-LDH 
Monocytes
S/P-Phosphorus 
Neutrophils
S/P-Magnesium
S/P-Potassium
S/P-Sodium 
Coagulation
S/P-Total Bilirubin 
PTT
S/P-Total Protein 
Prothrombin time or INR*
Urinalysis or urine dipstick
U-blood
U-Protein
U-Glucose
* Either prothrombin time or INR may be assessed; there is no need for performing both tests.
The volume of blood to be collected is summarised in Table 17.
Table 17 
Volume of Blood to be Collected
Note: If PK and ADA sample are taken at the same time, a total of 6 mL of blood will be collected for both 
PK and ADA. More detail is available in the Laboratory Manual.
Additionally, at the Screening Visit, a pregnancy test (serum or urine tests are acceptable 
based on the site’s standard clinical practice) will be collected for women of childbearing 
potential only.
The investigator should make an assessment of the available results with regard to
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Assessment
Volume (mL/visit)
Safety
Haematology
3 (approximately)
Biochemistry
5 (approximately)
Coagulation
Assessment to be included in biochemistry sample
Serum drug concentration
3.5
Antidrug antibody
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Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
clinically relevant abnormalities. The laboratory results should be signed and dated and 
retained at centre as source data for laboratory variables. For information on how AEs 
based on laboratory tests should be recorded and reported, see Section 7.8.2.1.8.
NB. In case a patient shows an AST or ALT  3 x ULN together with total bilirubin 
2 x ULN at any point during the study following the start of study medication 
irrespective of an increase of alkaline phosphatase (potential Hy’s Law), please refer to 
APPENDIX A ‘Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law’, for further instructions.
A urine dipstick test or urinalysis will be performed at screening, predose on Day 1 of 
each cycle and on Days 8 and 15 of Cycle 1 and at the study treatment discontinuation 
visit. In the event that the urinalysis or urine dipstick shows  2 + proteinuria, a 24-hour 
urine should be collected. Dose adjustment for proteinuria should be handled as described 
in Sections 7.6.7.1 and 7.6.7.2.
7.8.2.5 
Vital Signs, Physical Examination, and Other Safety Evaluations
7.8.2.5.1 
Vital Signs
Vital signs will be assessed according to the schedule in Table 13 and will include 
systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), and body 
temperature (°C). Assessments will be performed predose, at the visits as shown in the 
schedule in Table 13, and on occurrence of any cardiac AE. Additionally at the discretion 
of the investigator if clinically indicated. Home monitoring of blood pressure is 
encouraged when the patient is taking IP.
Any changes in vital signs should be recorded as an AE if applicable.
Patients should be seated and allowed to rest for at least 5 minutes before taking the 
blood pressure measurement (standardize body position and allow for patients to be calm) 
and pulse rate. At the Screening Visit, blood pressure needs to be assessed 3 times with at 
least 5 minute intervals for each assessment. Each visit's blood pressure measurement 
should be taken before any infusion of pre-medications, combination drugs, or FKB238/
EU-Avastin. A blood pressure cuff appropriate for the size of the patient's arm should be 
used to ensure accuracy of the measurement.
7.8.2.5.2 
Weight and Height
Weight will be performed at screening and then Day 1 of each cycle as well as the 
Discontinuation Visit. Height will be assessed at screening only.
7.8.2.5.3 
Physical Examination
Physical examinations will be conducted according to the schedule in Table 13. A 
physical examination will be performed and include an assessment of the following: 
general appearance, skin, head and neck (including ears, eyes, nose and throat), 
respiratory, cardiovascular, abdomen, lymph nodes, thyroid, musculo-skeletal (including
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Study Drug Name: FKB238
spine and extremities) and neurological systems. Findings during the screening and 
baseline visits should be recorded as medical history on the eCRF.
7.8.2.5.4 
12-lead Electrocardiogram
ECGs are required within 7 days prior to starting study treatment, on Day 1 of Cycle 1, 
2 hours within predose and postdose, and when clinically indicated and at the Follow-up 
visit after the patient has discontinued the study treatment.
Twelve-lead ECGs will be obtained after the patient has been rested in a supine position 
for at least 5 minutes in each case. All 12-lead ECGs should be recorded while the patient 
is in the supine position. The investigator or designated physician will review the data 
each of the timed 12-lead ECGs on each of the study days when they are collected.
ECGs will be recorded at 25 mm/sec. All ECGs should be assessed by the investigator as 
to whether they are clinically significantly abnormal / not clinically significantly 
abnormal. If there is a clinically significant abnormal finding, the investigator will record 
it as an AE on the eCRF. A copy of the ECG indicating the study number and E-code will 
be included in the study file. Additional ECGs may be performed at the investigator’s 
discretion.
7.8.2.5.5 
ECOG PS
Patients should have an ECOG PS of 0 or 1 at Screening to be included in the study. The 
investigator will assess ECOG PS at Screening, and during the Study Treatment Period, 
and Follow-up Period as noted in Table 13. An ECOG PS that worsens during the study 
will not require withdrawal from treatment. Refer to APPENDIX B for definitions of 
ECOG PS grades.
7.8.3 Other Assessments
7.8.3.1 
Immunogenicity Assessment
Serum for measurement of the presence of ADAs for FKB238 and EU-Avastin will be 
collected according to the schedule in Table 18 and will be analysed using validated 
methods. A tiered analysis approach will be followed where samples positive for ADA at 
screening step will be confirmed for ADA presence. The confirmed positive samples will 
then be assessed for ADA titre and the presence of neutralising antibodies.
Table 18 
Schedule of Pharmacokinetic and Antidrug Antibody Sampling
1 Follow-up samples will be taken every 12 weeks (up to 1 year [± 14 days] after randomisation) until death, 
or the patient is lost to follow-up, whichever occurs first.
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Cycle 1
Day 1
Cycle 2
Day 1
Cycle 4
Day 1
Cycle 6
Day 1
Study treatment 
discontinuation visit
Follow-
up
Predose
PK/ADA
PK/ADA
PK/ADA
PK/ADA
PK/ADA
PK/ADA1
Immediately after 
completion of IP 
infusion
PK
PK


Centus Biotherapeutics 
Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
7.8.3.2 
Pharmacokinetics Measurement
Serum for IP concentration measurement will be collected to obtain pharmacokinetics of 
IP according to the schedule in Table 18 and will be analysed using validated methods.
7.9 
Statistical Methods
7.9.1 Determination of Sample Size
Assuming a dropout rate of 10%, it is anticipated that approximately 730 patients will be 
randomised into the study in a 1:1 ratio (365 patients in the FKB238 group and 
365 patients in the Avastin group) in order to have a total of 656 patients who complete 
study treatment. Sample size was determined to meet both the EMA and FDA 
requirements, which differ in several aspects.
To fulfil the EMA requirements, a meta-analysis of available randomised clinical studies 
of Avastin demonstrated that the risk-difference for the ORR for the control arm 
compared to the Avastin treatment arms was calculated to be 0.1938 (80% confidence 
interval [CI]: [0.1564, 0.2312]). Based on the result of the meta-analysis, an equivalence 
margin for the risk-difference was determined to be 0.1221, which preserves 22% of the 
treatment effect characterised by the lower 80% CI for the risk-difference of ORR.
The NCSS PASS 2005 statistical software was used for the sample size calculation. With 
the adverse events margin for the risk-difference of 0.1221, an expected response rate of 
35% in both treatment arms, the study design employing a two one-sided test (TOST) 
procedure, and an overall Type I error rate of 2.5%, a sample size of 656 patients (328 
per group) was calculated to provide 80% power to demonstrate that the 95% CI about 
the risk-difference comparing FKB238 and EU-Avastin falls completely within ± 0.1221. 
Approximately 730 NS-NSCLC patients (allowing for a dropout rate of 10%) will be 
randomised either to the FKB238 group or Avastin group in a 1:1 ratio in a parallel group 
study.
Per the FDA requirements, a meta-analysis was performed on data from relevant clinical 
trials of Avastin, resulting in an estimate of the risk-ratio of 0.5212 along with a 70% CI, 
(0.4775, 0.5689). With lower and upper equivalence margins of 0.73 and 1.38, which 
preserve 50% treatment effects determined by the lower and upper limits respectively of 
the 70% CI, an expected response rate of 35% in both treatment arms, a TOST procedure 
for equivalence, and the overall Type I error rate at 5%, a sample size of 656 patients 
(328 per group) provides 80% power to demonstrate that the 90% CI for the risk-ratio 
comparing FKB238 and EU-Avastin is entirely enclosed within 0.73 to 1.38. Accounting 
for potential 10% dropouts, approximately 730 patients will be randomised.
7.9.2 Patient Populations Analysed
The following analysis populations will be included for this study:
ITT: all patients randomised to treatment. Patients will be included in the treatment 
group according to the randomisation assigned, regardless of the treatment actually given.
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Study Drug Name: FKB238
All efficacy analyses will be performed on the ITT population. These analyses will be 
treated as the primary analysis for the FDA requirement and as sensitivity analysis 
otherwise.
PPS: all patients randomised to treatment who received at least 1 dose of IP with no 
important protocol violations or deviations (see Section 7.9.4). Patients will be included 
in the treatment group according to the treatment actually given. All efficacy analyses 
will be performed on the PPS population. These analyses will be treated as the primary 
analysis for the EMA requirement and as sensitivity analysis otherwise.
Safety Population: all patients randomised to treatment who received at least 1 dose of 
IP. Patients will be included in the treatment group according to the treatment actually 
given. All safety analyses will be performed on the Safety Population.
PK Population: all PPS patients who have at least one serum drug concentration data, 
which is defined in the study protocol, after IP administration.
7.9.3 General Considerations
Safety and efficacy analyses will be based on data collected prior to data cut-off.
Descriptive summary statistics for continuous variables will include the number of 
patients (N), mean, standard deviation, minimum, median, and maximum.
Descriptive summary statistics for categorical variables will include frequency counts and 
percentages (n [%]). Unless otherwise stated, the denominator for percentage calculations 
will be the number of patients in the analysis population.
Unless otherwise stated, associations of treatment with clinical outcomes will be adjusted 
for the following covariates:
• 
EGFR mutation and ALK gene arrangement status (both are tested and known
negative versus status unknown for either)
• 
ECOG PS (0 versus 1)
• 
Geographical region (North America, Western Europe, East Asia, All Other
Regions)
• 
Prior weight loss over the previous 6 months (< 5% yes versus no)
• 
Disease stage (advanced or recurrent)
• 
Gender
• 
Smoking history
• 
Age
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Study Drug Name: FKB238
The primary endpoint analysis will be performed using a TOST procedure. All data 
processing, summarisation and analyses will be performed using SAS Enterprise Guide 
version 5.1 (or higher) on the SAS Hosted Environment.
7.9.4 Important Protocol Violations
Protocol violations and deviations will be tracked and recorded throughout the study and 
presented in a by-patient Listing. Patients with important protocol violations will be 
excluded from the PPS. Important protocol violations will be identified before database 
lock and will be described in the SAP.
7.9.5 Efficacy Analysis
7.9.5.1 
Primary Efficacy Outcome Measures
The number (%) of patients with a best response of CR or PR will be presented by 
treatment arm.
The TOST procedure will be used for testing the null hypothesis of non-equivalence 
against the alternative hypothesis of equivalence. To fulfil the EMA’s requirement, the 
TOST procedure will be carried out using PPS by comparing a 95% CI for the ORR 
difference between FKB238 and EU-Avastin to the margin [± 0.1221], which is deemed 
to represent a clinically acceptable difference with respect to ORR. If the true CI is within 
the interval [± 0.1221], an equivalence between FKB238 and EU-Avastin, with respect to 
the ORR, is confirmed. To meet the FDA’s requirements, the TOST procedure will be 
performed based on ITT population by comparing a 90% CI for the ORR ratio between 
FKB238 and EU-Avastin to the margin [0.73, 1.38], which is deemed to represent a 
clinically acceptable difference with respect to ORR. If the true CI is within the interval 
[0.73, 1.38], an equivalence between FKB238 and EU-Avastin, with respect to the ORR, 
is confirmed.
7.9.5.2 
Secondary Efficacy Outcome Measures
The logistic regression model will be fitted for the overall response and treatment 
adjusted for the covariates. The adjusted odds ratio and corresponding 95% CI will be 
presented.
Kaplan-Meier curves for PFS, OS, and DOR showing medians and corresponding 
95% CI based on the Kaplan-Meier estimator per treatment arm will be presented.
The multiple Cox proportional hazards model will be fitted for all time to event endpoints 
including treatment group adjusted for the covariates. The hazard ratios and 
corresponding 95% CI for treatment effect and the covariates will be presented.
DCR and ORR at week 19 will be estimated and compared between treatment groups, 
using descriptive statistics.
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Study Drug Name: FKB238
7.9.6 Safety Analysis
Safety variables include incidence of AEs, laboratory test results, vital signs, ECG 
results, ECOG PS, and physical examination findings. All safety analyses will be based 
on the Safety Population. No formal statistical analysis of the safety data will be 
performed.
Summary tables will be provided for all AEs by treatment group. The incidence of AEs, 
SAEs, AEs leading to discontinuation of the study treatment, AEs leading to death, AEs 
of special interest (well-known AEs of Avastin), etc., will be presented by Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) and preferred 
term.
The AE summary tables will include counts of patients. Therefore, if a patient 
experiences more than 1 episode of a particular AE, the patient will be counted only once 
for that event. If a patient has more than 1 AE that is coded to the same preferred term, 
the patient will be counted only once for that preferred term. Similarly, if a patient has 
more than 1 AE within a SOC, the patient will be counted only once in that SOC.
Laboratory test variables will be summarised by treatment group and visit using
descriptive statistics (number of patients, mean, standard deviation, minimum, maximum, 
and mean change from baseline). Shift tables from baseline to the worst NCI CTCAE 
grade at post-baseline will be produced for the laboratory parameters. Data obtained from 
laboratory tests not required by the protocol will not be summarised, but will be listed.
Descriptive statistics of vital signs and ECG results at each visit will be presented by 
treatment group. Physical examination findings will be listed for each patient.
7.9.7 Other Outcome Measures
7.9.7.1 
Immunogenicity Outcome Measures
The ADA incidence rate produced by FKB238 and EU-Avastin at each time point will be 
assessed using descriptive statistics. The impact of ADA formation on serum drug 
concentrations will be assessed using descriptive statistics, if relevant.
7.9.7.2 
Pharmacokinetics Outcome Measures
Ctrough will be compared between treatment groups and descriptive statistics will be 
provided. The impact of ADA on Ctrough will be assessed descriptively. The PK data from 
this study may be combined with that previously obtained in healthy volunteers using a 
population PK analysis method. If done, this analysis will be reported separately from the 
CSR for this study.
7.9.8 Interim Analysis
Review of study safety data by the DMC will be conducted during the study. For 
additional information, refer to Section 7.5.
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Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
There is no formal interim analysis for efficacy planned.
8.
STUDY MANAGEMENT BY PAREXEL
8.1 
Pre-study Activities
Before the first patient is screened for the study, it is necessary for a representative of 
PAREXEL to visit the investigational study site. For details, please refer to the study 
manual.
8.2 
Training of Study Site Personnel
Before the first patient is entered into the study, a PAREXEL representative will review 
and discuss the requirements of the clinical study protocol and related documents with 
the investigational staff and also train them in any study specific procedures.
The investigator will ensure that appropriate training relevant to the study is given to all 
of the staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. The investigator will maintain a training record of all 
individuals involved in the study (medical, nursing and other staff). For details, please 
refer to the study manual.
8.3 
Monitoring of the Study
During the study, a PAREXEL representative will have regular contacts with the study 
site. For details, please refer to the study manual.
8.4 
Source Data
Refer to the Clinical Study Agreement for location of source data.
8.5 
Study Agreements
The investigator at each centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of 
any inconsistency between this clinical study protocol and the Clinical Study Agreement, 
the terms of clinical study protocol shall prevail with respect to the conduct of the study 
and the treatment of patients and in all other respects, not relating to study conduct or 
treatment of patients, the terms of the Clinical Study Agreement shall prevail. For details, 
please refer to the study manual.
8.6 
Archiving of Study Documents
The investigator follows the principles outlined in the Clinical Study Agreement.
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Study Drug Name: FKB238
9.
DATA MANAGEMENT AND QUALITY CONTROL BY PAREXEL
9.1 
Electronic Data Capture
The investigator should keep the original document of all patient data, including case 
history and visit record, in the original source documentation, to be stored at the study 
site. All individual, patient-specific study data will also be entered into an electronic data 
capture (EDC) system or eCRF in a timely fashion. For data that will only be documented 
in the eCRF (eg, CTCAE grade, investigator assessed tumour response, etc.), respective 
eCRF data will be regarded as source data.
An eCRF must be completed for each patient who signs an ICF and undergoes any pre-
screening or screening procedures, according to the eCRF completion instructions. The 
Sponsor, or CRO, will review the supporting source documentation against the data 
entered into the eCRFs to verify the accuracy of the electronic data. The investigator will 
ensure that corrections are made to the eCRFs and that data queries are resolved in a 
timely fashion by the study staff.
The investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the investigator reviewed and approved the 
data on the eCRF, the data queries, and the site notifications.
All data generated from external sources (eg, PK, ADA, central readers of radiological 
imaging) will be integrated with the patient’s eCRF data in accordance with the Data 
Management Plan.
SAEs, pregnancies, and patient disposition will be collected via paper forms during the 
Extended Treatment Period as detailed in Section 7.7.5.
9.2 
Monitoring
A Sponsor or CRO study monitor will be given access, both during and after this study, 
to conduct inspections and to audit and review medical records pertinent to the clinical 
study as permitted by the regulations. The study monitor will verify the study conduct, 
completed ICF documentation, accurate eCRF completion, source documentation 
completion and retention, accurate study drug accountability, and other records relevant 
to the conduct of this study.
The study monitor will visit the study site at suitable intervals and be in frequent contact 
through verbal and written communication. It is essential that the study monitor have 
access to all documents (related to the study and the individual participants) at any time 
these are requested. In turn, the study monitor will adhere to all requirements for patient 
confidentiality as outlined in the ICF and in accordance with the Health Insurance 
Portability and Accountability Act (HIPAA) and local regulations. The investigator and 
investigator’s staff will be expected to cooperate with the study monitor, to be available 
during a portion of the monitoring visit to answer questions, and to provide any missing 
information.
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Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
9.3 
Data Quality Assurance
Data quality will be monitored by a study monitor through programmed edit checks in the 
EDC system, and through data review meetings. The study monitor will visit the study 
sites on a regular schedule and verify data entered into the eCRF against source 
documents stored at the study site. Queries and clarifications will be entered into the 
EDC system and the changes will be tracked according to the requirements of 21 US 
Code of Federal Regulations (CFR) Part 11. Edit checks programmed into the EDC 
system will flag data that does not conform to the required data entry specifications and 
programmed cross-checks will ensure that data entry is consistent if entered in more than 
1 eCRF page. Flagged data will trigger a query to the site in the EDC system and 
responses and changes will be tracked. Periodic reviews for data consistency across 
eCRF pages will also be performed by data management personnel and CRO clinical 
personnel and any queries to the site will be issued in the EDC system.
9.4 
Records Retention
All source data, or copies thereof (eg, laboratory records, data sheets, hospital records,
X-rays, autopsy reports, correspondence, photographs, and computer records), which are 
a result of the original observations and activities of the study will be retained by the 
investigator. Source data should be retained until at least 2 years after the last approval of 
the study drug marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed 
since the formal discontinuation of clinical development of the study drug.
The Sponsor (or its designee), the IRB/IEC, and regulatory agencies will be permitted 
access to the study records, upon request, for trial-related monitoring and audits.
9.5 
Confidentiality
All data collected and stored for this study will conform to the principles of patient right 
to protection against invasion of privacy, HIPAA, and applicable local regulations. All 
patient data will be identified via a unique numerical code and all personal identifying 
information will be redacted from any records supplied to the Sponsor or CRO as part of 
the study conduct. All unpublished information that the Sponsor gives to the investigator 
shall be kept confidential and shall not be published or disclosed to a third party without 
the prior written consent of the Sponsor.
However, in compliance with US FDA and ICH guidelines, to verify compliance with 
this protocol, the investigator will permit the study monitor, Sponsor representatives, 
regulatory agency representatives, and IRB/IEC representatives to review a patient’s 
primary medical records (source data), which can include (but are not limited to): 
laboratory test results, ECG reports, hospital discharge summaries during a patient’s 
study participation, and autopsy reports for deaths occurring during the study.
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Clinical Protocol 
Protocol No.: FKB238-002
Study Drug Name: FKB238
10. 
REFERENCES
1. FKB238 Investigator’s Brochure. Fujifilm Kyowa Kirin Biologics Co., Ltd. 2009. 
version 1.
2. 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(24):2542-2550.
3. Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine 
with either placebo or bevacizumab as first-line therapy for nonsquamous non-small- 
cell lung cancer: AVAiL. J Clin Oncol. 2009;27(8):1227-1234.
4. 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). Ann Oncol.
2010;21(9):1804-1809.
5. Hurwitz HI, Bekaii-Saab TS, Bendell JC, et al; ARIES Study Investigators. Safety 
and effectiveness of bevacizumab treatment for metastatic colorectal cancer: final 
results from the Avastin® Registry – Investigation of Effectiveness and Safety 
(ARIES) observational cohort study. Clin Oncol (R Coll Radiol). 2014;26(6):323-
332.
6. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-
based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized 
phase III study. J Clin Oncol. 2009;26(12):2013-2019.
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11. 
APPENDICES
APPENDIX A
Actions Required in Cases of Combined Increase of Aminotransferase and Total
Bilirubin – Hy’s Law
1. INTRODUCTION
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law. It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries.
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The investigator participates, together with PAREXEL and Sponsor clinical project 
representatives, in review and assessment of cases meeting PHL criteria to agree whether 
Hy’s Law (HL) criteria are met. HL criteria are met if there is no alternative explanation 
for the elevations in liver biochemistry other than Drug Induced Liver Injury (DILI) 
caused by the Investigational Medicinal Product (IMP).
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the 
outcome of the review and assessment in line with standard safety reporting processes.
2. DEFINITIONS
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT)  3 x Upper 
Limit of Normal (ULN) together with Total Bilirubin (TBL)  2 x ULN at any point 
during the study following the start of study medication irrespective of an increase in 
Alkaline Phosphatase (ALP).
Hy’s Law (HL)
AST or ALT  3 x ULN together with TBL  2 x ULN, where no other reason, other 
than the IMP, can be found to explain the combination of increases, eg, elevated ALP 
indicating cholestasis, viral hepatitis, another drug.
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, 
on the same day) the elevation in TBL, but there is no specified timeframe within which 
the elevations in transaminases and TBL must occur.
3. IDENTIFICATION OF POTENTIAL HY’S LAW CASES
In order to identify cases of PHL it is important to perform a comprehensive review of
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laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:
• 
ALT  3 x ULN
• 
AST  3 x ULN
• 
TBL  2 x ULN
The investigator will remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the investigator will:
• 
Notify the PAREXEL representative
• 
Request a repeat of the test (new blood draw) by the local laboratory
• 
Complete the appropriate unscheduled laboratory CRF module(s) with the
original local laboratory test result
When the identification criteria are met from local laboratory results, the investigator will 
without delay:
• 
Determine whether the patient meets PHL criteria (see Section 2 of this Appendix
for definition) by reviewing laboratory reports from all previous visits (including
local laboratory results)
The investigator will, without delay, review each new laboratory report and if the 
identification criteria are met will:
• 
Notify the PAREXEL representative
• 
Determine whether the patient meets PHL criteria (see Section 2 of this Appendix
for definition) by reviewing laboratory reports from all previous visits
• 
Promptly enter the laboratory data into the laboratory CRF
4. FOLLOW-UP
4.1 Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the investigator will:
• 
Inform the PAREXEL representative that the patient has not met PHL criteria.
• 
Perform follow-up on subsequent laboratory results according to the guidance
provided in the Clinical Study Protocol.
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4.2 Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the investigator will:
• 
Determine whether PHL criteria were met at any study visit prior to starting study
treatment (see Section 6)
• 
Notify the PAREXEL representative who will then inform the central Study Team
The PAREXEL medical monitor contacts the investigator, to provide guidance, discuss 
and agree an approach for the study patients’ follow-up and the continuous review of 
data. Subsequent to this contact, the investigator will:
• 
Monitor the patient until liver biochemistry parameters and appropriate clinical
symptoms and signs return to normal or baseline levels, or as long as medically
indicated
• 
Investigate the aetiology of the event and perform diagnostic investigations as
discussed with the PAREXEL medical monitor
• 
Complete the relevant Liver CRF Modules as information becomes available
• 
If at any time (in consultation with the PAREXEL medical monitor) the PHL case
meets seriousness criteria, report it as an SAE using standard reporting procedures
5. REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES
The instructions in this Section should be followed for all cases where PHL criteria are 
met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the 
PAREXEL medical monitor contacts the investigator in order to review available data 
and agree on whether there is an alternative explanation for meeting PHL criteria other 
than DILI caused by the IMP. The Sponsor (or its representative) will also be involved in 
this review.
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for a SAE:
• 
If the alternative explanation is not an AE, record the alternative explanation on
the appropriate CRF
• 
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF
accordingly
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If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:
• 
Report an SAE (report term ‘Hy’s Law’).
o The ‘Medically Important’ serious criterion should be used if no other
serious criteria apply
o As there is no alternative explanation for the HL case, a causality
assessment of ‘related’ should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary 
to assess whether or not the case meets the criteria for HL, then it is assumed that there is 
no alternative explanation until such time as an informed decision can be made:
• 
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and
causality assessment as per above
• 
Continue follow-up and review according to agreed plan. Once the necessary
supplementary information is obtained, repeat the review and assessment to
determine whether HL criteria are met. Update the SAE report according to the 
outcome of the review
6. ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW CRITERIA ARE 
MET BEFORE AND AFTER STARTING STUDY TREATMENT
This section is applicable to patients with liver metastases who meet PHL criteria on 
study treatment having previously met PHL criteria at a study visit prior to starting study 
treatment.
At the first on study treatment occurrence of PHL criteria being met the investigator will:
•
Determine if there has been a significant change in the patients’ condition#
compared with the last visit where PHL criteria were met#
o If there is no significant change no action is required
o If there is a significant change notify the PAREXEL representative, who 
will inform the central Study Team, then follow the subsequent process
described is Section 4.2 of this Appendix
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in 
isolation or in combination, or a clinically relevant change in associated symptoms. The 
determination of whether there has been a significant change will be at the discretion of 
the investigator; this may be in consultation with the PAREXEL representative if there is 
any uncertainty.
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7. ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’S
LAW
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) 
of PHL is based on the nature of the alternative cause identified for the previous 
occurrence.
The investigator should determine the cause for the previous occurrence of PHL criteria 
being met and answer the following question:
• 
Was the alternative cause for the previous occurrence of PHL criteria being met
found to be the disease under study e.g. chronic or progressing malignant disease,
severe infection or liver disease, or did the patient meet PHL criteria prior to 
starting study treatment and at their first on study treatment visit as described in 
Section 6?
If No: follow the process described in Section 4.2 of this Appendix
If Yes: Determine if there has been a significant change in the patient’s condition# 
compared with when PHL criteria were previously met
• 
If there is no significant change no action is required
• 
If there is a significant change follow the process described in Section 4.2 of this
Appendix
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in 
isolation or in combination, or a clinically relevant change in associated symptoms. The 
determination of whether there has been a significant change will be at the discretion of 
the investigator; this may be in consultation with the PAREXEL representative if there is 
any uncertainty.
8. REFERENCES
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
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APPENDIX B – Eastern Collective Oncology Group Performance Status
Description
Scale
Normal activity
0
Symptomatic but ambulatory self-care
1
Ambulatory more than 50% of the time
2
Ambulatory 50% or less of time, nursing care needed
3
Bedridden, may need hospitalisation
4
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APPENDIX C – Response Evaluation Criteria (RECIST v1.1)
1. INTRODUCTION
This appendix details the implementation of RECIST 1.1 Guidelines (Eisenhauer et al 
2009) for the FKB238-002 study with regards to investigator assessment of tumour 
burden including protocol-specific requirements for this study.
2. DEFINITION OF MEASURABLE, NON-MEASURABLE, TARGET AND
NON-TARGET LESIONS
Only patients with measurable disease at baseline should be included in the study. 
Measurable disease is defined by the presence of at least one measurable lesion which has 
not been previously irradiated.
Measurable:
A lesion, not previously irradiated, that can be accurately measured at baseline 
as  10 mm in the longest diameter (except lymph nodes which must have short 
axis  15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) 
and which is suitable for accurate repeated measurements.
Non-measurable:
• 
All other lesions, including small lesions (longest diameter < 10 mm or
pathological lymph nodes with  10 to < 15 mm short axis at baseline*)
• 
Truly non-measurable lesions include the following: bone lesions, leptomeningeal
disease, ascites, pleural/pericardial effusion, inflammatory breast disease,
lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by CT or 
MRI
• 
Previously irradiated lesions**
• 
Brain metastasis***
• 
Skin lesions assessed by clinical examination***
* Nodes with < 10 mm short axis are considered non-pathological and should not be 
recorded or followed as NTL.
**Localised post-radiation changes which affect lesion sizes may occur. Therefore, 
lesions that have been previously irradiated will not be considered measurable and must 
be selected as non-target lesions (NTL) at baseline and followed up as part of the NTL 
assessment.
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***Skin lesions assessed by clinical examination and brain lesions are considered as NTL 
in this study.
Special cases:
• 
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue
components, can be considered measurable if the soft tissue component meets the
definition of measurability. Blastic lesions are considered non-measurable.
• 
Cystic metastases can be considered measurable lesions if they meet the criteria
for measurability from a radiological point of view, but if non-cystic lesions are
present in the same patient, these should be selected as TLs.
Target lesions:
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), 
representative of all lesions involved suitable for accurate repeated measurement, should 
be identified as target lesions (TL) at baseline.
Non-Target lesions:
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.
3. METHODS OF ASSESSMENT
The same method of assessment and the same technique should be used to 
characterise each identified and recorded lesion at baseline and during follow-up 
visits.
A summary of the methods to be used for RECIST assessment is provided below and 
those excluded from tumour assessments for this study are highlighted, with the rationale 
provided.
Table 1: Summary of Methods of Assessment
Target Lesions  
Non-Target Lesions 
New Lesions
CT (preferred) 
MRI
CT (preferred)
MRI
Clinical examination
X-ray, Chest X-ray
CT (preferred)
MRI
Clinical examination
X-ray, Chest X-ray 
Ultrasound
Bone Scan
FDG-PET
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3.1 CT and MRI
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TL selected for response assessment and to assess NTL and 
identification of any new lesions.
In the FKB238-002 study it is recommended that CT examinations of the chest and 
abdomen will be used to assess tumour burden at baseline and follow-up visits. 
CT examination with intravenous (i.v.) contrast media administration is the preferred 
method. MRI should be used where CT is not feasible or it is medically contra-indicated. 
For brain lesion assessment, MRI is the preferred method.
3.2 Clinical examination
In the FKB238-002 study, clinical examination will not be used for assessment of TL. 
Clinically detected lesions can be selected as TLs if they are assessed by CT or MRI 
scans. Clinical examination can be used to assess NTL and to identify the presence of 
new lesions.
3.3 X-Ray
3.3.1 Chest X-Ray
In the FKB238-002 study, chest X-ray assessment will not be used for assessment of TL 
as they will be assessed by CT examination or MRI examination. Chest X-ray can, 
however, be used to assess NTL and to identify the presence of new lesions.
3.3.2 Plain X-Ray
In the FKB238-002 study, plain X-ray may be used as a method of assessment for bone 
NTL and to identify the presence of new bone lesions.
3.4 Ultrasound
In the FKB238-002 study, ultrasound examination will not be used for assessment of TL 
and NTL as it is not a reproducible method, does not provide an accurate assessment of 
tumour size and it is subjective and operator dependent. Ultrasound examination can, 
however, be used to identify the presence of new lesions. If new clinical symptoms occur 
and an ultrasound is performed then new lesions should be confirmed by CT or MRI 
examination.
3.5 Endoscopy and laparoscopy
In the FKB238-002 study, endoscopy and laparoscopy will not be used for tumour 
assessments as they are not validated in the context of tumour assessment.
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3.6 Tumour markers
In the FKB238-002 study, tumour markers will not be used for tumour response 
assessments as per RECIST 1.1.
3.7 Cytology and histology
In the FKB238-002 study, histology will not be used as part of the tumour response 
assessment as per RECIST 1.1.
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumour has met criteria for response or 
stable disease. In such circumstances, the cytology is necessary to differentiate between 
response / stable disease (an effusion may be a side effect of the treatment) and 
progressive disease (if the neoplastic origin of the fluid is confirmed). Where cytology 
findings are not available, any effusion that significantly worsens (from trace to large) or 
appearance of clinically significant effusion (requiring change in drug therapy) during the 
study treatment will be considered to be progression of NTL, or disease progression due 
to new lesions.
3.8 Isotopic bone scan
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI 
or X-ray at baseline should be recorded as NTL and followed by the same method as per 
baseline assessment.
In the FKB238-002 study, isotopic bone scans may be used as a method of assessment to 
identify the presence of new bone lesions at follow-up visits. New lesions will be 
recorded where a positive hot-spot that was not present on the baseline bone scan 
assessment is identified on a bone scan performed at any time during the study. The 
Investigator should consider the positive hot-spot to be a significant new site of
malignant disease and represent true disease progression in order to record the new
lesion. Confirmation by CT, MRI and X-ray is recommended where bone scan findings 
are equivocal.
3.9 FDG-PET scan
In the FKB238-002 study, FDG-PET scans may be used as a method for identifying new 
lesions, according with the following algorithm: New lesions will be recorded where 
there is positive FDG uptake* not present on baseline FDG-PET scan or in a location 
corresponding to a new lesion on CT/MRI at the same follow-up visit. If there is no 
baseline FDG-PET scan available, and no evidence of new lesions on CT/MRI scans then 
follow-up CT/MRI assessments should be continued, scheduled as per-protocol or 
clinical indicated, in order to confirm new lesions.
* A positive FDG-PET scan lesion should be reported only when an uptake greater than 
twice that of the surrounding tissue is observed.
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4. TUMOUR RESPONSE EVALUATION
4.1 Schedule of evaluation
Baseline assessments should encompass all areas of known predilection for metastases in 
the disease under evaluation and should additionally investigate areas that may be 
involved based on signs and symptoms of individual patients and should be performed no 
more than 28 days before the start of study treatment. Follow-up assessments will be 
performed every 6 weeks (± 1 week) for 24 weeks, then every 9 weeks (± 1 week) for the 
remainder of the treatment period. Any other sites at which new disease is suspected 
should also be appropriately imaged. To be performed within ± 7 days until PD 
(Progressive Disease) as defined by RECIST 1.1. Any other sites at which new disease is 
suspected should also be adequately imaged at follow-up.
If an unscheduled assessment was performed and the patient has not progressed, every 
attempt should be made to perform the subsequent assessments at their scheduled visits. 
This schedule is to be followed in order to minimise any unintentional bias caused by 
some patients being assessed at a different frequency than other patients.
4.2 Target lesions (TL)
4.2.1 Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes), representative of all lesions involved should be identified as TL at 
baseline. TLs should be selected on the basis of their size (longest diameter for non-nodal 
lesions or short axis for nodal lesions), but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, 
the largest lesion does not lend itself to reproducible measurement in which circumstance 
the next largest lesion, which can be measured reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter 
for non-nodal lesions (or short axis for lymph nodes). All measurements should be 
recorded in millimeters. At baseline the sum of the diameters for all TL will be calculated 
and reported as the baseline sum of diameters. At follow-up visits the sum of diameters 
for all TL will be calculated and reported as the follow-up sum of diameters.
Special cases:
• 
For TL measurable in 2 or 3 dimensions, always report the longest diameter. For
pathological lymph nodes measurable in 2 or 3 dimensions, always report the
short axis.
• 
If the CT/MRI slice thickness used is > 5 mm, the minimum size of measurable
disease at baseline should be twice the slice thickness of the baseline scan.
• 
If a lesion has completely disappeared, the longest diameter should be recorded as
0 mm.
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• 
If a TL splits into two or more parts, then record the sum of the diameters of those
parts.
• 
If two or more TL merge then the sum of the diameters of the combined lesion
should be recorded for one of the lesions and 0 mm recorded for the other
lesion(s).
• 
If a TL is believed to be present and is faintly seen but too small to measure, a
default value of 5 mm should be assigned. If an accurate measure can be given,
this should be recorded, even if it is below 5 mm.
• 
If a TL cannot be measured accurately due to it being too large, provide an
estimate of the size of the lesion.
• 
When a TL has had any intervention e.g. radiotherapy, embolisation, surgery etc.,
during the study, the size of the TL should still be provided where possible.
4.2.2 Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumour 
visit response for TL.
Table 2: Evaluation of target lesions
Complete Response (CR) 
Disappearance of all target lesions since baseline. Any pathological
lymph nodes selected as target lesions must have a reduction in short 
axis to < 10 mm.
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of TL, taking as
reference the baseline sum of diameters.
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to
qualify for PD.
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of target lesions, taking
as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, 
the sum must also demonstrate an absolute increase of at least 5 mm.
Not Evaluable (NE) 
Only relevant if any of the target lesions were not assessed or not
evaluable or had a lesion intervention at this visit. Note:  If the sum of 
diameters meets the progressive disease criteria, progressive disease 
overrides not evaluable as a target lesion response.
4.3 Non-Target lesions (NTL)
4.3.1 Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline. Measurements are not required for these lesions, but their status should be 
followed at subsequent visits. At each visit an overall assessment of the NTL response
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should be recorded by the investigator. This section provides the definitions of the criteria 
used to determine and record overall response for NTL at the investigational site at each 
visit.
Table 3: Evaluation of Non-Target Lesions
Complete Response (CR) 
Disappearance of all non-target lesions since baseline. All lymph nodes
must be non-pathological in size (< 10 mm short axis).
Non CR/Non PD 
Persistence of one or more NTL.
Progression (PD) 
Unequivocal progression of existing non-target lesions. Unequivocal
progression may be due to an important progression in one lesion only or 
in several lesions. In all cases the progression MUST be clinically 
significant for the physician to consider changing (or stopping) therapy.
Not Evaluable (NE) 
Only relevant when one or some of the non-target lesions were not
assessed and, in the investigator's opinion, they are not able to provide an 
evaluable overall non-target lesion assessment at this visit.
Note:  For patients without target lesions at baseline, this is relevant if 
any of the non-target lesions were not assessed at this visit and the 
progression criteria have not been met.
To achieve ‘unequivocal progression’ on the basis of non-target lesions, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of 
SD or PR in TLs, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.
4.4 New lesions
Details of any new lesions will also be recorded with the date of assessment. The 
presence of one or more new lesions is assessed as progression.
A lesion identified at a follow-up assessment in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate disease progression.
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 tumour.
If a new lesion is equivocal, for example because of its small size, the treatment and 
tumour assessments should be continued until the new lesion has been confirmed. If 
repeat scans confirm there is a new lesion, then the progression date should be declared 
using the date of the initial scan.
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4.5 Symptomatic deterioration
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy.
Patients with ‘symptomatic deterioration’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumour 
assessments where possible until objective disease progression is observed.
4.6 Evaluation of overall visit response
The overall visit response will be derived using the algorithm shown in Table 4.
Table 4: Overall Visit Response
Target lesions 
Non-Target lesions 
New lesions 
Overall response
CR 
CR 
No 
CR
CR 
NA 
No 
CR
NA 
CR 
No 
CR
CR 
Non CR/Non PD  
No 
PR
CR 
NE 
No  
PR
PR 
Non PD or NE 
No 
PR
SD  
Non PD or NE 
No 
SD
NA 
Non CR/Non PD 
No 
SD (Non CR/Non PD)
NE 
Non PD or NE 
No 
NE
NA 
NE 
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, NE = not 
evaluable, NA = not applicable.
5. CONFIRMATION OF RESPONSE
Not applicable.
6. CENTRAL REVIEW
The CRO appointed by the Sponsor to perform the independent central review for this 
study will provide specifications for radiological imaging protocols in standard 
acquisition guidelines documentation.
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7. SPECIFICATIONS FOR RADIOLOGICAL IMAGING
These notes are recommendations for use in clinical studies. The use of standardized 
protocols for CT and MRI allows comparability both within and between different 
studies, irrespective of where the examination has been undertaken.
7.1 CT scan
CT scans of the chest, abdomen, and pelvis should be contiguous throughout all the 
anatomic region of interest.
The most critical CT image acquisition parameters for optimal tumour evaluation using 
RECIST 1.1 are anatomic coverage, contrast administration, slice thickness, and 
reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most solid tumours is the chest, 
abdomen and pelvis. Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that 
may be involved based on signs and symptoms of individual patients. Because a lesion 
later identified in a body part not scanned at baseline would be considered as a new lesion 
representing disease progression, careful consideration should be given to the extent of 
imaging coverage at baseline and at subsequent follow-up time points. This will enable 
better consistency not only of tumour measurements but also identification of new 
disease.
b. IV contrast administration: Optimal visualisation and measurement of metastases in 
solid tumours requires consistent administration (dose and rate) of IV contrast as well as 
timing of scanning. Typically, most abdominal imaging is performed during the portal 
venous phase and (optimally) about the same time frame after injection on each 
examination. An adequate volume of a suitable contrast agent should be given so that the 
metastases are demonstrated to best effect and a consistent method is used on subsequent 
examinations for any given patient. It is very important that the same technique be used at 
baseline and on follow- up examinations for a given patient. For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to whether
non-contrast CT or MRI (enhanced or non-enhanced) should be performed should also be
based on the tumour type, anatomic location of the disease and should be optimised to 
allow for comparison to the prior studies if possible. Each case should be discussed with 
the radiologist to determine if substitution of these other approaches is possible and, if 
not, the patient should be considered not evaluable from that point forward. Care must be 
taken in measurement of TLs on a different modality and interpretation of non-target 
disease or new lesions, since the same lesion may appear to have a different size using a 
new modality. Oral contrast is recommended to help visualise and differentiate structures 
in the abdomen.
If iodine contrast media is medically contra-indicated at baseline or at any time during the 
course of the study then the recommended methods are: CT thoracic examination without 
contrast and abdominal and pelvis MRI with contrast. If MRI cannot be performed then
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CT without i.v. contrast is an option for the thorax, abdomen and pelvis examination. For 
brain lesions assessment, MRI is the preferred method.
c. Slice thickness and reconstruction interval: It is recommended that CT scans be 
performed at 5 mm contiguous slice thickness and this guideline presumes a minimum 
5 mm thickness in recommendations for measurable lesion definition. Exceptionally, 
particular institutions may perform medically acceptable scans at slice thicknesses greater 
than 5 mm. If this occurs, the minimum size of measurable lesions at baseline should be 
twice the slice thickness of the baseline scans.
All window settings should be included in the assessment, particularly in the thorax 
where lung and soft tissue windows should be considered. When measuring lesions, the 
TL should be measured on the same window setting for repeated examinations 
throughout the study. All images from each examination should be included in the 
assessment and not “selected” images of the apparent lesion.
7.2 MRI scan
MRI has excellent contrast, spatial and temporal resolution; however, there are many 
image acquisition variables involved in MRI, which greatly impact image quality, lesion 
conspicuity and measurement. Furthermore, the availability of MRI is variable globally. 
The modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. Generally, axial 
imaging of the abdomen and pelvis with T1 and T2 weighted imaging along with 
gadolinium-enhanced imaging should be performed. The field of view, matrix, number of 
excitations, phase encode steps, use of fat suppression and fast sequences should be 
optimised for the specific body part being imaged as well as the scanner utilised. It is 
beyond the scope appendix to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts and diseases. Ideally, the same type of scanner should be used and 
the image acquisition protocol should be followed as closely as possible to prior scans. 
Body scans should be performed with breath-hold scanning techniques if possible.
For these reasons, CT is the imaging modality of choice.
7.3 FDG-PET scans
FDG-PET has gained acceptance as a valuable tool for detecting, staging and restaging 
several malignancies. If FDG-PET scans are included in a protocol, an FDG uptake 
period of 60 min prior to imaging has been decided as the most appropriate for imaging 
of patients with malignancy. Whole-body acquisition is important since this allows for 
sampling of all areas of interest and can assess if new lesions have appeared thus 
determining the possibility of interval progression of disease. Images from the base of the 
skull to the level of the mid-thigh should be obtained 60 min post injection. PET camera 
specifications are variable and manufacturer specific, so every attempt should be made to 
use the same scanner, or the same model scanner, for serial scans on the same patient. 
Whole-body acquisitions can be performed in either 2- or 3-dimensional mode with 
attenuation correction, but the method chosen should be consistent across all patients and
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Study Drug Name: FKB238
serial scans in the clinical trial.
7.3.1 PET/CT scans
At present, low dose or attenuation correction CT portions of a combined PET–CT are of 
limited use in anatomically based efficacy assessments and it is therefore suggested that 
they should not be substituted for dedicated diagnostic contrast enhanced CT scans for 
tumour measurements by RECIST 1.1. In exceptional situations, if a site can document 
that the CT performed as part of a PET–CT is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast) then the CT portion of the PET–CT can be used 
for RECIST measurements. However, this is not recommended because the PET portion 
of the CT introduces additional data that may bias an investigator if it is not routinely or 
serially performed.
8. REFERENCES
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J 
Cancer 45 (2009) 228-247.
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APPENDIX D – Excipients of the IPs 
FKB238
Monosodium Glutamate
Sorbitol
Polysorbate 80
Diluted Hydrochloric Acid
Water for injections
EU-Avastin
Trehalose dehydrate
Sodium phosphate
Polysorbate 20
Water for injections
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Study Drug Name: FKB238
APPENDIX E – Cockcroft-Gault Formula i
The Cockcroft- Gault formula for estimated glomerular filtration rate (GFR, mL/min) is:
(140age)weight(0.85if femaleor 1.0 if male)
72serumcreatinine
where age is in years, weight is in kg and serum creatinine is in mg/dL.
i Cockcroft DW and Gault MH. Prediction of Creatinine Clearance from Serum Creatinine. Nephron 1976;16(1):31-41.
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SAP_001.pdf: 
 
 
Official Title: 
A Randomised, Parallel, Double Blinded Study to Compare the 
Efficacy and Safety of FKB238 to Avastin® In 1st Line Treatment 
for Patients with Advanced/Recurrent Non-Squamous Non-Small 
Cell Lung Cancer in Combination of Paclitaxel and Carboplatin 
AVANA 
 
 
NCT Number: 
NCT02810457 
 
 
Document Date: 
SAP Version 2.0: 07 May 2019