Conditions: Cholangiocarcinoma
Keywords: Phase II Safety Tolerability Efficacy Amphinex-induced Photochemical Internalisation PCI Amphinex Gemcitabine Cisplatin Inoperable CCA Cholangiocarcinoma Bile duct cancer Photodynamic therapy Extrahepatic Perihilar Distal Fimaporfin Pivotal RELEASE PDT FimaChem Klatskin First line treatment Standard of care SOC Chemotherapy Local treatment
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 41
Healthy volunteers: no

Brief summary:
This study will assess the safety and effectiveness of fimaporfin-induced photochemical internalisation (PCI) of gemcitabine complemented by systemic gemcitabine/cisplatin chemotherapy compared to gemcitabine/cisplatin alone, in patients with inoperable cholangiocarcinoma (CCA). Participants will be randomly assigned to one of the treatment groups and will receive study treatment for 6 months, followed by assessments every 3 months, as applicable.

Detailed description:
Cholangiocarcinoma (CCA) is an uncommon adenocarcinoma arising from cells lining the bile ducts. Standard treatment options for CCA include surgery, radiotherapy and chemotherapy, dependent upon if the CCA is intra- or extra-hepatic. Surgical removal of the tumor is the only potential cure, and CCA is very resistant to standard pharmaceutical drug treatment, though chemotherapy has some effect. Current chemotherapy uses cisplatin plus gemcitabine. Photochemical internalisation (PCI) is a novel technology, where photochemical reactions are used to enhance the effect of drugs by increasing their ability cross cell membranes to interact with their intended target. This study will assess the safety and effectiveness of fimaporfin-induced PCI of gemcitabine complemented by systemic gemcitabine/cisplatin chemotherapy compared to gemcitabine/cisplatin alone, in patients with inoperable CCA.

NOTE: Participants are no longer being recruited to this study.

Arms:
arm 1: Arm A: Fimaporfin-induced photochemical internalisation (PCI) of gemcitabine complemented by gemcitabine/cisplatin chemotherapy arm 2: Arm B: Gemcitabine/cisplatin chemotherapy

Interventions: intervention 1: Fimaporfin and Gemcitabine intervention 2: Gemcitabine/Cisplatin chemotherapy
Intervention descriptions: intervention 1: PCI treatment consists of IV administration of Amphinex solution for injection (investigational product) at 0.22 mg/kg dose of fimaporfin, followed 4 days later by a standard dose of gemcitabine infusion (1000 mg/m²) and intraluminal laser light application. Up to 2 PCI treatments will be given. intervention 2: Up to 8 cycles of gemcitabine/cisplatin combination chemotherapy will be administered.

Protocol document:
Prot_SAP_000.pdf: 
CLINICAL STUDY PROTOCOL 
EudraCT Number: 2018-002647-29 
US IND Number: 128897 
A Multi-Centre, Randomised, Open-Label, Phase 2 Study to Assess the 
Safety, Tolerability and Efficacy of Fimaporfin-Induced Photochemical 
Internalisation of Gemcitabine Complemented by Gemcitabine/Cisplatin 
Chemotherapy Versus Gemcitabine/Cisplatin Alone in Patients With 
Inoperable Cholangiocarcinoma 
 
PCIA 203/18 
 
Sponsor: 
PCI Biotech AS 
Ullernchausséen 64 
0379 Oslo 
Norway 
Sponsor Contact: 
Amir Snapir, MD 
Chief Medical Officer 
Telephone: +47 67 11 54 00 
Medical Monitor: 
Irena Federowicz, MD, PhD 
Associate Medical Director, PPD 
49 Domaniewska Street 
Trinity Park III; 1st floor 
02-672 Warsaw, Poland 
Telephone: +44 1223 374240 
Version of Protocol:  
Final/3.0 (Global Amendment 2) 
Date of Protocol:  
13 Jul 2020 
 
CONFIDENTIAL  
All financial and nonfinancial support for this study will be provided by PCI Biotech AS. The 
concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of PCI Biotech. 
The study will be conducted according to the International Council for Harmonisation 
harmonised tripartite guideline E6 (R2): Good Clinical Practice.  


PCI Biotech AS 
Amphinex 
Protocol: PCIA 203/18 Final/3.0 (Global Amendment 2) 
13 Jul 2020 
 
Protocol Approval – Sponsor Signatory 
Study Title 
A Multi-Centre, Randomised, Open-Label, Phase 2 Study to Assess 
the Safety, Tolerability and Efficacy of Fimaporfin-Induced 
Photochemical Internalisation of Gemcitabine Complemented by 
Gemcitabine/Cisplatin Chemotherapy Versus Gemcitabine/Cisplatin 
Alone in Patients With Inoperable Cholangiocarcinoma 
Protocol Number PCIA 203/18 
Protocol Date 
13 Jul 2020 
 
Protocol accepted and approved by: 
Chief Medical Officer 
Amir Snapir, MD 
PCI Biotech AS 
Ullernchausséen 64 
0379 Oslo 
Norway 
 
 
 
Signature 
 
Date 
 


PCI Biotech AS 
Amphinex 
Protocol: PCIA 203/18 Final/3.0 (Global Amendment 2) 
13 Jul 2020 
 
Protocol Approval – Principal/Coordinating Investigator 
Study Title 
A Multi-Centre, Randomised, Open-Label, Phase 2 Study to Assess the 
Safety, Tolerability and Efficacy of Fimaporfin-Induced Photochemical 
Internalisation of Gemcitabine Complemented by 
Gemcitabine/Cisplatin Chemotherapy Versus Gemcitabine/Cisplatin 
Alone in Patients With Inoperable Cholangiocarcinoma 
Protocol Number 
PCIA 203/18 
Protocol Date 
13 Jul 2020 
 
Protocol accepted and approved by: 
Principal/Coordinating Investigator 
Prof. Dr. Jörg Trojan 
Universitätsklinikum Frankfurt 
Medizinische Klinik I 
Studienambulanz / Haus 11 / 3. OG 
Theodor-Stern-Kai 7 
60590 Frankfurt 
Germany 
 
 
 
Signature 
 
Date 
 
 


PCI Biotech AS 
Amphinex 
Protocol: PCIA 203/18 Final/3.0 (Global Amendment 2) 
13 Jul 2020 
 
Protocol Approval – Lead Statistician 
Study Title 
A Multi-Centre, Randomised, Open-Label, Phase 2 Study to Assess 
the Safety, Tolerability and Efficacy of Fimaporfin-Induced 
Photochemical Internalisation of Gemcitabine Complemented by 
Gemcitabine/Cisplatin Chemotherapy Versus Gemcitabine/Cisplatin 
Alone in Patients With Inoperable Cholangiocarcinoma 
Protocol Number PCIA 203/18 
Protocol Date 
13 Jul 2020 
 
Protocol accepted and approved by: 
Lead Statistician 
Nicola Little, MPhil 
Block 23 Alderley Park 
Alderley Edge 
Cheshire SK10 4TG 
UK 
 
 
 
Signature 
 
Date 
 


PCI Biotech AS 
Amphinex 
Protocol: PCIA 203/18 Final/3.0 (Global Amendment 2) 
13 Jul 2020 
 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Multi-Centre, 
Randomised, Open-Label, Phase 2 Study to Assess the Safety, Tolerability and Efficacy of 
Fimaporfin-Induced Photochemical Internalisation of Gemcitabine Complemented by 
Gemcitabine/Cisplatin Chemotherapy Versus Gemcitabine/Cisplatin Alone in Patients With 
Inoperable Cholangiocarcinoma” and the accompanying Investigator’s Brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 3.0, dated 13 Jul 2020, the International Council 
for Harmonisation harmonised tripartite guideline E6(R2): Good Clinical Practice and all 
applicable government regulations. I will not make changes to the protocol before consulting 
with PCI Biotech AS or implement protocol changes without an approval from the 
independent ethics committee and regulatory authorities, except to eliminate an immediate 
risk to patients. I agree to administer study treatment only to patients under my personal 
supervision or the supervision of a sub-investigator. 
I will not supply the investigational drug to any person not authorised to receive it. 
Confidentiality will be protected. Patient identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorisation from PCI Biotech AS. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 


PCI Biotech AS 
Amphinex 
Protocol: PCIA 203/18 Final/3.0 (Global Amendment 2) 
13 Jul 2020 
 
Summary of Changes 
Protocol Amendment History and Reasons for Amendment 
Version 
Date 
Reason for Amendment 
Version 1.0 
30 Aug 2018 
Original Protocol 
Version 2.0 
(Global 
Amendment 1) 
04 Dec 2019 
• To add clarifications to the original protocol documented in the 
administrative letters (dated 31 Oct 2018 and 24 Jan 2019) and 
incorporate the content of each of the local amendments (Norway, 
Germany and Denmark) and requests made by the French, Italian 
and UK Authorities and the US Food and Drug Agency. 
o 
List of abbreviations was updated. 
o 
Exploratory objective 2 wording was clarified to distinguish 
between standard tumour markers and exploratory biomarkers. 
o 
Definition of any measurable disease for purposes of 
randomisation stratification clarified. 
o 
Hospitalisation details for patients in Arm A were added. 
o 
Stent placement - text revised for clarity.  
o 
Specific safety evaluation criteria were added that must be 
fulfilled before patients receive the second PCI treatment. 
o 
Updated information on the currently-ongoing Phase 1/2 study 
(PCIA 202/12) with fimaporfin-induced PCI of gemcitabine. 
o 
Detailed justification was provided for the chosen dose and the 
regimen. 
o 
Merged inclusion criterion 3 and former inclusion criterion 7 to 
clarify that CCA needs to be perihilar or distal, with a stenosis 
that has been stented or requires stenting, and that is accessible 
for PCI light treatment. 
o 
Inclusion criterion 4 expanded to clarify the ‘inoperable’ 
includes being considered unsuitable for ‘partial liver resection 
or liver transplantation’. 
o 
Specified exclusion of patients with a history of frequently 
recurring septic biliary events caused by non-malignant 
strictures (exclusion criteria 3). 
o 
Excluded patients receiving prior treatment with amiodarone 
during the last 12 months (exclusion criterion 11). 
o 
Clarified acceptable forms of highly effective contraception and 
that contraception should be continued for at least 9 months 
after last dose of Amphinex or 6 months after last dose of 
chemotherapy (exclusion criterion 19). 
o 
Acceptable creatinine clearance limit in exclusion criterion 23 
was clarified. Patients with inadequate renal function (defined as 
creatinine clearance <60 mL/min) were excluded from the 
study. 
o 
Specific criteria for study patient’s discontinuation from 
treatment, or withdrawal from the study were added per ICH 


PCI Biotech AS 
Amphinex 
Protocol: PCIA 203/18 Final/3.0 (Global Amendment 2) 
13 Jul 2020 
 
Guideline E6(R2). 
o 
Additional guidance provided on precautions to be taken by 
patients during and after administration of Amphinex, for the 
prevention of skin and eye photosensitivity reactions. 
o 
Updated the number of study sites globally. 
o 
Added dose modification criteria for Amphinex, gemcitabine, 
and cisplatin. 
o 
Updated and clarified information on contraception and 
pregnancy. 
o 
Pregnancy testing was added after the end of the active 
treatment period (end of treatment period Day 30). 
o 
Clarification that assessment of tumour responses for the 
purposes of efficacy assessment must be according to 
RECIST 1.1; clinical assessment of symptomatic progression 
not sufficient without continued follow-up for radiological 
RECIST progression. 
o 
Definition of progressive disease per RECIST 1.1 for non-
measurable disease has been clarified. 
o 
Clarified tumour response criteria for non-target lesions, 
including advice on assessing non-measurable disease. 
o 
Biomarkers assessments clarified to distinguish between 
standard tumour markers (CA 19-9, CA-125 and CEA) and 
exploratory biomarkers. 
o 
Clarification that events clearly associated with the underlying 
disease should not be recorded as AEs was added. 
o 
Central laboratory was updated to local laboratory. 
o 
Updated reporting responsibilities for SAEs. 
o 
Reporting responsibilities and reporting timelines for SUSARs 
were updated. 
o 
Clarified that standard tumour markers will be analysed from 
serum samples collected for clinical chemistry. 
o 
Peripheral blood mononuclear cells (PBMCs) removed from 
exploratory biomarker assessments and exploratory biomarkers 
now measured in plasma only (not plasma and serum). 
o 
The PK sampling schedule has been revised; Group 1 - rich 
sampling - will include 20 patients randomised to Arm A, 
enabling non-compartmental analyses of fimaporfin PK, 
whereas Group 2 - sparse sampling - will provide data from the 
remaining Arm A pts to enable a later population PK analysis. 
Groups 3 and 4 have been deleted. On Day -4 and Cycle 4, 
Day 18, the PK samples will be time matched with ECG: For 
PK Group 1, PK sampling will be performed before, 
approximately 30 minutes after, and 4 hours after Amphinex 
administration, and for PK Group 2, PK sampling will be 
performed before Amphinex administration. 
o 
Updated blood sampling volume drawn from the patients. 
o 
Calculation of QTcB and QTcF added to ECG parameters. 
o 
ECG on Day -4 and Cycle 4, Day 18, will be performed before 


PCI Biotech AS 
Amphinex 
Protocol: PCIA 203/18 Final/3.0 (Global Amendment 2) 
13 Jul 2020 
 
Version 
Date 
Reason for Amendment 
and approximately 30 minutes (anticipated maximal plasma 
concentration) and 4 hours after Amphinex administration, to 
align with plasma PK sampling timepoints. 
o 
Updated definition of disease control rate (DCR). 
o 
Exploratory endpoint for standard tumour markers and 
exploratory biomarkers simplified for clarity. 
o 
Updated text for sample size calculations. 
o 
Distinct groups for subgroup analyses defined: primary; primary 
with liver metastases; primary with local lymph nodes; and 
primary with liver metastases and local lymph nodes. 
o 
Statistical model for analysis of the primary endpoint was 
updated to use the Efron approach for estimating HR and 
corresponding 95% CIs. 
o 
Kaplan-Meier landmark PFS estimates at 6 months and 
12 months with corresponding CIs were added to the analysis 
method for the primary endpoint. 
o 
Revised Section 7.7.2.3 to provide comparative SAP for key 
secondary endpoint ORR. 
o 
Primary endpoint for interim analysis will be ORR rather than 
PFS. 
o 
Study to have at least 80% power to detect a clinically 
meaningful improvement in the key secondary endpoint of OS. 
o 
A detailed multiplicity control strategy added to Section 7.7.7.1. 
o 
Removed the need for legal guardian as the patient participating 
in this study will be 18 years or older and capable of 
understanding/providing signed and witnessed written informed 
consent as per inclusion criteria 1 and 2. 
o 
Clarified clinical or administrative reasons when the Sponsor 
reserves the right to discontinue the study at any time. 
o 
Definition of end of study amended from last patient last visit to 
date of final database lock. 
o 
Schedule of events (Appendix A) has been split into 2 tables, 
one for each treatment arm.  
o 
Pharmacokinetic sampling has now been integrated into study 
treatment and follow-up schedules. 
o 
Clarification that serious adverse events will be reported during 
the survival follow-up period was added. 
Version 3.0 
(Global 
Amendment 2) 
13 Jul 2020 
• To add clarifications to Version 2.0 of the protocol, to incorporate 
requests made by the US Food and Drug Agency, and to revise the 
eligibility criteria to better match the real world patient population 
and support patient recruitment. 
o 
Sponsor contact details (Chief Medical Officer) was updated 


PCI Biotech AS 
Amphinex 
Protocol: PCIA 203/18 Final/3.0 (Global Amendment 2) 
13 Jul 2020 
 
from Hans Olivecrona, MD to Amir Snapir, MD. 
o 
The Medical Monitor details were updated. 
o 
List of abbreviations was updated. 
o 
List of definitions was added. 
o 
The analysis of exploratory biomarkers was removed from the 
exploratory objectives, exploratory endpoints and throughout 
the protocol. 
o 
It was clarified that documented or objective disease 
progression must be determined by radiology. 
o 
The term “background treatment” has consistently been replaced 
with the term “standard of care”. 
o 
It was clarified that the second PCI treatment should be 
administered at least 3 months after the first PCI treatment and 
that patient-related factors may lead to postponement to a later 
cycle. The possible reasons for postponement or omission of the 
second PCI treatment were updated as requested by the US 
Food and Drug Agency. 
o 
Hospitalisation details for patients in Arm A were clarified. 
o 
Clarification was added regarding cycles for patients who have 
started gemcitabine/cisplatin treatment before screening. 
o 
The study design figure was updated to reflect the changes to 
the study. 
o 
Stent placement text was revised for clarity. 
o 
The rationale for study design was updated with information on 
the recently completed study PCIA 202/12. Some paragraphs 
were reworded for readability. 
o 
Safety data from studies PCI 101/06, PCIA 202/10, and PCIA 
202/12 were added as part of the benefit/risk assessment. 
o 
Inclusion criterion 6: the definition of metastatic disease 
allowed in the study was updated to include tissues other than 
bone or the central nervous system instead of liver parenchyma 
and/or local lymph nodes (within close proximity to the 
hepatoduodenal ligament). This is expected to match real world 
patient population and recruit additional patients, no difference 
in safety is expected. 
o 
Exclusion criterion 1: added the exception of previous treatment 
of up to 2 cycles of gemcitabine/cisplatin. PCI treatment is 
expected to improve response to gemcitabine when given later 
than in cycle 1 of gemcitabine/cisplatin treatment. This is 
consistent with real world patients where chemotherapy may be 
initiated before further evaluation at central hospital. No 
difference in safety is expected. 
o 
Exclusion criterion 3: clarified that exclusion is based on 
frequently recurring septic biliary events regardless of cause. 
o 
Exclusion criterion 5: it was added that a second primary cancer 
that has been treated with intent to cure may be allowed after 
consultation with the study Medical Monitor. The risk of 
recurrence of a second cancer that has been properly treated 


PCI Biotech AS 
Amphinex 
Protocol: PCIA 203/18 Final/3.0 (Global Amendment 2) 
13 Jul 2020 
 
with curative intent is, in most cases, low. Revised to better 
match the general population and support patient recruitment. 
o 
Exclusion criterion 16 was deleted (significant hearing 
impairment). This criterion is covered by exclusion criterion 13 
(contraindication to the use of cisplatin). 
o 
Exclusion criterion 19 (now criterion 18): the footnote detailing 
the interaction of hormonal contraception with investigational 
medicinal product was deleted as it is not applicable. 
o 
Exclusion criterion 22 (now criterion 21): biliary drainage was 
specified in place of biliary tree stenting. The definition of 
inadequate liver function was revised: serum (total) bilirubin 
persisting at > 2.5 × ULN changed to > 5 × ULN. Changed to 
expand the target eligible population to support patient 
recruitment. The safety risk potentially associated with higher 
bilirubin level is considered negligible in the settings of the 
study. Considering the significant anti-tumour activity observed 
in earlier studies, the estimated benefit/risk ratio balance is 
considered ethical. 
o 
The wording regarding discontinuation from study treatment 
and withdrawal from study were updated for clarity. 
o 
Stratification was updated to remove the specification of 
‘hepatic’ from the presence or absence of metastases, in 
accordance with revised inclusion criterion 6. 
o 
Guidance on precautions to be taken by patients during and after 
administration of Amphinex, for the prevention of skin and eye 
photosensitivity reactions was updated. 
o 
Data on photosensitivity AEs from previous studies was added. 
o 
It was clarified that estimation of GFR, according to local 
practice, is considered equivalent to EDTA clearance if there is 
a >25% increase of serum creatinine compared to the baseline. 
o 
The definitions of permitted and prohibited treatments were 
updated. 
o 
The male patient contraception requirements were clarified, and 
aligned with the end of relevant systemic exposure.  
o 
Updated and clarified information on pharmacokinetic sample 
collection. 
o 
The timing of electrocardiograms was clarified. 
o 
Updated blood sampling volume drawn from the patients, as 
samples for exploratory biomarker analysis are no longer taken. 
o 
The definition of ORR in the study was updated. ORR will be 
assessed in all randomised patients (ITT population), as 
requested by the US FDA. The Evaluable for Response analysis 
set was removed. 
o 
The description of the subgroups to be analysed was updated.  
o 
The exploratory endpoint for tumour response was updated. 
o 
Updated text for sample size calculations. 
o 
A detailed description of the Blinded Independent Central 
Review was added for clarification. 


PCI Biotech AS 
Amphinex 
Protocol: PCIA 203/18 Final/3.0 (Global Amendment 2) 
13 Jul 2020 
 
Version 
Date 
Reason for Amendment 
o 
The interim analysis of ORR will be based on the assessment of 
the Blinded Independent Central Review, as requested by the 
US FDA. Improvement in ORR adjusted. 
o 
The multiple testing strategy was revised to incorporate US 
FDA requirement for O’Brien and Fleming boundary, and 
further simplified. 
o 
Added reference to SAP for detailed pooling strategy for 
handling small strata as requested by US FDA. 
o 
Change of analysis method for secondary endpoint ORR as 
requested by US FDA. Sensitivity analysis was added.  
o 
Schedules of events (Appendix A and Appendix B) were 
updated in line with changes made to the protocol. Screening 
period was updated from 14 to 21 days. 
o 
Throughout: Minor editorial revisions. 
 
For details of Amendment 1 and 2, see Appendix E (Section 13.5). 


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Page 12 
Table of Contents 
Summary of Changes .................................................................................................................6 
Table of Contents .....................................................................................................................12 
List of Tables ............................................................................................................................18 
List of Figures ..........................................................................................................................18 
Protocol Synopsis.....................................................................................................................19 
List of Abbreviations................................................................................................................28 
1 
Introduction ......................................................................................................................31 
1.1 
Cholangiocarcinoma ...............................................................................................31 
1.2 
Current Standard Treatment for Patients with Cholangiocarcinoma ......................32 
1.3 
Photodynamic Therapy ...........................................................................................33 
1.4 
Photochemical Internalisation .................................................................................34 
2 
Study Objectives...............................................................................................................35 
2.1 
Primary Objective ...................................................................................................35 
2.2 
Secondary Objectives..............................................................................................35 
2.3 
Exploratory Objectives ...........................................................................................36 
3 
Investigational Plan ..........................................................................................................37 
3.1 
Study Design ...........................................................................................................37 
3.2 
Treatment Assignment ............................................................................................37 
3.2.1 
Arm A ......................................................................................................38 
3.2.2 
Arm B ......................................................................................................39 
3.3 
Treatment Schedule .................................................................................................39 
3.3.1 
Stent Placement........................................................................................39 
3.3.2 
Arm A ......................................................................................................39 
3.3.3 
Arm B ......................................................................................................43 
3.4 
Rationale of Study Design ......................................................................................44 
3.4.1 
Rationale for Patient Population ..............................................................44 
3.4.2 
Rationale for Study Endpoints .................................................................44 
3.4.3 
Clinical Precedence..................................................................................45 
3.4.4 
Rationale for Dose ...................................................................................48 


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3.4.5 
Rationale for Treatment Regimen ............................................................49 
3.4.6 
Benefit/Risk and Ethical Assessment ......................................................50 
4 
Patient Selection and Withdrawal Criteria .......................................................................55 
4.1 
Selection of Study Population .................................................................................55 
4.1.1 
Inclusion Criteria .....................................................................................55 
4.1.2 
Exclusion Criteria ....................................................................................55 
4.2 
Discontinuation/Withdrawal of Patients From Study Treatment and/or the Study 58 
4.2.1 
Discontinuation From Study Treatment ...................................................58 
4.2.2 
Withdrawal From Study ...........................................................................59 
4.2.3 
Handling of Discontinuations/Withdrawals .............................................60 
4.2.4 
Replacements ...........................................................................................61 
5 
Study Treatments ..............................................................................................................62 
5.1 
Method of Assigning Patients to Treatment Arms ..................................................62 
5.2 
Identity of Investigational Products/Standard of Care Treatment...........................62 
5.2.1 
Amphinex.................................................................................................63 
5.2.1.1 
Fimaporfin-Associated Photosensitivity ..................................................63 
5.2.2 
Gemcitabine .............................................................................................67 
5.2.3 
Cisplatin ...................................................................................................68 
5.2.4 
Stenting ....................................................................................................68 
5.2.5 
Light Source .............................................................................................68 
5.2.6 
Dose Modifications ..................................................................................69 
5.2.6.1 
Dose Modifications for Amphinex and PCI treatment ............................69 
5.2.6.2 
Dose Modifications for Systemic Chemotherapy Cycles ........................69 
5.3 
Management of Clinical Supplies ...........................................................................72 
5.3.1 
Study Drug Packaging and Storage .........................................................72 
5.3.2 
Test Article and Device Accountability ...................................................72 
5.3.3 
Other Supplies..........................................................................................73 
5.4 
Treatment Compliance ............................................................................................73 
5.4.1 
Light Protection Compliance ...................................................................73 
5.5 
Concomitant Treatments .........................................................................................74 
5.5.1 
Permitted Treatments ...............................................................................74 
5.5.2 
Prohibited Therapies ................................................................................75 
5.5.3 
Photosensitising Drugs ............................................................................75 


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5.6 
Contraception ..........................................................................................................76 
6 
Study Assessments and Procedures ..................................................................................78 
6.1 
Efficacy Assessments ..............................................................................................78 
6.1.1 
Tumour Assessment .................................................................................78 
6.1.2 
Quality of Life Measurements .................................................................81 
6.2 
Pharmacokinetic Assessments ................................................................................81 
6.3 
Standard Tumour Markers ......................................................................................82 
6.4 
Safety Assessments .................................................................................................83 
6.4.1 
Adverse Events ........................................................................................83 
6.4.1.1 
Definitions of Adverse Events .................................................................83 
6.4.1.2 
Serious Adverse Events ...........................................................................83 
6.4.1.3 
Eliciting and Documenting Adverse Events ............................................84 
6.4.1.4 
Reporting Adverse Events .......................................................................84 
6.4.1.5 
Reporting Serious Adverse Events ..........................................................85 
6.4.1.6 
Suspected Unexpected Serious Adverse Reactions and Adverse Events of 
Special Interest .........................................................................................86 
6.4.1.7 
Assessment of Severity ............................................................................87 
6.4.1.8 
Assessment of Causality ..........................................................................87 
6.4.1.9 
Follow-Up of Patients Reporting Adverse Events ...................................88 
6.4.2 
Adverse Incidents/Unanticipated Adverse Device Effects ......................89 
6.4.2.1 
Reporting of Adverse Incidents/Unanticipated Adverse Device Effects .90 
6.4.3 
Laboratory Analyses ................................................................................90 
6.4.3.1 
Safety Laboratory Analyses .....................................................................90 
6.4.3.2 
Hepatotoxicity ..........................................................................................92 
6.4.4 
Loco-Regional Tumour-Related Events and Biliary Complications .......93 
6.4.5 
Vital Signs ................................................................................................93 
6.4.6 
Electrocardiograms ..................................................................................94 
6.4.7 
Photosensitivity and Skin Reactions ........................................................94 
6.4.8 
Medical History .......................................................................................94 
6.4.9 
Physical Examinations .............................................................................94 
6.5 
Independent Data Monitoring Committee ..............................................................95 
6.6 
Pregnancy ................................................................................................................95 
7 
Statistical and Analytical Plan ..........................................................................................96 


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7.1 
Primary Endpoint ....................................................................................................96 
7.1.1 
Progression-Free Survival........................................................................96 
7.2 
Secondary Endpoints ..............................................................................................96 
7.2.1 
Overall Survival .......................................................................................96 
7.2.2 
Best Overall Response .............................................................................96 
7.2.3 
Objective Response Rate .........................................................................96 
7.2.4 
Duration of Response...............................................................................96 
7.2.5 
Disease Control Rate ...............................................................................96 
7.2.6 
Change in Tumour Size............................................................................97 
7.2.7 
Safety .......................................................................................................97 
7.2.8 
Pharmacokinetics .....................................................................................97 
7.2.9 
Quality of Life Assessment ......................................................................97 
7.3 
Exploratory Endpoints ............................................................................................98 
7.4 
Sample Size Calculations ........................................................................................98 
7.5 
Analysis Sets ...........................................................................................................99 
7.6 
Description of Subgroups to be Analysed .............................................................100 
7.7 
Statistical Analysis Methodology .........................................................................100 
7.7.1 
Analysis of Primary Endpoint ...............................................................101 
7.7.2 
Analysis of Secondary Endpoints ..........................................................102 
7.7.2.1 
Overall Survival .....................................................................................102 
7.7.2.2 
Best Overall Response ...........................................................................103 
7.7.2.3 
Objective Response Rate .......................................................................104 
7.7.2.4 
Duration of Response.............................................................................105 
7.7.2.5 
Disease Control Rate .............................................................................105 
7.7.2.6 
Change in Tumour Size..........................................................................105 
7.7.2.7 
Blinded Independent Central Review ....................................................105 
7.7.2.8 
Quality of Life Measurements ...............................................................107 
7.7.3 
Analyses of Exploratory Endpoints .......................................................107 
7.7.4 
Pharmacokinetic/Pharmacodynamic Analyses ......................................107 
7.7.5 
Safety Analyses ......................................................................................107 
7.7.6 
Other Analyses .......................................................................................107 
7.7.7 
Interim Analyses ....................................................................................108 
7.7.7.1 
Multiplicity and Control of Type 1 Error ...............................................108 
7.7.8 
Independent Data Monitoring Committee .............................................109 


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8 
Data Quality Assurance .................................................................................................. 111 
8.1 
Data Management ................................................................................................. 111 
9 
Ethics .............................................................................................................................. 112 
9.1 
Independent Ethics Committee or Institutional Review Board ............................ 112 
9.2 
Ethical Conduct of the Study ................................................................................ 112 
9.3 
Patient Information and Consent .......................................................................... 112 
10 Investigator’s Obligations .............................................................................................. 114 
10.1 Confidentiality ...................................................................................................... 114 
10.2 Financial Disclosure and Obligations ................................................................... 114 
10.3 Study Conduct ....................................................................................................... 115 
10.4 Adherence to Protocol........................................................................................... 115 
10.5 Adverse Events and Study Report Requirements ................................................. 116 
10.6 Investigator’s Final Report ................................................................................... 116 
10.7 Records Retention ................................................................................................. 116 
10.8 Publications ........................................................................................................... 116 
11 Study Management ......................................................................................................... 118 
11.1 Monitoring ............................................................................................................ 118 
11.1.1 
Independent Data Monitoring Committee ............................................. 118 
11.1.2 
Monitoring of the Study ......................................................................... 118 
11.1.3 
Inspection of Records ............................................................................ 118 
11.2 Management of Protocol Amendments and Deviations........................................ 119 
11.2.1 
Modification of the Protocol .................................................................. 119 
11.2.2 
Protocol Deviations................................................................................ 119 
11.3 Study Termination .................................................................................................120 
11.4 Final Report ..........................................................................................................120 
12 Reference List.................................................................................................................122 
13 Appendices .....................................................................................................................126 
13.1 Appendix A: Schedule of Events for the Active Treatment Period ......................127 
13.2 Appendix B: Schedule of Events for the Follow-Up Period.................................136 
13.3 Appendix C: RECIST 1.1 .....................................................................................139 


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13.4 Appendix D: Health-Related Quality of Life Questionnaires ...............................140 
13.4.1 
EORTC QLQ-C30 .................................................................................140 
13.4.2 
EORTC QLQ-BIL21..............................................................................143 
13.5 Appendix E: Protocol Amendments......................................................................145 
 


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List of Tables 
Table 1 
Precautions for the Prevention of Skin and Eye Photosensitivity Reactions .. 65 
Table 2 
Dose Modifications for Haematological Toxicities ........................................ 70 
Table 3 
Dose Modifications for Non-Haematological Toxicities ................................ 71 
Table 4 
Medications with Photosensitising Potential .................................................. 76 
Table 5 
Tumour Response Criteria for Target Lesions ................................................ 79 
Table 6 
Tumour Response Criteria for Non-target Lesions ......................................... 79 
Table 7 
Blood Sampling Volume ................................................................................. 92 
Table 8 
Time Point Response: Patients With Measurable Disease ............................ 103 
Table 9 
Time Point Response: Patients With Non-Measurable Disease .................... 104 
Table 10 
Schedule of Events for the Active Treatment Period – Arm A Patients ........ 127 
Table 11 
Schedule of Events for the Active Treatment Period – Arm B Patients ........ 132 
Table 12 
Schedule of Events for the Follow-Up Period – Arm A and Arm B Patients 136 
 
List of Figures 
Figure 1 
Overall Study Design ...................................................................................... 37 
Figure 2 
Photochemical Internalisation (PCI) Treatment Schedule .............................. 40 
Figure 3 
PCI Treatment Sequence ................................................................................. 40 
Figure 4 
Multiple Testing Procedure ........................................................................... 109 
 


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Protocol Synopsis 
Protocol Number: 
PCIA 203/18 
Title: 
A Multi-Centre, Randomised, Open-Label, Phase 2 Study to 
Assess the Safety, Tolerability and Efficacy of 
Fimaporfin-Induced Photochemical Internalisation of 
Gemcitabine Complemented by Gemcitabine/Cisplatin 
Chemotherapy Versus Gemcitabine/Cisplatin Alone in Patients 
With Inoperable Cholangiocarcinoma 
Sponsor: 
PCI Biotech AS 
Ullernchausséen 64 
0379 Oslo 
Norway 
Study Phase: 
2 
Study Sites: 
Approximately 50 sites in Asia, Europe and North America  
Indication: 
Inoperable cholangiocarcinoma (CCA) 
Rationale: 
The purpose of this study is to evaluate the safety and efficacy of 
fimaporfin-induced photochemical internalisation (PCI) of 
gemcitabine complemented by gemcitabine/cisplatin systemic 
chemotherapy in patients with advanced inoperable CCA. 
Objectives: 
Primary Objective 
To assess the efficacy of fimaporfin-induced PCI of gemcitabine 
complemented by systemic gemcitabine/cisplatin chemotherapy 
versus gemcitabine/cisplatin alone in patients with inoperable 
CCA by assessment of progression-free survival (PFS) 
Secondary Objectives 
• To assess the longer-term efficacy of fimaporfin-induced PCI 
of gemcitabine complemented by systemic 
gemcitabine/cisplatin chemotherapy versus 
gemcitabine/cisplatin alone in patients with inoperable CCA 
by assessment of overall survival (OS);  
• To further assess the efficacy of fimaporfin-induced PCI of 
gemcitabine complemented by systemic 
gemcitabine/cisplatin chemotherapy versus 
gemcitabine/cisplatin alone in patients with inoperable CCA 
by assessment of best overall response (BOR), objective 
response rate (ORR), duration of response (DoR), disease 
control rate (DCR) at 6 and 12 months, and change in 
tumour size per Response Evaluation Criteria in Solid 
Tumours version 1.1 (RECIST 1.1); 


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• To assess the effects of fimaporfin-induced PCI on safety in 
terms of loco-regional tumour-related events and biliary 
complications;  
• To further assess the safety profile (adverse events [AEs], 
laboratory assessments, physical findings, and 
photosensitivity) of fimaporfin-induced PCI of gemcitabine 
complemented by systemic gemcitabine/cisplatin 
combination versus gemcitabine/cisplatin chemotherapy 
alone; 
• To further characterise the pharmacokinetic (PK) profile of 
fimaporfin in plasma; 
• To assess the health-related quality of life (HRQoL) and 
patient-reported outcome (PRO) measures of 
fimaporfin-induced PCI of gemcitabine complemented by 
systemic gemcitabine/cisplatin chemotherapy versus 
gemcitabine/cisplatin alone in patients with inoperable CCA. 
Exploratory Objectives 
• To assess tumour response (ORR, DCR, and PFS) by 
location of disease including loco-regional tumour control 
and metastatic lesions. 
• To explore changes in standard tumour markers for the 
assessment of their diagnostic and prognostic relevance in 
the disease, and for the treatment itself. 
Primary Endpoint 
Progression-free survival, defined as the time from 
randomisation to radiological disease progression or death from 
any cause. 
Secondary Endpoints 
• Overall survival (OS), calculated as the time from 
randomisation to the date of death from any cause 
• Best overall response (BOR), the best response recorded 
from the start of the treatment until disease 
progression/recurrence (using the smallest measurements 
recorded since the treatment started as reference for 
progressive disease) 
• Objective response rate (ORR), calculated as the proportion 
of patients who have at least one visit response with a 
complete response (CR) or partial response (PR) noted 


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• Duration of response (DoR), defined as time from first 
documented tumour response until the first documented 
disease progression, or death in the absence of disease 
progression 
• Disease control rate (DCR), defined as the proportion of 
patients with stable disease or better (ie, CR, PR or stable 
disease), assessed at 6 months and 12 months 
• Change in tumour size, defined as the best overall percentage 
change in tumour size from baseline 
• Toxicity profile (AEs, laboratory assessments and physical 
findings) of fimaporfin-induced PCI of gemcitabine with the 
gemcitabine/cisplatin combination, or the 
gemcitabine/cisplatin combination alone 
• Frequency and severity of loco-regional tumour-related 
events and biliary complications requiring unplanned 
hospital visits and inpatient care 
• Pharmacokinetic profile of fimaporfin 
• HRQoL/PRO assessments 
Exploratory Endpoints 
• Tumour response (ORR, DCR and PFS) by location of 
disease, as pre-defined further in the statistical analysis plan 
(SAP), including:  
o 
loco-regional tumour control  
o 
metastatic lesions  
o 
local lymph nodes 
• To analyse blood samples for standard tumour markers. 
Study Population: 
The main inclusion criteria include: 
• Male or female patient ≥18 years of age; 
• Cholangiocarcinoma verified as adenocarcinoma by 
histopathology or cytology with a perihilar or distal 
stenosis that has been stented or will require stenting, 
and that is accessible for PCI light treatment; 
• Cholangiocarcinoma must be considered inoperable with 
respect to radical resection (including partial liver 
resection or liver transplantation); 


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• At least 1 radiologically evaluable lesion (measurable 
and/or non-measurable) that can be assessed at baseline 
and is suitable for repeated radiological evaluation;  
• If metastatic disease, metastasis must be limited to 
tissues other than bone or the central nervous system; 
• Adequate biliary drainage (at least 50% of the liver 
volume or at least 2 sectors), with no evidence of active 
uncontrolled infection (patients on antibiotics are 
eligible); 
• Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1. 
• Estimated life expectancy of at least 12 weeks. 


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Study Design: 
This study is a multi-centre, randomised, open-label, Phase 2 
study with conditional marketing authorisation intent, to 
primarily evaluate the efficacy of fimaporfin-induced PCI of 
gemcitabine complemented by gemcitabine/cisplatin 
chemotherapy versus gemcitabine/cisplatin chemotherapy alone 
in patients with inoperable CCA, and to further evaluate the 
safety and tolerability of the PCI treatment(s).  
Approximately 186 patients will be randomised in a 1:1 ratio to 
receive: 
Arm A: PCI treatment, consisting of Amphinex® (fimaporfin) 
given once intravenously (IV) 4 days in advance of gemcitabine 
administration IV and intraluminal laser light application on 
Day 1, Cycle 1 as part of up to 8 gemcitabine/cisplatin cycles, 
with a second PCI treatment procedure aimed at the initiation of 
Cycle 5 or, if patient-related factors demand postponement, at 
initiation of a later cycle. The PCI treatments must be separated 
by at least 3 months. 
Arm B: up to 8 gemcitabine/cisplatin cycles alone. 
The randomisation will be stratified by 2 factors: any 
measurable disease at baseline (yes versus no) and presence or 
absence of metastases. Patients should continue their randomised 
chemotherapy treatment until a maximum of 
8 gemcitabine/cisplatin cycles, or until a treatment 
discontinuation criterion is met. 
Patients will be followed for PFS until approximately 
129 objective progression events (as defined by RECIST 1.1) 
have been observed for the primary analysis. Patients should be 
followed for radiological progression, regardless of whether they 
discontinue therapy or have symptomatic progression. After 
radiological progression, patients will enter the survival 
follow-up phase. A formal interim analysis of ORR will be 
performed after approximately 120 patients have been 
randomised and followed to their first follow-up scan to support 
a conditional marketing authorisation application.  
Data collection for OS will continue beyond the PFS analysis 
and an updated OS analysis will be performed after 
approximately 147 death events have occurred. The exact level 
of maturity will be determined based on the PFS and interim OS 
results, in discussion with regulatory authorities. 
An Independent Data Monitoring Committee (IDMC) will be 
enlisted to perform periodic review of accumulating safety data, 


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with particular focus on biliary tract events (Note: and possibly 
others, as to be defined in the IDMC charter) which are defined 
as AEs of special interest (AESI). The study will include an 
initial safety review by the IDMC after the initial 8 patients in 
Arm A have been administered 2 PCI treatments and followed 
up for 21 days. The IDMC will assess whether the second PCI 
treatment during the chemotherapy period should continue to be 
administered for future patients randomised to Arm A, in 
addition to the first PCI. Further, based on the periodic or ad hoc 
safety data reviews, the IDMC can make a recommendation to 
continue, amend, or stop the study at any point for safety 
reasons. Although there are no formal futility stopping rules in 
the study, the IDMC will review the results of the interim ORR 
analysis and provide a recommendation as to whether the study 
demonstrates a positive risk benefit that is clinically meaningful 
and meets the pre-defined statistical boundary for efficacy.  
Estimated Study 
Duration: 
In this rare disease, and with a variety of factors limiting final 
eligibility, recruitment rate per site is anticipated to be relatively 
low. The time from first patient, first visit, to the interim analysis 
(approximately 120 patients randomised) is estimated to be 
approximately 39 months. The study duration up to the PFS 
analysis (129 events/186 patients) is estimated to be 48 to 
51 months. The total study duration up to the final OS analysis 
(147 events/186 patients) is estimated to be 63 to 66 months. 
The study duration for a patient will be approximately 6 months 
during the active treatment period, with an additional number of 
assessments occurring every 3 months until progression, as 
individually applicable. 
Efficacy Assessments: 
Tumour response will be assessed, according to RECIST 1.1, 
every 12 weeks (±1 week) from randomisation until disease 
progression and should NOT follow delays incurred in the 
treatment period. 
The study will evaluate tumour responses as determined by the 
Investigator according to RECIST 1.1. The primary PFS analysis 
will be based on the local radiological assessment, which will be 
used to guide clinical management decisions. Note: In cases of 
symptomatic progression, patients will continue to be followed 
for radiological progression. 
A blinded independent central radiological review (BICR), 
blinded to treatment and to the local efficacy assessment, will 
also be performed for the tumour response data. 


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A supportive analysis of PFS will be performed based on data 
from the BICR. For the interim analysis of ORR, the BICR 
assessment will be considered the primary analysis. 
Pharmacokinetic, 
Pharmacodynamic, and 
Other Assessments: 
In order to evaluate the PK of fimaporfin in plasma, blood 
samples will be obtained from all patients in Arm A at the time 
points specified in PK sampling schedule. 
Quality of life will be measured by use of the European 
Organisation for Research and Treatment of Cancer (EORTC) 
Quality of Life Questionnaire (QLQ)-C30 and the EORTC 
QLQ-B21 questionnaire. 
The standard tumour markers carbohydrate antigen 19-9 
(CA 19-9), cancer antigen-125 (CA-125) and carcinoembryonic 
antigen (CEA) will be analysed from blood samples collected 
for safety laboratory assessments throughout the study. 
Safety Assessments: 
Safety will be assessed by AEs, serious AEs, deaths, 
loco-regional tumour-related events and biliary complications, 
clinical laboratory assessments, physical examinations, vital 
signs, electrocardiograms, and photosensitivity measures and 
skin reactions. 
Study Treatment, 
Dosage, and Route of 
Administration: 
The Arm A PCI treatment consists of IV administration of 
Amphinex solution for injection (investigational product) at 
0.22 mg/kg dose of fimaporfin, followed 4 days later by a 
standard dose of gemcitabine infusion (1000 mg/m2) and 
intraluminal laser light application (30 J/cm). The light source 
used to activate fimaporfin is a medical laser system 
(CE marked), emitting red light at 652 nm. Gemcitabine is 
currently not licensed for the treatment of patients with 
advanced inoperable CCA. 
All patients will receive the recognised standard of care for this 
indication (in addition to the PCI treatment for patients in 
Arm A); systemic chemotherapy consisting of 8 cycles of 
cisplatin, 25 mg/m2 plus gemcitabine, 1000 mg/m2. In Arm A, 
cisplatin will be omitted on days when PCI treatment is given 
(on Day 1 of Cycle 1, and on Day 1 of Cycle 5).  
Biliary stenting (plastic stents) is to be performed on all patients. 
Sample Size: 
Approximately 186 patients 
Statistical Methods: 
Approximately 186 patients with inoperable CCA will be 
randomised in a 1:1 ratio (fimaporfin-induced PCI of 
gemcitabine complemented by gemcitabine/cisplatin 


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chemotherapy versus gemcitabine/cisplatin chemotherapy alone) 
to this study.  
Primary Analysis: The primary endpoint is PFS and a 
hierarchical approach to the primary analysis will be employed. 
The primary analysis of PFS, as assessed by local radiological 
assessment, will be conducted when approximately 
129 progression events (69% maturity) have been observed. If 
the PFS result is statistically significant at the 3.95% 2-sided 
alpha level (adjusted for the interim analysis of ORR) an interim 
analysis of OS will be assessed. 
If the true PFS hazard ratio (HR) for the comparison of 
fimaporfin-induced PCI of gemcitabine complemented by 
gemcitabine/cisplatin chemotherapy versus 
gemcitabine/cisplatin chemotherapy alone is 0.6, 
129 progression events will provide approximately 80% power 
to demonstrate a statistically significant difference in PFS at a 
3.95%, 2-sided significance level (this may translate to an 
improvement in median PFS from 7.4 to 12.3 months, if PFS is 
exponentially distributed). A minimum or critical HR of 0.69 
(eg, 7.4 to 10.7 months) will be statistically significant, if 
observed. 
Progression-free survival will be analysed in the Intent-to-Treat 
(ITT) analysis set, using a log-rank test stratified by any 
measurable disease at baseline (yes versus no) and presence or 
absence of metastases. In the event of low numbers within a 
stratum, the data will be pooled across strata in the stratified 
analyses. Further details will be provided in the SAP. 
The primary analysis of PFS will be based on the local 
evaluation and will also be tested using the blinded independent 
central review (BICR) data. Summaries of secondary endpoints 
assessed by RECIST v1.1 will also be repeated using the BICR 
data. 
Interim Analyses: A formal interim analysis of ORR will be 
performed after approximately 120 patients (65%) have been 
randomised and followed to their first 12-week follow-up scan. 
Analysis will be based on BICR assessment. There will be >80% 
power to detect an improvement in ORR from 15% to 45% with 
2-sided p<0.0105 (O’Brien and Fleming boundary based on 65% 
information). A minimum improvement from 15% to 38% will 
be statistically significant, if observed. If the comparison of the 
interim ORR data between the arms based on a 
Cochran-Mantel-Haenszel test is statistically significant, it will 


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be summarised together with OS to support a conditional 
marketing authorisation application. Progression-free survival 
and DoR will be summarised descriptively with no formal 
comparison of PFS. 
A second interim analysis of OS will be performed in line with 
the PFS analysis when approximately 108 patients are predicted 
to have died. A 2-sided p<0.0173 will be required to demonstrate 
statistical significance.  
Updated OS Analysis: An updated (third) OS analysis will be 
performed with further survival follow-up after the PFS analysis. 
The final OS analysis will be triggered after approximately 
147 death events. There will be 80% power to detect an OS HR 
of 0.63 (eg, improvement in median OS from 11.7 to 
18.7 months) with 2-sided p<0.0447 (O’Brien and Fleming 
boundary adjusted for 2 interim analyses of OS). A minimum or 
critical HR of 0.72 (eg, 11.7 to 16.3 months), if observed, would 
be statistically significant. The exact level of maturity will be 
determined based on the PFS and interim OS results, in 
discussion with regulatory authorities. Overall survival will be 
analysed in the same manner as PFS. 
The secondary endpoints of ORR, BOR, DCR, and DoR will be 
summarised for the ITT analysis set (ie, all randomised patients). 
Summaries and waterfall plots indicating best percentage change 
from baseline in the sum of the diameters of target lesions will 
be produced.  
Kaplan-Meier plots will be produced to assess PFS and OS. 
Safety, including the incidence and characteristics of 
biliary/loco-regional tumour-related events leading to 
hospitalisation and/or interventions, will be summarised 
descriptively. Pharmacokinetic data will also be summarised 
descriptively.  
Version and Date of 
Protocol: 
Final/Version 3.0, 13 Jul 2020 


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List of Abbreviations 
Abbreviation 
Definition 
AE(s) 
adverse event(s) 
AESI(s) 
adverse event(s) of special interest 
AI(s) 
adverse incident(s) 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BICR 
blinded independent central review 
BOR 
best overall response 
CA-125 
cancer antigen 125 
CCA 
cholangiocarcinoma 
CEA 
carcinoembryonic antigen 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CR 
complete response 
CRC 
Cohort Review Committee 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DLTs 
dose-limiting toxicities 
DoR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDR 
early discrepancy rate 
EDTA 
ethylenediamine tetraacetic acid 
EORTC 
European Organisation for Research and Treatment of Cancer 
ERCP 
endoscopic retrograde cholangio-pancreatography 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 


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Abbreviation 
Definition 
GMP 
Good Manufacturing Practice 
HNSCC 
head and neck squamous cell carcinoma 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
HUS 
haemolytic uraemic syndrome 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
intravenous(ly) 
IWRS 
Interactive Web Response System 
KM 
Kaplan-Meier 
LDR 
late discrepancy rate 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intent-to-Treat 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NE 
not evaluable 
ORR 
objective response rate 
OS 
overall survival 
PCI 
photochemical internalisation 
PD 
progressive disease 
PDT 
photodynamic therapy 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PRES 
posterior reversible encephalopathy syndrome 
PRO 
patient-reported outcome 
PSC 
primary sclerosing cholangitis 


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Abbreviation 
Definition 
QLQ 
Quality of Life Questionnaire 
RECIST 
Response Evaluation Criteria in Solid Tumours 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SD 
stable disease 
SLT 
schedule-limiting toxicity 
SmPC 
summary of product characteristics 
SoC 
standard of care 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent AE 
UADE 
unanticipated adverse device effect 
ULN 
upper limit of normal 
WOCBP 
women of childbearing potential 
 
List of Definitions 
PCI treatment 
In the present protocol, a single PCI treatment consists of IV 
administration of Amphinex solution for injection (dose 0.25 mg/kg 
fimaporfin-di-olamine, equivalent to 0.22 mg/kg fimaporfin), 
followed 4 days later by gemcitabine IV infusion (1000 mg/m2) and 
bile duct intraluminal laser light application (light dose 30 J/cm).  
Amphinex® 
Amphinex solution for injection is a sterile solution containing active 
substance fimaporfin di-olamine; 30 mg/mL (equals 26 mg/mL of 
fimaporfin), tween 80 (3.0%), tris buffer pH 8.5, and 50 mM 
mannitol (2.8 %)  
Fimaporfin 
Active substance (salt form: fimaporfin di-olamine) 


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1 
Introduction 
1.1 Cholangiocarcinoma 
Cholangiocarcinoma (CCA) is an uncommon adenocarcinoma arising from the neoplastic 
transformation of cholangiocytes, the epithelial cells lining the intrahepatic and extra-hepatic 
bile ducts (Anderson et al 2004). Cholangiocarcinoma may arise anywhere in the biliary tree, 
from the small, peripheral hepatic ducts to the distal common bile duct. The term CCA 
includes all bile duct cancers (intrahepatic, perihilar and distal extrahepatic). 
Cholangiocarcinoma is the second most frequent type of primary liver cancer and accounts 
for about 3% of all digestive tumours (Global Burden of Disease Cancer Collaboration et al 
2015). It has an annual incidence of less than 6 cases per 100,000 in the western world, 
higher in some countries and regions such as South Korea and North Thailand, but rates of 
intra-hepatic CCA have been steadily rising over the past 3 decades while the incidence of 
peri-hilar and distal CCA has remained stable (Blechacz et al 2008) or seems to be 
decreasing (Banales et al 2016). Patients with these tumours have poor overall survival (OS) 
with a 5-year survival rate of about 5% (Vauthey and Blumgart 1994). Over 50% of patients 
present with advanced-stage disease, and the prognosis is poor with survival time of between 
6-12 months for unresected patients, even after biliary decompression.  
Up to 20% of all CCAs are intrahepatic, whereas 50% to 60% are perihilar, involving the 
bifurcation of the ducts. Peri-hilar CCAs are a subset of extrahepatic CCAs. Up to 20% of 
CCAs are distal extrahepatic tumours and 5% of tumours are multifocal (Khan et al 2002). 
Intra-hepatic CCA develops in the smaller bile duct branches inside the liver. Peri-hilar CCA 
develops at the hilum, where the left and right hepatic ducts have joined and are just leaving 
the liver. The distal CCA appears further down the bile duct, closer to the small intestine. 
There has a been a growing recognition that hilar CCA disease has a distinct biological 
behaviour and natural history compared to (distal) extrahepatic CCA, and an increasing 
acknowledgment that different therapeutic strategies are required (Wiedmann et al 2004). At 
initial presentation of patients with extrahepatic CCA, 30 to 50% have local lymph node 
involvement and 10 to 20% have metastatic spread typically to the liver and peritoneum. 
With hilar CCA, due to the long asymptomatic course, only 20% are resectable at the time of 
diagnosis (Henson et al 1992). 


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1.2 Current Standard Treatment for Patients with Cholangiocarcinoma 
Cholangiocarcinomas are generally asymptomatic in the early stages and are usually 
diagnosed when the disease has already metastasised, by combining non-specific biomarkers 
in serum and/or biopsy samples, as well as imaging methods. Late diagnosis compromises 
the effective therapeutic options, which are based on surgical resection and/or liver 
transplantation, whereas chemotherapies are virtually palliative given the marked 
chemoresistance of this cancer. Standard treatment options for CCA include surgery, 
radiotherapy and chemotherapy, dependent upon if the CCA is intra- or extrahepatic. Tumour 
resection is the only potential cure for CCA. Recent advances in transplantation using 
stringent selection criteria and utilisation of neoadjuvant chemoradiation have demonstrated 
encouraging results with 5-year survival rates of over 70% (Singal et al 2009), with even one 
series from the Mayo Clinic yielding a 5-year survival rate of 82% (Rea et al 2005). For the 
80% who present with unresectable disease, the utility of these modalities combined with 
biliary decompression interventions only provided a median survival time of 3-6 months 
from the time of diagnosis (Ito et al 2009). For these patients with inoperable advanced CCA, 
the main treatment aim is palliative to relieve local symptoms such as pain and jaundice. 
Surgery for these patients is primarily for creating a bypass in patients who cannot be stented. 
Cholangiocarcinoma is highly resistant to pharmacological therapy, but activity has been 
seen using chemotherapy. 
For patients who are unsuitable for curative resection, the current systemic combination 
chemotherapy is with cisplatin plus gemcitabine. This was established in the largest 
randomised Phase 3 study to date in non-operable biliary tract cancer which demonstrated a 
response rate of 26.1% and a disease control rate of 81.4%. The median progression-free 
survival (PFS) was 8.0 months (95% confidence interval [CI], 6.6 – 8.6) and OS was 
11.7 months (95% CI, 9.5 - 14.3); notably there was no statistically significant increase in 
toxicity when compared to gemcitabine monotherapy (Valle et al 2010). Unpublished data 
obtained from the authors of this study, showed that 33 patients with extrahepatic CCA 
treated with cisplatin plus gemcitabine had a response rate of 8.7%, median PFS of 7.89 
months (95% CI, 3.2 – 9.0) and a median OS of 8.8 months (95% CI, 5.8 – 16.1).  
In a recently published retrospective analysis of first line cisplatin plus gemcitabine treatment 
of biliary tract cancers, a response rate of 8.9%, median PFS of 6.4 months 


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(95% CI, 5.4 - 7.3) and median OS of 12.7 months (95% CI, 10.6 – 14.9) was reported for a 
subgroup of 79 patients with extrahepatic CCA (Kim et al 2017). 
1.3 Photodynamic Therapy 
Majority of patients with CCA (70%-80%) present with advanced stage and non-resectable 
tumours due to locally advanced disease or presence of distant metastases (Nathan et al 
2009). Palliative biliary stenting to alleviate obstructive cholestasis is the primary standard of 
care (SoC) (Moole and Puli 2015). With the development of improved interventional and 
endoscopic technologies, techniques aimed at gaining control of local disease have evolved, 
including local ablation, embolisation, brachytherapy, radio-frequency ablation and, most 
significantly, photodynamic therapy (PDT) (Kiesslich et al 2009). PDT is a local-ablative, 
tumour-specific treatment that involves administration of a photosensitising drug with 
affinity for neoplastic tissue. Photosensitisers are non-cytotoxic drugs that are activated 
following their administration by selective illumination with light at the defined wavelength 
matching their absorption. The resulting interaction between light and the photosensitising 
agent causes formation of oxygen free radicals (Henderson and Dougherty 1992), inducing 
death of tumour and neovascular cells by apoptosis, necrosis or autophagy, vascular 
shutdown, and may induce T-cell mediated immune response (Dolmans et al 2003). 
McCaughan et al (1991) described the first successful case of PDT for nonresectable CCA. 
Since then, the benefit of using PDT in patients with nonresectable CCA has been 
demonstrated in many studies, and with more than 2 decades of experience, local CCA 
treatment with PDT is part of the therapy options for nonresectable CCA patients in many 
specialised centres today (Zoepf et al 2005). Since PDT studies in CCA have often been 
small and included patients that additionally received other palliative treatments (surgery, 
radiotherapy, chemotherapy), a recent systematic review and meta-analysis 
(Moole et al 2017) exclusively investigated studies of PDT with biliary stenting versus 
biliary stenting alone. PDT appeared to be relatively safe and was superior to palliative 
stenting alone in terms of survival, successful biliary drainage, and Karnofsky performance 
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1.4 Photochemical Internalisation 
Photochemical internalisation (PCI) is a novel photochemical technology. With PCI, 
photochemical reactions are used to enhance the effect of drugs in illuminated areas of the 
body, by increasing the ability of such drugs to interact with their targets inside the cells. A 
common feature of candidate drugs that may be used in PCI is that they have an intracellular 
molecular target. For many drugs that do not readily pass the plasma membrane, cellular 
uptake may be limited. One way that such drugs could be taken up by the cells is by the 
normal cellular process of endocytosis. However, for many existing and potential therapeutic 
molecules this uptake leads to degradation or loss of the biological activity before it can 
reach its intracellular target. 
The molecular mechanism behind the PCI technology is based on the use of a 
photosensitising molecule (photosensitiser) localising specifically to the membranes in 
endocytic vesicles. Upon activation by light, the photosensitiser will induce photochemical 
reactions leading to damage to these membranes and to the rupture of the endocytic vesicles, 
thereby leading to the release of entrapped drugs into the cytosol. 


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2 
Study Objectives 
2.1 Primary Objective 
The primary objective of this study is to assess the efficacy of fimaporfin-induced PCI of 
gemcitabine complemented by systemic gemcitabine/cisplatin chemotherapy versus 
gemcitabine/cisplatin alone in patients with inoperable CCA by assessment of PFS. 
2.2 Secondary Objectives 
The secondary objectives of this study are: 
1. To assess the longer-term efficacy of fimaporfin-induced PCI of gemcitabine 
complemented by systemic gemcitabine/cisplatin chemotherapy versus 
gemcitabine/cisplatin alone in patients with inoperable CCA by assessment of OS;  
2. To further assess the efficacy of fimaporfin-induced PCI of gemcitabine 
complemented by systemic gemcitabine/cisplatin chemotherapy versus 
gemcitabine/cisplatin alone in patients with inoperable CCA by assessment of best 
overall response (BOR), objective response rate (ORR), duration of response (DoR), 
disease control rate (DCR) at 6 and 12 months, and change in tumour size per 
Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1); 
3. To assess the effects of fimaporfin-induced PCI on safety in terms of loco-regional 
tumour-related events and biliary complications;  
4. To further assess the safety profile (adverse events [AEs], laboratory assessments, 
physical findings, and photosensitivity) of fimaporfin-induced PCI of gemcitabine 
complemented by systemic gemcitabine/cisplatin combination versus 
gemcitabine/cisplatin chemotherapy alone; 
5. To further characterise the pharmacokinetic (PK) profile of fimaporfin in plasma; 
6. To assess the health-related quality of life (HRQoL) and patient-reported 
outcome (PRO) measures of fimaporfin-induced PCI of gemcitabine complemented by 
systemic gemcitabine/cisplatin chemotherapy versus gemcitabine/cisplatin alone in 
patients with inoperable CCA.  


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2.3 Exploratory Objectives 
The other objectives of this study are: 
1. To assess tumour response (ORR, DCR, and PFS) by location of disease including 
loco-regional tumour control and metastatic lesions. 
2. To explore changes in standard tumour markers for the assessment of their diagnostic 
and prognostic relevance in the disease, and for the treatment itself. 


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3 
Investigational Plan 
3.1 Study Design 
This study is planned to be a multi-centre, randomised, open-label, Phase 2 study with 
conditional marketing authorisation intent, to evaluate the efficacy of fimaporfin-induced PCI 
of gemcitabine complemented by gemcitabine/cisplatin chemotherapy versus 
gemcitabine/cisplatin chemotherapy alone in patients with inoperable CCA. It will also 
evaluate the safety and tolerability of the PCI treatment(s).  
Figure 1 
Overall Study Design 
 
Abbreviations: BOR, best overall response; CCA, cholangiocarcinoma; DCR, disease control rate; 
DoR, duration of response; HRQoL, health-related quality of life; ORR, objective response rate; OS, overall 
survival; PFS, progression-free survival; PK, pharmacokinetics; PRO, patient-reported outcome; SoC, standard 
of care.  
3.2 Treatment Assignment 
Patients will be randomly assigned in a 1:1 ratio to either Arm A or Arm B. All patients in 
both arms will be stented (Section 3.3.1). It is expected that approximately 93 patients will be 
randomly assigned to Arm A and approximately 93 patients will be randomly assigned to 
Arm B.  
Patients will be stratified at randomisation according to whether they have any measurable 
disease at baseline (as assessed by the Investigator) versus no measurable disease, and 
according to presence or absence of metastases. It is expected that approximately two-thirds 
of patients will have measurable disease at baseline.  


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3.2.1 Arm A 
Patients randomised to Arm A will be treated with PCI, integrated into 21-day cycles of 
gemcitabine/cisplatin combination chemotherapy (SoC treatment). 
Patients who have started gemcitabine/cisplatin treatment before the screening period should 
continue their treatment as scheduled. PCI treatment should be synchronised with the 
schedule of the ongoing gemcitabine/cisplatin treatment. Study cycles will be counted from 
enrolment – as for all patients in the study; however, the number of chemotherapy cycles 
with gemcitabine/cisplatin will be counted from first treatment. For clarification, treatment 
with gemcitabine/cisplatin cannot exceed 8 treatment cycles.  
Treatment schedule as follows: 
Cycle 1: Amphinex® (fimaporfin) will be administered on Day -4 (4 days before gemcitabine 
administration), followed by gemcitabine administration and laser light application on Day 1, 
and gemcitabine/cisplatin on Day 8. Note: Cisplatin is omitted from Cycle 1 Day 1 treatment. 
Cycles 2 to 3: Gemcitabine/cisplatin will be administered on Days 1 and 8. 
Cycle 4: Gemcitabine/cisplatin will be administered on Days 1 and 8. A second dose of 
Amphinex will be administered on Day 18 (4 days prior to Day 1 of Cycle 5).  
Cycle 5: Gemcitabine administration and laser light application will be given on Day 1, and 
gemcitabine/cisplatin on Day 8. Note: Cisplatin is omitted from Cycle 5 Day 1 treatment. 
Cycles 6 to 8: Gemcitabine/cisplatin will be administered on Days 1 and 8.  
Patient-related factors may demand postponement of the second PCI treatment to a later 
cycle. Please see Section 3.3.2 for more detailed information. 
Patients in Arm A may be admitted for overnight follow-up after laser light application and 
related procedures on Day 1 of Cycle 1 and on Day 1 of Cycle 5. 


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3.2.2 Arm B 
Patients randomised to Arm B (control arm) will be administered SoC treatment 
(gemcitabine/cisplatin chemotherapy) only, on Days 1 and 8 of each 21-day cycle, for up to 
8 cycles.  
Patients who have started gemcitabine/cisplatin treatment before the screening period should 
continue their treatment as scheduled. Cycle 1, Day 1 visit should be synchronised with the 
schedule of the ongoing gemcitabine/cisplatin treatment. Study cycles will be counted from 
enrolment – as for all patients in the study; however, the number of chemotherapy cycles 
with gemcitabine/cisplatin will be counted from first treatment. For clarification, treatment 
with gemcitabine/cisplatin cannot exceed 8 treatment cycles. 
3.3 Treatment Schedule 
3.3.1 Stent Placement 
Biliary stenting is to be performed on all patients according to local practice; however, the 
chosen stent must be of an exchangeable plastic type until radiological progression. Stenting 
must be performed at the latest before first study treatment (Arm B) or immediately after the 
first laser light application (Arm A). Patients who have already undergone stenting before 
screening should be reviewed to ensure the stent is of plastic type, correctly positioned and 
adequate liver drainage confirmed; at least 50% of liver volume, or at least 2 sectors, should 
be drained. Stents must be removed for the laser light application, and a new stent must be 
placed immediately after light application. Stent removal, laser light application, and stent 
replacement will take place during the same one procedure. 
3.3.2 Arm A 
Patients randomised to Arm A will receive up to 2 PCI treatments, separated by at least 
3 months, together with up to 8 cycles of gemcitabine/cisplatin combination chemotherapy 
(Figure 2).  


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Figure 2 
Photochemical Internalisation (PCI) Treatment Schedule 
 
First PCI treatment: 
A 0.22 mg/kg dose of fimaporfin will be administered intravenously (IV) on Day -4 followed 
4 days later by a standard dose of gemcitabine infusion (1000 mg/m2) and intraluminal laser 
light application (30 J/cm) on Day 1, as shown in Figure 3.  
Figure 3 
PCI Treatment Sequence 
 
This regimen replaces the gemcitabine/cisplatin administration of Day 1 in the first 
chemotherapy cycle. Patients will thereafter receive the remaining treatments as per SoC 
gemcitabine/cisplatin combination chemotherapy in Cycle 1 (Day 8) to Cycle 4 with cisplatin 
at 25 mg/m2 and gemcitabine at 1000 mg/m2, administered on Day 1 and Day 8 of each 
21-day cycle.  
Second PCI Treatment 
A second PCI treatment following the same schedule will be performed at the start of Cycle 5 
(Amphinex injection on Cycle 4, Day 18) followed by gemcitabine infusion and intraluminal 
laser light application on Cycle 5, Day 1. The second PCI treatment should be separated by at 
least 3 months from the first PCI treatment. 


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Patients will thereafter receive the gemcitabine/cisplatin standard combination chemotherapy 
(cisplatin at 25 mg/m2 and gemcitabine at 1000 mg/m2) on Day 8 of Cycle 5 and then on 
Day 1 and Day 8 of each 21-day treatment cycle for up to 8 cycles. 
If delays in the chemotherapy schedule have occurred or the schedule has been altered for 
any reason; or if a second PCI treatment in Cycle 5 is deemed medically inappropriate, 
temporarily unsafe, presents with an increased risk related to the endoscopy or PCI treatment; 
or if the patient strongly prefers its postponement for other reasons, or the patient has had 
chemotherapy before enrolment, the second PCI can be conducted in any of the later cycles 
at the discretion of the treating physician. However, the general goal should be to schedule 
the second PCI treatment at the start of Cycle 5 and avoid postponements unless an event or 
cause as outlined above is present to justify it.  
The second PCI treatment may be postponed if: 
• 
In the opinion of the Investigator, the single dose of gemcitabine cannot be given at the 
full 1000 mg/m2 dose due to residual toxicity 
• 
The Investigator determines that the patient will not tolerate a second PCI treatment at 
the scheduled time based on the patient’s poor tolerability of the first PCI treatment 
• 
In the view of the Investigator, there is evidence of ongoing inflammation within the 
PCI illumination area 
• 
In the opinion of the Investigator, the patient shows significant signs of photosensitivity 
• 
If one of the following criteria is present: 
o 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or alkaline 
phosphatase (ALP) >5 × the upper limit of normal (ULN) 
o 
ALT or AST or ALP >3 × ULN with the appearance of symptoms associated with 
a clinical diagnosis of hepatitis including right upper quadrant pain or tenderness, 
fever, rash or eosinophilia (>5%) 


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o 
ALT or AST >3 × ULN and total bilirubin >2.5 × ULN or international 
normalised ratio >1.51 or other evidence of impairment to the synthesis function 
of the liver 
o 
Total bilirubin >2.5 × ULN  
In contrast to postponing the second PCI, this treatment will not be given at all if any of the 
following criteria are fulfilled: 
• 
The patient experienced a PCI treatment-related schedule-limiting toxicity (SLT) 
defined as: 
o 
A clinically significant toxicity or abnormal laboratory value occurring after PCI 
treatment and during the first chemotherapy cycle, assessed as unrelated to the 
underlying disease, or concomitant medications, where there is a reasonable 
possibility that it is related to either PCI treatment or to the combination of PCI 
treatment with the cisplatin/gemcitabine systemic chemotherapy and meets any 
of the following criteria, based on National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0: 
▪ 
Photosensitivity Grade 3 outside the treatment area, except for areas 
exposed for skin sensitivity tests and areas exposed for re-introduction to 
normal light (patient compliance with light protection guidelines MUST be 
followed; non-compliance will be taken into account when determining 
SLT) 
▪ 
Phototoxicity Grade 4 inside the treatment area (eg, duodenal ulceration) 
▪ 
Non-haematological toxicity (excluding nausea and vomiting) ≥Grade 3 
▪ 
Neutropenia or thrombocytopenia Grade 4 
▪ 
All other Grade 3 toxicities that are clinically unexpected and considered 
related to the PCI treatment 
 
1 Unless on anti-coagulants 


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▪ 
The patient is expected not to be able to receive the single dose of 
gemcitabine at a dose of 1000 mg/m2 at any time 
Furthermore, if the patient is unwilling to undergo a second PCI treatment, the second PCI 
can be omitted; however, the patient can continue to receive the gemcitabine/cisplatin 
standard combination chemotherapy. 
If treatment is delayed, computed tomography (CT)/magnetic resonance imaging (MRI) 
scans should still be conducted at the scheduled time point relative to randomisation. This is 
to avoid the risk of a difference between arms in the primary endpoint of PFS that can be 
attributed to changes in scanning frequency rather than treatment. 
The second PCI treatment will continue to be included in the Arm A treatment schedule only 
if the first PCI treatment is found to be tolerable and recommended to be continued by an 
Independent Data Monitoring Committee (IDMC) based on an initial safety review of the 
first 8 patients treated with 2 PCI treatments; otherwise, only a single PCI administration 
schedule integrated in Cycle 1 will be employed. 
In patients on study treatment, the reason(s) for delays, postponement, or omitting of the 
second PCI must be adequately documented and recorded in the electronic case report form 
(eCRF). 
Patients should continue their randomised chemotherapy treatment until a maximum of 
8 gemcitabine/cisplatin cycles or until a treatment discontinuation criterion is met. 
3.3.3 Arm B 
Patients randomised to Arm B (control arm) will receive SoC treatment only, 
gemcitabine/cisplatin combination chemotherapy for nonresectable or metastatic CCA as 
follows: 
Cisplatin IV infusion at 25 mg/m2 plus gemcitabine IV infusion at 1000 mg/m2 on Days 1 
and 8 of each 21-day treatment cycle for up to 8 cycles. 
If treatment is delayed, CT/MRI scans should still be conducted at the scheduled time point 
relative to randomisation. This is to avoid the risk of a difference between arms in the 


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primary endpoint of PFS that can be attributed to changes in scanning frequency rather than 
treatment. 
Patients should continue their randomised chemotherapy treatment until a maximum of 
8 gemcitabine/cisplatin cycles or until a treatment discontinuation criterion is met. 
3.4 Rationale of Study Design 
The purpose of this study is to evaluate the safety and efficacy of fimaporfin-induced PCI of 
gemcitabine complemented by gemcitabine/cisplatin systemic chemotherapy in patients with 
advanced inoperable CCA. 
3.4.1 Rationale for Patient Population 
Local control of perihilar disease has been shown to be a major influencing factor for both 
OS and quality of life (Mihalache et al 2010) in CCA. Patients are at a high risk of dying 
early from complications of local tumour infiltration (eg, cholestasis, septic cholangitis, 
empyema, or liver failure) rather than systemic disease. In most cases, treatment consists of 
biliary stenting followed by systemic chemotherapy. Thus, it is proposed that PCI of 
gemcitabine complemented by gemcitabine/cisplatin chemotherapy in patients with 
inoperable extrahepatic CCA should demonstrate an advantage in this subset of patients. 
3.4.2 Rationale for Study Endpoints 
The primary endpoint for the study is PFS, which is a commonly used surrogate for OS 
(Fleming 2005). An analysis of 104 chemotherapy trials in 2810 patients with advanced 
biliary tract carcinoma, demonstrated a strong association between time to tumour 
progression and OS (correlation coefficient [r]=0.73, p<0.001). A 1 month increase in time to 
tumour progression corresponded to a 1.3 month increase of OS (Eckel and Schmid 2007). 
In a second publication, 17 randomised trials with a total of 2148 patients were analysed. Of 
all the evaluated efficacy endpoints, the strongest correlation was observed between median 
OS and median PFS hazard ratios (HRs) (Moriwaki et al 2016). In trials with 
gemcitabine-containing therapies and targeted agents, the coefficient of determination (r2) 
value was 0.78 and the surrogate threshold effect was estimated at 0.81. Surrogate threshold 
effect is defined as the minimum treatment effect on the surrogate endpoint (ie, PFS) that is 


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necessary to predict a non-zero effect on the true endpoint (ie, OS HR<1). Therefore, based 
on the study by Moriwaki et al, a PFS HR<0.81 is necessary to predict for OS HR<1.  
The authors discussed that a PFS HR<0.7 observed in a randomised clinical trial of advanced 
biliary tract cancer treatment with a superiority design could translate to a 20% improvement 
in OS. 
3.4.3 Clinical Precedence 
Fimaporfin has been evaluated in 3 cancer studies to date: 1 completed study and 
1 terminated study with fimaporfin-induced PCI of bleomycin, and one completed study with 
fimaporfin-induced PCI of gemcitabine. As of June 2020, 69 patients have received 
fimaporfin; 46 with bleomycin and 23 with gemcitabine. Thirteen patients have received 
fimaporfin-induced PCI of gemcitabine at the dose level of this study, 0.22 mg/kg fimaporfin 
(equivalent to 0.25 mg/kg fimaporfin di-olamine) and 30 J/cm light dose.  
The first completed study, PCI 101/06 was a Phase 1, dose escalation and safety and 
tolerability study in patients with local recurrent or advanced/metastatic, subcutaneous and 
cutaneous malignancies. Amphinex (fimaporfin) was administered as a single IV injection 
4 days prior to a single administration of bleomycin and light application to the tumour 
surface. In total, 19 patients were treated in 4 dose groups: 0.25, 0.50, 1.00, and 1.50 mg/kg 
body weight. These doses were based on fimaporfin di-olamine weight, and are equivalent to 
fimaporfin doses of 0.22, 0.43, 0.87 and 1.30 mg/kg, respectively. An extension to 
PCI 101/06 (PCI 101/06 Extension) was also conducted. In this extension study, fimaporfin 
was given to 3 patients as a single administration at a reduced concentration 
(dose 0.125 mg/kg body weight, equivalent to fimaporfin 0.11 mg/kg) prior to a single 
administration of bleomycin and superficial laser light application. Two of these patients 
were subsequently re-treated at a dose of 0.50 mg/kg body weight (equivalent to fimaporfin 
0.43 mg/kg). In PCI 101/06, 15 patients experienced 62 treatment-related AEs. Of these 
62 treatment-related AEs, 7 were considered serious AEs (SAEs) – cellulitis at treatment site, 
thrombocytopenia, tongue oedema, renal failure, swelling of the hands, blisters on the back 
of the hands, and postoperative wound infection. These 7 SAEs occurred in 6 patients. 
The second terminated study, PCIA 202/10, was a Phase 2 open-label, single-arm, 
multi-centre study to evaluate the safety and efficacy of Amphinex in combination with 
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unsuitable for surgery and radiotherapy. Amphinex was administered as a single IV injection 
at a dose of 0.22 mg/kg fimaporfin, 4 days prior to bleomycin and superficial and/or 
interstitial laser light application. In total, 24 patients were treated in 5 treatment groups: 60, 
30, 20, and 10 J/cm interstitial laser light, and 60 J/cm2 superficial laser light. Initially, 
6 patients were treated with 60 J/cm interstitial laser light and 2 patients were treated with 
superficial light. Following the reporting of suspected unexpected serious adverse reactions 
(SUSARs) in patients treated with multiple interstitial fibres, the clinical study protocol was 
amended to include a light dose escalation (run in part) for interstitial laser light application. 
Eleven additional patients were treated with interstitial light application under the amended 
protocol; 3 patients were treated with 10 J/cm, 7 patients with 20 J/cm and one patient was 
treated with 30 J/cm interstitial laser light. Five more patients received superficial laser light 
application only (at an unchanged light dose of 60 J/cm2). The study was terminated and 
inclusion of patients ceased from June 2015. Patients on study were followed up as per 
protocol before termination of the study. Nine treatment-related AEs were 
SAEs – application site pain, facial oedema, soft tissue injury (3 patients), dysphagia, 
necrosis, arthralgia, fistula, respiratory tract oedema, and ischaemia of the tongue (5 of these 
SAEs were observed in patients treated with 60 J/cm interstitial laser light). 
The decision to cease recruitment and terminate the study was not caused by safety concerns 
but was based on the rapid evolvement of new therapies as alternatives to bleomycin for the 
indication, leaving PCI with a diminishing role as a treatment option in the indication. In 
addition, the technical challenges presented by the requirement of multiple access routes for 
interstitial laser illumination and a proper illumination dose evaluation became more 
complicated than anticipated. 
The third study, PCIA 202/12 was a Phase 1 study to assess the safety, tolerability and 
efficacy of fimaporfin-induced PCI of gemcitabine followed by gemcitabine/cisplatin 
chemotherapy in patients with advanced inoperable CCA. A total of 23 patients were 
included, 20 males and 3 females, in 5 cohorts. 
Sixteen patients were treated in the single-arm dose escalation part of the study. Three 
patients were treated at a fimaporfin dose of 0.05 mg/kg with a light dose of 15 J/cm 
(Cohort 1), 3 patients at a fimaporfin dose of 0.05 mg/kg and a light dose of 30 J/cm 
(Cohort 2), 4 patients at a fimaporfin dose of 0.10 mg/kg and light dose of 30 J/cm 
(Cohort 3), and 6 patients at a fimaporfin dose of 0.22 mg/kg and a light dose of 30 J/cm 


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(Cohort 4). No dose-limiting toxicities (DLTs) were reported and the dose of Cohort 4 was 
selected for future studies. 
Seven patients were enrolled in the extended Phase 1 part, with the objective of determining 
safety and tolerability of a two-dose regimen of PCI treatment at the selected dose from the 
dose escalation part. A total of 5 patients underwent the 2 PCI treatment procedures and 
completed the required 21-day safety window following the second procedure as per 
protocol. All SLT criteria were assessed and no SLTs were reported; therefore, the Cohort 
Review Committee (CRC) concluded that the procedure was tolerable based on the fact that 
no SLTs were observed in the 5 eligible patients who completed both PCI procedures.  
Cholangitis was the most frequently reported SAE from study PCIA 202/12 (16 patients, 
43 events). Overall, no correlation between PCI treatment and time to onset of cholangitis 
was evident. The rates of cholangitis seen are similar to those seen in published Bismuth III 
and IV hilar CCA endoscopic procedure studies (Pisello et al 2009; Talreja et al 2013).  
Encouraging preliminary signs of efficacy have been seen in the Phase 1 dose escalation part 
of the study. Based on evaluation of radiology data from patients treated in Cohorts 3 and 4, a 
response rate (complete response [CR] + partial response [PR]) of 55% has been observed in 
the 9 evaluable patients. In the extended Phase 1 part of the study, one patient had PR out of 
the 5 evaluable patients (ORR of 20%). Overall, 6 out of 19 evaluable patients had a BOR of 
confirmed CR or PR (ORR of 31.6%) and 15 of the 22 evaluable patients (68.2%) were 
progression-free at their 6-month scan. The median OS of all 23 patients was 16.1 months. 
The PCIA 202/12 protocol was designed as a proof-of-concept study with up to 60 patients 
being randomised either to an active treatment arm (PCI + SoC treatment with gemcitabine 
and cisplatin), or to a control arm (SoC treatment with gemcitabine and cisplatin, only). 
However, based on the encouraging preliminary efficacy and safety findings in the Phase 1 
part, the Phase 2 part of the study PCIA 202/12 is replaced by the current study with the aim 
of this becoming a registration study. Refer to the current edition of the Amphinex 
(fimaporfin) Investigator’s Brochure (IB) for a complete summary of nonclinical and clinical 
information including safety, PK, and efficacy. 


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3.4.4 Rationale for Dose 
In terms of safety, Amphinex has been well tolerated in doses up to the maximum tolerated 
dose of 0.87 mg/kg as established in the Phase 1 study PCI 101/06 and as shown by the 
absence of DLTs in the Phase 1 dose escalation part of the study PCIA 202/12 in CCA. 
Overall, Amphinex shows a suitable safety and tolerability profile for the treatment of 
advanced CCA. Based on the limited available data, no clear dose-dependency relationship 
has been observed for safety. Clear evidence of efficacy has been seen at several doses 
evaluated for efficacy so far, as manifested by rapid responses. 
The PCI treatment with Amphinex in combination with chemotherapeutic substances 
bleomycin and gemcitabine has been shown to be tolerated in preclinical and clinical studies. 
In the completed Phase 1 PCI 101/06 and PCI 101/06 Extension studies, Amphinex was 
given in combination with a fixed dose of bleomycin and laser light. Amphinex doses 
between 0.11 and 0.87 mg/kg were well-tolerated, and doses between 0.22 and 1.3 mg/kg 
showed early signs of efficacy. In the Phase 2 PCIA 202/10 study of Amphinex in 
combination with bleomycin and laser light, an Amphinex dose of 0.22 mg/kg was given 
with a fixed dose of bleomycin and varying light doses. Preliminary signs of efficacy were 
shown in patients receiving superficial light application. 
The Phase 1 PCIA 202/12 study was completed with good safety, tolerability and anti-tumour 
activity at different dose levels, including the 2-administration schedule. For the PCI 
treatment, all patients received the standard gemcitabine dose of 1000 mg/m2. 
Twenty-one of the 23 enrolled patients completed the safety evaluation window and no DLTs, 
SLTs or other safety concerns were reported. The Amphinex dose administered in Cohorts 1 
and 2 was regarded too low for achieving tumour effects. An evaluation of radiology data 
from patients treated in Cohorts 3 and 4 concluded that a total of 9 patients were evaluable 
for BOR and 5 of these had confirmed objective tumour response. 
The selection of the dose of Amphinex and light applied in Cohort 4 of the Phase 1 of 
PCIA 202/12, as well as the standard gemcitabine dose of 1000 mg/m2, is based on the 
observed well-tolerated safety profile and early promising signs of antitumour activity, 
combined with experience from the previous clinical studies with Amphinex (including 
PCIA 202/10). In HNSCC, a higher light dose of 60 J/cm was associated with serious local 


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adverse reactions, whereas, the 2 lower photochemical doses were regarded too low for 
achieving tumour effects. 
Based on these cumulative data, the dose of 0.22 mg/kg Amphinex and intraluminal light 
dose of 30 J/cm with the standard gemcitabine dose (1000 mg/m2) were selected for further 
studies. 
Photochemical dose (light and photosensitiser): The light dose is based on both the data from 
the Phase 1 study in CCA (PCIA 202/12) and from the clinical experience from the study in 
HNSCC (PCIA 202/10). In HNSCC, a higher light dose of 60 J/cm was associated with 
serious local adverse reactions. In the Phase 1 dose escalation part of study PCIA 202/12, 
several combinations of fimaporfin and light doses were tested (see Section 3.4.3). However, 
the 2 lower photochemical doses were regarded too low for achieving tumour effects. 
Therefore, a light dose of 30 J/cm combined with 0.22 mg/kg Amphinex dose was chosen. 
3.4.5 Rationale for Treatment Regimen 
A single treatment schedule of Amphinex-induced PCI of gemcitabine has been found to be 
both well-tolerated and clinically active in Cohorts 3 and 4 of the Phase 1 dose escalation 
part of study PCIA 202/12. This has raised the question as to whether a 2-administration 
schedule would increase the clinical effectiveness of Amphinex-induced PCI of gemcitabine 
by further treating any residual tumour while maintaining the tolerability profile. 
In the extended part of Phase 1 in study PCIA 202/12, the 2-administration schedule was to 
be considered non-tolerated if 2 or more of the first 6 evaluable patients experienced an SLT. 
If none or 1 of the first 6 evaluable patients experienced an SLT (see definition in 
Section 3.3.2), the 2-administration schedule was to be considered tolerated. 
A total of 5 patients underwent the 2 PCI treatment procedures and completed the required 
21-day safety window following the second procedure as per protocol. All SLT criteria were 
assessed and no SLTs were reported in these 5 eligible patients. The CRC concluded that the 
procedure was tolerable based on the fact that no SLTs were observed in the 5 eligible 
patients. Therefore, the 2-administration schedule can be considered tolerated. 
Based on results from Studies PCI 101/06 and PCIA 202/10, the plasma half-life of 
fimaporfin in Amphinex is 15 to 22 days; therefore, the separation between the first and 


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second Amphinex dose would be almost 4 half-lives, minimising the risk of accumulation 
and additional toxicity. 
Results from Study PCIA 202/12 show that there is greater variation in half-life values, 
ranging from 21 to 93 days; however, as reported above, there were no SLTs reported in any 
of the 5 patients who received a second administration. Therefore, even if there is some 
accumulation of fimaporfin, it is not considered to be a safety issue that would affect the 
timing between the first and second administration. If, in the opinion of the Investigator, the 
patient shows significant signs of photosensitivity, the second administration can be 
postponed. 
In this study (PCIA 203/18), an IDMC will be convened to perform periodic reviews of 
accumulating safety data, with focus on biliary tract events which are defined as AEs of 
special interest (AESIs). The study will include an initial safety review by the IDMC after the 
initial 8 patients in Arm A have been administered 2 PCI treatments and followed up for 
21 days. The IDMC will assess whether the second PCI treatment during the chemotherapy 
period should continue to be administered for future patients randomised to Arm A. 
3.4.6 Benefit/Risk and Ethical Assessment 
Potential benefits 
The potential benefits of PCI treatment of CCA include improved biliary drainage and 
improvement of malignant biliary disease in the hilar region. Repeated PCI treatment may 
provide an enhanced effect in line with the results obtained with repeated PDT treatment 
effects. 
Potential risks 
Patients in the present study will be treated with fimaporfin-induced PCI of gemcitabine, and 
intraluminal laser light application will be by use of a single optical fibre. 
The Phase 1 studies (PCI 101/06 and PCI 101/06 extension) in patients with cutaneous or 
subcutaneous malignancies demonstrated that the treatment conditions with superficial light 
application at a light dose of 60 J/cm2 did not raise any safety concerns with fimaporfin doses 
ranging from 0.22 to 0.87 mg/kg body weight. 


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In the Phase 2 study PCIA 202/10 (HNSCC), there were cases of local tissue loss in patients 
who received interstitial PCI with bleomycin for glossal and floor of mouth tumours. In these 
patients, the treatment caused more tissue destruction than expected in the tumour area. The 
most likely contributing factor is the light dose (60 J/cm) with multiple parallel light fibres 
(ie, 13-16 fibres).  
In patients treated with lower light doses (10 J/cm, 20 J/cm, and 30 J/cm), there have been no 
reports of excessive tissue loss. In study PCIA 202/12 in patients with CCA, only one light 
fibre was used for the intraluminal application. The fibre was manipulated within an 
endoscopic retrograde cholangio-pancreatography (ERCP) catheter to ensure full coverage of 
the area to be treated, which may be longer than the cylindrical light diffuser that provides 
the laser light illumination. In the dose escalation phase, the initial light dose applied was 
15 J/cm in the first cohort, and in the second, third and fourth cohorts the light dose applied 
as 30 J/cm. Based on safety data obtained, as well as preliminary efficacy findings, the light 
dose of 30 J/cm was selected for the extended Phase 1 study. 
The PCI treatment is designed to activate an intracellular release of gemcitabine in the 
tumour cells. Therefore, the laser light is intentionally directed towards tumour tissue in the 
bile duct. Its intensity and thus its ability to activate fimaporfin is strongly (exponentially) 
reduced by increasing distance from the light source. The light dose will be progressively 
diminishing with the distance into the tissue. The maximum distance for delivery of an 
effective light dose is expected to be 1.0 to 1.5 cm away from the light source. Thus, only a 
local activation of gemcitabine occurs, and only a minimal light dose will reach the normal 
tissue surrounding the tumour, meaning that only small and localised reactions in the normal 
tissues may be expected.  
There has been no evidence of long-term, local adverse reactions. Local tissue swelling and 
necrosis resulting from the PCI treatment is difficult to visualise, but certain clinical 
symptoms and signs may be inferred. The most frequent clinical symptom observed has been 
transient (<24 hours) abdominal pain, presumably due to inflammation and swelling. Other 
possible symptoms include haematemesis, biliary infective episodes such as cholangitis and 
biliary sepsis, which could arise from the endoscopy/stenting procedure itself in these 
patients and are not specifically related to PCI. Furthermore, a temporary occlusion due to an 
initial local oedema is a potential risk in case of a suboptimal biliary drainage. 


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In the current study, a second PCI treatment is introduced at the onset of Cycle 5 of the 
combination chemotherapy regimen. The window of at least 3 months between the PCI 
treatments will allow for local reactions (in terms of inflammatory response) to cease, and for 
potentially weakened, normal tissue to revert to normal or fibrotic tissue. The decision to add 
a second PCI treatment was based on safety and efficacy findings from the Phase 1 dose 
escalation and extended part of Study PCIA 202/12 in which a repeat PCI treatment using the 
same dose (fimaporfin dose of 0.22 mg/kg and a light dose of 30 J/cm) was found safe. 
Besides the time span between treatments, the patients are additionally protected by the 
maintenance of a functional stent, ameliorating any potential risk of biliary structure injury. 
For the study population as a whole in the current study, the safety of a second PCI treatment 
will be additionally reviewed by the IDMC after the first 8 patients have undergone the 
second PCI treatment (with a safety window of a month). On an individual patient level in 
Arm A, the second PCI treatment may be removed in patients where safety considerations or 
other concerns indicate a limited tolerability or a potential safety risk. 
The repeat PCI treatment is expected to cause similar events, including potential abdominal 
pain, as those occurring after the initial PCI treatment. Intensive safety monitoring will be 
undertaken to ensure the safety of the patients, including laboratory assessments to monitor 
for adverse effects of gemcitabine treatment. 
There is a theoretical risk that the bile duct may weaken as a result of the first PCI treatment 
and the additional necrosis caused by the second treatment (aimed at destroying any residual 
tumour) could damage the bile duct such that it could perforate, leading to bile fluid leakage 
into the peritoneum. However, based on studies with PDT in bile duct cancer, the risk of bile 
duct perforation is considered to be low. Several studies have been performed with PDT in 
bile duct cancer, mainly using the photosensitiser porfimer sodium (Photofrin). In many of 
these studies, patients have received repeated PDT treatments and up to 6 treatments have 
been reported. The primary conclusion from these studies seems to be that repeating the PDT 
treatment enhances the therapeutic effect, including survival parameters, and that a good 
local response can be observed. In these studies, no serious safety concerns associated with 
repeated PDT treatments were reported (Amphinex [fimaporfin] IB).  
The risks associated with general anaesthesia/sedation are those that would normally be 
anticipated with minor surgical procedures. 


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Photosensitivity following PCI treatment is a known risk factor from previous clinical 
experience. Patients will be advised on precautions to prevent skin and eye sensitivity 
reactions from exposure to light, and on avoidance of other treatments which are also known 
to cause photosensitivity.  
Data from clinical studies (studies PCI 101-06, PCIA 202-10, and PCIA 202-12) showed that 
all photosensitivity-related AEs were mild or moderate. No severe AEs related to 
photosensitivity were reported among 41 subjects treated in those studies with the same dose 
of fimaporfin that is given in the current study. 
The fimaporfin-induced PCI of gemcitabine could be expected to increase the genotoxic 
effect of gemcitabine in the tumour area treated with laser light, since the therapeutic effect 
of gemcitabine is due to various forms of DNA damage. This is, however, a desired effect 
leading to a better and more specific therapeutic response to gemcitabine. 
Please refer to the Amphinex (fimaporfin) IB for further details about the potential risks and 
benefits associated with this study. 
Summary benefit/risk statement 
In general, patients with CCA have a poor prognosis, with an average 5-year survival rate of 
5% to 10% for locally advanced disease. Surgery provides the only possibility for a cure, but 
approximately half of all perihilar lesions are inoperable (Nakeeb et al 1996) and even in 
patients who undergo potentially curative resection, tumour-free margins can be obtained in 
only 20% to 40% (Sakamoto et al 1998). Hence, there remains a significant unmet medical 
need for patients with inoperable hilar CCA. 
All patients in this study will be treated with current SoC for the disease, 
gemcitabine/cisplatin treatment. In addition, patients in the active Arm A will receive PCI 
treatment. No major safety concerns have been raised with the study dose of 0.22 mg/kg 
fimaporfin and 30 J/cm intraluminal light used in study PCIA 202/12. In all clinical data sets 
so far, there has not been evidence of any significant biochemical or haematological toxicity 
solely attributed to the PCI treatment.  
In a previous clinical study (PCIA 202/12), radiological response has been observed in 32% 
of 19 patients treated with the fimaporfin dose that is given in this study. Fifteen of the 


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22 evaluable patients (68.2%) were progression-free at 6 months. The median OS of all 
23 patients was 16.1 months. 
The study design aims to minimise the potential risks, and routine safety monitoring is in 
place to protect the study patients. The potential benefits of PCI treatment of CCA include 
improved biliary drainage and improvement of malignant biliary disease. Thus, the 
benefit/risk assessment for this Phase 2 study is considered acceptable. 


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4 
Patient Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
Approximately 186 patients with inoperable CCA will be enrolled at approximately 50 sites 
in Asia, Europe and North America. Patients will be assigned to study treatment only if they 
meet all of the inclusion criteria and none of the exclusion criteria. 
4.1.1 Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in this study: 
1. Capable of understanding the written informed consent, provides signed and witnessed 
written informed consent, and agrees to comply with protocol requirements; 
2. Male or female patient ≥18 years of age; 
3. Cholangiocarcinoma verified as adenocarcinoma by histopathology or cytology with a 
perihilar or distal stenosis that has been stented or will require stenting, and that is 
accessible for PCI light treatment; 
4. Cholangiocarcinoma must be considered inoperable with respect to radical resection 
(including partial liver resection or liver transplantation); 
5. At least 1 radiologically evaluable lesion (measurable and/or non-measurable) that can 
be assessed at baseline and is suitable for repeated radiological evaluation;  
6. If metastatic disease, metastasis must be limited to tissues other than bone or the 
central nervous system; 
7. Adequate biliary drainage (at least 50% of the liver volume or at least 2 sectors), with 
no evidence of active uncontrolled infection (patients on antibiotics are eligible); 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; 
9. Estimated life expectancy of at least 12 weeks. 
4.1.2 Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the study: 
1. Previously received any anti-tumour (either local or systemic) treatment for CCA, 
except for previous treatment of up to 2 cycles of gemcitabine/cisplatin; 


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2. Severe visceral disease other than CCA; 
3. A history of frequently recurring septic biliary events; 
4. Porphyria or hypersensitivity to porphyrins; 
5. A second primary cancer with a disease-free interval of <5 years. A second primary 
cancer that has been treated with intent to cure may be allowed after consultation with 
the study Medical Monitor. Adequately treated basal cell carcinoma, squamous cell 
carcinoma or other non-melanomatous skin cancer, in-situ carcinoma of the uterine 
cervix, or prostate cancer that is controlled by hormone therapy (patients may continue 
hormone therapy while on study) are allowed; 
6. Unable to undergo contrast-enhanced CT or MRI; 
7. Currently participating in any other interventional clinical study; 
8. Planned surgery, endoscopic examination, or dental treatment in the first 30 days after 
PCI treatment; 
9. Co-existing ophthalmic disease likely to require slit-lamp examination within the first 
90 days after PCI treatment; 
10. Clinically significant and uncontrolled cardiac disease including unstable angina, 
acute myocardial infarction within 6 months prior to baseline, congestive heart failure, 
and arrhythmia requiring therapy, except for extra systoles or minor conduction 
abnormalities and controlled and well treated chronic atrial fibrillation; 
11. Known allergy or sensitivity to photosensitisers, (the active substance and/or any of 
the excipients); or chronic use of other photosensitising therapies (Section 5.5.3); 
treatment with amiodarone during the last 12 months; 
12. Known hypersensitivity to or contraindication to the use of gemcitabine (the active 
substance and/or any of the excipients); 
13. Known hypersensitivity, or contraindication to the use of cisplatin (the active 
substance and/or any of the excipients);  
14. Ataxia telangiectasia; 


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15. Upon the Investigator’s discretion, evidence of any other medical conditions (such as 
psychiatric illness, physical examination or laboratory findings) that may interfere 
with the planned PCI treatment, affect patient compliance or place the patient at high 
risk from treatment-related complications;  
16. Plans to have, or has recently had, vaccination with a live vaccine, including for 
yellow fever; 
17. Concurrently receiving treatment with phenytoin; 
18. Male patients unwilling to use highly effective contraception, or women of 
childbearing potential (WOCBP) (see definition in Section 5.6) unwilling to use a 
highly effective form of contraception such as the following: 
o Combined (oestrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation (oral, intravaginal 
and transdermal) 
o Progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, or implantable) 
o Intrauterine devices 
o Intrauterine hormone-releasing system 
o Bilateral tubal ligation 
o Vasectomised partner2 (Section 5.6) 
o Sexual abstinence3 
Patients must continue the use of contraception during PCI treatment and subsequent 
chemotherapy, and for at least 9 months after last dose of Amphinex or 6 months after 
last dose of chemotherapy, whichever is the latest. 
 
2 Vasectomised partner is a highly effective birth control method only if the partner is the sole sexual partner of 
the WOCBP study participant and if the vasectomised partner has received medical assessment of the surgical 
success. 
3 Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual 
lifestyle of the patient. 


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19. Breastfeeding women or women with a positive pregnancy test at baseline; 
20. Inadequate bone marrow function as evidenced by one of the following: 
o Absolute neutrophil count (ANC) <1.5 × 109/L  
o Platelet count <100 × 109/L 
o Haemoglobin <6 mmol/L (transfusion allowed); 
21. Inadequate liver function despite satisfactory biliary drainage, defined as: 
o Serum (total) bilirubin persisting at >5 × the ULN for the institution 
o AST or ALT >3.0 × ULN (>5 × ULN if liver metastases are present) 
o ALP levels >5.0 × ULN; 
22. Inadequate renal function, as determined by local practice for patients on fractionated 
platinum-based chemotherapy. Patients with creatinine clearance <60 mL/min must 
not be included. 
4.2 Discontinuation/Withdrawal of Patients From Study Treatment and/or 
the Study 
4.2.1 Discontinuation From Study Treatment 
Study treatment will continue until a maximum of 8 gemcitabine/cisplatin chemotherapy 
cycles or criteria for discontinuation of treatment are met. A study patient is free to 
discontinue study treatment prematurely at any time. If so, the patient shall always be asked 
about the reason(s) for treatment discontinuation, and the presence of SAEs and AEs. If AEs 
are ongoing, these will be followed up as detailed in the study plan. 
A patient may discontinue study treatment in any of the following situations:  
• Severe non-compliance to study protocol 
• Incorrect enrolment and randomisation 
• Progressive disease  
• Development of toxicity 
o 
Arm A patients after first PCI treatment: the development of toxicity, which 
precludes further treatment with both: 


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▪ 
PCI treatment, see SLT definition in Section 3.3.2 and 
▪ 
standard gemcitabine/cisplatin combination chemotherapy, as per local 
practice 
Note: If a patient can no longer receive PCI treatment due to toxicity but can 
continue on the standard gemcitabine/cisplatin combination chemotherapy, or 
vice versa, then the patient will not be considered as discontinued from 
treatment. 
o 
Arm A patients after second PCI treatment and Arm B patients: the development of 
toxicity, which precludes further treatment with standard gemcitabine/cisplatin 
combination chemotherapy, as per local practice 
• Patient refusal to receive further study treatment 
 
Note: If a patient no longer wishes to receive PCI treatment but can continue on the 
standard gemcitabine/cisplatin combination chemotherapy, or vice versa, then the 
patient will not be considered as discontinued from treatment. 
• Lost to follow-up 
• Intercurrent illness precluding further study treatment 
• Pregnancy 
• Any other reasons not listed above as per Investigator discretion 
The reason for treatment discontinuation must be adequately documented and recorded in the 
eCRF. 
4.2.2 Withdrawal From Study 
In case of death, the randomised patient will be considered withdrawn from the study. 
Further, a patient will be withdrawn from the study in any of the following situations:  
• Patient is lost to follow-up  
• Patient decides to withdraw consent from participating in the study 


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• Screen failure 
• Study terminated by Sponsor 
• Other 
The reason for withdrawal from the study must be adequately documented and recorded in 
the eCRF. 
Patients who choose to withdraw from the study shall always be asked about the reason(s) for 
withdrawal from study. Patients should always be asked specifically whether they consent to 
be contacted for determination of survival follow-up. If patients who withdraw do not 
consent to survival follow-up, no further study procedures or follow-up assessments will be 
performed following withdrawal, and no further data will be collected through patient 
interactions. 
For patients whose reason for withdrawal is not death, if permitted, determination of survival 
may be collected through publicly available death registry information. 
4.2.3 Handling of Discontinuations/Withdrawals 
Patients are free to withdraw from the study or discontinue study treatment at any time upon 
request. Patient participation in the study may be stopped at any time at the discretion of the 
Investigator or at the request of the Sponsor. 
Patients who discontinue study treatment or active participation in the study will no longer 
receive study treatment from the Sponsor. When a patient withdraws from the study 
treatment or active participation in the study, the reason(s) for withdrawal shall be recorded 
by the Investigator on the relevant page of the eCRF. Patients who discontinue study 
treatment prematurely will continue to be followed for radiological progression and survival. 
Patients who fail to return for final assessments will be contacted by the site (eg, 2 
documented phone calls followed by 1 registered letter) in an attempt to have them comply 
with the protocol. 
To achieve the goals of the study and maintain patient safety, it is vital to obtain follow-up 
data on any patient withdrawn from the study. In every case, efforts must be made to 
undertake protocol-specified, safety, follow-up procedures. 


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All randomised patients will be included in the primary Intent-to-Treat (ITT) analysis set 
regardless of treatment received. 
4.2.4 Replacements 
Randomised patients who discontinue treatment or withdraw from the study will not be 
replaced. If a randomised patient is withdrawn, the patient identifier number will not be 
reused. 


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5 
Study Treatments 
5.1 Method of Assigning Patients to Treatment Arms 
Upon completion of all screening evaluations to confirm eligibility to participate in the study, 
eligible patients will be randomised via the Interactive Web Response System (IWRS). 
The randomisation will be stratified by 2 factors: any measurable disease at baseline 
(yes versus no) and presence or absence of metastases. Once the patient is randomised 
through the IWRS, the patient will be considered enrolled in the study. Specific instructions 
for the central enrolment and registration/randomisation procedures will be provided to the 
centre in a separate IWRS Procedure Manual. Approximately 186 patients will be enrolled at 
approximately 50 sites and randomised in a 1:1 ratio (fimaporfin-induced PCI of gemcitabine 
complemented by gemcitabine/cisplatin chemotherapy versus gemcitabine/cisplatin 
chemotherapy alone). 
Sites will be required to complete a Screening Log of all screened patients, regardless of 
whether the patient is randomised in the study. Randomised patients will be assigned a 
unique patient identifier number. If a randomised patient is withdrawn, the patient identifier 
number will not be reused. 
5.2 Identity of Investigational Products/Standard of Care Treatment 
A single PCI treatment consists of IV administration of Amphinex solution for injection 
(dose 0.25 mg/kg fimaporfin-di-olamine, equivalent to 0.22 mg/kg fimaporfin), followed 
4 days later by gemcitabine IV infusion (1000 mg/m2) and bile duct intraluminal laser light 
application (light dose 30 J/cm).  
Gemcitabine is currently not licensed for the treatment of patients with advanced inoperable 
CCA, but it is part of the current recognised SoC therapy. All patients will also receive SoC 
treatment (Arm A: SoC treatment plus PCI treatment, Arm B: SoC treatment alone). The 
current recognised SoC for nonresectable or metastatic CCA is cisplatin IV infusion, dose 
25 mg/m2 on Days 1 and 8, plus gemcitabine IV infusion, dose 1000 mg/m2 on Days 1 and 8, 
in up to 8 cycles of 21 days (Valle et al 2016; National Comprehensive Cancer Network 
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5.2.1 Amphinex 
Amphinex solution for injection is a sterile solution containing the following:  
• Active substance fimaporfin di-olamine; 30 mg/mL (equals 26 mg/mL of fimaporfin)  
• Tween 80 (3.0 %)  
• Tris buffer pH 8.5  
• 50 mM Mannitol (2.8 %)  
Amphinex appears as a dark purple solution, supplied as 2 mL fill in 2 mL clear vials. It is 
stored at 2°C to 8°C and protected from light. 
Amphinex should be handled and administered according to the instructions in the Pharmacy 
Manual. It is recommended to adjust the vials to room temperature for at least 30 minutes 
prior to administration to ensure low viscosity of Amphinex during dosing. Vials should be 
shaken carefully before administration. Amphinex should be used immediately after opening. 
Amphinex will be administered systemically as an IV injection by an authorised member of 
the study team. Since the dark purple colour of the solution makes a visual check for 
particulates impossible, an in-line filter (0.2 µm) will be used as a precautionary measure. 
Please refer to the Pharmacy Manual for a detailed description of the dosing and 
administration of Amphinex. 
5.2.1.1 
Fimaporfin-Associated Photosensitivity 
All patients who receive Amphinex (fimaporfin) are expected to become temporarily 
photosensitive and must take precautions to protect the skin and the eyes in order to prevent 
photosensitivity reactions.  
Data from clinical studies (studies PCI 101-06, PCIA 202-10 and PCIA 202-12) showed that 
all photosensitivity-related AEs were mild or moderate. No severe AEs related to 
photosensitivity were reported among 41 subjects treated in those studies with the same dose 
of fimaporfin that is given in the current study.  
Based on non-clinical data (Gederaas et al 2017) it is expected that fimaporfin 
photoactivation properties are diminished upon exposure to light (“bleaching” effect) and 


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therefore a gradual return to normal light conditions is recommended to shorten the time of 
light sensitivity.  
Luxmeters will be provided to the patients to enable them to measure light in their 
surroundings and to guide the gradual increase in exposure. The duration and degree of 
photosensitivity varies between patients, and patients must be encouraged to follow guidance 
and test for skin sensitivity. 
Photosensitivity precautions to be taken before, during and immediately after administration 
of Amphinex include the following: 
• As there is a potential for exacerbation of skin photosensitivity if Amphinex is used 
with other medicinal products known to induce skin-photosensitising reactions, 
precautions should be applied if these medications are being taken while Amphinex is 
being administered. A list of common photosensitising agents is provided in Table 4. 
• Patients must wear glasses that protect against laser emission wavelength, and all 
wavelength that activates fimaporfin, ie, ultravisible and visible light (dark glasses). 
The eyewear will be provided by the Sponsor. 
• As some pulse oximeters produce red light of a wavelength close to 652 nm, 
oximeters must be repositioned at least every 10 to 15 minutes to avoid the risk of 
local skin burns. Any non-compliance with regard to light protection should be 
adequately documented and recorded in the eCRF. 
• Immediately after administration of Amphinex, the injection site should be protected 
from light by a dressing.  
Following Amphinex injection, precautions should be taken for at least 4 weeks to avoid 
exposure of skin and eyes to direct sunlight or bright indoor light. Procedures for gradual 
re-introduction to light are provided in Table 1. Investigator must inform the patient of these 
procedures and document this counselling in the eCRF. In addition, all patients who receive 
Amphinex will receive a patient leaflet with information on how to protect from light, how to 
test for light sensitivity and how to gradually increase exposure to light. 


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Table 1 
Precautions for the Prevention of Skin and Eye Photosensitivity 
Reactions 
Time after Amphinex 
(fimaporfin) injection 
Precautions to prevent skin and eye photosensitivity reactions 
Patients should be made aware that there can be marked variation in sensitivity and duration of 
sensitivity between people. 
Day 1 
(0–24 hours) 
Patients should avoid direct exposure of eyes to any light sources and avoid 
direct and indirect daylight exposure. 
• 
The patient should stay indoors with low intensity (dim) indoor light (max 
100 lux). 
• 
Patients should avoid watching television or using computers, tablets, or 
smart phones.  
• 
To avoid exposure to daylight from the window, curtains and blinds should 
be closed.  
Lighting choice: warm white light bulbs (not more than 800 lumen: max 60W 
tungsten filament warm light bulb, 13W energy saver, or 6W LED) 
Day 2-7: 
 
Indoors: Patients should avoid direct daylight coming through the window 
or direct light from household appliances such as reading lamps.  
Beginning at 100 lux on Day 1, patients may gradually return to normal indoor 
lighting by a stepwise increase in the light of 100 lux per day, to reach 700 lux 
by Day 7. 
Outdoors: Patients may go outdoors after dusk.  
If need to travel during the day, such as to hospital appointments, the patient 
must sit away from windows and cover all skin including face and hands, 
and wear the dark glasses provided by Sponsor.  
The type of clothes and accessories the patient must wear are: 
• 
Wide-brimmed hat: for head, neck, face, nose and ears 
• 
Scarf: for head and neck 
• 
Dark glasses with side panels: for eyes and skin around eyes  
• 
Long sleeved top: for upper body/arms 
• 
Long trousers: for lower body/legs 
• 
Gloves: for hands, wrist and fingers 
• 
Socks: for feet and ankles 
• 
Closed shoes: for feet 
• 
An umbrella/parasol can give additional protection 
Skin photosensitivity reactions are caused by visible light. Sunscreens that 
protect from ultraviolet light will not protect from visible light. Dark, tightly 
woven clothing should be worn. Very thin clothing will not protect from strong 
light. 
If exposed to excessive bright light, the patient may feel a burning 
sensation on the skin. The patient must move away from the light source. If 
a photosensitivity reaction develops, contact the Clinical Investigator for 


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Time after Amphinex 
(fimaporfin) injection 
Precautions to prevent skin and eye photosensitivity reactions 
advice (see below).  
Day 8-15: 
 
Indoors: Patients should avoid direct daylight coming through the window 
or direct light from household appliances such as reading lamps.  
Continue to gradually return to normal indoor lighting by a stepwise increase in 
the light (by 100 lux per day, ie, from 800 lux on Day 8 to 1500 lux on Day 15). 
Outdoors: Patients may go outdoors but only if it is cloudy, shaded and not 
sunny.  
If need to travel during the day, such as to hospital appointments, the patient 
must sit away from windows and cover all skin including face and hands, 
and wear the dark glasses provided by Sponsor.  
 
Skin test: Patient should try cautious exposure only to back of hands over 
5-15 minutes on non-sunny days. If any prickling or discomfort occurs then 
patient should stop exposure immediately, cover up and go indoors. 
If there is no reaction 24 hours later, patient can continue to extend and 
gradually build up exposure time. 
 
If exposed to excessive bright light, the patient may feel a burning 
sensation on the skin. The patient must move away from the light source. If 
a photosensitivity reaction develops, contact the Clinical Investigator for 
advice (see below).  
After 2 weeks: 
 
A gradual increase in exposure to light should be encouraged, and the 
patient should continue to test for skin photosensitivity as described above. 
If there are no reactions 24 hours after the exposure, the duration of light 
exposure can be increased by 15 minutes per day. 
Indoors: gradually build up to normal levels of exposure. Patients should 
still take precautions to avoid exposure of skin to direct sunlight or bright 
indoor light for at least 4 weeks following administration of Amphinex. Eyes 
can remain sensitive to bright light for 3 months. 
Outdoors: During the first days of outdoor exposure the patient should stay in 
shaded areas or go out only when cloudy. The patient should continue to wear 
dark glasses and dark, tightly woven clothing. Two weeks after Amphinex 
injection, the patient should start to gradually return to normal levels of direct 
sunlight exposure. 
The patient’s eyes may be very sensitive to bright light during the first 
3 months; therefore, when outdoors, the patient should continue to wear the 
dark glasses provided by the Sponsor. 
 
If at any time the patient experiences symptoms – prickling, discomfort or 
redness – then he/she should cover up and go indoors and let the symptom 
settle fully before repeating exposure. 
Surgery: 
Surgery or dental treatment involving the use of light for visualisation or 


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Time after Amphinex 
(fimaporfin) injection 
Precautions to prevent skin and eye photosensitivity reactions 
 
treatment should be avoided during the first 4 weeks following Amphinex 
administration, unless it is absolutely necessary and only if the potential 
benefits for the patient outweigh the risks. Direct illumination of the patient 
with the operating room lights, including the surgeon’s headlamp, should be 
avoided. If an acute surgical intervention is needed, yellow or green light 
should be used. Ideally this could come from a sodium lamp but it may be more 
practical to use green filters that absorb wavelengths that activate fimaporfin 
(around 415 nm and 652 nm, contact Sponsor for advice). All incisions should 
be shielded from light.  
Some pulse oximeters may produce red light of a wavelength close to that used 
for the photoactivation of fimaporfin. To avoid the risk of local skin burns, 
pulse oximeters must be repositioned every 10 minutes and must not be used 
for longer than needed. 
Up to 3 months: 
For at least 3 months following PCI treatment: 
Eye tests that use bright lights should be avoided. Patients should contact their 
Investigator if eye tests using bright light are planned.  
Patients should avoid ultraviolet tanning beds and should not sunbathe. 
After 3 months 
Some patients may experience photosensitivity reactions beyond 3 months. 
Hence, the precautionary measures may be required for longer. 
Liver or renal impairment may prolong the elimination of fimaporfin, requiring 
longer periods of light protection. 
Patients should continue to test for photosensitivity periodically as described 
above until such time that no reactions are observed. 
Treatment of 
photosensitivity 
reactions 
If patients experience skin photosensitivity reactions, they can be treated in the 
same way as sunburn: Use of cooling emollients, skin moisturiser, topical 
corticosteroids. Analgesics can be considered for symptomatic relief. Extra care 
must be taken to protect skin while it heals. 
 
5.2.2 Gemcitabine 
Gemcitabine will be provided from the pharmacy stock. The gemcitabine bag used for 
administration will be labelled according to the local routines and regulatory requirements. 
The investigational site will be responsible for ordering gemcitabine. In the event that the 
investigational site cannot source gemcitabine locally for any reason, the Sponsor may 
provide gemcitabine centrally. The manufacturer and batch numbers will be documented. 
Refer to the Summary of Product Characteristics (SmPC)/Prescribing Information for further 
information on gemcitabine. 


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5.2.3 Cisplatin 
Cisplatin will be provided from the pharmacy stock. The cisplatin bag used for 
administration will be labelled according to the local routines and regulatory requirements. 
The investigational site will be responsible for ordering cisplatin. In the event that the 
investigational site cannot source cisplatin locally for any reason, the Sponsor may provide 
cisplatin centrally. The manufacturer and batch numbers will be documented. Refer to the 
SmPC/prescribing information for further information on cisplatin. 
5.2.4 Stenting 
Refer to Section 3.3.1. 
5.2.5 Light Source 
Laser light is used to activate fimaporfin. The light source used in this study will be supplied 
by the Sponsor and is a CE-marked medical laser system, emitting red light at 652 nm. A 
fibre-optic cylindrical light diffuser is connected to the laser system and inserted into a 
catheter during laser light application. The cylindrical light diffuser and catheter to be used 
will be provided by the Sponsor. The monitor will verify that the laser light application 
procedure is correctly documented and recorded in the eCRF. Laser light source handling is 
performed according to the laser system Instructions for Use. Performance of the laser 
system after treatment of each patient must be adequately documented and recorded in the 
eCRF (did the laser system perform as intended? yes/no). Operators should adhere to safety 
instructions provided.  
During laser light application, operators and persons assisting during the treatment must wear 
glasses protecting against the laser emission wavelength 652 nm (green glasses). Patients 
must wear glasses that protect against laser emission wavelength, and all wavelength that 
activates fimaporfin, ie, ultravisible and visible light (dark glasses). Some pulse oximeters 
may produce red light of a wavelength close to that used for the photoactivation of 
fimaporfin. Oximeters must be repositioned at least every 10-15 minutes to avoid the risk of 
local skin burns. Laser light application will be performed 3 hours (±1 hour) after end of the 
gemcitabine administration. Access routes to the biliary system in the study can be through 
the percutaneous transhepatic approach or by the endoscopic retrograde transpapillary 
approach. The procedure will be performed in accordance with local practice with adequate 
analgesic cover. Under fluoroscopic guidance a translucent ERCP catheter will be advanced 


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into the stenosis. Placement of the cylindrical light diffuser inside the ERCP catheter is 
described in the Procedure Manual. The entire stenosis should be illuminated. 
5.2.6 Dose Modifications 
5.2.6.1 
Dose Modifications for Amphinex and PCI treatment 
No dose modifications are allowed for Amphinex or gemcitabine given as part of the PCI 
treatment. See Section 3.3.2 regarding postponements or omissions of PCI treatment. 
5.2.6.2 
Dose Modifications for Systemic Chemotherapy Cycles 
The investigator site is expected to follow local practice for dose modification of the standard 
gemcitabine/cisplatin combination chemotherapy; however, the following information is 
provided for guidance. 
Haematological Toxicity 
The absolute neutrophil count must be ≥1,500 × 106/L and the platelet count must be 
≥100,000 × 106/L in order to administer full doses of gemcitabine and cisplatin in 
combination. Patients should be monitored prior to each dose for platelet, leucocyte and 
granulocyte counts, and, if necessary, the dose of gemcitabine and cisplatin may be either 
reduced or withheld in the presence of haematological toxicity according to the following 
scale (Table 2). 
 


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Table 2 
Dose Modifications for Haematological Toxicities 
Day 1 
Absolute 
neutrophil count 
(× 106 /L) 
 
Platelet count  
(× 106 /L) 
Percent (%) of 
full dose 
gemcitabine 
Percent (%) of 
full dose cisplatin 
≥1,500 
and/or 
≥100,000 
100 
100 
≥500 - <1,000 
and/or 
≥50,000 - <100,000 
delay dose until 
recovery, then 75 
100 
<500 
and/or 
<50,000 
omit dose until 
recovery, then 75 
omit dose until 
recovery, then 75 
Day 8 
Absolute 
neutrophil count 
(× 106 /L) 
 
Platelet count  
(× 106 /L) 
Percent (%) of 
full dose 
gemcitabine 
Percent (%) of 
full dose cisplatin 
≥1,000 
and/or 
≥100,000 
100 
100 
≥500 - <1,000 
and/or 
≥50,000 - <100,000 
omit dose until 
recovery, then 75 
100 
<500 
and/or 
<50,000 
omit dose until 
recovery, then 75 
omit dose until 
recovery, then 75 
 
Non-Haematological Toxicity 
Renal toxicity: The creatinine clearance must be ≥ 60 mL/min in order to administer the full 
dose of cisplatin. Serum creatinine should be checked before each cycle of treatment. If there 
is a >25% increase of serum creatinine compared to the baseline, then the ethylenediamine 
tetraacetic acid (EDTA) clearance (or equivalent, including estimation of GFR, according to 
local practice) must be performed.  
Pulmonary toxicity: Transient dyspnoea occurs in <10% of patients after gemcitabine, 
secondary to mild bronchospasm. Rarely, more severe pulmonary toxicity characterised by 
tachypnoea, hypoxia diffuse interstitial infiltrates, acute respiratory distress syndrome and 
respiratory failure may also occur. The patient should be withdrawn from treatment. 


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Table 3 
Dose Modifications for Non-Haematological Toxicities 
 
Percent (%) of Full Dose 
Gemcitabine 
Percent (%) Full Dose 
Cisplatin 
Renal Function 
≥60 mL/min 
100 
100 
40–59 mL/min 
100 
50 
<40 mL/min 
Omit 
Omit 
Biliary Tract Obstruction 
Bilirubin >2.5 × ULN 
Omit 
Omit 
AST/ALT/ALP >5.0 × ULN 
Omit 
Omit 
Peripheral Neuropathy 
Grade 1–2 
100 
Delay until recovery, then 
100 
Grade 3–4 
100 
Discontinue 
Tinnitus 
If full recovery between cycles 
100 
100 
If no full recovery between cycles 
100 
Omit 
Lethargy 
Grade 3–4 
75 (if no response, stop 
treatment) 
100 
Oedema 
Grade 3–4  
75 (if no response, stop 
treatment) 
100 
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST; aspartate aminotransferase; 
ULN, upper limit of normal. 
Gemcitabine-Specific Non-Haematological Toxicity 
Posterior Reversible Encephalopathy Syndrome: Reports of posterior reversible 
encephalopathy syndrome (PRES) with potentially severe consequences have been reported 
in patients receiving gemcitabine as a single agent or in combination with other 
chemotherapeutic agents. Acute hypertension and seizure activity were reported in most 
gemcitabine patients experiencing PRES, but other symptoms such as headache, lethargy, 
confusion and blindness could also be present. Diagnosis is optimally confirmed by MRI. 
Posterior reversible encephalopathy syndrome was typically reversible with appropriate 
supportive measures. Gemcitabine should be permanently discontinued and supportive 


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measures implemented, including blood pressure control and anti-seizure therapy, if PRES 
develops during therapy. 
Haemolytic Uraemic Syndrome: Clinical findings consistent with the haemolytic uraemic 
syndrome (HUS) were rarely reported (postmarketing data) in patients receiving 
gemcitabine. Haemolytic uraemic syndrome is a potentially life-threatening disorder. 
Gemcitabine should be discontinued at the first signs of any evidence of microangiopathic 
haemolytic anaemia, such as rapidly falling haemoglobin with concomitant 
thrombocytopenia, and/or elevation of serum bilirubin, serum creatinine, blood urea nitrogen 
or lactate dehydrogenase. Renal failure may not be reversible with discontinuation of therapy 
and dialysis may be required. 
5.3 Management of Clinical Supplies 
5.3.1 Study Drug Packaging and Storage 
Amphinex will be labelled, packaged and stored by: 
Curida AS 
Solbærvegen 5 
NO-2409 Elverum 
Norway 
PCI Biotech (the Sponsor) will be responsible for supplying Amphinex to the clinical sites.  
Amphinex will be manufactured according to Good Manufacturing Practice (GMP) and 
labelled according to Good Clinical Practice (GCP), GMP and the national requirements for 
each site. 
The labels will include storage conditions for the drug. 
5.3.2 Test Article and Device Accountability 
The Investigator and/or Pharmacist will be responsible for drug and device accountability. 
The study medication and laser will be kept in a secure place with limited access and will 
only be supplied to patients in the study under the supervision of the Investigator. The 
Investigator and the pharmacy (if applicable) are responsible for maintaining accurate 
records of the dispensing of study medication and use of the laser. Provision will be made in 


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the eCRF and drug accountability section of investigator site file to verify that laser use and 
dosing has taken place in accordance with this protocol, respectively. Used study medication 
will be stored safely until destruction and must be accounted for by the Investigator. Any 
study medication accidentally or deliberately destroyed will be accounted for. Any 
discrepancies between study medication amounts dispensed and returned will be explained. 
The Monitor will check drug accountability during the monitoring visits. After study 
termination, all unused (and used, if applicable) study medication and clinical supplies at a 
site will be sent to an authorised institution for destruction. The procedures for destruction of 
clinical supplies will be described in the study-specific Pharmacy Manual. 
5.3.3 Other Supplies 
Study sites will be provided with protective eyewear for the operators (ie, glasses protecting 
against the laser emission wavelength [652 nm]). Study sites will also be provided with 
protective eyewear for patients, protecting against the laser emission wavelength (652 nm) 
and all other ultravisible and visible light that activate fimaporfin, and optical fibres and 
catheters for the laser light application.  
Only the supplies provided by the Sponsor should be used. Additional items supplied by the 
Sponsor are described in the Procedure Manual and Laboratory Manual. 
5.4 Treatment Compliance 
The details of the study treatment will be adequately documented and recorded in the eCRF 
and drug accountability forms as applicable. All study treatment-related procedures will be 
performed at the investigational site by qualified health care personnel. All instances of non-
compliance and all resulting protocol deviations will be adequately documented and recorded 
in the eCRF. 
5.4.1 Light Protection Compliance 
Investigators must counsel patients to observe the light protection precautions described in 
Table 1 to prevent photosensitivity reactions. It should be adequately documented and 
recorded in the eCRF that the patient was thoroughly informed on the light protection 
precautions. Any non-compliance with regard to light protection should also be adequately 
documented and recorded in the eCRF.  


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5.5 Concomitant Treatments 
5.5.1 Permitted Treatments 
Any medication except those as noted in Section 5.5.2, which are considered necessary for 
the patient’s welfare, and which will not interfere with the study treatment, may be given at 
the discretion of the Investigator. 
Patients will be allowed to receive supportive care therapies (including cytokine growth 
factors) concomitantly during the study. Other than the chemotherapy given during the 
course of the study, the use of any other chemotherapy, immunotherapy, radiation therapy, or 
experimental medications is prohibited during the study treatment period. Patients with 
prostate cancer that is controlled by hormone therapy may continue that therapy while on 
study. Disease progression requiring other specific anti-tumour therapy will be cause for 
discontinuation from the study treatment.  
Prophylactic anti-emetic and antibiotic therapy is permitted where indicated. During stent 
placement and the light application procedure, sedation with adequate analgesic cover is 
preferred; however, general anaesthesia is also permitted.  
Any prior, concurrent, or procedural medications or therapy given to or taken by the patient 
will be recorded in the eCRF along with the indication for its use. All concomitant 
medication taken from the time that the informed consent form (ICF) is signed, until 30 days 
after end of treatment, will be recorded in the eCRF. The date of first administration and 
reason for use will be recorded in the eCRF. Major changes in dose, schedule, or reason for 
use will also be recorded in the eCRF.  
After this period, only relevant medication (eg, medication in patients with treatment-related 
AEs including antibiotic treatment in biliary events, any anti-cancer therapy) will be recorded 
in the eCRF. Both generic and trade names may be recorded. However, the generic name is 
generally preferred because of its specificity, whereas trade names are preferred for 
combination products. 


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5.5.2 Prohibited Therapies 
The following therapies are prohibited during the study treatment period: 
• Clozapine: The use of clozapine is not permitted during the study due to an increased 
risk for agranulocytosis. 
• Live vaccines: Vaccination with a live vaccine, such as the vaccine against yellow 
fever, has resulted in severe and fatal infections when used in combination with 
immunosuppressive chemotherapeutics. This risk increases in patients with existing 
immune suppression because of the underlying disease. If possible, use of an 
inactivated vaccine (poliomyelitis) is recommended. 
• Cyclosporine, tacrolimus: prohibited due to a risk of excessive immune suppression 
with risk of lymphoma proliferation. 
• Phenytoin 
• Anti-cancer treatment other than the study treatments. Hormone therapy for prostate 
cancer that started before randomisation is allowed to continue during the study. 
• Any experimental treatment other than PCI treatment. 
5.5.3 Photosensitising Drugs 
There may be a potential for exacerbation of skin photosensitivity if Amphinex is used with 
other photosensitising drugs. Precautions should therefore be applied if medicinal products 
known to induce skin-photosensitising reactions are to be administered together with 
Amphinex. A list of common medications with photosensitising potential is provided in 
Table 4. Due to the long half-life of amiodarone, Amphinex must not be administered in 
patients treated with amiodarone during the last 12 months. For other listed compounds in 
Table 4 that are exchangeable or can be terminated, termination should allow for a completed 
systemic clearance before Amphinex administration, usually corresponding to the respective 
half-life times 5. 


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Table 4 
Medications with Photosensitising Potential 
Psoralenes 
Phenothiazines 
Tetracyclines 
Quinolones 
8-Methoxypsoralene 
5-Methoxypsoralene 
Trimethylpsoralene 
 
Chlorpromazine 
Promethazine 
Demeclocycline 
Doxycycline 
Tetracycline 
Norfloxacin 
Ciprofloxacin 
Potential Inducers of 
Photosensitivity 
PDT Photosensitisers 
Miscellaneous 
 
Fibrates 
NSAIDs 
5-aminolevulinic acid 
Methyl-5-
aminolevulinic acid 
Hexaminolevulinate 
Photofrin 
Musk fragrances 
Amiodaronea 
St. John’s wort 
Furosemide  
Sulfonylureas 
Antifungals 
Sunscreens (PABA-
esters, 
benzophenones) 
 
Abbreviation: NSAIDs, non-steroidal anti-inflammatory drugs; PABA, p-aminobenzoic acid; PDT, 
photodynamic therapy. 
a. 
Due to the long half-life of amiodarone, Amphinex must not be administered in patients treated with 
amiodarone during the last 12 months. 
5.6 Contraception 
A woman is considered of childbearing potential (WOCBP), ie, fertile, following menarche 
and until becoming postmenopausal unless permanently sterile. Permanent sterilisation 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A 
postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient. A WOCBP must continue the use of contraception 
during treatment and until the end of relevant systemic exposure (at least 9 months after last 
dose of Amphinex or 6 months after last dose of chemotherapy, whichever is the latest). 
Only men with pregnant or non-pregnant partners considered of childbearing potential will 
need to follow contraception requirements. A condom is also required to be used by 
vasectomised men to prevent delivery of the drug via seminal fluid. As the treatment includes 


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genotoxic investigational medicinal products, the male patient should use condoms during 
treatment and until the end of relevant systemic exposure in the male patient (at least 
9 months after last dose of Amphinex or 6 months after last dose of chemotherapy, whichever 
is the latest).  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments. 
The reliability of sexual abstinence will need to be evaluated by site personnel in relation to 
the duration of the clinical study and the preferred and usual lifestyle of the patient. 
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method are not acceptable 
methods of contraception. Female condom and male condom should not be used together. 


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6 
Study Assessments and Procedures 
All study assessments will be performed at the visits indicated in the study plan in the 
schedule of events for the active treatment period (Table 10 and Table 11) and the schedule of 
events for the follow-up period (Table 12). 
Prior to performing any study procedures, all potential patients will sign an ICF. Patients will 
have the opportunity to have any questions answered before signing the ICF. The Investigator 
must address all questions raised by the patient. The Investigator or designee will also sign 
the ICF. 
6.1 Efficacy Assessments 
6.1.1 Tumour Assessment 
The study will evaluate tumour responses as determined by Investigator according to 
RECIST 1.1. The primary PFS analysis will be based on the local radiological assessment, 
which will be used to guide clinical management decisions. Note: In cases of symptomatic 
progression, patients will continue to be followed for radiological RECIST progression. 
From the Investigator’s review of the imaging scans, the RECIST tumour response data will 
be used to determine each patient’s visit response according to RECIST v1.1. At each visit, 
patients will be programmatically assigned a RECIST v1.1 visit response of CR, PR, SD, or 
progressive disease (for measurable/target lesions) or CR, progressive disease, or non-
CR/non-PD (for non-measurable/non-target lesions) depending on the status of their disease 
compared with baseline and previous assessments. If a patient has had a tumour assessment 
which cannot be evaluated, then the patient will be assigned a visit response of not evaluable 
(NE). 
Radiological assessments use images from contrast-enhanced CT or MRI scans, collected 
during screening/baseline and at regular follow-up intervals following study treatment. The 
RECIST 1.1 guidelines (link in Appendix C) provide a method of assessment of change in 
tumour burden in response to treatment. Screening/baseline imaging should be performed no 
more than 28 days before the randomisation. The RECIST 1.1 assessments of baseline 
images identify target (measurable), and non-target (non-measurable) lesions, and each lesion 
is evaluated in subsequent follow-up images. The same imaging modality and contrast 
protocol used at baseline must be used for all subsequent follow-up imaging. This allows 


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follow-up determination of target lesion response, non-target lesion response, and overall 
time point tumour responses (CR, PR, SD, non-CR/non-PD, progressive disease, or NE). 
Table 5 and Table 6 provide a definition of the different response criteria for tumour 
evaluation of target and non-target lesions. 
Table 5 
Tumour Response Criteria for Target Lesions 
Response 
Evaluation of Target Lesions 
Complete Response 
Disappearance of all target lesions. Any pathological lymph nodes 
should be reduced to <10 mm in the short axis. 
Partial Response 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum of diameters. 
Progressive Disease 
At least a 20% relative and a 5 mm absolute increase in the sum of 
diameters of target lesions, taking as reference the smallest sum of 
diameters recorded on study (including baseline) or the appearance 
of 1 or more new lesions. 
Stable Disease 
Neither sufficient shrinkage to qualify for partial response nor 
sufficient increase to qualify for progressive disease, taking as 
reference the smallest sum of diameters while on study. 
Abbreviation: LD, longest diameter 
Table 6 
Tumour Response Criteria for Non-target Lesions 
Response 
Evaluation of Non-target Lesions 
Complete Response 
Disappearance of all non-target lesions. All lymph nodes should be 
non-pathological in size (<10 mm in the short axis) 
Non-CR/Non-PD 
Persistence of 1 or more non-target lesion(s) 
Progressive Disease 
Appearance of 1 or more new lesion(s) and/or unequivocal 
progression of existing non-target lesions 
Abbreviations: CR, Complete response; PD, progressive disease. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all 
lesions are truly non-measurable), a useful test that can be applied when assessing patients 
for unequivocal progression is to consider if the increase in overall disease burden based on 
the change in non-measurable disease is comparable in magnitude to the increase that would 
be required to declare progressive disease for measurable disease, ie, an increase in tumour 
burden representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% 
increase in diameter in a measurable lesion) or an increase that is sufficient to require a 
change in therapy. 


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If a patient has a response of SD or PR for target lesions, a modest ‘increase’ in size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression status. 
Tumour response will be assessed according to RECIST 1.1 every 12 weeks (±1 week), from 
randomisation until disease progression and should NOT follow delays incurred in the 
treatment period. Patients will be followed for radiological progression, regardless of 
whether they discontinue therapy or have symptomatic progression. 
It is important to follow the imaging assessment schedule as closely as possible. If an 
unscheduled imaging assessment is performed and the patient has not progressed, every 
attempt should be made to perform the subsequent assessments at the next scheduled imaging 
visit. Computed tomography and/or MRI scans should be performed of the abdomen/pelvis 
only, unless clinically indicated or if disease progression is suspected. 
The local radiological assessment will be used to guide clinical management decisions and 
will be the basis for the primary analysis of PFS. In addition, a blinded independent central 
radiological review (BICR), blinded to the assessment of the local radiologist and/or 
oncologist, will be performed for the tumour response data. The data from the BICR will 
provide data for a supportive analysis of PFS. For the interim analysis of ORR, the 
assessment made by the BICR will be considered the primary analysis. 
Survival follow-up phase 
Survival status will be documented for all patients in an extended follow-up phase. Patients 
who have progressed will enter the survival follow-up phase of the study, and otherwise be 
managed according to standard clinical practice.  
At the time of the data cut-off for the primary PFS analysis, further data collection of 
RECIST data will stop. Patients who have not yet progressed will enter the survival 
follow-up phase of the study and will continue to receive randomised treatment. Following 
discontinuation of randomised treatment, patients will be followed up for survival and 
information on any subsequent anti-cancer treatments as detailed in the study plan, unless 
they have withdrawn their consent. 
Additional survival contacts (ie, outside of the 12-weekly calls) may be conducted around the 
time of interim ORR analysis and PFS analysis at data cut-off to ensure that the survival 


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information is as up to date as possible for the analysis of OS. Determination of survival may 
be collected through publicly available death registry information, where permitted locally. 
6.1.2 Quality of Life Measurements 
Health-related quality of life (HRQoL) is a multi-dimensional construct of an individual’s 
subjective assessment of the impact of an illness or treatment on their physical, 
psychological, social, and somatic functioning and general well-being. 
In this study, HRQoL will be measured by use of the European Organisation for Research 
and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and the 
EORTC QLQ-BIL21 questionnaire (Appendix D). Patients will complete the questionnaires 
at the time points specified in Table 10, Table 11 and Table 12, preferably before any other 
study assessments are performed. To obtain feedback on the suggested questionnaire’s 
feasibility, an exercise of patient/carer opinion and assessment of feasibility was conducted at 
an annual CCA patient conference (UK, May 2018). This included an 8-question survey 
followed by one-to-one interviews on the selected compiled questionnaire, timing of 
measurements, and other patient feedback. The suggested instrument was overall confirmed 
as relevant and the feasibility of PRO completion at multiple time points and at follow-up 
endorsed. 
6.2 Pharmacokinetic Assessments 
In order to evaluate the PK of fimaporfin in plasma, blood samples will be obtained from all 
patients in Arm A as specified in Table 10. The actual time points of the blood sample 
collections will be captured to the nearest minute and will be recorded in the eCRF. 
Blood samples (each 5 mL) for PK analysis will be collected into collection tubes with 
sodium citrate. Plasma samples will be shipped to the designated bioanalytical laboratory for 
quantification of plasma fimaporfin concentrations using a validated analytical method. 
Details concerning handling of the PK plasma samples, including labelling and shipping 
instructions, will be provided in the study Laboratory Manual. 


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6.3 Standard Tumour Markers  
The standard tumour markers cancer antigen 125 (CA-125), carbohydrate antigen 19-9 
(CA 19-9) and carcinoembryonic antigen (CEA) will be analysed from blood samples 
collected for safety laboratory assessments throughout the study. 
The dynamics of tumour markers, alone or combined, are routinely followed as a 
measurement of recurrence and method to predict the disease process. CA 19-9, CEA and 
CA-125 are the most investigated tumour markers in patients with hilar CCA. Combined 
CA 19-9 and CEA levels are widely used in the diagnosis of hilar CCA and have been 
reported to be associated with advanced tumour stage and poor survival outcome 
(Juntermanns et al 2010). 
CA-125 is a member of the mucin family glycoproteins, secreted by epithelial cells in 
various organs. It is clinically most used in ovarian cancer but is also recognised as a 
prognostic marker in various gastrointestinal cancers. In a study of perihilar CCA, the cut-off 
value for CA-125 to predict resectability was 25.9 U/mL with a sensitivity of 78.6% and 
specificity of 67.5%. It has also been demonstrated that preoperative serum CA-125 level can 
be used to predict recurrence in all forms of CCA (Hu et al 2016). 
CA 19-9, the most commonly used serum marker in clinical practice, is a sialylated Lewis 
blood group antigen targeted by the monoclonal antibody described in 1979 as a 
tumour-associated antigen in a colorectal cancer cell line. CA 19-9 has a wide variation in 
sensitivity (50%-90%) and specificity (54%-98%) (Patel et al 2000). It is elevated in 
approximately 75% to 85% of patients with CCA and has a specificity of 50-80%. Very high 
levels of CA 19-9 (≥1000 U/mL) have been associated with metastatic intrahepatic CCA; 
significantly elevated postoperative CA 19-9 levels are associated with early recurrence 
(LaFemina and Jarnigan 2012).  
CEA is a set of glycoproteins involved in cell adhesion, found in healthy subjects at around 
20 ng/mL, and initially detected in colon cancer cells. It can be elevated in a variety of 
tumour types, but with variable sensitivity, and a specificity affected by other factors 
(eg, smoking). In intrahepatic CCA, CEA has been found to be significantly associated with 
OS (Ishimoto et al 2018). In one of the larger studies that included all types of CCA, the data 
showed no correlation between tumour location and serum level of CEA and the sensitivity 


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and specificity of CEA for diagnosis of CCA was found to be 66.0% and 81.5%, respectively 
(Deng et al 2017). 
6.4 Safety Assessments 
6.4.1 Adverse Events 
6.4.1.1 
Definitions of Adverse Events 
The Investigator is responsible for reporting all treatment-emergent AEs (TEAEs) that are 
observed or reported during the study, regardless of their relationship to study treatment or 
their clinical significance. 
An AE is defined as any untoward medical occurrence in a patient enrolled into this study 
regardless of its causal relationship to study treatment. Patients will be instructed to contact 
the Investigator at any time after randomisation if any symptoms develop. 
A TEAE is defined as any event not present before exposure to study treatment or any event 
already present that worsens in either intensity or frequency after exposure to study 
treatment. 
6.4.1.2 
Serious Adverse Events 
An SAE is defined as any event that 
• results in death 
• is immediately life threatening 
• requires inpatient hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
Important medical events that may not result in death, be life threatening, or require 
hospitalisation may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the patient or may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 


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dyscrasias or convulsions that do not result in inpatient hospitalisation, or the development of 
drug dependency or drug abuse. 
6.4.1.3 
Eliciting and Documenting Adverse Events 
Adverse events will be recorded from the time of the patient signing the ICF up to 30 days 
after the last administration of any study treatment. 
Serious AEs that occur more than 30 days after the last dose of study treatment need not be 
reported unless the Investigator considers them related to study treatment and/or procedures. 
At every study visit, patients will be asked a standard nonleading question to elicit any 
medically related changes in their well-being. They will also be asked if they have been 
hospitalised, had any accidents, used any new medications, or changed concomitant 
medication regimens (both prescription and over the counter medications). 
In addition to patient observations, AEs identified from any study data (eg, laboratory values, 
physical examination findings, electrocardiogram [ECG] changes) or identified from review 
of other documents (eg, patient diaries) that are relevant to patient safety will be documented 
on the AE page in the eCRF. 
6.4.1.4 
Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF. 
Information to be collected includes the following: 
• event term 
• time of onset 
• Investigator-specified assessment of severity and relationship to study treatment 
• time of resolution of the event 
• seriousness 
• any required treatment or evaluations 
• outcome 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications or progression of disease states must also be reported. All 


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AEs will be followed to adequate resolution. The Medical Dictionary for Regulatory 
Activities (MedDRA) will be used to code all AEs. 
Any medical condition that is present at the time that the patient is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during the 
study, it should be recorded as an AE. 
Events that are clearly consistent with the expected pattern of progression of the underlying 
disease should not be recorded as AEs. These data will be captured as efficacy assessment 
data only. In most cases, the expected pattern of progression will be based on RECIST 1.1. In 
rare cases, the determination of clinical progression will be based on symptomatic 
deterioration. However, every effort should be made to document progression radiologically. 
If there is any uncertainty as to whether an event is due to disease progression, it should be 
reported as an AE. 
6.4.1.5 
Reporting Serious Adverse Events 
The Investigator must report any AE that meets SAE criteria (Section 6.4.1.2) to PPD, Inc, 
using the electronic data capture (EDC) system, immediately (ie, within 24 hours) after the 
time the site personnel first learn about the event.  
In the event the EDC entry is not possible (eg, system failure or access problems), the study 
site should complete the paper SAE report form and fax the form to PPD Pharmacovigilance 
within 24 hours of awareness. The EDC system should be updated as soon as it is available.  
A full description of every SAE will need to be provided to PPD Pharmacovigilance (this 
may be supported by source documentation such as discharge summary or laboratory report 
should the patient be hospitalised). 
The following contact information is to be used for SAE reporting: 
Pharmacovigilance 
PPD, Inc. 
Fleming House 
Strathclyde Business Park 


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Bellshill ML4 3NJ 
Scotland, UK 
 
SAE Hotline: +44 1223 374 240 
 
SAE Fax line: +44 (0) 1223 374102 
 
Email: EMEAASIASafetyCentral.SM@ppdi.com 
6.4.1.6 
Suspected Unexpected Serious Adverse Reactions and Adverse 
Events of Special Interest 
The Sponsor will promptly evaluate all SUSARs and AESIs against cumulative product 
experience to identify and expeditiously communicate possible new safety findings to 
Investigators, Independent Ethics Committees/Institutional Review Boards (IECs/IRBs), and 
applicable health authorities based on applicable legislation. 
The Sponsor will ensure that all relevant information about SUSARs that are fatal or 
life-threatening is recorded and reported as soon as possible to the competent authorities in 
all the Member States concerned, and to the IECs/IRBs, and in any case no later than 
7 calendar days after knowledge by the Sponsor of such a case, and that relevant follow-up 
information is subsequently communicated within an additional 8 calendar days. 
All other SUSARs will be reported to the competent authorities concerned in accordance 
with their specific requirement and to the IECs/IRBs concerned as soon as possible but 
within a maximum of 15 calendar days of first knowledge by the Sponsor. The Sponsor will 
also inform all Investigators. 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference documents: 
• Amphinex (fimaporfin) IB 
• SmPC and prescribing information for gemcitabine 
The Sponsor will compare the severity of each SUSAR and the cumulative event frequency 
reported for the study with the severity and frequency reported in the applicable reference 
document. 


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Reporting requirements will also be based on the Investigator’s assessment of causality and 
seriousness, with allowance for upgrading by the Sponsor as needed. 
The AESIs (serious and non-serious) defined for this study include cholangitis and related 
biliary events, as specified in the IDMC charter. The period of observation and 
documentation for AESIs will commence after randomisation and include 30 days after the 
last study treatment but shall be reported also thereafter if categorised as an SAE related to 
study treatment. 
All AESIs will be assessed by the IDMC as specified / laid out in the IDMC charter. 
6.4.1.7 
Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the patient’s 
daily activities. The intensity of all AEs will be graded in accordance with the current version 
of NCI CTCAE. Guidance for events that cannot be graded according to the NCI CTCAE is 
provided below:  
Mild: 
An AE that is usually transient in nature and generally does not interfere with 
normal activities. 
Moderate: 
An AE that is sufficiently discomforting to interfere with normal activities. 
Severe: 
An AE that interrupts a patient’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually incapacitating. 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. Adverse events characterised 
as intermittent do not require documentation of onset and duration of each episode. 
6.4.1.8 
Assessment of Causality 
The Investigator’s assessment of an AE’s relationship to study treatment is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 
The Investigator’s opinion of the relationship of the AE to the study treatment and procedures 
(ie, Amphinex administration, gemcitabine administration, cisplatin administration, stent 
placement and laser light application procedure) will be collected for all AEs. 


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The relationship or association of the study treatment/procedure in causing or contributing to 
the AE will be characterised using the following classification and criteria: 
Unrelated: 
This relationship suggests that there is no association between the study 
treatment/procedure and the reported event. 
 
Possible: 
This relationship suggests that study treatment/procedure caused or contributed 
to the AE, ie, the event follows a reasonable temporal sequence from the time 
of study treatment administration or follows a known response pattern to the 
study treatment but could also have been produced by other factors. 
 
Probable: 
This relationship suggests that a reasonable temporal sequence of the event 
with study treatment administration/procedure exists and, based upon the 
known pharmacological action of the drug, known or previously reported 
adverse reactions to the drug or class of drugs, or judgment based on the 
Investigator’s clinical experience, the association of the event with the study 
treatment/procedure seems likely. The event disappears or decreases on 
cessation or reduction of the dose of study treatment. 
 
Definite: 
This relationship suggests that a definite causal relationship exists between 
study treatment administration/procedure and the AE, and other conditions 
(concurrent illness, progression/expression of disease state, or concurrent 
medication reaction) do not appear to explain the event. The event reappears or 
worsens if the study treatment is re-administered. 
 
If relationship of the AE is categorised as ‘possible’, ‘probable’, or ‘definite’, the Investigator 
should specify in the eCRF/SAE form whether relationship is described with respect to 
Amphinex, gemcitabine, cisplatin, stent placement or laser light application procedure. For 
reporting purposes ‘possible’, ‘probable’, and ‘definite’ will be considered as related. 
6.4.1.9 
Follow-Up of Patients Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the Investigator deems the event to be chronic or not clinically 
significant, or until the patient is considered to be stable. 


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6.4.2 Adverse Incidents/Unanticipated Adverse Device Effects 
An adverse incident (AI) (or Incident) is “any malfunction or deterioration in the 
characteristics and/or performance of a device, as well as any inadequacy in the labelling or 
the instructions for use which, directly or indirectly, might lead to or might have led to the 
death of a patient, user, or other person, or to a serious deterioration in their state of health.” 
(Definition of an Adverse Incident from the Medical Device Directive 93/42/EEC, Art. 10). 
A “malfunction or deterioration” should be understood as a failure of the device to perform in 
accordance with its intended purpose when used in accordance with the manufacturer’s 
instructions. 
Per US Title 21 Code of Federal Regulations (21 CFR) Part 812.3 (s), unanticipated adverse 
device effect (UADE) is defined as any serious adverse effect on health or safety or any 
life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in 
the investigational plan or application (including a supplementary plan or application), or any 
other unanticipated serious problem associated with a device that relates to the rights, safety, 
or welfare of patients. 
Please note that for this study light emanating from the laser should be considered separate to 
the laser device itself. Thus, an AE related to the laser light should not be considered an 
UADE, but an AE related to study treatment. 
An AI/UADE that results in: 
1. Death of a patient, user or other person 
2. Serious deterioration in state of health of a patient, user or other person 
will need to be reported as both an AI/UADE and an SAE. 
A serious deterioration in state of health can include: 
a) life-threatening illness 
b) permanent impairment of a body function or permanent damage to a body structure 
c) a condition necessitating medical or surgical intervention to prevent a) or b) 


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Examples: 
- Clinically relevant increase in the duration of a surgical procedure 
- A condition that requires hospitalisation or significant prolongation of existing 
hospitalisation 
d) any indirect harm as a consequence of an incorrect diagnostic or intravenous test 
result, when used within manufacturer’s instructions for use 
e) foetal distress, foetal death or any congenital abnormality or birth defects 
A deterioration in state of health is considered unanticipated if the condition leading to the 
event was not considered in the device risk analysis. 
6.4.2.1 
Reporting of Adverse Incidents/Unanticipated Adverse Device 
Effects 
The Investigator must report all AIs/UADEs involving the laser/study device, occurring in 
the period of observation (see Section 6.4.1.3). 
All AIs require the completion of a study-specific AI/UADE Form. For AIs/UADEs 
involving patient harm, the AE page in the eCRF must also be completed and where the 
event meets any serious criteria a separate SAE report form must be completed. Information 
not available at the time of the initial report (eg, device analysis) must be documented in a 
follow-up form.  
The Investigators are responsible for reporting of any AIs/UADEs occurring during the study 
to the Sponsor and to the reviewing IECs/IRBs. The Sponsor shall conduct an evaluation of 
any AI/UADE and shall ensure reporting of the results of such evaluation to the regulatory 
agencies and to all reviewing IECs/IRBs and participating Investigators. PPD will be 
responsible for submission of such reports to the regulatory agencies. 
6.4.3 Laboratory Analyses 
6.4.3.1 
Safety Laboratory Analyses 
Blood and urine samples will be collected at times specified in the schedule of events 
(Table 10, Table 11 and Table 12) and sent to a local laboratory for analysis. Details of 


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sample collection, processing, shipping and storage will be described in the Laboratory 
Manual. The following laboratory variables should be measured: 
Clinical Chemistry 
Haematology 
S/P – alanine aminotransferase  
B – haemoglobin  
S/P – aspartate aminotransferase 
B – white blood cell count 
S/P – alkaline phosphatase 
B – absolute leukocyte count 
S/P – gamma-glutamyltransferase 
 
Neutrophils 
S/P – bilirubin, total 
 
Lymphocytes 
S/P – calcium 
 
Monocytes 
S/P – creatininea 
 
Basophils 
S/P – C-reactive protein 
 
Eosinophils 
S/P – glucose (fasting) 
B – platelet count 
S/P – magnesium 
B – haematocrit 
S/P – phosphate 
 
S/P – potassium 
Coagulation 
S/P – sodium 
B – international normalised ratio  
S/P – urea or blood urea nitrogen 
B – activated partial thromboplastin time 
S/P – amylase 
 
S/P – lipase 
Urinalysis 
S/P – chloride 
U – albumin or total protein 
S/P – protein, total 
U – glucose  
S/P – lactate dehydrogenase 
U – blood 
 
U - bilirubin 
Standard Tumour Markers 
 
S – CA-125, CA 19-9, CEA 
 
Abbreviations: B, blood; CA-125, cancer antigen-125; CA 19-9, carbohydrate antigen 19-9; CEA, 
carcinoembryonic antigen; P, plasma; S, serum; U, urine. 
a Serum creatinine should be checked before each cycle of treatment. If there is a >25% increase compared to 
the baseline, then the ethylenediamine tetraacetic acid (EDTA) clearance or equivalent, including estimation of 
GFR, according to local practice, must be performed and cisplatin dosing modified accordingly. 
Standard tumour markers will be analysed from serum samples collected for clinical 
chemistry. 


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Additionally, a urine or blood serum sample will be collected from all WOCBP at screening, 
on the first day of each cycle of chemotherapy, and at the end of treatment (Day 30), for a 
highly sensitive pregnancy test. 
Laboratory values that meet the criteria for CTCAE Grade 3 or have changed significantly 
from baseline and are considered to be of clinical concern will be repeated/confirmed within 
7 days and followed up as appropriate. 
For blood volumes to be drawn, see Table 7. 
Table 7 
Blood Sampling Volume 
Tests 
Patients 
Blood volume each 
patient and each 
sampling point 
Sampling points 
Number of samples 
Total blood 
volume 
Arm A 
Total blood 
volume 
Arm B 
Amphinex 
pharmacokinetics 
 
Arm A patients 
5 mL 
Up to 19 sampling points 
95 mL 
NA 
Clinical chemistry 
(including standard 
tumour markers in 
serum) 
20 mL for serum 
22 sampling points in 
Arm A  
20 sampling points in 
Arm B 
440 mL 
400 mL 
Haematology 
3.5 mL (EDTA 
plasma) 
22 sampling points 
77 mL 
77 mL 
Coagulation 
3.5 mL (citrate 
plasma) 
10 sampling points in 
Arm A 
9 sampling points in 
Arm B 
35 mL 
31.5 mL 
Totala 
647 mL 
508.5 mL 
Abbreviations: EDTA, ethylenediamine tetraacetic acid; NA, not applicable. 
a The total volume that will be drawn from each patient in this study will vary depending on how long the 
patient stays on study 
6.4.3.2 
Hepatotoxicity 
In the event that a patient shows AST or ALT ≥3 × ULN or total bilirubin ≥2 × ULN 
indicative of hepatotoxicity related to chemotherapy (ie, with an ensured proper biliary 
drainage in place and a clinical picture indicative of a correlation to chemotherapy 
treatments), the delay, postponement or omission of the following chemotherapy 


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administration is to be decided at the discretion of the treating physician as per local standard 
procedures applicable to gemcitabine/cisplatin treatment. 
If, however, symptoms indicative of cholangitis are concurrently present (fever/septicaemia 
with or without chills; pain or tenderness in the right upper quarter of the abdomen, the chest, 
the upper back or the right shoulder), with or without jaundice, the patient is to be 
hospitalised with prompt measures to confirm the diagnosis by clinical and radiological 
investigations and by bacterial culturing. Antibiotic treatment is to be immediately 
administered and emergency endoscopic or transhepatic biliary drainage optimised. 
6.4.4 Loco-Regional Tumour-Related Events and Biliary Complications 
Unless caused by a terminal, intractable overgrowth of the loco-regional tumour in patients 
with established progressive disease, unplanned or emergency hospital visits caused by 
clinical signs of sudden bile duct obstruction, including but not limited to malaise, pain, 
jaundice, septicaemia, or several symptoms combined, and with clinical, laboratory and 
radiological findings confirmatory of unexpected, biliary obstruction leading to unplanned 
hospitalisation will be recorded and reported as SAEs (see Section 6.4.1.5). The nature of the 
event (diagnosis and MedDRA classification), duration of hospital stay, need for endoscopic 
or other intervention, and antibiotic treatment days shall be captured in the eCRF. Also, the 
time elapsed since the last endoscopic ERCP intervention and PCI treatment (if relevant) 
must be recorded. 
6.4.5 Vital Signs 
Systolic and diastolic blood pressure and pulse rate will be measured in the sitting position 
after at least 10 minutes rest. Body temperature will be measured in degrees Celsius. Any 
changes in vital signs should be recorded as an AE if deemed clinically significant by the 
Investigator. 
Vital signs on Day -4 and Cycle 4, Day 18 must be collected both before and after Amphinex 
administration.  


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6.4.6 Electrocardiograms 
Twelve-lead ECGs will be obtained after the patient has been resting semi-supine for at least 
10 minutes. A standardised ECG machine will be used and the patient should be examined 
using the same machine throughout the study, where feasible. 
After paper ECGs have been recorded, the Investigator or designated physician will review 
each of the ECGs and may refer to a local Cardiologist if appropriate. A signed and dated 
copy, with relevant results noted by the Investigator, should be filed in the patient’s medical 
records. If an abnormal ECG finding at screening is considered to be clinically significant by 
the Investigator, it should be reported as a concurrent condition. For all ECGs, details of 
rhythm, PR, R-R, QRS and QT intervals and an overall evaluation will be recorded. 
Corrected QT intervals will be calculated using Bazett’s formula (QTcB) and Fridericia’s 
formula (QTcF). 
The ECG on Day -4 and on Cycle 4, Day 18 must be performed before and approximately 
30 minutes and 4 hours after Amphinex administration.  
6.4.7 Photosensitivity and Skin Reactions 
In both study arms, skin reactions and photosensitivity reactions will be documented as AEs 
in the eCRF and coded using MedDRA and followed to adequate resolution. 
6.4.8 Medical History 
Medical history to be collected at the pre-treatment evaluation includes evaluation of the 
history of the patient’s CCA and method of confirmation, its previous therapy, pre-existing 
diseases, and current medication.  
6.4.9 Physical Examinations 
A complete physical examination with weight will be performed. Height will be recorded at 
screening only. Body surface area will be calculated. 
Performance status will be assessed at the visits as indicated in the study plan according to 
US ECOG criteria as follows: 
0 =  
Fully active, able to carry out all pre-disease activities without restrictions 


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1 =  
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature eg, light housework, office work 
2 =  
Ambulatory and capable of self-care, but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 =  
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 =  
Completely disabled, cannot carry on self-care, totally confined to bed or chair  
6.5 Independent Data Monitoring Committee 
An IDMC will be employed during the course of the study to periodically assess safety. 
Further details are provided in Section 11.1.1.  
6.6 Pregnancy 
Pregnancy is not regarded as an AE unless there is a suspicion that an investigational product 
may have interfered with the effectiveness of a contraceptive medication. The Investigator 
must report any pregnancies which come to the attention of the Investigator during the study 
and up to 30 days after completion of the study to the Sponsor. Pregnancies of both female 
patients and partners of male patients should be reported. Patients who become pregnant will 
be followed until completion of pregnancy. 
Any pregnancy that occurs during study participation must be reported using the same 
procedures as an SAE (Section 6.4.1.5). To ensure patient safety, each pregnancy must be 
reported within 2 weeks of learning of its occurrence. The pregnancy must be followed up to 
determine outcome (including spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) and status of mother and child, even if the patient was discontinued 
from the study. Pregnancy complications and elective terminations for medical reasons must 
be reported as an AE or SAE. Spontaneous miscarriages must be reported as an SAE. 
Any SAE occurring in association with a pregnancy, brought to the Investigator’s attention 
after the patient has completed the study, and considered by the Investigator as possibly 
related to the study treatment, must be promptly reported. 


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7 
Statistical and Analytical Plan 
7.1 Primary Endpoint 
7.1.1 Progression-Free Survival 
Progression-free survival is defined as the time from randomisation until the date of 
radiological disease progression or death (by any cause in the absence of progression) 
regardless of whether the patient withdraws from therapy or receives another anti-cancer 
therapy prior to progression.  
7.2 Secondary Endpoints 
7.2.1 Overall Survival 
Overall survival (OS) is calculated as the time from randomisation to the date of death from 
any cause.  
7.2.2 Best Overall Response 
The BOR is the best response recorded from the start of the treatment until disease 
progression/recurrence. 
7.2.3 Objective Response Rate 
The ORR is calculated as the proportion of patients who have at least one visit response with 
a CR or PR noted. 
7.2.4 Duration of Response 
The DoR is defined as the time from the first documented tumour response until radiological 
disease progression, or death in the absence of disease progression.  
7.2.5 Disease Control Rate 
The DCR is defined as the proportion of patients with stable disease or better (ie, CR, PR or 
SD); it will be assessed at 6 and 12 months.  


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7.2.6 Change in Tumour Size 
Change in tumour size, defined as the best overall percentage change in tumour size from 
baseline. Tumour size is defined as the sum of the lengths of the longest diameters of the 
RECIST 1.1 target lesions. 
7.2.7 Safety 
Safety will be assessed using the Safety Analysis Set and will include assessment of AEs, 
SAEs, and deaths, clinical laboratory assessments, physical findings, vital signs, ECGs and 
photosensitivity assessments. Data from all cycles of treatment will be combined and used 
for the reporting of AE summary tables. The effects of fimaporfin-induced PCI on safety in 
terms of loco-regional tumour-related events and biliary complications will also be assessed. 
Secondary endpoints for safety include the following: 
• Toxicity profile (AEs, laboratory assessments and physical findings) of 
fimaporfin-induced PCI of gemcitabine with the gemcitabine/cisplatin combination, or 
the gemcitabine/cisplatin combination alone. 
• Frequency and severity of loco-regional tumour-related events and biliary complications 
requiring unplanned hospital visits and inpatient care. 
7.2.8 Pharmacokinetics 
In order to characterise the PK profile of fimaporfin in plasma, PK samples will be analysed 
to obtain plasma fimaporfin concentration-time data. Fimaporfin PK parameters (area under 
the plasma concentration-time curve [AUC], maximum observed concentration [Cmax], time 
to Cmax [Tmax], etc) will be determined using standard non-compartmental methods and actual 
PK sampling times. The fimaporfin plasma concentration-time data and PK parameters will 
be summarised descriptively. A population PK approach may be adopted to explore the 
influence of covariates on PK. Further details will be provided in the statistical analysis plan 
(SAP). 
7.2.9 Quality of Life Assessment 
An evaluation and comparison of HRQoL/PRO associated with the fimaporfin-induced PCI 
of gemcitabine complemented by gemcitabine/cisplatin chemotherapy versus 
gemcitabine/cisplatin alone, will be conducted by use of EORTC QLQ-30 and QLQ-BIL21. 


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7.3 Exploratory Endpoints 
The following exploratory endpoints will be evaluated in this study: 
• Tumour response (ORR, DCR, and PFS) by location of disease, as pre-defined further in 
the SAP, including: 
o 
Loco-regional tumour control 
o 
Metastatic lesions 
o 
Local lymph nodes 
• To analyse blood samples for standard tumour markers. 
7.4 Sample Size Calculations 
Sample size calculations will be performed using nQuery Advanced Version 8. 
Approximately 186 patients with inoperable CCA will be randomised in a 1:1 ratio 
(fimaporfin-induced PCI of gemcitabine complemented by gemcitabine/cisplatin 
chemotherapy versus gemcitabine/cisplatin chemotherapy alone) to this study. The primary 
analysis of PFS, as assessed by local radiological review, will be conducted when 
approximately 129 progression events (69% maturity) have been observed. If the PFS result 
is statistically significant at the 3.95% 2-sided alpha level (adjusted for interim analysis of 
ORR), an interim analysis of OS will then be assessed, as detailed in Section 7.7.7.  
If the true HR for the comparison of fimaporfin-induced PCI of gemcitabine complemented 
by gemcitabine/cisplatin chemotherapy versus gemcitabine/cisplatin chemotherapy alone is 
0.6, 129 progression events will provide approximately 80% power to demonstrate a 
statistically significant difference in PFS at a 3.95% 2-sided significance level (this may 
translate to an improvement in median PFS from 7.4 to 12.3 months, if PFS is exponentially 
distributed). A minimum or critical HR of 0.69 (eg, 7.4 to 10.7 months), if observed, would 
give a 2-sided p<0.0395, but there is only 50% power associated with the critical HR. 
Assuming linear recruitment of 186 patients over 48 months with a site set-up period of 
approximately 6 months, 129 PFS events are expected to occur between approximately 
48 and 51 months (4 to 4.3 years) from the date on which the first patient was randomised. 


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In addition to the interim analysis of OS at the time of the PFS analysis (approximately 58% 
of patients are predicted to have died at this point), data collection for OS will continue 
beyond the PFS analysis and an updated OS analysis will be performed. The final OS 
analysis will occur after approximately 147 death events have been observed in 186 patients 
(>75% maturity). Assuming a true OS HR of 0.63, there will be 80% power to detect an 
improvement in median OS from 11.7 to 18.7 months with 2-sided p<0.0447 (O’Brien and 
Fleming boundary adjusted for 2 interim analyses of OS). A minimum or critical HR of 0.72 
(eg, 11.7 to 16.3 months), if observed, would be statistically significant. The exact level of 
maturity will be determined based on the PFS and interim OS results, in discussion with the 
regulatory authorities. The 147 death events are expected to occur at approximately 63 to 
66 months from first patient randomised. 
Further details on the interim analyses are provided in Section 7.7.7. 
7.5 Analysis Sets 
The following analysis sets will be used in the statistical analyses. 
• The ITT analysis set will include all randomised patients. The ITT analysis set will be 
used for efficacy analyses and treatment arms will be compared on the basis of 
randomised study treatment, regardless of the treatment actually received.  
• The modified ITT (mITT) analysis set will include all randomised patients who have 
received at least one dose of study treatment and have a RECIST assessment at baseline. 
The mITT analysis set will be used to assess the impact on the primary PFS results of any 
patients who are randomised but not treated, or who are not assessed for RECIST at 
baseline.  
• The PK analysis set will include all patients who receive at least 1 dose of fimaporfin and 
have at least 1 measured concentration at a scheduled PK time point postdose with no 
important AEs or protocol deviations that may impact PK. 


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• The Safety Analysis Set will consist of all patients who received at least one dose of 
study treatment and for whom postdose data are available. Safety data will not be 
formally analysed but summarised using the Safety Analysis Set according to the 
treatment received; ie, erroneously treated patients (eg, those randomised to Arm A 
treatment but actually given treatment for Arm B) will be summarised according to the 
treatment they actually received.  
7.6 Description of Subgroups to be Analysed 
Subgroup analyses will be performed for the stratification factors used at the point of 
randomisation (measurable disease – yes versus no and presence or absence of metastases). 
Exploratory subgroup analyses will also be performed to assess key endpoints by 
loco-regional tumour control, metastatic lesions and local lymph nodes. Four distinct groups 
will be explored: primary; primary with metastases; primary with local lymph nodes; and 
primary with metastases and local lymph nodes. An additional subgroup analysis will be 
performed to compare patients with and without primary sclerosing cholangitis (PSC) at 
study entry. If there are too few events available for a meaningful analysis of a particular 
subgroup, the relationship between that subgroup and PFS/OS will not be assessed. In this 
case, only descriptive summaries will be provided. Further details and any other exploratory 
subgroups of interest will be provided in the SAP. 
7.7 Statistical Analysis Methodology 
Statistical analysis will be performed using SAS software Version 9.3 or later. Continuous 
variables will be summarised using the mean, the standard deviation, median, minimum 
value, and maximum value. Categorical variables will be summarised using frequency counts 
and percentages. Data will be listed in data listings. 
Details of the statistical analyses, methods, and data conventions are described in the SAP. 
Given the open-label design, measures will be taken to minimise bias. These include: 
• Blinding of Sponsor and Investigators to study results ie, no aggregate summaries of 
efficacy data by treatment will be shared during the study. Only the IDMC will receive 
aggregated summaries of efficacy data. 
• Ensuring that appropriate measures are in place to control access to unblinded data.  


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• Not loading blinded independent central review (BICR) data into the clinical database 
during the study. 
7.7.1 Analysis of Primary Endpoint 
The primary endpoint for this study is PFS. Progression-free survival will be analysed using 
the ITT analysis set and supportive analyses will be performed using the BICR data and also 
the mITT analysis set. 
Patients who have not progressed or died at the time of analysis will be censored at the time 
of the latest date of assessment. Participants lacking an evaluation of tumour response after 
randomisation will have their PFS time censored on the date of randomisation with the 
duration of 1 day. Participants with documentation of progressive disease or death after a 
long interval (2 or more incomplete or non-evaluable assessments) since the last tumour 
assessment will be censored at the time of last objective assessment that did not show 
progressive disease.  
The length of PFS will be calculated as:  
PFS time (months) = progression/death date (censor date) - randomisation date + 1.  
The PFS time for each patient will always be derived based on the scan/assessment dates and 
not visit dates. 
Progression is defined using RECIST-1.1; a 20% increase in the sum of diameters of target 
lesions and the sum must also demonstrate an absolute increase of at least 5 mm, or 
unequivocal progression of existing non-target lesions or the appearance of new lesions. 
RECIST assessments/scans contributing towards a particular visit may be performed on 
different dates. The following rules will be applied: 
• Date of progression will be determined based on the earliest of the dates of the 
component that triggered the progression. 
• When censoring a patient for PFS, the patient will be censored at the latest of the dates 
contributing to a particular overall visit assessment.  
Progression-free survival, as assessed by local radiological review, will be analysed using a 
log-rank test stratified by any measurable disease at baseline (yes versus no), and presence or 


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absence of metastases. If these 2 stratification factors lead to low numbers 
(eg, <5 progression events) within a single stratum, data will be pooled across strata in the 
stratified analyses. The criteria for pooling will be pre-defined in the SAP.  
The HR will be estimated using a stratified Cox-proportional hazards model using the Efron 
approach for handling ties (Efron 1977), together with the associated 95% CI for the HR 
based on the Wald method. 
The effect of treatment will be estimated by the HR together with its corresponding 95% CI 
and p-value for the ITT analysis set. 
The primary analysis of PFS based on the local evaluation will be repeated using the BICR 
data as a supportive analysis. 
A Kaplan-Meier (KM) plot of PFS will be presented by treatment group. Median PFS with 
95% CIs will be presented. In addition, KM landmark PFS estimates at 6 months and 
12 months with corresponding CIs will also be presented using KM methodology. 
KM estimates may be presented for other timepoints of interest. The assumption of 
proportionality will be assessed. In the event of non-proportionality, the HR will be 
interpreted as an average HR over the observed extent of follow-up.  
Sensitivity analyses for PFS will be defined in the SAP. 
7.7.2 Analysis of Secondary Endpoints 
7.7.2.1 
Overall Survival 
Any patient not known to have died at the time of analysis will be censored on the basis of 
the last recorded date on which the patient was known to be alive. Overall survival will be 
descriptively summarised (n, deaths, median, quartiles), and KM plots will be provided as 
appropriate. The length of OS will be calculated as: 
OS time (months) = death date (censor date) - randomisation date + 1 
Overall survival data will be analysed using the same methodology, analysis set and model as 
for the analysis of PFS provided there are sufficient events available for a meaningful 
analysis (>20 deaths [if not, descriptive summaries will be provided]). 


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Data collection for OS will continue beyond the PFS analysis and an updated OS analysis 
will be performed.  
7.7.2.2 
Best Overall Response 
The patient’s BOR assignment will depend on findings of both target and non-target disease 
and will also take into consideration the appearance of new lesions. Table 8 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable disease at baseline, 
Table 9 should be used. 
Table 8 
Time Point Response: Patients With Measurable Disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR / Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, non-evaluable; PD, progressive disease; PR, partial response; 
SD, stable disease.  
 


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Table 9 
Time Point Response: Patients With Non-Measurable Disease 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR / Non-PD 
No 
Non-CR / Non-PD* 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, non-evaluable; PD, progressive disease. 
*Non-CR/Non-PD is preferred over stable disease for non-target disease. 
The BOR will be summarised for the ITT analysis set and may be further grouped by 
measurable/non-measurable disease at entry. Summaries and waterfall plots indicating best 
percentage change from baseline in the sum of the diameters of target lesions will be 
produced. Bars will be differentially shaded by RECIST 1.1 response. 
7.7.2.3 
Objective Response Rate 
For randomised studies, a confirmatory scan to confirm the response is not required per 
RECIST-1.1. Data obtained up until progression, or last evaluable assessment in the absence 
of progression, will be included in the analysis of ORR. Any patient who discontinues 
treatment without progression, receives subsequent therapy and then responds will not be 
included as responders in the ORR.  
The ORR will be summarised using the ITT analysis set (ie, all randomised patients). ORR 
will be compared between treatment arms using a Cochran-Mantel-Haenszel (CMH) test 
stratified by presence of any measurable disease at baseline (yes versus no), and 
presence/absence of metastases at baseline (1 or 0). 
In addition to presenting the ORR and associated exact 95% CI for each treatment arm, the 
treatment effect will be described using the CMH estimate of the common odds ratio together 
with its associated 95% CI (Emerson 1994). 
As sensitivity analyses, the ORR will be further summarised by measurable/non-measurable 
disease at entry (as integrated directly from the IVRS to the eCRF) and compared between 
the arms using the CMH test stratified by presence/absence of metastases at baseline (1 or 0). 
The ORR analyses will also be repeated using the mITT analysis set. 


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7.7.2.4 
Duration of Response 
The DoR is calculated only for those with a documented response of CR or PR and is defined 
as the time from the date of first documented tumour response until the first date of 
radiological disease progression or death, whichever is earlier. If a patient does not progress 
following a response, then their DoR will be censored at the PFS censoring time. The DoR 
will not be defined for those patients who do not have documented responses. The DoR will 
be summarised for the ITT analysis set. 
7.7.2.5 
Disease Control Rate 
Data obtained up until progression or last evaluable assessment in the absence of progression, 
will be included in the analysis of DCR. Any patient who discontinues treatment without 
progression, receives subsequent therapy, and then responds will not be included as 
responders in the DCR. 
The DCR will be summarised for the ITT analysis set at 6 months and 12 months (ie, best 
response of CR, PR or SD at 6 or 12 months) and may be further summarised by 
measurable/non-measurable disease at entry. Summaries and waterfall plots indicating best 
percentage change from baseline in the sum of the diameters of target lesions will be 
produced. Bars will be differentially shaded by RECIST 1.1 response.  
7.7.2.6 
Change in Tumour Size 
Percentage change in tumour size will be determined for patients with measurable disease at 
baseline and is derived at each visit by the percentage change in the sum of the diameters of 
target (ie, measurable) lesions compared to baseline. The change in tumour size endpoint will 
be defined as the best overall percentage change in tumour size from baseline. 
The change in tumour size will be summarised for patients with measurable disease at study 
entry. Summaries and waterfall plots indicating best percentage change from baseline in the 
sum of the diameters of target lesions will be produced. Bars will be differentially shaded by 
RECIST 1.1 response.  
7.7.2.7 
Blinded Independent Central Review 
For each patient, the BICR will define the overall visit response (ie, the response obtained 
overall at each visit by independently assessing target lesions, non-target lesions and new 


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lesion data). If a patient has had a tumour assessment that cannot be evaluated then the 
patient will be assigned a visit response of NE (unless there is evidence of progression in 
which case the response will be assigned as PD; for example, if the target lesions are NE but 
there is evidence of a new lesion). 
A BICR will be performed for the interim analysis of ORR (primary data), which will cover 
all scans up to the data cut-off for the interim analysis, and for the final database lock for 
PFS, which will cover all of the scans up to the data cut-off (supportive data).  
Endpoints (ORR, BOR, PFS, and DoR) will be derived programmatically using the visit 
responses provided by the BICR. 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 1.1 assessment conducted by the Investigator. 
Cross-tabulations will be produced to describe the consistency between the BICR and local 
Investigator assessment for the following: 
• Best overall response 
• Timing of PD 
o 
Early discrepancy rate (EDR): the frequency at which the local review declares 
progression early relative to the BICR in each arm as a proportion of the total 
number of locally assessed progressions; and 
o 
Late discrepancy rate (LDR): the frequency at which the local review declares 
progression later than the BICR in each arm as a proportion of the total 
discrepancies in each arm.  
The EDR and LDR will be calculated for each treatment arm and the differential discordance 
will be summarised as the rate on the experimental arm minus the rate on the control arm. If 
the discrepancies are similar between the arms, this suggests an absence of evaluation bias 
that favours one arm. A negative differential discordance for the EDR and/or positive 
differential discordance for the LDR may be indicative of bias in the local evaluation 
favouring the experimental arm (Amit et al 2011). 
Analyses of PFS by BICR will be described in the SAP. 


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7.7.2.8 
Quality of Life Measurements 
Quality of life will be measured by use of the EORTC QLQ-C30 and the EORTC QLQ-B21 
questionnaires. Absolute values and changes from baseline will be calculated and 
summarised descriptively. Further analyses to assess the proportion of patients who show a 
change in symptoms, time to deterioration of symptoms, and modelling of symptom data will 
be described in the SAP. 
7.7.3 Analyses of Exploratory Endpoints 
The exploratory objectives/endpoints of this study are located in Section 2.3. A description of 
the analysis of the exploratory endpoints in this study will be included in the SAP.  
7.7.4 Pharmacokinetic/Pharmacodynamic Analyses 
Pharmacokinetic and pharmacodynamic data will be summarised descriptively. 
7.7.5 Safety Analyses 
Safety and tolerability will be assessed descriptively in terms of AEs, SAEs, deaths, 
laboratory data, physical findings, vital signs and ECGs. AEs will be listed individually by 
patient. 
Any AEs occurring before treatment will be included in the data listings but will not be 
included in the summary tables of AEs. 
Any AE occurring within 30 days of discontinuation of investigational product will be 
included in the AE summaries. Any events in this period that occur after a patient has 
received further therapy for cancer (following discontinuation of study treatment) will be 
flagged in the data listings.  
7.7.6 Other Analyses 
Descriptive summary statistics will be provided for demographics, medical history, physical 
examination and other variables collected at baseline. 


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7.7.7 Interim Analyses 
A formal interim analysis of ORR will be performed after approximately 120 patients (65%) 
have been randomised and followed to their first 12-week follow-up scan (estimated to be at 
approximately 39 months from first patient dosed). There will be >80% power to detect an 
improvement in ORR from 15% to 45% with 2-sided p<0.0105 (O’Brien and Fleming 
boundary based on 65% information). A minimum improvement from 15% to 38% will be 
statistically significant, if observed. If the comparison of the interim ORR data between the 
arms based on a CMH test is statistically significant, OS data will be formally compared 
between the arms and summarised to support a conditional marketing authorisation 
application. PFS and DoR will be summarised descriptively with no formal comparison of 
PFS. 
Three analyses of OS will be performed: at the time of the interim ORR analysis, at the time 
of the PFS assessment and at an updated (final) analysis. 
7.7.7.1 
Multiplicity and Control of Type 1 Error 
The multiple testing procedure will strongly control the Type I error probability (alpha) at 5% 
(2-sided) amongst the key efficacy endpoints (PFS, ORR, OS). Strong control of alpha 
ensures that the probability of rejecting any (ie, one or more) true null hypothesis, in either 
direction, is at most 5%, irrespective of how many and which null hypotheses are true or 
false 
At the interim and final analysis points, the key endpoints will be tested in a hierarchical 
order as shown in Figure 4. If any previous analysis in the sequence is not statistically 
significant, the alpha cannot be transferred to subsequent endpoints. Note: A non-statistically 
significant ORR result at the interim analysis will not preclude testing of PFS at the final 
analysis. 
An interim analysis of ORR will be conducted after 120 out of 186 patients have been 
randomised (65% information) and 1.05% of alpha will be spent on the comparison of ORR, 
based on an O’Brien and Fleming spending function. 
In the case both null hypotheses are true (ie, there is no true difference between the arms, 
neither for ORR nor for PFS) and assuming independence between these 2 endpoints, the 
final significance level for PFS can be set at 3.95%.  


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In the event that the null hypotheses for both ORR and PFS are false, alpha needs to be 
controlled at 5% over the 3 planned OS analyses; for example, assuming 55 death events 
(37% information) at the first analysis, 108 death events (73% information) at the second 
analysis and 147 death events (100% information) at the final OS analysis, the significance 
levels according to a Lan and De Mets O’Brien and Fleming spending function (Lan and de 
Mets 1983) will be 0.05%, 1.73% and 4.47%, respectively. 
The exact significance levels will be adjusted for the actual information fractions. 
Figure 4 
Multiple Testing Procedure 
The numbers are 2-sided significance levels 
 
Abbreviations: ORR, objective response rate; OS, overall survival; PFS, progression-free survival. 
 
7.7.8 Independent Data Monitoring Committee 
An IDMC will be enlisted to perform periodic review of accumulating safety data, with 
particular focus on biliary tract events (Note: and possibly others, as to be defined in charter) 
which are defined as AESI. The IDMC will review the incidence, causality, and severity of 
AESIs in Arm A compared with Arm B as further defined in the IDMC charter.  
The first planned periodic IDMC assessment will be performed after the initial 8 patients in 
Arm A have been followed up for 21 days following a second PCI treatment. In addition to 
the review of AESIs and other safety parameters, the IDMC will recommend whether or not 
the second PCI treatment during the chemotherapy period is to continue to be administered 
for future patients randomised to Arm A.  


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In addition to the planned meetings, ad hoc IDMC meetings will be required if an 
Investigator reports an AE/SAE that meets any of the safety stopping criteria as defined in 
the IDMC charter or induced as a result of aggregate safety or AESIs data, as per definitions 
in the charter. 
Based on these periodic or ad hoc data reviews the IDMC may recommend modifying or 
stopping the study early due to safety concerns.  
The IDMC will comprise at least 2 independent medical professionals relevant to the 
treatment indication and who are qualified to review the data and 1 independent statistician. 
The mandate, composition and operating mode of the IDMC will be described in the IDMC 
charter.  
The IDMC will be advisory to the Trial Steering Committee. The Trial Steering Committee 
will be responsible for promptly reviewing the IDMC recommendations, to decide whether to 
continue or terminate the study, and to determine whether amendments to the protocol or 
changes in the study conduct are required. 
Although there are no formal futility stopping rules in the study, the IDMC will review the 
ongoing safety data and the results of the interim ORR analysis, and provide a 
recommendation as to whether the study demonstrates a positive risk benefit that is clinically 
meaningful and meets the pre-defined statistical boundary for efficacy. Further details on the 
interim efficacy analysis and boundaries for stopping are provided in Section 7.7.7.  
Stopping Rules 
Further recruitment into the study will be suspended if: 
• an AESI (cholangitis and related biliary events) of severity Grade 4 or Grade 5 is reported 
in Arm A (the PCI treatment arm). An ad hoc IDMC meeting will be held. 
• otherwise recommended by the IDMC.  
Based on the safety findings, the IDMC may recommend continuing the study, modifying the 
study or stopping the study early due to safety concerns. 


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8 
Data Quality Assurance 
This study will be conducted according to the International Council for Harmonisation (ICH) 
E6(R2) risk and quality processes described in the applicable procedural documents. The 
quality management approach to be implemented in this study will be documented and will 
comply with the current ICH guidance on quality and risk management (ICH Q9). 
8.1 Data Management 
As part of the responsibilities assumed by participating in the study, the Investigator agrees to 
maintain adequate case histories for the patients treated as part of the research under this 
protocol. The Investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include laboratory reports and 
questionnaires. 
PPD will supply the eCRF. 
Investigative site personnel will enter patient data into Medidata RAVE. The analysis data 
sets will be a combination of these data and data from other sources (eg, laboratory data). 
Clinical data management will be performed in accordance with applicable PPD standards 
and data cleaning procedures to ensure the integrity of the data, eg, removing errors and 
inconsistencies in the data. Adverse event terms will be coded using the MedDRA, an 
internal validated medical dictionary, and concomitant medications will be coded using the 
World Health Organisation Drug Dictionary (WHODRUG). 
After database lock, each study site will receive a CD-ROM containing all of their 
site-specific eCRF data as entered into Medidata RAVE for the study, including full 
discrepancy and audit history. Additionally, a CD-ROM copy of all of the study site’s data 
from the study will be created and sent to the Sponsor for storage. PPD will maintain a 
duplicate CD-ROM copy for their records. In all cases, patient initials will not be collected 
nor transmitted to the Sponsor. Access to data on these CD-ROMs will be 
password-protected. 


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9 
Ethics 
9.1 Independent Ethics Committee or Institutional Review Board 
Federal regulations and the ICH guidelines require that approval be obtained from an 
IEC/IRB before participation of human subjects in research studies. Before study onset, the 
protocol, informed consent, advertisements to be used for the recruitment of study patients 
and any other written information regarding this study to be provided to the patient must be 
approved by the IEC/IRB. Documentation of all IEC/IRB approvals and of the IEC/IRB 
compliance with ICH harmonised tripartite guideline E6(R2): GCP will be maintained by the 
site and will be available for review by the Sponsor or its designee. 
All IEC/IRB approvals should be signed by the IEC/IRB chairman or designee and must 
identify the IEC/IRB name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favourable opinion was granted. 
Investigator is responsible for providing written summaries of the progress and status of the 
study at intervals not exceeding 1 year or otherwise specified by the IEC/IRB. The 
Investigator must promptly supply the Sponsor or its designee, the IEC/IRB, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to the study patients. 
9.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, the protocol, and all applicable regulations. 
9.3 Patient Information and Consent 
A written informed consent, in compliance with regulatory authority regulations (21 CFR 
Part 50, European Union Directive 2001/20/EC and its associated Detailed Guidances, 
European Union GCP Directive 2005/28/EC), ICH GCP Guideline, Section 4.8, and the 
terms of the Declaration of Helsinki (current), shall be obtained from each patient before 
entering the study or performing any unusual or nonroutine procedure that involves risk to 
the patient. An informed consent template may be provided by the Sponsor to investigative 
sites. If any institution-specific modifications to study-related procedures are proposed or 
made by the site, the consent should be reviewed by the Sponsor or its designee or both 


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before IRB/IEC submission. Once reviewed, the consent will be submitted by the 
Investigator to his or her IRB/IEC for review and approval before the start of the study. If the 
ICF is revised during the course of the study, all active participating patients must sign the 
revised form. 
Before recruitment and enrolment, each prospective patient will be given a full explanation 
of the study and be allowed to read the approved ICF. Once the Investigator is assured that 
the patient understands the implications of participating in the study, the patient will be asked 
to give consent to participate in the study by signing the ICF. 
The Investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the patient. 


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10 Investigator’s Obligations 
The following administrative items are meant to guide the Investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the 
IRB/IEC but will not result in protocol amendments. 
10.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the patient, except as necessary for monitoring and auditing by the Sponsor, its 
designee, the regulatory agencies/authorities, or the IRB/IEC. 
The Investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the Sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
10.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the Sponsor to 
submit the complete and accurate certification or disclosure statements required per 
applicable regulatory requirements. In addition, the Investigator must provide to the Sponsor 
a commitment to promptly update this information if any relevant changes occur during the 
course of the investigation and for 1 year following the completion of the study. 
Neither the Sponsor nor PPD is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the Sponsor nor PPD is financially responsible for 
further treatment of the patient’s disease. 


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Prior to beginning the study, the Investigator will be asked to comply with ICH E6(R2) 8.2 
and/or 21 CFR by providing the following essential documents, including but not limited to: 
• IEC/IRB approval 
• Original Investigator-signed Investigator agreement page of the protocol 
• Form Food and Drug Administration (FDA) 1572, fully executed, and all updates on a 
new fully executed Form FDA 1572 (if compatible with local legislations) 
• Curriculum vitae for the Investigator and each Sub-Investigator listed on Form FDA 1572 
• Financial disclosure information to allow the Sponsor to submit complete and accurate 
certification or disclosure statements required under regional regulations. In addition, the 
Investigators must provide to the Sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study. 
• IEC/IRB-approved informed consent, samples of site advertisements for recruitment for 
this study, and any other written information regarding this study that is to be provided to 
the patient, and 
• Laboratory certifications and normal ranges for any local laboratories used by the site, in 
accordance with regional regulatory requirements.  
10.3 Study Conduct 
The Investigator agrees that the study will be conducted according to the principles of ICH 
E6(R2). The Investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. Study information from this protocol will be 
posted by the Sponsor on publicly available clinical trial registers before enrolment of 
patients begins. 
10.4 Adherence to Protocol 
The Investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6(R2) and all applicable guidelines and regulations. 


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10.5 Adverse Events and Study Report Requirements 
By participating in this study, the Investigator agrees to submit reports of SAEs and 
AIs/UADEs to the Sponsor or designee and/or IEC/IRB according to the time line and 
method outlined in the protocol and Study Plans. In addition, the Investigator agrees to 
submit annual reports to the study site IEC/IRB as appropriate. 
10.6 Investigator’s Final Report 
Upon completion of the study, the Investigator, where applicable, should inform the 
institution; the Investigator/institution should provide the IEC/IRB with a summary of the 
study’s outcome and the Sponsor and regulatory authority(ies) with any reports required. 
10.7 Records Retention 
The Investigator will maintain all study records according to ICH GCP and applicable 
regulatory requirement(s). Essential documents should be retained until at least 2 years after 
the last approval of a 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 investigational product. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the Sponsor. It is the responsibility of the 
Sponsor to inform the Investigator/institution as to when these documents no longer need to 
be retained. 
If the Investigator withdraws from the responsibility of keeping the study records, custody 
must be transferred to a person willing to accept the responsibility. The Sponsor must be 
notified in writing if a custodial change occurs. 
10.8 Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the Sponsor will be 
responsible for these activities and will work with the Investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and other related issues. The Sponsor has final approval authority over all 
such issues. 


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Data are the property of the Sponsor and cannot be published without prior authorisation 
from the Sponsor, but data and publication thereof will not be unduly withheld. 


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11 Study Management 
The administrative structure will include an IDMC. 
11.1 Monitoring 
11.1.1 Independent Data Monitoring Committee 
All information related to the IDMC for this study is located in Section 7.7.8. 
11.1.2 Monitoring of the Study 
The Clinical Monitor, as a representative of the Sponsor, has the obligation to follow the 
study closely. In doing so, the Monitor will visit the Investigator and study site at periodic 
intervals, in addition to maintaining necessary telephone and letter contact. The Monitor will 
maintain current personal knowledge of the study through observation, review of study 
records and source documentation, and discussion of the conduct of the study with the 
Investigator and personnel. 
All aspects of the study will be carefully monitored, by the Sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
11.1.3 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/IEC review, and regulatory inspections by providing direct access to all study 
records. In the event of an audit, the Investigator agrees to allow the Sponsor, representatives 
of the Sponsor, or a regulatory agency, access to all study records. 
The Investigator should promptly notify the Sponsor and PPD of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the 
Sponsor. 


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11.2 Management of Protocol Amendments and Deviations 
11.2.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the patient, must be reviewed and approved by the Sponsor or its 
designee. Amendments to the protocol must be submitted in writing to the Investigator’s 
IRB/IEC and regulatory authorities for approval before patients can be enrolled into an 
amended protocol. 
11.2.2 Protocol Deviations 
The Investigator or designee must document and explain in the patient’s source 
documentation any deviation from the approved protocol. The Investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
patients without prior IEC/IRB approval. As soon as possible, after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IEC/IRB for review and approval, to the Sponsor for agreement, 
and to the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the Sponsor and the IEC/IRB and agreed to by the 
Investigator. A significant deviation occurs when there is non-adherence to the protocol by 
the patient or Investigator that results in a significant, additional risk to the patient. 
Significant deviations can include non-adherence to inclusion or exclusion criteria, or 
non-adherence to FDA regulations or ICH GCP guidelines, and will lead to the patient being 
withdrawn from the study (Section 4.2). 
Significant protocol deviations for this study may include 1) use of prohibited concomitant 
medications during the study treatment period, 2) tumour assessments (RECIST) for 
screening not performed within 28 days prior to randomisation, 3) patients who received the 
wrong treatment, etc. 
Protocol deviations will be documented by the Clinical Monitor throughout the course of 
monitoring visits. Principal Investigators will be notified in writing by the Monitor of 
deviations. IEC/IRB should be notified of all protocol deviations in a timely manner. 


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Important protocol deviations will be listed and summarised in the Clinical Study Report. 
11.3 Study Termination 
Although PCI Biotech has every intention of completing the study, PCI Biotech reserves the 
right to discontinue the study at any time for clinical or administrative reasons, including but 
not limited to: 
• Occurrence of AEs not seen previously which by virtue of their nature, severity and 
duration are considered to necessitate study termination; OR the unexpected 
incidence or severity of known AEs 
• Sponsor decision 
• Medical or ethical reasons affecting the continued performance of the study 
• Difficulties in the recruitment of patients 
• Cancellation of the drug development as such or for the given indication. 
The end of the study is defined as the date of the final database lock. 
If the study is terminated (ie, ended prematurely) for any reason other than for safety, all 
randomised patients will be allowed to complete their planned treatment and will be followed 
up for safety for 30 days after the last dose of study treatment. In this case, end of study will 
be the end of treatment follow-up visit which will take place 30 days after discontinuation or 
completion of study treatment. 
11.4 Final Report 
Whether the study is completed or prematurely terminated, the Sponsor will ensure that the 
clinical study reports are prepared and provided to the regulatory agency(ies) as required by 
the applicable regulatory requirements. The Sponsor will also ensure that the clinical study 
reports in marketing applications meet the standards of the ICH harmonised tripartite 
guideline E3: Structure and content of clinical study reports.  
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the Clinical Study Report. The Investigator will be provided 


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reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results. 
Upon completion of the Clinical Study Report, the Sponsor will provide the Investigator with 
the full summary of the study results. The Investigator is encouraged to share the summary 
results with the study patients, as appropriate. The study results will be posted on publicly 
available clinical trial registers. 


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12 Reference List 
Amit O, Mannino F, Stone AM, et al. Blinded independent central review of progression in 
cancer clinical trials: results from a meta-analysis. Eur J Cancer. 2011;47(12):1772-8. 
Anderson CD, Pinson CW, Berlin J, et al. Diagnosis and treatment of cholangiocarcinoma. 
Oncologist. 2004;9(1):43-57. 
Banales JM, Cardinale V, Carpino G, et al. Expert consensus document: 
Cholangiocarcinoma: current knowledge and future perspectives consensus statement from 
the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev 
Gastroenterol Hepatol. 2016;13(5):261-80. 
Blechacz B, Gores GJ. Cholangiocarcinoma: advances in pathogenesis, diagnosis, and 
treatment. Hepatology. 2008;48(1):308-21. 
Deng Y, Zhong R, Xie X, et al. Serum CEA, CA125, CA19-9, and CA724 levels for the 
diagnosis and staging of cholangiocarcinoma. Biomedical Res. 2017;28(3):1413-18. 
Dolmans DE, Fukumura D, Jain RK. Photodynamic therapy for cancer. Nat Rev Cancer. 
2003;3(5):380-7. 
Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: a pooled analysis 
of clinical trials. Br J Cancer. 2007;96(6):896-902. 
Efron B. The Efficiency of Cox’s Likelihood Function for Censored Data. J Am Stat Assoc. 
1977;72(359):557-65. 
Emerson JD. Combining estimates of the odds ratio: the state of the art. Stat Methods Med 
Res. 1994;3(2):157-78. 
Fleming TR. Surrogate endpoints and FDA’s accelerated approval process. Health Aff 
(Millwood). 2005;24(1):67-78. 
Gederaas OA, Johnsson A, Berg K, et al. Photochemical internalization in bladder cancer – 
development of an orthotopic in vivo model. Photochem Photobiol Sci. 
2017;16(11):1664-76. 


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Global Burden of Disease Cancer Collaboration. The global burden of cancer 2013. JAMA 
Oncol. 2015;1(4):505-27. 
Henderson BW, Dougherty TJ. How does photodynamic therapy work? Photochem 
Photobiol. 1992;55(1):145–57. 
Henson DE, Albores-Saavedra J, Corle D. Carcinoma of the extrahepatic bile ducts. 
Histologic types, stage of disease, grade, and survival rates. Cancer. 1992;70(6):1498-501. 
Hu HJ, Mao H, Tan YQ, et al. Clinical value of preoperative serum CA 19-9 and CA-125 
levels in predicting the resectability of hilar cholangiocarcinoma. Springerplus. 2016;5:551. 
Ishimoto U, Kondo S, Ohba A, et al. Prognostic factors for survival in patients with advanced 
intrahepatic cholangiocarcinoma treated with gemcitabine plus cisplatin as first-line 
treatment. Oncology. 2018;94(2):72-8. 
Ito F, Cho CS, Rikkers LF, et al. Hilar cholangiocarcinoma: current management. Ann Surg. 
2009;250(2):210-8. 
Juntermanns B, Radunz S, Heuer M, et al. Tumor markers as a diagnostic key for hilar 
cholangiocarcinoma. Eur J Med Res. 2010;15(8):357–61. 
Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of 
cholangiocarcinoma: consensus document. Gut. 2002;51 Suppl 6:VI1-9. 
Kiesslich T, Wolkersdorfer G, Neureiter D, et al. Photodynamic therapy for non-resectable 
perihilar cholangiocarcinoma. Photochem Photobiol Sci. 2009;8(1):23-30. 
Kim BJ, Hyung J, Yoo C, et al. Prognostic factors in patients with advanced biliary tract 
cancer treated with first-line gemcitabine plus cisplatin: retrospective analysis of 
740 patients. Cancer Chemother Pharmacol. 2017;80(1):209-15. 
LaFemina J, Jarnagin WR. Surgical management of proximal bile duct cancers. Langenbecks 
Arch Surg. 2012;397(6):869–79.  
Lan KKG and DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70(3):659–63. 


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McCaughan JS Jr., Mertens BF, Cho C, et al. Photodynamic therapy to treat tumors of the 
extrahepatic biliary ducts. A case report. Arch Surg. 1991;126(1):111-3. 
Mihalache F, Tantau M, Diaconu B, et al. Survival and quality of life of cholangiocarcinoma 
patients: a prospective study over a 4 year period. J Gastrointestin Liver Dis. 
2010;19(3):285-90. 
Moole H, Puli SR. Tu1928 complications of metal vs plastic stents in malignant distal biliary 
strictures: a meta-analysis and systematic review. Gastroenterology. 2015;148(4):S-937. 
Moole H, Tathireddy H, Dharmapuri S, et al. Success of photodynamic therapy in palliating 
patients with nonresectable cholangiocarcinoma: A systematic review and meta-analysis. 
World J Gastroenterol. 2017;23(7):1278–88. 
Moriwaki T, Yamamoto Y, Gosho M, et al. Correlations of survival with progression-free 
survival, response rate, and disease control rate in advanced biliary tract cancer: a meta-
analysis of randomised trials of first-line chemotherapy. Br J Cancer 2016;114(8):881–8. 
Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, 
perihilar and distal tumors. Ann Surg. 1996;224(4):463-73. 
Nathan H, Aloia TA, Vauthey JN, et al. A proposed staging system for intrahepatic 
cholangiocarcinoma. Ann Surg Oncol. 2009;16(1):14–22. 
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: 
Hepatobiliary Cancers. Version 4. 2020 – June 19 1, 2020. 
Patel AH, Harnois DM, Klee GG, et al. The utility of CA 19-9 in the diagnoses of 
cholangiocarcinoma in patients without primary sclerosing cholangitis. Am J Gastroenterol 
2000;95(1):204-7. 
Pisello F, Geraci G, Modica G, et al. Cholangitis prevention in endoscopic Klatskin tumour 
palliation: air cholangiography technique. Langenbecks Arch Surg. 2009;394(6):1109-14.  
Rea DJ, Heimbach JK, Rosen CB, et al. Liver transplantation with neoadjuvant 
chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg. 
2005;242(3):451-61. 


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Sakamoto E, Nimura Y, Hayakawa N, et al. The pattern of infiltration at the proximal border 
of hilar bile duct carcinoma: a histologic analysis of 62 resected cases. Ann Surg. 
1998;227(3):405-11. 
Singal A, Welling TH, Marrero JA. Role of liver transplantation in the treatment of 
cholangiocarcinoma. Expert Rev Anticancer Ther. 2009;9(4):491-502. 
Talreja JP, DeGaetani M, Ellen K, et al. Photodynamic therapy in unresectable 
cholangiocarcinoma: not for the uncommitted. Clin Endosc. 2013;46(4):390-94. 
Valle JW, Borbath I, Khan SA, et al. Biliary cancer: ESMO clinical practice guidelines for 
diagnosis, treatment, and follow-up. Ann Oncol. 2016;27(suppl 5):v28-v37. 
Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary 
tract cancer. New Engl J Med. 2010;362(14):1273-81. 
Vauthey JN, Blumgart LH. Recent advances in the management of cholangiocarcinomas. 
Semin Liver Dis. 1994;14(2):109-14. 
Wiedmann M, Berr F, Schiefke I, et al. Photodynamic therapy in patients with non-resectable 
hilar cholangiocarcinoma: 5-year follow-up of a prospective phase II study. Gastrointest 
Endosc. 2004;60(1):68-75. 
Zoepf T, Jakobs R, Arnold JC, et al. Palliation of nonresectable bile duct cancer: improved 
survival after photodynamic therapy. Am J Gastroenterol. 2005;100(11):2426-30. 


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13 Appendices 


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13.1 Appendix A: Schedule of Events for the Active Treatment Period 
Table 10 
Schedule of Events for the Active Treatment Period – Arm A Patients 
  
Screeningb 
Randomisationc 
Treatment period 
Visita 
PCI 
treatment  
No 1 
  
PCI 
treatment  
No 2d 
  
Cycle (C)/Day (D) 
 
C1, D1 
C1, D8 
C1, D15 
C2, D1 
C2, D8 
C3, D1 
C3, D8 
C4, D1 
C4, D8 
C4, D18 
C5, D1 
C5, D8 
C6, D1 
C6, D8 
C7, D1 
C7, D8 
C8, D1 
C8, D8 
Day 
-4 
1 
-4 
1 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stentinge 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Assessments 
 
Histology/Cytologyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination and ECOGh 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Vital signsi 
X 
XX 
X 
X 
X 
X 
X 
X 
X 
X 
X 
XX 
X 
X 
X 
X 
X 
X 
X 
X 
ECGj 
X 
XXX 
X 
 
 
X 
 
X 
 
X 
 
XXX 
X 
 
X 
 
X 
 
X 
 
Adverse eventsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Screeningb 
Randomisationc 
Treatment period 
Visita 
PCI 
treatment  
No 1 
  
PCI 
treatment  
No 2d 
  
Cycle (C)/Day (D) 
 
C1, D1 
C1, D8 
C1, D15 
C2, D1 
C2, D8 
C3, D1 
C3, D8 
C4, D1 
C4, D8 
C4, D18 
C5, D1 
C5, D8 
C6, D1 
C6, D8 
C7, D1 
C7, D8 
C8, D1 
C8, D8 
Day 
-4 
1 
-4 
1 
Unanticipated adverse device 
effects/Adverse incidents 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Xl 
 
 
 
 
 
 
 
Photosensitivity evaluation and skin 
reactionsm 
 
X 
X 
X 
X 
X 
X 
X 
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 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of life assessmentn 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
Tumour assessment (CT or MRI 
RECIST 1.1)o 
X 
Every 12 weeks ( 1 week) from randomisation until progressive disease observed 
Laboratory Assessments 
 
Clinical chemistry and haematologyp 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumour biomarkers (CA 19-9, CA-125, 
CEA)q 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Urinalysisr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Creatinine clearances 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulationt 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Pregnancy testu 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
Fimaporfin pharmacokinetics (Group 1)v 
 
XXX 
X 
X 
 
 
X 
 
X 
 
X 
XXX 
X 
X 
 
X 
 
X 
 
X 


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Screeningb 
Randomisationc 
Treatment period 
Visita 
PCI 
treatment  
No 1 
  
PCI 
treatment  
No 2d 
  
Cycle (C)/Day (D) 
 
C1, D1 
C1, D8 
C1, D15 
C2, D1 
C2, D8 
C3, D1 
C3, D8 
C4, D1 
C4, D8 
C4, D18 
C5, D1 
C5, D8 
C6, D1 
C6, D8 
C7, D1 
C7, D8 
C8, D1 
C8, D8 
Day 
-4 
1 
-4 
1 
Fimaporfin pharmacokinetics (Group 2)v 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
X 
 
 
IMP Administration 
 
Fimaporfin (Amphinex) 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Gemcitabine for PCI 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Study Procedure 
 
Laser light application procedurew 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
SoC Treatment 
 
Systemic cisplatin and gemcitabine 
chemotherapyx 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: APTT, activated partial thromboplastin time; CA-125, cancer antigen-125; CA 19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; 
CT, computed tomography; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; ERCP, endoscopic retrograde cholangio-
pancreatography; IMP, investigational medicinal product; INR, international normalised ratio; MRI, magnetic resonance imaging; No., number; PCI, 
photochemical internalisation; RECIST, Response Evaluation Criteria in Solid Tumours; SAE, serious adverse event; SoC, standard of care. 
a. 
Patients who have started gemcitabine/cisplatin treatment before the screening period should continue their treatment as scheduled, including during the 
screening period. Study visits should be synchronised with ongoing SoC chemotherapy. Study cycles will be counted for all patients from first treatment after 
enrolment (PCI treatment No. 1). Chemotherapy cycles will be counted from first chemotherapy treatment and cannot exceed 8 cycles. 
b. Screening evaluations are to be performed after the patient has signed and dated the informed consent form and within 21 days prior to randomisation. 
Tumour assessment may be performed within 28 days prior to randomisation. Histology/cytology is to be performed/confirmed before randomisation. 


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c. 
Upon completion of all screening evaluations, eligible patients will be randomised via the Interactive Web Response System. 
d. A second PCI treatment procedure aimed at the initiation of Cycle 5 or, if patient-related factors demand postponement, at initiation of a later cycle 
(Section 3.3.2). The PCI treatments must be separated by at least 3 months. 
e. 
Biliary stenting is to be performed on all patients according to local practice; however, the chosen stent must be of an exchangeable plastic type until 
radiological progression is declared. Stenting may be performed at any time from confirmation of histological/cytological diagnosis until immediately after 
the first laser light application. Patients who have already undergone stenting before screening should be reviewed to ensure the stent is of plastic type, 
correctly positioned and adequate liver drainage confirmed. Stents must be removed for the laser light application, and a new stent must be placed 
immediately after light application. Stent removal, laser light application, and stent replacement will take place during the same one procedure. 
f. 
Histology/cytology to be performed if patient does not already have confirmed disease. 
g. Medical history includes evaluation of the history of cholangiocarcinoma and method of confirmation, its previous therapy, pre-existing diseases, and current 
medication. 
h. Physical examination includes height (screening only), weight, ECOG performance status, and body surface area. 
i. 
Vital signs including pulse rate, systolic and diastolic blood pressure (sitting), and temperature. Vital signs will be performed before and after Amphinex 
administration on Day -4 and Cycle 4, Day 18. 
j. 
Standard 12-lead ECG. Tracings must be interpreted, dated, and signed by the Investigator or his/her designee and filed with the patient’s source documents. 
On Day -4 and Cycle 4, Day 18, ECG will be performed before, approximately 30 minutes after, and approximately 4 hours after Amphinex administration. 
k. Adverse events/SAEs are to be recorded from the time of informed consent up to 30 days following the last administration of study treatment. Thereafter, 
only SAEs considered related to the study treatments/procedures are to be reported. 
l. 
If the second PCI treatment is postponed, unanticipated adverse device effects/adverse incidents recording will be done on the day of administration of 
postponed second PCI treatment (laser light application). 
m. Patients will be asked about possible skin and photosensitivity reactions and their exposure to light during study visits for 3 months following the last 
Amphinex administration. 
n. Quality of life assessments will be performed at selected time points during treatment and thereafter every 12 weeks, preferably before any other study 
assessments are performed. 
o. Radiographic tumour assessment with diagnostic contrast-enhanced CT or MRI scan and clinical assessment performed every 12 weeks (±1 week) from 
randomisation until disease progression. Baseline (screening) measurement may be performed within 28 days prior to randomisation. CT/MRI scan of 
abdomen/pelvis only unless clinically indicated or disease progression is suspected. The same imaging modality and contrast protocol used at screening must 
be used throughout the study. 
p. Clinical chemistry includes sodium, potassium, calcium, magnesium, phosphate, chloride, glucose (fasting), creatinine, total bilirubin, 
gamma glutamyltransferase, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, C-reactive protein, urea/blood urea nitrogen, 
total protein, serum amylase, serum lipase, and lactate dehydrogenase. Haematology includes haemoglobin, haematocrit, white blood cell count, 
differentials (absolute), and platelet count. Safety blood samples do not need to be repeated on Day -4 prior to Amphinex administration if the screening 
evaluation was done 1 day before. Samples taken within 3 days of Day 1 for any chemotherapy cycle do not need to be repeated on Day 1. 
q. Standard tumour markers will be analysed from serum samples collected for clinical chemistry. 


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r. 
Urinalysis dipstick for albumin or total protein, glucose, bilirubin and blood (microscopy is to be done if there is more than one positive test). 
s. 
A creatinine clearance at baseline is required. Creatinine clearance prior to treatment should be ≥60 mL/min. Serum creatinine should be checked before each 
cycle of treatment. If there is a >25% increase in serum creatinine compared to the baseline, then the ethylenediamine tetraacetic acid (EDTA) clearance or 
equivalent, including estimation of GFR, according to local practice, must be performed and cisplatin dosing modified accordingly. 
t. 
Coagulation tests including INR and APTT should be performed on Day 1 of each 21-day chemotherapy cycle except if patient is receiving warfarin, in which 
case, assessments should also be done on Day 8 of each cycle and Day 15 of Cycle 1. Tests do not need to be repeated on Day -4 prior to Amphinex 
administration if done 1 day before. 
u. For women of childbearing potential only. A highly sensitive urine or serum pregnancy test is acceptable.  
v. PK samples will be collected from all patients in Arm A. Group 1: the 20 first patients randomised to Arm A; Group 2: all other patients randomised to 
Arm A. On Day -4 and Cycle 4, Day 18, the PK samples will be time matched with ECG: For PK Group 1, PK sampling and ECG will be performed before, 
approximately 30 minutes after, and approximately 4 hours after Amphinex administration; for PK Group 2, PK sampling and ECG will be performed before 
Amphinex administration, only ECG will be performed 30 minutes after and approximately 4 hours after Amphinex administration.  
w. Laser light application procedure is to be performed 3 hours (±1 hour) after end of the gemcitabine administration. Patients may be admitted for overnight 
follow-up after the laser light application and related procedures on Day 1 of Cycle 1 and Day 1 of Cycle 5. 
x. Day 15 visit (±3 days) required in Cycle 1 of chemotherapy only for standard safety evaluation; no cyclic chemotherapy will be administered on Day 15 visit. 
 


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Table 11 
Schedule of Events for the Active Treatment Period – Arm B Patients 
Visita 
Screeningb 
Randomisationc 
Treatment period 
Cycle (C)/Day (D) 
C1, D1 
C1, D8 
C1, D15 
C2, D1 
C2, D8 
C3, D1 
C3, D8 
C4, D1 
C4, D8 
C5, D1 
C5, D8 
C6, D1 
C6, D8 
C7, D1 
C7, D8 
C8, D1 
C8, D8 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stentingd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Assessments 
 
Histology/Cytologye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination and 
ECOGg 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECGi 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Adverse eventsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Visita 
Screeningb 
Randomisationc 
Treatment period 
Cycle (C)/Day (D) 
C1, D1 
C1, D8 
C1, D15 
C2, D1 
C2, D8 
C3, D1 
C3, D8 
C4, D1 
C4, D8 
C5, D1 
C5, D8 
C6, D1 
C6, D8 
C7, D1 
C7, D8 
C8, D1 
C8, D8 
Photosensitivity evaluation and 
skin reactions 
 
 
X 
X 
X 
X 
X 
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 
X 
X 
X 
X 
X 
X 
Quality of life assessmentk 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Tumour assessment (CT or MRI 
RECIST 1.1)l 
X 
Every 12 weeks (±1 week) from randomisation until progressive disease observed 
Laboratory Assessments 
 
Clinical chemistry and 
haematologym 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumour biomarkers (CA 19-9, 
CA-125, CEA)n 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Urinalysiso 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Creatinine clearancep 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulationq 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Pregnancy testr 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 


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Visita 
Screeningb 
Randomisationc 
Treatment period 
Cycle (C)/Day (D) 
C1, D1 
C1, D8 
C1, D15 
C2, D1 
C2, D8 
C3, D1 
C3, D8 
C4, D1 
C4, D8 
C5, D1 
C5, D8 
C6, D1 
C6, D8 
C7, D1 
C7, D8 
C8, D1 
C8, D8 
SoC Treatment 
 
Systemic cisplatin and 
gemcitabine chemotherapys 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: APTT, activated partial thromboplastin time; CA-125, cancer antigen 125; CA 19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; 
CT, computed tomography; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; INR, international normalised ratio; MRI, magnetic 
resonance imaging; RECIST, Response Evaluation Criteria in Solid Tumours; SAE, serious adverse event; SoC, standard of care. 
a. 
Patients who have started gemcitabine/cisplatin treatment before the screening period should continue their treatment as scheduled, including during the 
screening period. Study visits should be synchronised with ongoing SoC chemotherapy. Chemotherapy cycles will be counted from first chemotherapy 
treatment and cannot exceed 8 cycles. 
b. Screening evaluations are to be performed after the patient has signed and dated the informed consent form and within 21 days prior to randomisation. 
Tumour assessments may be performed within 28 days prior to randomisation. Stenting and histology/cytology are to be performed/confirmed before 
randomisation. 
c. 
Upon completion of all screening evaluation, eligible patients will be randomised via the Interactive Web Response System. 
d. Biliary stenting is to be performed on all patients according to local practice, however, the chosen stent must be of an exchangeable plastic type until 
radiological progression is declared. Stenting may be performed at any time from confirmation of histological/cytological diagnosis until Cycle 1 Day 1. 
Patients who have already undergone stenting before screening should be reviewed to ensure the stent is of plastic type, correctly positioned and adequate 
liver drainage confirmed.  
e. 
Histology/cytology to be performed if patient does not already have confirmed disease. 


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f. 
Medical history includes evaluation of the history of cholangiocarcinoma and method of confirmation, its previous therapy, pre-existing diseases, and current 
medication. 
g. Physical examination includes height (screening only), weight, ECOG performance status, and body surface area. 
h. Vital signs including pulse rate, systolic and diastolic blood pressure (sitting), and temperature. 
i. 
Standard 12-lead ECG. Tracings must be interpreted, dated, and signed by the Investigator or his/her designee and filed with the patient’s source documents. 
j. 
Adverse events/SAEs are to be recorded from the time of informed consent up to 30 days following the last administration of study treatment. Thereafter, 
only SAEs considered related to the study treatments/procedures are to be reported. 
k. Quality of life assessments will be performed at selected time points during treatment and thereafter every 12 weeks, preferably before any other study 
assessments are performed. 
l. 
Radiographic tumour assessment with diagnostic contrast-enhanced CT or MRI scan and clinical assessment performed every 12 weeks (±1 week) from 
randomisation until disease progression. Baseline (screening) measurement may be performed within 28 days prior to randomisation. CT/MRI scan of 
abdomen/pelvis only unless clinically indicated or disease progression is suspected. The same imaging modality and contrast protocol used at screening must 
be used throughout the study. 
m. Clinical chemistry includes sodium, potassium, calcium, magnesium, phosphate, chloride, glucose (fasting), creatinine, total bilirubin, 
gamma glutamyltransferase, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, C-reactive protein, urea/blood urea nitrogen, 
total protein, serum amylase, serum lipase and lactate dehydrogenase. Haematology includes haemoglobin, haematocrit, white blood cell count, 
differentials (absolute), and platelet count. Samples taken within 3 days of Day 1 for any chemotherapy cycle do not need to be repeated on Day 1 prior to 
dosing. 
n. Standard tumour markers will be analysed from serum samples collected for clinical chemistry. 
o. Urinalysis dipstick for albumin or total protein, glucose, bilirubin and blood (microscopy is to be done if there is more than one positive test). 
p. A creatinine clearance at baseline is required. Creatinine clearance prior to treatment should be ≥60 mL/min. Serum creatinine should be checked before each 
cycle of treatment. If there is a >25% increase in serum creatinine compared to the baseline then the ethylenediamine tetraacetic acid (EDTA) clearance or 
equivalent, including estimation of GFR, according to local practice, must be performed and cisplatin dosing modified accordingly. 
q. Coagulation tests including INR and APTT should be performed on Day 1 of each 21-day chemotherapy cycle except if patient is receiving warfarin, in which 
case, assessments should also be done on Day 8 of each cycle and Day 15 of Cycle 1.  
r. 
For women of childbearing potential only. A highly sensitive urine or serum pregnancy test is acceptable.  
s. 
Day 15 visit (±3 days) required in Cycle 1 of chemotherapy only for standard safety evaluation; no cyclic chemotherapy will be administered on Day 15 visit. 


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13.2 Appendix B: Schedule of Events for the Follow-Up Period 
Table 12 
Schedule of Events for the Follow-Up Period – Arm A and Arm B Patients 
Visit 
End of Treatment 
Follow-up Period 
Tumour response  
follow-upa 
Survival follow-upb 
Day 
7c 
30d 
Every 12 Weeks 
±3 days 
±1 week 
±4 weeks 
Study Assessments 
 
Physical examination and ECOG performance status 
X 
X 
X 
 
ECG 
 
X 
 
 
Adverse events 
X 
X 
X 
 
Photosensitivity evaluation (Arm A only) 
X 
X 
Xe 
 
Concomitant medications 
X 
X 
 
 
Quality of life assessmentsf 
 
X 
X 
 
Tumour assessments 
Every 12 weeks (±1 week) from randomisation 
until progressive disease observed 
X 
 
Laboratory Assessments/Biomarker Assessments 
 
Clinical chemistry and haematology 
X 
X 
 
 
Standard tumour markers (CA 19-9, CA-125, CEA) 
 
 
X 
 
Urinalysis 
X 
X 
 
 
Pregnancy testg  
 
X 
X 
 
Follow-up Assessments 
 
Record details of subsequent anti-cancer therapy 
 
 
X 
X 
Serious adverse eventsh 
 
 
 
X 
Survivali 
X 
X 
X 
X 


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Visit 
End of Treatment 
Follow-up Period 
Tumour response  
follow-upa 
Survival follow-upb 
Day 
7c 
30d 
Every 12 Weeks 
±3 days 
±1 week 
±4 weeks 
Pharmacokinetic and ECG Assessment 
(Arm A patients only) 
 
 
 
 
Fimaporfin pharmacokinetics 
 
X 
Xj 
 
ECG 
 
X 
Xj 
 
Abbreviations: CA-125, cancer antigen-125; CA 19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; ECG, electrocardiogram; ECOG, Eastern 
Cooperative Oncology Group.  
a. 
For patients who have not progressed, follow-up should be performed every 12 weeks, (±1 week) relative to randomisation until radiological disease 
progression. 
b. For patients who have progressed, follow-up should be performed every 12 weeks (±4 weeks) until death. Additional survival contacts (ie, outside of the 
12-weekly calls) may be conducted around the time of the interim and final (data cut-off) analyses to ensure that the survival information is as up to date as 
possible for the analysis of overall survival. 
c. 
Patients discontinuing treatment because of disease progression or discontinuation for any reason other than planned completion of treatment will have a 
discontinuation follow-up visit up to 7 days after treatment discontinuation. 
d. All patients will have an end of treatment follow-up visit 30 days (±3 days) after the last dose of study treatment. 
e. 
Patients in Arm A will be asked about possible skin photosensitivity reactions and their exposure to light for 3 months following the last Amphinex 
administration.  
f. 
Quality of life assessments will be performed at selected time points during treatment and thereafter every 12 weeks, preferably before any other study 
assessments are performed. 
g. For women of childbearing potential only. A highly sensitive urine or serum pregnancy test is acceptable.  
h. Serious adverse events that occur more than 30 days after the last dose of study treatment do not need to be reported unless the Investigator considers them 
related to study treatment and/or procedures. 


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i. 
Survival status will be assessed for all patients (eg, in a telephone call) every 12 weeks, with a window of ±4 weeks after confirmation of disease 
progression, discontinuation for any other reason, or study withdrawal if patient has consented to be followed up, until death from any cause. 
j. 
A pharmacokinetic blood sample and corresponding ECG should be taken at the time of the 2 tumour assessments after end of treatment. 
 


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13.3 Appendix C: RECIST 1.1  
For RECIST 1.1 criteria, please refer to the website located at: 
https://project.eortc.org/recist/wp-content/uploads/sites/4/2015/03/RECISTGuidelines.pdf 


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13.4 Appendix D: Health-Related Quality of Life Questionnaires 
13.4.1 EORTC QLQ-C30 
 
 
Not  
A little 
Quite  
Very 
at all 
a bit 
much 
1. Do you have any trouble doing 
strenuous activities, like carrying a 
heavy shopping bag or a suitcase?  
 1        
 2 
3                         4 
2. Do you have any trouble taking a long 
walk? 
 1        
 2 
3                         4 
3. Do you have any trouble taking a short 
walk outside of the house?  
 1        
 2 
3                         4 
4. Do you need to stay in bed or a chair 
during the day? 
 1        
 2 
3                         4 
5. Do you need help with eating, 
dressing, washing yourself or using the 
toilet?  
 1        
 2 
3                         4 
During the past week: 
  
6. Were you limited in doing either your 
work or other daily activities?  
 1        
 2 
3                         4 
7. Were you limited in pursuing your 
hobbies or other leisure time 
activities? 
 1        
 2 
3                         4 
8. Were you short of breath? 
 1        
 2 
3                         4 
9. Have you had pain? 
 1        
 2 
3                         4 
10. Did you need to rest?  
 1        
 2 
3                         4 
11. Have you had trouble sleeping?  
 1        
 2 
3                         4 


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Not  
A little 
Quite  
Very 
at all 
a bit 
much 
12. Have you felt weak? 
 1        
 2 
3                         4 
13. Have you lacked appetite? 
 1        
 2 
3                         4 
14. Have you felt nauseated? 
 1        
 2 
3                         4 
15. Have you vomited? 
 1        
 2 
3                         4 
16. Have you been constipated?  
 1        
 2 
3                         4 
17. Have you had diarrhea?  
 1        
 2 
3                         4 
18. Were you tired? 
 1        
 2 
3                         4 
19. Did pain interfere with your daily 
activities?  
 1        
 2 
3                         4 
20. Have you had difficulty in 
concentrating on things, like reading a 
newspaper or watching television? 
 
 1        
 2 
3                         4 
21. Did you feel tense? 
 1        
 2 
3                         4 
22. Did you worry? 
 1        
 2 
3                         4 
23. Did you feel irritable?  
 1        
 2 
3                         4 
24. Did you feel depressed? 
 1        
 2 
3                         4 


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Not  
A little 
Quite  
Very 
at all 
a bit 
much 
25. Have you had difficulty remembering 
things? 
 1        
 2 
3                         4 
26. Has your physical condition or medical 
treatment interfered with your family 
life? 
 
 1        
 2 
3                         4 
27. Has your physical condition or medical 
treatment interfered with your social 
activities? 
 
 1        
 2 
3                         4 
28. Has your physical condition or medical 
treatment caused you financial 
difficulties? 
 
 1        
 2 
3                         4 
For the following questions please circle the number between 1 and 7 that best applies to you 
 
Very poor 
Excellent 
29. How would you rate your overall 
health during the past week? 
1            2            3            4            5           6            7 
30. How would you rate your overall 
quality of life during the past week? 
1            2            3            4            5           6            7 
 
 


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13.4.2 EORTC QLQ-BIL21 
During the past week: 
Not  
A little 
Quite  
Very 
at all 
a bit 
much 
31. Have you had trouble with eating? 
 1        
 2 
3                         4 
32. Have you felt full up too quickly after 
beginning to eat? 
 1        
 2 
3                         4 
33. Have you had problems with your 
sense of taste? 
 1        
 2 
3                         4 
34. Were you restricted in the types of 
food you can eat as a result of your 
disease or treatment? 
 
 1        
 2 
3                         4 
35. Have your skin or eyes been yellow 
(jaundiced)? 
 1        
 2 
3                         4 
36. Have you had itching? 
 1        
 2 
3                         4 
37. Have you been worried about your skin 
being yellow? 
 1        
 2 
3                         4 
38. Have you been less active than you 
would like to be? 
 1        
 2 
3                         4 
39. Have you felt "slowed down"? 
 1        
 2 
3                         4 
40. Have you felt lacking in energy? 
 1        
 2 
3                         4 
41. Did you have pain during the night? 
 1        
 2 
3                         4 
42. Have you had pain in your stomach 
area? 
 1        
 2 
3                         4 


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During the past week: 
Not  
A little 
Quite  
Very 
at all 
a bit 
much 
43. Have you had pain in your back? 
 1        
 2 
3                         4 
44. Did you have a bloated feeling in your 
abdomen? 
 1        
 2 
3                         4 
45. Have you felt stressed? 
 1        
 2 
3                         4 
46. Have you felt less able to enjoy 
yourself? 
 1        
 2 
3                         4 
47. Have you worried about your health in 
the future? 
 1        
 2 
3                         4 
48. Were you worried about your family in 
the future? 
 1        
 2 
3                         4 
49. To what extent have you been troubled 
with side-effects from your treatment? 
 1        
 2 
3                         4 
50. Have you had difficulties with drainage 
tubes/bags? 
 1        
 2 
3                         4 
51. Have you worried about losing weight? 
 1        
 2 
3                         4 
 
 


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13.5 Appendix E: Protocol Amendments 
The changes made in the amended protocol have been detailed below. The newly added text 
has been presented in bold whereas the text that has been removed has been marked as 
strikethrough.  
Versio
n 
Date 
Changes 
Version
 1.0 
30 Au
g 2018 
Original Protocol 
Version
 2.0 
Global 
Amend
ment 1 
04 Dec 
2019 
Principal/Coordinating Investigator 
Deleted ‘Europe’ from Dr Trojan’s signature page ie, “Principal/Coordinating 
Investigator (Europe)” 
Removed principal/coordinating investigator signature page for North America: 
 
 
Investigator’s declaration page 
Added information that protocol changes may also require approval by regulatory 
authorities (not only CEC/IRB) as per request from Swedish Medical Products Agency. 
Removed the country name ‘Europe’ from the ‘Declaration of Investigator’ ie, Signature 
of Principal Investigator (Europe) and Printed Name of Principal Investigator (Europe). 
Removed ‘Declaration of Investigator’ page for Principal Investigator in North America. 
 
 
Summary of Changes 
Protocol Amendment History and Reasons for Amendment 
Table added to present an overview of rationale for the changes made in the amended 
protocol. 


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Versio
n 
Date 
Changes 
 
 
List of Abbreviations 
 
 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CA-125 
cancer antigen 125 
CI 
confidence interval 
CRC 
Cohort Review Committee 
EDC 
electronic data capture 
EDTA 
ethylenediamine tetraacetic acid 
FSH 
follicle-stimulating hormone 
HNSCC 
head and neck squamous cell carcinoma 
HUS 
haemolytic uraemic syndrome 
KM 
Kaplan-Meier 
NCI 
National Cancer Institute 
PD 
progressive disease 
PRES 
posterior reversible encephalopathy 
syndrome 
PSC 
primary sclerosing cholangitis 
PTC 
percutaneous transhepatic cholangiography 
RP2D 
recommended Phase 2 dose 
SLT 
schedule-limiting toxicity 
SmPC 
summary of product characteristics 
TEAE 
treatment-emergent AE 
WOCBP 
women of childbearing potential 
 
 
Section 2.3, Exploratory Objectives 
2. To explore changes in standard tumour markers and exploratory tumour 
biomarkers for the assessment of their diagnostic and prognostic relevance in the 
disease, and for the treatment itself. 
 
 
Section 3.1, Study Design 


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Versio
n 
Date 
Changes 
Updated Figure 1 (Overall Study Design) to revise the stratification factors at 
randomisation from: 
i) presence or absence of measurable/non-measurable disease at baseline and ii) ECOG 
performance status (0 vs 1)  
to 
i) presence or absence of measurable/non-measurable disease at baseline and ii) presence 
or absence of hepatic metastases 
 
 
Section 3.2, Treatment Assignment 
Patients will be stratified at randomisation according to whether they have any 
measurable disease at baseline (as assessed by the Investigator) versus no measurable 
disease, and according to Eastern Cooperative Oncology Group (ECOG) performance 
status (0 or 1) presence or absence of hepatic metastases. Patients with any 
measurable disease must have at least 1 measurable lesion (bile duct or liver). It is 
expected that approximately two-thirds of patients will have measurable disease at 
baseline. 
 
 
Section 3.2.1, Arm A 
“Cycles 2 to 4: Gemcitabine/cisplatin will be administered on Days 1 and 8. In Cycle 4, 
a second dose of Amphinex will be administered on Day 18 (4 days prior to Day 1 of 
Cycle 5).” 
Was split into: 
“Cycles 2 to 3: Gemcitabline/cisplatin will be administered on Days 1 and 8. 
Cycle 4: Gemcitabine/cisplatin will be administered on Days 1 and 8. In Cycle 4, 
A second dose of Amphinex will be administered on Day 18 (4 days prior to Day 1 of 
Cycle 5).” 


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Versio
n 
Date 
Changes 
 
 
Section 3.2.1, Arm A 
Added the following text under Cycles 6 to 8:  
Patient-related factors may demand postponement of the second PCI treatment to 
Cycle 6, 7 or 8. Please see Section 3.3.2 for more detailed information. 
It is expected that all patients in Arm A will be hospitalised for one night after the 
endoscopic retrograde cholangio-pancreatography (ERCP)/laser light applications 
on Day 1 of Cycle 1 and on Day 1 of Cycle 5.  
For some patients, 1 to 3 days of hospitalisation after Amphinex administration 
may be required to ensure adequate initial protection from light. This will be at the 
Investigator’s discretion, as it could depend on factors such as time of year and 
weather conditions (risk of inadvertent exposure to sunshine or bright daylight) or 
the patient’s disposition and ability to comply with light protection guidance, travel 
distance, etc. 
 
 
Section 3.3.1, Stent Placement 
Biliary stenting is to be performed on all patients according to local practice; however, 
the chosen stent must be of an exchangeable (plastic) type throughout the active 
treatment period of the study until radiological progression. Stenting is to may be 
performed at any time from confirmation of histological/cytological diagnosis until the 
day of Cycle 1 Day 1 (immediately after the first laser light application, for patients in 
Arm A). Patients who have already undergone stenting before screening should be 
reviewed to ensure the stent is of an acceptable type, correctly positioned and adequate 
liver drainage confirmed. Stents will must be removed before for the laser light 
application procedure, and a new plastic stents will be inserted after stent must be 
placed immediately after light application. Stent removal, laser light application, 
and stent replacement will take place during the same ERCP procedure. 
Refer to the Procedure Manual for a description of the stenting procedure and potential 
variations. At least 50% of liver volume should be drained. Allowing for pathological 
changes with atrophy of chronically obstructed segments, this effectively means 2 of 3 
sectors (ie, either all of the right or left liver lobe and either anterior or posterior sector 
of right liver lobe). This may require a combination of percutaneous transhepatic 
cholangiography (PTC) biliary drainage and endoscopic retrograde cholangio-
pancreatography (ERCP) drainage but is optimally achieved by ERCP endoscopic 
drainage. 
 
 
Section 3.3.2, Arm A, Second PCI Treatment 
Added the following text:  
The second PCI treatment may be postponed if: 
• 
In the opinion of the Investigator, the single dose of gemcitabine cannot be 
given at the full 1000 mg/m2 dose due to residual toxicity 
• 
In the view of the Investigator there is evidence of ongoing inflammation 
within the PCI illumination area 
• 
In the opinion of the Investigator, the patient shows significant signs of 
photosensitivity 


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• 
If one of the following criteria is present: 
o 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
or alkaline phosphatase (ALP) >5 × the upper limit of normal (ULN) 
o 
ALT or AST or ALP >3 × ULN with the appearance of symptoms 
associated with a clinical diagnosis of hepatitis including right upper 
quadrant pain or tenderness, fever, rash or eosinophilia (>5%) 
o 
ALT or AST >3 × ULN and total bilirubin >2.5 × ULN or 
international normalised ratio >1.51 or other evidence of impairment 
to the synthesis function of the liver 
In contrast to postponing the second PCI, this treatment will not be given at all if 
any of the following criteria are fulfilled: 
• 
The patient experienced a PCI treatment-related schedule-limiting toxicity 
(SLT) defined as: 
o 
A clinically significant toxicity or abnormal laboratory value 
occurring after PCI treatment and during the first chemotherapy 
cycle, assessed as unrelated to the underlying disease, or concomitant 
medications, that is related to either PCI treatment or related to the 
combination of PCI treatment with the cisplatin/gemcitabine systemic 
chemotherapy and meets any of the following criteria, based on 
National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0: 
▪ 
Photosensitivity Grade 3 outside the treatment area, except for 
areas exposed for skin sensitivity tests and areas exposed for 
re-introduction to normal light (patient compliance with light 
protection guidelines MUST be followed; non-compliance will 
be taken into account when determining SLT) 
▪ 
Phototoxicity Grade 4 inside the treatment area (eg, duodenal 
ulceration) 
▪ 
Non-haematological toxicity (excluding nausea and vomiting) 
≥Grade 3 
▪ 
Neutropenia or thrombocytopenia Grade 4 
▪ 
All other Grade 3 toxicities that are clinically unexpected and 
considered related to the PCI treatment 


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▪ 
The patient is expected not to be able to receive the single dose 
of gemcitabine at a dose of 1000 mg/m2 at any time 
Furthermore, if the patient clearly displays poor tolerability of the first is unwilling to 
undergo a second PCI treatment, the second PCI should can be omitted., however, the 
patient can continue to receive the gemcitabine/cisplatin standard combination 
chemotherapy. 
If treatment is delayed, computed tomography (CT)/magnetic resonance imaging (MRI) 
scans should still be conducted at the scheduled time point relative to randomisation. 
This is to avoid the risk of a difference between arms in the primary endpoint of PFS 
that can be attributed to changes in scanning frequency rather than treatment. 
The second PCI treatment will continue to be included in the Arm A treatment schedule 
only if the first PCI treatment is found to be tolerable and recommended to be continued 
by an Independent Data Monitoring Committee (IDMC) based on an initial safety 
review of the first 8 patients treated with 2 PCI treatments; otherwise, only a single PCI 
administration schedule integrated in Cycle 1 will be employed. 
In patients still in the study (ie, not formally discontinued or withdrawn), the reason(s) 
for delays, postponement, or omitting of the second PCI must be documented and 
recorded in the electronic case report form (eCRF). 
Patients should continue their randomised chemotherapy treatment until a 
maximum of 8 systemic gemcitabine/cisplatin cycles or RECIST 1.1-defined 
progression or until a treatment discontinuation criterion is met. 
1 Unless on anti-coagulants 
 
 
Section 3.3.3, Arm B 
Patients in both arms should continue their randomised chemotherapy treatment until a 
maximum of 8 systemic gemcitabine/cisplatin cycles or RECIST 1.1-defined 
progression or until a treatment discontinuation criterion is met. 
 
 
Section 3.4.1, Rationale for Patient Population 
Thus, it is proposed that PCI of gemcitabine complemented by gemcitabine/cisplatin 
chemotherapy in patients with advanced inoperable extrahepatic CCA should 
demonstrate and advantage in this subset of patients. 


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Section 3.4.3, Clinical Precedence 
Fimaporfin has been evaluated in 3 cancer studies to date: 1 completed study and 1 
terminated study with fimaporfin-induced PCI of bleomycin, and one ongoing study 
with fimaporfin-induced PCI of gemcitabine. As of June 2018 September 2019, 68 69 
patients have received fimaporfin; 46 with bleomycin and 2223 with gemcitabine. 
TwelveThirteen patients have received fimaporfin-induced PCI of gemcitabine at the 
recommended Phase 2 dose (RP2D), established as 0.22 mg/kg fimaporfin (equivalent to 
0.25 mg/kg fimaporfin di-olamine) and 30 J/cm light dose. 
The third study, PCIA 202/12 is a currently-ongoing Phase 1/2 study to assess the safety, 
tolerability and efficacy of fimaporfin-induced PCI of gemcitabine followed by 
gemcitabine/cisplatin chemotherapy in patients with advanced inoperable CCA. 
Enrollment into the study has been completed. 
To date, 16Sixteen patients have been treated in the completed single-arm dose 
escalation part (Phase 1) of the study. 
Seven patients have been enrolled in the extended Phase 1 part, with the objective 
of determining safety and tolerability of a two-dose regimen of PCI treatment. A 
total of 5 patients underwent the 2 PCI treatment procedures and completed the 
required 21-day safety window following the second procedure as per protocol. All 
SLT criteria were assessed and it was concluded that no SLTs were reported in the 
5 eligible patients who completed both PCI procedures. The Cohort Review 
Committee (CRC) concluded that the procedure was tolerable based on the fact 
that no SLTs were observed in the 5 eligible patients. Study enrolment was 
therefore closed. 
Cholangitis is the SAE most frequently reported from the ongoing study with 
fimaporfin-induced PCI of gemcitabine. Fifteen Nine patients have experienced SAEs 
of hepatobiliary disorders: cholestasis (2 events) biliary sepsis with liver abscess (1 
event), and cholangitis (632 events). The rates of cholangitis seen in the ongoing study 
PCIA 202/12, are similar to those seen in published Bismuth III and IV hilar CCA 
endoscopic procedure studies (Pisello et al 2009; Talreja et al 2013). Furthermore, there 
was no temporal association between the PCI treatment and these events. 
Six patients have been enrolled to date in the ongoing extended Phase 1 part, with the 
objective of determining safety and tolerability of a two-dosing regimen of PCI 
treatment. Six to 12 patients will be treated in this part, and the results were intended to 
inform the dosing schedule to be selected for Phase 2. 
Encouraging preliminary signs of efficacy have been seen in the Phase 1 dose escalation 
part of the study. A Based on evaluation of 6-month radiology data from patients 
treated in Cohorts 3 and 4, a response rate (complete response [CR] + partial response 
[PR]) of 4050% has been observed in the 10 patients treated in Cohorts 3 and 4 (5763% 
if based on the 78 patients with measurable disease at baseline) and the interim average 
OS of all 16 patients was 18.519.5 months in August 2018July 2019. 
 
 
Section 3.4.4, Rationale for Dose 
In terms of safety, Amphinex has been well-tolerated in doses up to the maximum 
tolerated dose of 0.87 mg/kg as established in the Phase 1 study PCI 101/06 and as 
shown by the absence of dose-limiting toxicities in the Phase 1 dose escalation of the 
ongoing study PCIA 202/12 in CCA. Overall, Amphinex shows a suitable safety and 
tolerability profile for the treatment of advanced CCA. Based on the limited 
available data, no clear dose-dependency relationship has been observed for safety. 


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Clear evidence of efficacy has been seen at several doses evaluated for efficacy so 
far, as manifested by rapid responses. 
The PCI treatment with Amphinex in combination with chemotherapeutic 
substances bleomycin and gemcitabine has been shown to be tolerated in preclinical 
and clinical studies. In the completed Phase 1 studies in patients with local 
recurrent or advanced/metastatic subcutaneous and cutaneous malignancies (PCI 
101/06 and PCI 101/06 Extension), Amphinex was given in combination with a 
fixed dose of bleomycin and laser light. Amphinex doses between 0.11 and 
0.87 mg/kg were well-tolerated, and doses between 0.22 and 1.3 mg/kg showed early 
signs of efficacy. In the Phase 2 study of Amphinex in combination with bleomycin 
and laser light in patients with recurrent HNSCC (PCIA 202/10), an Amphinex 
dose of 0.22 mg/kg was given with a fixed dose of bleomycin and varying light 
doses. Preliminary signs of efficacy were shown in patients receiving superficial 
light application. 
The Phase 1 dose escalation part of the ongoing study PCIA 202/12 in patients with 
advanced CCA has been completed with good tolerability and promising early 
signs of efficacy. In total, 16 patients have been treated, 13 males and 3 females, in 4 
cohorts (see Section 3.4.3). For the PCI treatment, all patients received the 
standard gemcitabine dose of 1000 mg/m2. 
Fourteen of the 16 enrolled patients completed the safety evaluation window and no 
dose-limiting toxicities or other safety concerns were reported. The Amphinex dose 
administered in Cohorts 1 and 2 was regarded too low for achieving tumour effects. 
An evaluation of 6 months radiology data from patients treated in Cohorts 3 and 4 
concluded that a total of 7 patients had radiologically evaluable cancer and 5 of 
these had objective tumour response, of which 2 were CRs. Specifically, of the 3 
evaluable patients in Cohort 3, the radiology evaluation concluded that there were 
1 CR, 1 PR, and 1 stable disease (SD) at 6 months after the PCI treatment. In 
Cohort 4, there were 1 CR, 2 PR and 1 progressive disease. 
A proposal to proceed to Phase 2 with the highest dose of Amphinex and light 
applied in Phase 1 of PCIA 202/12, as well as the standard gemcitabine dose of 1000 
mg/m2, is based on these early promising signs of tumour response in the last dose 
cohorts, combined with experience from the previous clinical studies with 
Amphinex. 
Based upon assessment of cumulative safety data, a dose of 0.22 mg/kg Amphinex 
and intraluminal light dose of 30 J/cm with the standard gemcitabine dose (1000 
mg/m2) were selected as safe and tolerable. 
Photochemical dose (light and photosensitiser): The light dose is based on both the 
data from the Phase 1 study in CCA (PCIA 202/12) and from the clinical 
experience from the study in HNSCC (PCIA 202/10). In HNSCC, a higher light 
dose of 60 J/cm was associated with serious local adverse reactions. In the Phase 1 
dose escalation part of study PCIA 202/12, several combinations of fimaporfin and 
light doses were tested (see Section 3.4.3). However, the 2 lower photochemical 
doses were regarded too low for achieving tumour effects. Therefore, a light dose of 
30 J/cm combined with 0.22 mg/kg Amphinex dose was chosen. 
 
 
Section 3.4.5, Rationale for Treatment Regimen 
A single treatment schedule of Amphinex-induced PCI of gemcitabine has been 
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1 dose escalation part of study PCIA 202/12. This has raised the question as to 
whether a 2-administration schedule would increase the clinical effectiveness of 
Amphinex-induced PCI of gemcitabine by further treating any residual tumour 
while maintaining the tolerability profile. 
During the extended part of Phase 1 in study PCIA 202/12, the 2-administration 
schedule will be considered non-tolerated if 2 or more of the first 6 evaluable 
patients experience an SLT. If none or 1 of the first 6 evaluable patients experience 
an SLT (see definition in Section 3.3.2), the 2-administration schedule will be 
considered tolerated. 
A total of 5 patients underwent the 2 PCI treatment procedures and completed the 
required 21-day safety window following the second procedure as per protocol. All 
SLT criteria were assessed and it was concluded that no SLTs were reported in 
these 5 eligible patients who completed both PCI procedures. The CRC concluded 
that the procedure was tolerable based on the fact that no SLTs were observed in 
the 5 eligible patients. Therefore, the 2-administration schedule can be considered 
tolerated. 
Based on results from studies PCI 101/06 and PCIA 202/10, the plasma half-life of 
fimaporfin in Amphinex is 15 to 22 days; therefore, the separation between the first 
and second Amphinex dose would be almost 4 half-lives, minimising the risk of 
accumulation and additional toxicity. 
Preliminary results from study PCIA 202/12 show that there is greater variation in 
half-life values, ranging from 21 to 93 days; however, as reported above, there were 
no SLTs reported in any of the 5 patients who received a second administration. 
Therefore, even if there is some accumulation of fimaporfin, it is not considered to 
be a safety issue that would affect the timing between the first and second 
administration. If, in the opinion of the Investigator, the patient shows significant 
signs of photosensitivity, the second administration can be postponed. 
In this study PCIA 203/18, an IDMC will be convened to perform periodic reviews 
of accumulating safety data, with focus on biliary tract events which are defined as 
AEs of special interest (AESIs). The study will include an initial safety review by 
the IDMC after the initial 8 patients in Arm A have been administered 2 PCI 
treatments and followed up for 21 days. The IDMC will assess whether the second 
PCI treatment during the chemotherapy period should continue to be administered 
for future patients randomised to Arm A. 
 
 
Section 3.4.6, Benefit/Risk and Ethical Assessment 
In the Phase 2 study PCIA 202/10 (HNSCC), there were cases of local tissue loss in 
patients who received interstitial PCI with bleomycin for glossal and floor of mouth 
tumours. 
In the on-going ongoing study PCIA 202/12 in patients with CCA, only one light fibre is 
used for the intraluminal application. The fibre is manipulated within an ERCP catheter 
to ensure full coverage of the area to be treated lesion, which may be longer than the 
cylindrical light diffuser that provides the laser light illumination. 
The decision to add a second PCI treatment was based on safety and efficacy findings 
from the Phase 1 dose escalation phase and extended part of the study PCIA 202/12 in 
which a repeat PCI treatment using the same dose (fimaporfin dose of 0.22 mg/kg and a 
light dose of 30 J/cm) was found safe. 


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Section 4.1, Selection of Study Population 
Approximately 186 patients with inoperable CCA will be enrolled at approximately 
4050 sites in Asia, Europe and North America and Europe. 
 
 
Section 4.1.1, Inclusion Criteria 
3. 
Histopathologically/cytologically (C5) verified adenocarcinoma consistent with 
CCA; Cholangiocarcinoma verified as adenocarcinoma by histopathology or 
cytology (C5) with a perihilar or distal stenosis that has been stented or will 
require stenting, and that is accessible for PCI light treatment; 
4. 
Cholangiocarcinoma must be considered inoperable with respect to radical 
resection (including partial liver resection or liver transplantation); 
5. 
At least 1 radiologically evaluable lesion (measurable and/or non-measurable but 
evaluable) that can be accurately assessed at baseline and is suitable for repeated 
radiological evaluation 
6. 
If metastatic, metastases disease, metastasis must be limited to the liver 
parenchyma only and/or restricted only to the local lymph nodes with peritoneal 
engagement locally (within close proximity to the hepatoduodenal ligament;); 
7. 
Biliary lesion causing bile obstruction that requires stenting and is accessible for 
PCI light treatment; 
 
 
Section 4.1.2, Exclusion Criteria 
1. 
Previously received any prior anti-tumour (either local or systemic) treatment for 
CCA; 
3. 
A history of frequently recurring septic biliary events caused by non-
malignant strictures (primary sclerosing cholangitis [PSC], autoimmune 
hepatitis or advanced chronic liver dysfunction); 
7. 
Currently participating in in any other interventional clinical trialstudy; 
11. Known allergy or sensitivity to photosensitisers, (the active substance and/or any 
of the excipients); or chronic use of other photosensitising therapies 
(Section 5.5.3); treatment with amiodarone during the last 12 months; 
19. Male patients unwilling to use highly effective contraception or female patients 
women of childbearing potential (WOCBP) (see definition in Section 5.6) 
unwilling to use a highly effective form of contraception such as the following: 
o 
Hormonal contraceptivesCombined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation2 (oral, 
intravaginal and transdermal) 
o 
Progestogen-only hormonal contraception associated with inhibition of 
ovulation2 (oral, injectable, or patchesimplantable) 
o 
Intrauterine devices (hormonal-eluting or not) 
o 
Intrauterine hormone-releasing system 
o 
Bilateral tubal ligation 
o 
Vasectomised partner3 (Section 5.6) 


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o 
Male sterilisation 
o 
Double-barrier (condoms with spermicide) 
o 
Sexual abstinence4 
Patients must continue the use of contraception during PCI treatment and subsequent 
chemotherapy, and for at least 69 months thereafter after last dose of Amphinex or 6 
months after last dose of chemotherapy, whichever is the latest. 
 
Footnotes: 
2 Hormonal contraception may be susceptible to interaction with the investigational 
medicinal product, which may reduce the efficacy of the contraception method. 
3 Vasectomised partner is a highly effective birth control method only if the partner 
is the sole sexual partner of the WOCBP study participant and if the vasectomised 
partner has received medical assessment of the surgical success. 
4 Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the clinical study and the preferred and usual lifestyle 
of the patient. 
23. Inadequate renal function, defined as creatinine clearance <60 mL/min or <45 
mL/min as determined by local practice for patients on fractionated platinum-based 
chemotherapy. Patients with creatinine clearance <60 mL/min must not be 
included. 
 
 
Section 4.2.1, Discontinuation From Study Treatment 
In addition, a patient may be discontinued from study treatment in any of the following 
situations:  
• 
Severe non-compliance to study protocol 
• 
Incorrect enrolment and randomisation 
• 
Progressive disease  
• 
Development of toxicity  
o 
Arm A patients after first PCI treatment: the development of toxicity, 
which precludes further treatment with both: 
▪ 
PCI treatment, see SLT definition in Section 3.3.2 and 
▪ 
standard gemcitabine/cisplatin combination chemotherapy, as per 
local practice 


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Note: If a patient no longer can receive PCI treatment due to 
toxicity but can continue on the standard gemcitabine/cisplatin 
combination chemotherapy, or vice versa, then the patient will not 
be considered as discontinued from treatment. 
o 
Arm A patients after second PCI treatment and Arm B patients: the 
development of toxicity, which precludes further treatment with 
standard gemcitabine/cisplatin combination chemotherapy, as per local 
practice 
• 
Patient refusal to receive further study treatment 
 
Note: If a patient no longer wishes to receive PCI treatment but can 
continue on the standard gemcitabine/cisplatin combination chemotherapy, 
or vice versa, then the patient will not be considered as discontinued from 
treatment. 
• 
Lost to follow-up 
• 
Intercurrent illness precluding further study treatment 
• 
Pregnancy 
• 
Any other reasons not listed above as per Investigator discretion 
The reason for treatment discontinuation must be adequately documented and recorded 
in the eCRF. 
 
 
Section 4.2.2, Withdrawal From Study 
Further, a patient will be withdrawn from the study in any of the following situations:  
• 
Patient is lost to follow-up 
• 
Patient decides to withdraw consent from participating in the study 
• 
Screen failure 
• 
Study terminated by Sponsor 
• 
Other 
The reason for withdrawal from the study must be adequately documented and 
recorded inon the eCRF. 
 
 
Section 4.2.3, Handling of Discontinuations/Withdrawals 
Added the text: 
All randomised patients will be included in the primary Intent-to-Treat (ITT) 
analysis set regardless of treatment received. 


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Section 4.2.4, Replacements 
Randomised patients who discontinue treatment or withdraw from the study will not 
be replaced. If a randomised patient is withdrawn, the patient identifier number 
will not be reused. 
All randomised patients must be included in the primary analysis under the 
principles of ITT and therefore collection of follow-up data for patients who 
discontinue is important. 
 
 
Section 5.1, Method of Assigning Patients to Treatment Arms 
The randomisation will be stratified by 2 factors: any measurable disease at baseline 
(yes versus no) and ECOG performance status (0 or 1) presence or absence of hepatic 
metastases. 
Approximately 186 patients will be enrolled at approximately 4050 sites and randomised 
in a 1:1 ratio (fimaporfin-induced PCI of gemcitabine complemented by 
gemcitabine/cisplatin chemotherapy versus gemcitabine/cisplatin chemotherapy alone). 
If a randomised patient is withdrawn and replaced, the patient identifier number will not 
be reused. 
 
 
Section 5.2, Identity of Investigational Products/Background Treatment 
A single PCI treatment consists of IV administration of Amphinex solution for injection 
(dose 0.25 mg/kg fimaporfin-di-olamine, equivalent to 0.22 mg/kg fimaporfin), followed 
4 days later by gemicitabine IV infusion (1000 mg/m2) and intraluminal laser light 
application (light dose 30 J/cm). As gemcitabine Gemcitabine is currently not licensed 
for the treatment of patients with advanced inoperable CCA, gemcitabine used in 
combination with Amphinex for PCI treatment will be treated as an investigational 
product. 
 
 
Section 5.2.1.1, Fimaporfin-Associated Photosensitivity 
All patients who receive Amphinex (fimaporfin) are expected to become temporarily 
photosensitive and must take precautions to protect skin and eyes in order to 
prevent photosensitivity reactions. A gradual return to normal light conditions is 
required. Luxmeters will be provided to the patients to enable them to measure 
light in their surroundings and to guide the gradual increase in exposure. The 
duration and degree of photosensitivity varies between patients, and patients must be 
encouraged to follow guidance and test for skin sensitivity. 
• 
As some pulse oximeters produce red light of a wavelength close to 652 nm, 
oximeters must be repositioned at least every 10 to 15 minutes to avoid the risk 
of local skin burns. Any non-compliance with regard to light protection should 
be adequately documented and recorded in the eCRF. 


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For at least 4 weeks following Amphinex injection, precautions must be taken to avoid 
exposure of skin and eyes to direct sunlight or bright indoor light. Procedures for gradual 
re-introduction to light are provided in Table 1. Investigator must inform the patient of 
these procedures and document this counselling in the eCRF. In addition, all patients 
who receive Amphinex will receive a patient leaflet with information on how to 
protect from light, how to test for light sensitivity, and how to gradually increase 
exposure to light. 
Table 1, Precautions for the Prevention of Skin and Eye Photosensitivity Reactions 
Time after Amphinex 
(fimaporfin) injection 
Precautions to prevent skin and eye photosensitivity 
reactions 
Patients should be made aware that there can be marked variation in sensitivity 
and duration of sensitivity between people. 
Day 1 
(0–24 hours) 
Patients should avoid direct exposure of eyes to any 
light sources and avoid exposure to direct and indirect 
daylight exposure. 
• 
The patient should stay indoors with low intensity 
(dim) indoor light (max 100 lux). 
• 
Patients should avoid watching television or using 
computers, tablets, or smart phones.  
• 
To avoid exposure to daylight from the window, 
curtains and blinds should be closed.  
Lighting choice: warm white light bulbs (not more 
than 800 lumen: max 60W tungsten filament warm 
light bulb, 13W energy saver, or 6W LED) 
First 2 Weeks Day 2-7: 
 
Indoors: Patients should avoid direct daylight coming 
through the window or direct light from household 
appliances such as reading lamps.  
Beginning at 100 lux on Day 1, patients may gradually 
return to normal indoor lighting by a stepwise increase 
in the light (by of 100 lux per day), to reach 700 lux by 
Day 7. 
Outdoors: Patients may go outdoors after dusk.  
If it is absolutely necessary need to go outdoors travel 
during the hours of daylight day, such as to hospital 
appointments, the patient must sit away from 
windows and cover all skin including face and hands, 
and wear the dark glasses provided by Sponsor.  
The type of clothes the patient must wear are: 
• 
Wide-brimmed hat: for head, neck, face, nose 
and ears 


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• 
Scarf: for head and neck 
• 
Dark glasses with side panels provided by 
Sponsor: for eyes and skin around eyes  
• 
Long sleeved top: for upper body/arms 
• 
Long trousers: for lower body/legs 
• 
Gloves: for hands, wrist and fingers 
• 
Socks: for feet and ankles 
• 
Closed shoes: for feet 
Skin photosensitivity reactions are caused by visible 
light. Sunscreens that protect from ultraviolet light will 
not protect from visible light. Dark, tightly woven 
clothing should be worn. Very thin clothing will not 
protect from strong light and dark, closely woven 
clothing should be worn. 
If exposed to excessive bright light, the patient may feel 
a burning sensation on the skin. The patient must then 
move away from the light source immediately, and. If a 
photosensitivity reaction develops, contact the 
Clinical Investigator for advice (see below).  
Day 8-15: 
 
Indoors: Patients should avoid direct daylight 
coming through the window or direct light from 
household appliances such as reading lamps.  
Continue to gradually return to normal indoor 
lighting by a stepwise increase in the light (by 
100 lux per day, ie, from 800 lux on Day 8 to 
1500 lux on Day 15). 
Outdoors: Patients may go outdoors but only if it is 
cloudy, shaded and not sunny.  
If need to travel during the day, such as to hospital 
appointments, the patient must sit away from 
windows and cover all skin including face and 
hands, and wear the dark glasses provided by 
Sponsor.  
 
Skin test: Patient should try cautious exposure only 
to back of hands over 5-15 minutes on non-sunny 
days. If any prickling or discomfort occurs then 
patient should stop exposure immediately, cover up 
and go indoors. 
If there is no reaction 24 hours later, patient can 
continue to extend and gradually build up exposure 
time. 
 
If exposed to excessive bright light, the patient may 


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feel a burning sensation on the skin. The patient 
must move away from the light source immediately. 
If a photosensitivity reaction develops, contact the 
Clinical Investigator for advice (see below).  
After 2 Weeks: 
 
A gradual increase in exposure to light should be 
encouraged, and the patient should continue to test for 
skin sensitivity photosensitivity as described above. If 
there are no reactions 24 hours after the exposure, 
the duration of light exposure can be increased by 
15 minutes per day. 
Indoors: gradually build up to normal levels of 
exposure. Patients should still take precautions to avoid 
exposure of skin to direct sunlight or bright indoor light 
for at least 4 weeks following administration of 
Amphinex. Eyes can remain sensitive to bright light for 
23 months. 
Outdoors: During the first days of outdoor exposure the 
patient should stay in shaded areas or go out only when 
cloudy. The patient should continue to wear dark 
glasses and dark, closely woven clothing tightly woven 
clothing. Two weeks after Amphinex injection, the 
patient should start to gradually return to normal 
levels of direct sunlight exposure. 
The patient’s eyes may also be very sensitive to bright 
light during the first 23 months; therefore, patients 
when outdoors the patient should continue to wear 
the dark glasses (provided by the Sponsor). 
If at any time the patient experiences a burning 
sensation symptoms – prickling, discomfort or skin 
reddening after exposure to sun, (s) redness – then 
he/she should wait for at least 2 days or until the 
reaction disappears, whichever is the later, before re-
exposing the skin to light.cover up and go indoors 
and let the symptom settle fully before repeating 
exposure. 


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Surgery: 
 
Surgery or dental treatment involving the use of light 
for visualisation or treatment should be avoided during 
the first 4 weeks following Amphinex administration, 
unless it is absolutely necessary and only if the 
potential benefits for the patient outweigh the risks. 
Direct illumination of the patient with the operating 
room lights, including the surgeon’s headlamp, should 
be avoided. If an acute surgical intervention is needed, 
yellow or green light should be used. Ideally this could 
come from a sodium lamp but it may be more practical 
to use green filters that absorb wavelengths that activate 
fimaporfin (around 415 nm and 652 nm, contact 
Sponsor for advice). All incisions should be shielded 
from light.  
Some pulse oximeters may produce red light of a 
wavelength close to that used for the photoactivation 
of fimaporfin. To avoid the risk of local skin burns, 
pulse oximeters must be repositioned every 10 
minutes and must not be used for longer than 
Testing for skin sensitivity 
After 2 weeks patients are advised to test their 
skin sensitivity by exposing the back of a hand to 
sunlight for a maximum of 5 minutes.  
Exposure should be stopped immediately if 
tingling, burning or stinging sensations occur in 
the exposed area.  
The patient should wait for 24 hours after the 
exposure to see any erythema, oedema, or 
blistering appears. If such reactions occur, the 
patient should contact the investigator 
immediately who will advise the patient. The 
patient should wait 2 days before repeating the 
test. If there is no reaction, the patient can go 
outdoors, but only for 15 minutes on the first 
day. If there are no reactions 24 hours after the 
first outdoor exposure, the duration of light 
exposure can be increased by 15 minutes per 
day. 


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needed. 
Up to 3 Months: 
For at least 3 months following PCI treatment: 
Eye tests that use bright lights should be avoided. 
Patients should contact their Investigator if eye tests 
using bright light are planned.  
Patients should avoid ultraviolet tanning beds and 
should not sunbathe. 
After 3 Months 
Some patients may experience photosensitivity 
reactions beyond 3 months. Hence, the precautionary 
measures may be required for longer. 
Liver or renal impairment may prolong the elimination 
of fimaporfin, requiring longer periods of light 
protection. 
Patients should continue to test for photosensitivity 
periodically as described above until such time that no 
reactions are observed. 
Treatment of 
photosensitivity 
reactions 
If patients experience skin photosensitivity 
reactions, they can be treated in the same way as 
sunburn: Use of cooling emollients, skin moisturiser, 
topical corticosteroids. Analgesics can be considered 
for symptomatic relief. Extra care must be taken to 
protect skin while it heals. 
 
 
Section 5.2.5, Light Source 
A fibre-optic cylindrical light diffuser is connected to the laser system, and inserted into 
an ERCP or PTCpercutaneous transhepatic cholangiography catheter during laser 
light application. The monitor will verify that the laser light application procedure is 
correctly documented and recorded in the eCRF. Laser light source handling is 
performed according to the laser system Instructions for Use. Performance of the laser 
system after treatment of each patient must be adequately documented and recorded in 
the eCRF (did the laser system perform as intended? yes/no). Operators should adhere to 
safety instructions provided.  
Access routes to the biliary system in the study can be through the percutaneous 
transhepatic approach or by the endoscopic retrograde transpapillary approach. 
The procedure will be performed in accordance with local practice with adequate 
analgesic cover. Under fluoroscopic guidance a translucent ERCP catheter will be 
advanced into the stenosis. Placement of the cylindrical light applicator fibres and light 
application will be performed in accordance with local practices with adequate analgesic 
coverdiffuser inside the ERCP catheter, both of which will be provided by the 
Sponsor, is described in the Procedure Manual. The entire stenosis should be 
illuminated. 
 
 
Section 5.2.6, Dose Modification 
5.2.6.1 Dose Modifications for Amphinex and PCI treatment 


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No dose modifications are allowed for Amphinex or gemcitabine given as part of 
the PCI treatment. See Section 3.3.2 regarding postponements or omissions of PCI 
treatment. 
5.2.6.2 Dose Modifications for Systemic Chemotherapy Cycles 
The investigator site is expected to follow local practice for dose modifications of 
the standard gemcitabine/cisplatin combination chemotherapy; however, the 
following information is provided for guidance. 
Haematological Toxicity 
The absolute neutrophil count must be ≥1,500 × 106/L and the platelet count must 
be ≥100,000 × 106/L in order to administer full doses of gemcitabine and cisplatin in 
combination. Patients should be monitored prior to each dose for platelet, leucocyte 
and granulocyte counts, and, if necessary, the dose of gemcitabine and cisplatin 
may be either reduced or withheld in the presence of haematological toxicity 
according to the following scale (Table 2). 
Table 2 Dose Modifications for Haematological Toxicities 
Day 1 
Absolute 
neutrophil 
count (× 106 /L) 
 
Platelet count  
(× 106 /L) 
Percent (%) of full 
dose gemcitabine 
Percent (%) of full 
dose cisplatin 
≥1,500 
and/or 
≥100,000 
100 
100 
≥500 - <1,000 
and/or 
≥50,000 - 
<100,000 
delay dose until 
recovery, then 75 
100 
<500 
and/or 
<50,000 
omit dose until 
recovery, then 75 
omit dose until 
recovery, then 75 
Day 8 
Absolute 
neutrophil 
count (× 106 /L) 
 
Platelet count  
(× 106 /L) 
Percent (%) of full 
dose gemcitabine 
Percent (%) of full 
dose cisplatin 
≥1,000 
and/or 
≥100,000 
100 
100 
≥500 - <1,000 
and/or 
≥50,000 - 
<100,000 
omit dose until 
recovery, then 75 
100 
<500 
and/or 
<50,000 
omit dose until 
recovery, then 75 
omit dose until 
recovery, then 75 
 


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Non-Haematological Toxicity 
Renal toxicity: The creatinine clearance must be ≥ 60 mL/min in order to 
administer the full dose of cisplatin. Serum creatinine should be checked before 
each cycle of treatment. If there is a >25% increase of serum creatinine compared 
to the baseline, then the ethylenediamine tetraacetic acid (EDTA) clearance (or 
equivalent) must be performed.  
Pulmonary toxicity: Transient dyspnoea occurs in <10% of patients after 
gemcitabine, secondary to mild bronchospasm. Rarely, more severe pulmonary 
toxicity characterised by tachypnoea, hypoxia diffuse interstitial infiltrates, acute 
respiratory distress syndrome and respiratory failure may also occur. The patient 
should be withdrawn from treatment. 
Table 3 Dose Modifications for Non-Haematological Toxicities 
 
Percent (%) of Full Dose 
Gemcitabine 
Percent (%) Full Dose 
Cisplatin 
Renal Function 
≥60 mL/min 
100 
100 
40–59 mL/min 
100 
50 
<40 mL/min 
Omit 
Omit 
Biliary Tract Obstruction 
Bilirubin >2.5 × ULN 
Omit 
Omit 
AST/ALT/ALP >5.0 × ULN 
Omit 
Omit 
Peripheral Neuropathy 
Grade 1–2 
100 
Delay until recovery, then 
100 
Grade 3–4 
100 
Discontinue 
Tinnitus 
If full recovery between cycles 
100 
100 
If no full recovery between cycles 
100 
Omit 
Lethargy 
Grade 3–4 
75 (if no response, stop 
treatment) 
100 
Oedema 
Grade 3–4  
75 (if no response, stop 
treatment) 
100 
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST; aspartate 
aminotransferase; ULN, upper limit of normal. 
 


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Gemcitabine-Specific Non-Haematological Toxicity 
Posterior Reversible Encephalopathy Syndrome: Reports of posterior reversible 
encephalopathy syndrome (PRES) with potentially severe consequences have been 
reported in patients receiving gemcitabine as a single agent or in combination with 
other chemotherapeutic agents. Acute hypertension and seizure activity were 
reported in most gemcitabine patients experiencing PRES, but other symptoms 
such as headache, lethargy, confusion and blindness could also be present. 
Diagnosis is optimally confirmed by MRI. Posterior reversible encephalopathy 
syndrome was typically reversible with appropriate supportive measures. 
Gemcitabine should be permanently discontinued and supportive measures 
implemented, including blood pressure control and anti-seizure therapy, if PRES 
develops during therapy. 
Haemolytic Uraemic Syndrome: Clinical findings consistent with the haemolytic 
uraemic syndrome (HUS) were rarely reported (post-marketing data) in patients 
receiving gemcitabine. Haemolytic uraemic syndrome is a potentially life-
threatening disorder. Gemcitabine should be discontinued at the first signs of any 
evidence of microangiopathic haemolytic anaemia, such as rapidly falling 
haemoglobin with concomitant thrombocytopenia, and/or elevation of serum 
bilirubin, serum creatinine, blood urea nitrogen or lactate dehydrogenase. Renal 
failure may not be reversible with discontinuation of therapy and dialysis may be 
required. 
 
 
Section 5.3.1, Study Drug Packaging and Storage 
The labels will comply with the legal requirements of the country. They will include 
storage conditions for the drug but no information about the study. 
 
 
Section 5.3.3, Other Supplies 
Added the text: 
Only the supplies provided by the Sponsor should be used. Additional items 
supplied by the Sponsor are described in the Procedure Manual and Laboratory 
Manual. 
 
 
Section 5.4, Treatment Compliance 
The details of the study treatment will be adequately documented and recorded in the 
eCRF and drug accountability forms as applicable. All study treatment-related 
procedures will be performed at the investigational site by qualified health care 
personnel. All instances of noncompliancenon-compliance and all resulting protocol 
deviations will be adequately documented and recorded in the eCRF. 
 
 
Section 5.4.1, Light Protection Compliance 
Investigators must counsel patients to observe light protection precautions described in 
Table 1 to prevent photosensitivity reactions. It should be adequately documented and 
recorded in the eCRF that the patient was thoroughly informed on the light protection 
precautions. Any non-compliance with regard to light protection should be adequately 
documented and recorded in the eCRF. 
 
 
Section 5.6, Contraception 
A woman is considered of childbearing potential (WOCBP), ie, fertile, following 
menarche and until becoming postmenopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and 


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bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 
months without an alternative medical cause. A high follicle-stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a postmenopausal 
state in women not using hormonal contraception or hormonal replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. A WOCBP must continue the use of contraception 
during treatment and until the end of relevant systemic exposure (at least 9 months 
after last dose of Amphinex or 6 months after last dose of chemotherapy, whichever 
is the latest). 
Only men with pregnant or non-pregnant partners considered of childbearing 
potential will need to follow contraception requirements. A condom is also required 
to be used by vasectomised men to prevent delivery of the drug via seminal fluid. 
As the treatment includes genotoxic investigational medicinal products, the male 
patient should use condoms during treatment and until the end of relevant systemic 
exposure in the male patient (at least 9 months after last dose of Amphinex or 6 
months after last dose of chemotherapy, whichever is the latest), plus a further 90 
days.  
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments. The reliability of sexual abstinence will need to be 
evaluated by site personnel in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the patient. 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method are not acceptable methods of contraception. Female condom and male 
condom should not be used together. 
 
 
Section 6.1.1, Tumour Assessment 
The study will evaluate tumour responses as determined by Investigator according to 
radiological (RECIST 1.1) and/or clinical assessment. Efficacy assessments of PFS, 
ORR, DoR, and DCR will be derived using Investigator RECIST 1.1 assessments and/or 
clinical assessment. Note: in cases of symptomatic progression, patients will 
continue to be followed for radiological RECIST progression. 
From the Investigator’s review of the imaging scans, the RECIST tumour response data 
will be used to determine each patient’s visit response according to RECIST v1.1. At 
each visit, patients will be programmatically assigned a RECIST v1.1 visit response of 
CR, PR, stable disease (SD), or progressive disease (for measurable/target lesions) or 
CR, progressive disease, or non-CR/non-PD (for non-measurable/non-target 
lesions) depending on the status of their disease compared with baseline and previous 
assessments. If a patient has had a tumour assessment which cannot be evaluated, the 
patient will be assigned a visit response of not evaluable unless there is any evidence of 
progression in which case the response will be assigned as progressive disease. 
Radiological assessments use images from contrast-enhanced CT or MRI scans, 
collected during screening/baseline and at regular follow-up intervals following study 
treatment. The RECIST 1.1 guidelines (link in Appendix C) provide a method of 
assessment of change in tumour burden in response to treatment. Screening/baseline 
imaging should be performed no more than 28 days before the start of study 
treatmentrandomisation. The RECIST 1.1 assessments of baseline images identify 


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target, (measurable), and non-target (non-measurable) lesions, and each lesion is 
evaluated in subsequent follow-up images (the same imaging modality and contrast 
protocol used at baseline must be used for all subsequent follow up imaging). This 
allows determination of follow-up target lesion response, non-target lesion response, and 
overall time point tumour responses (CR, PR, SD, non-CR/non-PD, progressive 
disease, or not evaluable). 
 
Table 5, Tumor Response Criteria for Target Lesions 
Stable Disease: Neither sufficient shrinkage to qualify for partial response nor sufficient 
increase to qualify for progressive disease, taking as reference the smallest sum of 
diameters since the treatment startedwhile on study. 
 
Table 6 Tumour Response Criteria for NontargetNon-target Lesions Outside of the 
Bone 
Response 
Evaluation of NontargetNon-target Lesions Outside of the Bone 
Complete Response 
Disappearance of all nontargetnon-target lesions. All lymph nodes should 
be non-pathological in size (<10 mm in the short axis) 
Non-CR/Non-PD 
Persistence of 1 or more nontargetnon-target lesion(s) 
Progressive Disease 
Appearance of 1 or more new lesionslesion(s) and/or unequivocal 
progression of existing nontargetnon-target lesions 
 
Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non measurable), a useful test that can be applied when 
assessing patients for unequivocal progression is to consider if the increase in 
overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare 
progressive disease for measurable disease, ie, an increase in tumour burden 
representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% 
increase in diameter in a measurable lesion) or an increase that is sufficient to 
require a change in therapy. 
If a patient has a response of SD or PR for target lesions, a modest ‘increase’ in size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. 
Tumour response will be assessed according to RECIST 1.1 every 12 weeks (±1 week), 
from randomisation until disease progression and should NOT follow delays incurred in 
the treatment period. Patients will be followed for objectiveradiological progression, 
regardless of whether they discontinue therapy or have symptomatic progression. 
The local radiological assessment will be used to guide clinical management decisions. 
The primary analysis of PFS and the secondary RECIST 1.1-based endpoints will also 
be based on the local radiological assessment. In addition, an independent central 
radiological review, blinded to the assessment of the local radiologist and/or oncologist, 
will be performed for the tumour response data. The data from the independent central 
reviewer(s) will provide data for the supportive/sensitivity analysis. 


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Survival follow-up phase 
Following discontinuation of randomised treatment, patients will be followed up for 
survival and information on any subsequent anti-cancer treatments as detailed in the 
study plan, unless they have withdrawn their consent. 
Additional survival contacts (ie, outside of the 12-weekly calls) may be conducted 
around the time of interim ORR analysis and final PFS analysis at data cut-off to ensure 
that the survival information is as up to date as possible for the analysis of OS. 
Determination of survival may be collected through publicly available death 
registry information, where permitted locally. 
 
 
Section 6.1.2, Biomarkers 
Section 6.1.2, Biomarkers was moved to Section 6.3, Biomarkers (and the existing 
Section 6.3, Exploratory Biomarkers became Section 6.3.2) and was amended as 
follows: 
Section 6.3 
Standard Tumour Markers and Exploratory Biomarkers 
Section 6.3.1 
CA-125, CA 19-9, and CEAStandard Tumour Markers 
The standard tumour markers cancer antigen 125 (CA-125), carbohydrate antigen 
19-9 (CA 19-9) and carcinoembryonic antigen (CEA) will be analysed from blood 
samples collected for safety laboratory assessments throughout the study. 
Section 6.3.2 
Exploratory Biomarkers 
Plasma and serumBlood samples (each 5ml20 mL) for exploratory biomarkers in 
plasma will be collected at baseline and at approximately 3-month intervals throughout 
the study. Samples will be banked for a collective post hoc analysis, enabling an 
evaluation of the relative importance and covariance of various biochemical changes to 
treatment outcome in the 2 study arms. As described in Section 6.3.1, traditional 
tumour diagnostic markers may exhibit low sensitivity and there is an urgent need 
for novel, more sensitive, and easy to detect biomarkers which can be used in 
cancer diagnosis and prognosis. For example, cell free nucleic acids such as 
microRNA (a type of small non-coding RNA molecule) may have a potential 
application as specific and sensitive biomarkers for clinical diagnosis or prognosis. 
As the study is well-sized in consideration of this rare cancer population, an exploratory 
assessment of changes over time and with treatment by multiplex analyses of genetic 
cancer pathways and immunological characteristics is highly motivated. In addition, in a 
subset of study sites with facilities and resources for the purpose, sampling for the 
characterisation of circulating cells (tumour and leukocyte subsets) will be collected and 
analysed in known and novel biomarkers over time, and with treatment, is highly 
motivated. 
 
 
Section 6.1.2, Quality of Life Measurements 
In this study, HRQoL will be measured by use of the European Organisation for 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 
and the EORTC QLQ-B21QLQ-BIL21 questionnaire (Appendix D). Patients will 
complete the questionnaires at the time points specified in Table 10, Table 11 and Table 
12, preferably before any other study assessments are performed. 
 
 
Section 6.2, Pharmacokinetic Assessments 
Blood samples (50 mL each 5 mL) for PK analysis will be collected into 
ethylenediamine tetraacetic acid (EDTA) collection tubes. 


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Section 6.4.1.4, Reporting Adverse Events 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs. These data will be captured as 
efficacy assessment data only. In most cases, the expected pattern of progression 
will be based on RECIST 1.1. In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration. However, every effort 
should be made to document progression through the use of objective criteria. If 
there is any uncertainty as to whether an event is due to disease progression, it 
should be reported as an AE. 
 
 
Section 6.4.1.5, Reporting Serious Adverse Events 
The investigator must report any Any AE that meets SAE criteria (Section 6.4.1.2) 
must be reported to PPD, Inc, using the electronic data capture (EDC) system, 
immediately (ie, within 24 hours) after the time the site personnel first learn about the 
event. 
 
 
Section 6.4.1.6, Suspected Unexpected Serious Adverse Reactions and Adverse 
Events of Special Interest 
The Sponsor will ensure that all relevant information about SUSARs that are fatal 
or life threatening is recorded and reported as soon as possible to the competent 
authorities in all the Member States concerned, and to the IECs/IRBs, and in any 
case no later than 7 calendar days after knowledge by the Sponsor of such a case, 
and that relevant follow-up information is subsequently communicated within an 
additional 8 calendar days. 
All other SUSARs will be reported to the competent authorities concerned in 
accordance with their specific requirement and to the IECs/IRBs concerned as soon 
as possible but within a maximum of 15 calendar days of first knowledge by the 
Sponsor. The Sponsor will also inform all Investigators. 
 
 
Section 6.4.1.7, Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the 
patient’s daily activities. The intensity of all AEs will be graded in accordance with the 
current version of NCI CTCAE version 4.03 or later. 
 
 
Section 6.4.3.1, Safety Laboratory Analysis 
Blood and urine samples will be collected at times specified in the schedule of events 
(Table 8 and Table 10, Table 10, Table 11 and Table 12) and sent to central a local 
laboratory for analysis.  
Added standard tumour markers (S – CA - 125, CA 19-9, CEA) to the list of 
laboratory variables that should be measured in the study. 
Updated footnote ‘a’: Serum creatinine should be checked before each cycle of 
treatment. If there is a >25% increase compared to the baseline then the 
ethylenediamine tetraacetic acid (EDTA) clearance or equivalent method must be 
performed and cisplatin dosing modified accordinglyCreatinine clearance will be 
calculated and checked before each cyclic chemotherapy treatment. 
Standard tumour markers will be analysed from serum samples collected for 
clinical chemistry. 
Additionally, a urine or blood serum sample will be collected from all females of 
childbearing potential WOCBP at screening, and on the first day of each cycle of 


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chemotherapy and at the end of treatment (Day 30), for a highly sensitive pregnancy 
test. 
Table 7 Blood Sampling Volume:  
Tests 
Patients 
Blood volume 
each patient and 
each sampling 
point 
Sampling points 
Number of samples 
Total blood 
volume 
Arm A 
Total blood 
volume 
Arm B 
Analysis of Exploratory 
Biomarkers in plasma 
and serum 
All patients (Arm A and 
B) 
20 mL (Total) 10 
mL; 
5 mL for plasma 
5 mL for serum) 
• Screening 
• Baseline 
• In cycle 4 
• In cycle 8 
• Every third month 
 
6 sampling points 
estimated 
60120 mL 
60120 mL 
Analysis of Exploratory 
Biomarkers in blood 
(PBMCs) 
Subset of patients at 
dedicated site 
Arm A and B 
20 mL 
• Screening 
• In cycle 4 
• In cycle 8 
• Every third month 
 
6 sampling points 
estimated 
120 mL 
120 mL 
Amphinex 
Pharmacokinetics 
Arm A patients 
5 mL 
10 Up to 19 sampling 
points 
5095 mL 
NA 
Clinical chemistry 
(including standard 
tumour markers in 
serum) 
20 mL for serum 
22 sampling points in 
Arm A  
20 sampling points in 
Arm B 
440 mL 
440 400 mL 
Haematology 
3.5 mL (EDTA 
plasma) 
22 sampling points 
77 mL 
77 mL 
Coagulation 
3.5 mL (citrate 
plasma) 
10 sampling points in 
Arm A 
9 sampling points in 
Arm B 
35 mL 
35 31.5 mL 
Totala 
782767 mL 
732628.5 mL 
 
 
Section 6.4.3.2, Hepatotoxicity 
In the event that a patient shows AST or ALT ≥3 × ULN indicative of hepatotoxicity 
related to chemotherapy (ie, with an ensured proper biliary drainage in place and a 
clinical picture indicative of a correlation to chemotherapy treatments), the delay, 
postponement or omission of the following chemotherapy administration is to be 
decided at the discretion of the treating physician as per local standard procedures 
applicable to gemcitabine/cisplatin treatment. 
 
 
Section 6.4.4, Loco-Regional Tumour-Related Events and Biliary Complications 
Unless caused by a terminal, intractable overgrowth of the loco-regional tumour in 
patients with established progressive disease, unplanned or emergency hospital visits 
caused by clinical signs of sudden bile duct obstruction, including but not limited to 
malaise, pain, jaundice, septicaemia, or several symptoms combined, and with clinical, 


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laboratory and radiological findings confirmatory of unexpected, biliary obstruction 
leading to unplanned hospitalisation will be recorded and reported as SAEs (see 
Section 6.4.1.5). 
 
 
Section 6.4.5, Vital Signs 
The Vital signs on Day -4 and Cycle 4, Day 18vital signs must be collected both before 
and after Amphinex administration. 
 
 
Section 6.4.6, Electrocardiograms 
For all ECGs, details of rhythm, PR, R-R, QRS and QT intervals and an overall 
evaluation will be recorded. Corrected QT intervals will be calculated using Bazett’s 
formula (QTcB) and Fridericia’s formula (QTcF). 
The ECG on Day -4 and on Cycle 4, Day 18ECG must be performed before and 
30 minutes and 4 hours after Amphinex administration. 
 
 
Section 6.4.7, Photosensitivity Measurements and Skin Reactions 
The title of this section was amended to include and Skin Reactions. 
The following text was added: 
For patients in both treatment arms, skin reactions will be documented and 
recorded in the eCRF. 
 
 
Section 7.1.1, Progression-Free Survival 
Progression-free survival is defined as the time from randomisation until the date of 
objectiveradiological disease progression or death (by any cause in the absence of 
progression) regardless of whether the patient withdraws from therapy or receives 
another anti-cancer therapy prior to progression. 
 
 
Section 7.2.5, Disease Control Rate 
The DCR is defined as the proportion of patients with BOR of stable disease or better 
(ie, CR, PR or SD); it will be assessed at 6 and 12 months. 
 
 
Section 7.3, Exploratory Endpoints 
• 
To serially collectanalyse blood samples for the subsequent analysis of 
treatment effects onstandard tumour markers and exploratory tumour 
biomarkers (multiplex analysis of cancer pathways and cancer immune 
profiling), as well as (in as subset of patients) changes in circulating leukocyte 
subtypes, cancer cells and DNA. 
 
 
Section 7.4, Sample Size Calculations 
The primary (final) analysis of PFS, as assessed by local radiological review, will be 
conducted when approximately 120129 progression events (6569% maturity) have been 
observed. If the PFS result is statistically significant at the 4.9% (2-sided) alpha level, 
ORR will be compared between the arms and an interim analysis of OS will then be 
assessed, as detailed in Section 7.7.7.  
If the true HR for the comparison of fimaporfin-induced PCI of gemcitabine 
complemented by gemcitabine/cisplatin chemotherapy versus gemcitabine/cisplatin 
chemotherapy alone is 0.6, 120 129 progression events will provide approximately 80% 
power to demonstrate a statistically significant difference in PFS at a 4.9% 2-sided 
significance level (this may translate to an improvement in median PFS from 7.4 to 12.3 


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months, if PFS is exponentially distributed). A minimum or critical HR of 0.7 (eg, 7.4 to 
10.6 months), if observed, would give a 2-sided p<0.04904, but there is only 50% power 
associated with the critical HR. 
Assuming linear recruitment of 186 patients over 48 months with a site set-up period of 
approximately 6 months, 120129 PFS events are expected to occur between 
approximately 48 and 51 months (4 to 4.3 years) from the date on which the first patient 
was randomised. 
In addition to the potential interim analysis of OS at the time of the final PFS analysis 
(approximately 5058% of patients are predicted to have died at this point), data 
collection for OS will continue beyond the final PFS analysis and an updated OS 
analysis will be performed. The level of maturity will be determined based on the final 
PFS and interim OS results, in discussion with the regulatory authorities. For example, if 
the final The final OS analysis of OS will occur after approximately 155 147 death 
events (>80%) have been observed in 186 patients (>75% maturity,). Assuming a true 
OS HR of 0.763, there will be 6080% power to detect an improvement in median OS 
from 11.7 to 18.7 months with 2-sided p<0.046 (O’Brien and Fleming boundary 
based on interim OS at approximately 103 events). A minimum or critical HR of 
0.72 (eg, 11.7 to 16.7 months16.3 months), if observed, would be statistically 
significant. The exact level of maturity will be determined based on the final PFS 
and interim OS results, in discussion with the regulatory authorities. The 155147 
death events are expected to occur at approximately 7265 to 68 months from first patient 
randomised. 
Further details on the interim analyses are provided in Section 7.7.7. 
 
 
Section 7.6, Description of Subgroups to be Analysed 
Subgroup analyses will be performed for the stratification factors used at the point of 
randomisation (measurable disease – yes versus no and ECOG performance status – 0 or 
1presence or absence of hepatic metastases). Exploratory subgroup analyses will also 
be performed to assess key endpoints by loco regional tumour control, metastatic lesions 
within the liver parenchyma, and other metastatic lesions. Four distinct groups will be 
explored: primary; primary with liver metastases; primary with local lymph nodes; 
and primary with liver metastases and local lymph nodes. An additional subgroup 
analysis will be performed to compare patients with and without PSC at study 
entry. If there are too few events available for a meaningful analysis of a particular 
subgroup (it is not considered appropriate to present analyses where there are less than 
20 events per level in a subgroup), the relationship between that subgroup and PFS/OS 
will not be assessed. In this case, only descriptive summaries will be provided. Further 
details and any other exploratory subgroups of interest will be provided in the SAP 
 
 
Section 7.7.1, Analysis of Primary Endpoint 
The primary endpoint for this study is PFS. Progression-free survival will be analysed 
using the ITT populationanalysis set and a supportive analysis analyses will be 
performed using the BICR data and also the mITT populationanalysis set. 
Progression-free survival, as assessed by local radiological review, will be analysed 
using a log rank test stratified by any measurable disease at baseline (yes versus no), and 
ECOG performance status (0 and 1) presence or absence of hepatic metastases. If 
these 2 stratification factors lead to low numbers (eg, <10 progression events) within a 
single stratum, one or more stratification factors may be removed from the statistical 
analysis. The criteria for removal will be pre-defined in the SAP. The HR and CI will be 


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obtained directly from the U and V statistics (Selke and Siegmund 1983; Berry et al 
1991). A sensitivity/supportive analysis of PFS will be performed based on data assessed 
by BICR. 
The HR will be estimated using a stratified Cox-proportional hazards model using 
the Efron approach for handling ties (Efron 1977), together with the associated 
profile likelihood 95% CI for the HR. 
The effect of treatment will be estimated by the HR together with its corresponding 
95% CI and p-value for the ITT analysis set. 
The primary analysis of PFS based on the local evaluation will be repeated using 
the BICR data as a supportive analysis. 
A Kaplan-Meier (KM) plot of PFS will be presented by treatment group. Median PFS 
with 95% CIs will be presented. In addition, KM landmark PFS estimates at 6 
months and 12 months with corresponding CIs will also be presented using KM 
methodology. KM estimates may be presented for other timepoints of interest. The 
assumption of proportionality will be assessed. 
 
 
Section 7.7.2.2, Best Overall Response 
The BOR will be summarised for the ITT populationanalysis set and may be further 
grouped by measurable/non-measurable disease at entry. 
Summaries of BOR will also be repeated using the BICR data. Furthermore, two-
by-two tables will be produced to describe the consistency between the BICR and 
local evaluation assessment for BOR (and also the timing of PD to show how often 
the investigator declares PD at the same time, before or after the BICR). 
 
 
Section 7.7.2.3, Objective Response Rate 
For randomised studies, a confirmatory scan to confirm the response is not required per 
RECIST v1 1.1. 
The ORR will be summarised using the Evaluable for Response analysis set (ie, all 
randomised patients who have measurable disease at study entry). ORR will be 
compared between treatment arms using a logistic regression model with the 
covariate (stratification factor) of hepatic metastases. However, if there are <10 
patients within a stratum, this stratification factor will be removed from the 
statistical analysis. 
The results of the analysis will be presented in terms of an odds ratio together with 
its associated 95% profile likelihood CI. The p-value will be based on a test statistic 
that is calculated as twice the change in log-likelihood resulting from the addition 
of a treatment factor to a model that contains the covariates defined above. The test 
statistics is chi-squared distributed with 1 degree of freedom. 
 
 
Section 7.7.2.5, Disease Control Rate 
The DCR will be summarised for the ITT populationanalysis set at 6 months and 12 
months (ie, best response of CR, PR or SD at 6 or 12 months) and may be further 
summarised by measurable/non-measurable disease at entry. 
 
 
Section 7.7.2.6, Change in Tumour Size 
The change in tumour size will be summarised for the Evaluable for Response 
populationanalysis set. 
 
 
Section 7.7.7, Interim Analysis 
A formal interim analysis of PFSORR will be performed after approximately 60 


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progression events (defined in RECIST 1.1 [])120 patients (65%) have been observed 
(across both arms of the study). It is predicted that 60 PFS events will occur at 
approximately 36 months (3 years) from the date upon which the first patient was 
randomised; and at the point of data cut-off, approximately 120 and followed to their 
first 12-week follow-up scan. Based on an assumption that ~80 patients will have 
been recruited (ie, the PFS data will be approximately 50% mature).  
Assuming that the interim PFS analysis occurs after 60 events out of a planned 120 
events, a PFS HR of <0.46 would need to be observed measurable disease, there will 
be >80% power to conclude a detect an improvement in ORR from 20% to 57% 
with 2-sided p<0.01 (approximates an O’Brien and Fleming boundary based on 
65% information). An improvement from 20% to 47% will be statistically 
significant result at the 2-sided p<0.003 level, according to an O’Brien & Fleming 
boundary. 
, if observed. If the comparison of the interim PFSORR data between the arms is 
statistically significant (based on an O’Brien and Fleming boundary), the secondary 
endpoint of ORR will be assessed in a hierarchical manner at the same time as the 
interim PFS assessment and DoR , it will be summarised together with PFS and DoR 
to support a conditional marketing authorisation application. Assuming 80 of the 120 
patients recruited (ie, two-thirds) have measurable disease, an improvement in ORR 
from 20% on the SoC arm to 54% on the PCI arm would need to be observed to give 
p<0.003. The survival data available at the time of the interim PFS assessment will be 
survival data will be limited (<20 death events) at this point and will be summarised 
descriptively only. 
An interim analysis of OS will be performed at the time of the final PFS assessment 
(when approximately 50% of 103 patients are predicted to have died at this point) and 
an updated OS analysis will be performed at a later time point. A 2-sided p<0.015 will 
be required to demonstrate statistical significance. 
 
 
Section 7.7.7.1, Multiplicity and Control of Type 1 Error 
Updated section heading to ‘Multiplicity and Control of Type 1 Error’. Added a figure 
for multiple testing procedure and updated the text as follows: 
In order to provide strong control of the type I error rate at the 2-sided 5% level, the 
primary endpoint of PFS and key secondary endpoints of ORR and OS will be tested in 
this sequential (hierarchical) order. at the time of the primary analysis. If any previous 
analysis in the sequence is not statistically significant, the alpha cannot be transferred to 
subsequent analyses endpoints (ie, the multiple testing procedure will recycle the test 
mass to the endpoint not yet rejected in the hierarchy outlined in Figure 4). 
The Lan DeMets approach that approximates the O’Brien and Fleming spending 
function will be used to maintain an overall 2-sided 5% type I error across the interim 
(60 events) and final PFS analysis (120 events). The interim analysis of ORR will be 
conducted after approximately 120 out of 186 patients have been randomised. The 
significance level for the PFS analyses will be calculated by specifying the information 
fraction for each analysis. The information fraction is calculated as the number of PFS 
events at the analysis time-point divided by the total number of events at the final 
analysis time-point (for example, the information fraction would be entered as 0.5 
[60/120 events] for the main interim analysis resulting in a 2-sided p value of 0.003). 
Assuming 65% information at the interim, statistical significance will be declared 
for ORR if 2-sided p<0.01, which approximates an O’Brien and Fleming spending 


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function. 
The remaining 2-sided alpha (of 4.9%4%) will be spent at the final PFS analysis, which 
will be triggered after approximately 129 progression events. Note, a non-
statistically significant PFS ORR result at the interim analysis will not preclude further 
testing of PFS at the final analysis.  
If the final PFS is statistically significant at 2-sided p<0.04, the alpha will be 
recycled to ORR. If both are significant, an interim analysis of OS at the full 5% 
alpha will be performed. Statistical alpha will also be shared across the interim and 
final assessments of OS using the Lan DeMets approach. A detailed multiple testing 
strategy incorporating PFS, ORR and OS will be described in the SAP. Assuming 70% 
information (number of events at interim / number of events at final analysis) at the 
interim, statistical significance will be declared for interim OS if 2-sided p<0.015, 
based on an O’Brien and Fleming spending function. The exact significance levels 
will be adjusted for the actual information fractions. 
Figure 4, Multiple Testing Procedure 
 
 
 
Section 7.7.8, Independent Data Monitoring Committee 
Although there are no formal futility stopping rules in the study, the IDMC will review 
the ongoing safety data and the results of the interim PFSORR analysis and provide a 
recommendation as to whether the study demonstrates a positive risk benefit that is 
clinically meaningful and meets the pre-defined statistical boundary for efficacy. 
 
 
Section 9.1, Independent Ethics Committee or Institutional Review Board 
Before study onset, the protocol, informed consent, advertisements to be used for the 


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recruitment of study patients and any other written information regarding this study to be 
provided to the patient or the patient’s legal guardian must be approved by the IEC/IRB. 
 
 
Section 9.3, Patient Information and Consent 
Before recruitment and enrolment, each prospective patient or his or her legal guardian 
will be given a full explanation of the study and be allowed to read the approved ICF. 
Once the Investigator is assured that the patient/legal guardian understands the 
implications of participating in the study, the patient/legal guardian will be asked to give 
consent to participate in the study by signing the ICF. 
The Investigator shall retain the signed original ICF(s) and give a copy of the signed 
original form to the patient or legal guardian. 
 
 
Section 10.1, Confidentiality 
Clinical information will not be released without the written permission of the patient (or 
the patient’s legal guardian), except as necessary for monitoring and auditing by the 
Sponsor, its designee, the regulatory agencies/authorities, or the IRB/IEC. 
 
 
Section 10.2, Financial Disclosure and Obligations 
• 
IEC/IRB-approved informed consent, samples of site advertisements for 
recruitment for this study, and any other written information regarding this 
study that is to be provided to the patient or legal guardian, and 
 
 
Section 11.2.1, Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the patient, must be reviewed and approved by the Sponsor or its 
designee. Amendments to the protocol must be submitted in writing to the Investigator’s 
IRB/IEC and regulatory authorities for approval before patients can be enrolled into 
an amended protocol. 
 
 
Section 11.2.2, Protocol Deviations 
Significant protocol deviations for this study may include 1) use of prohibited 
concomitant medications during the study, 2) tumour assessments (RECIST) for 
screening not performed with 28 days of start of treatmentprior to randomisation, 3) 
patients who received the wrong treatment, etc. 
 
 
Section 11.3, Study Termination 
Although PCI Biotech has every intention of completing the study, PCI Biotech reserves 
the right to discontinue the study at any time for clinical or administrative reasons, 
including but not limited to: 
• 
Occurrence of AEs not seen previously which by virtue of their nature, 
severity and duration are considered to necessitate study termination; OR 
the unexpected incidence or severity of known AEs 
• 
Sponsor decision 
• 
Medical or ethical reasons affecting the continued performance of the 
study 
• 
Difficulties in the recruitment of patients 
• 
Cancellation of the drug development as such or for the given indication. 
The end of the study is defined as the date of the final database lockon which the last 
patient completes the last visit (includes follow-up visit). 


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Section 12, Reference List 
Berry G, Kitchin RM, Mock PA. A comparison of 2 simple hazard ratio estimators 
based on the logrank test. Stat Med. 1991;10(5):749-55. 
Efron B. The Efficiency of Cox’s Likelihood Function for Censored Data. J Am 
Stat Assoc 1977;72(359):557-65. 
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: 
Hepatobiliary Cancers. Version 4.2017 – October 9, 2017 Version 3.2019 – August 1, 
2019. 
Selke T, Siegmund D. Sequential analysis of the proportional hazards model. 
Biometrika. 1983;70(2):315-26. 
 
 
Appendix A: Schedule of Events for the Active Treatment Period 
Schedule of events was split for Arm A and Arm B patients. Updates were made to 
Table 10 to include only the event schedule for Arm A patients and a separate table 
(Table 11) was created for Arm B patients with additional details. 
 
 
Appendix A, Table 10 
The following changes were made to the schedule of events:  
• 
Removed footnote “b” from column heading ‘PCI treatment No 1’. 
• 
Orientation of the ‘Day’ row was made vertical to improve table formatting. 
• 
Day removed from the Screening column heading; clarification of time window for 
Screening evaluations is provided in footnote “a”. 
• 
Randomisation row removed and Randomisation added as a column heading after 
Screening to visually clarify that all Screening procedures must be performed prior 
to randomisation. 
• 
Removed empty columns for ‘Day -3’ ‘Day -2’ and ‘Day -1’ under ‘PCI treatment 
No. 1’ and ‘C4, D19’, ‘C4, D20’ and ‘C4, D21’ under ‘PCI treatment No. 2’, to 
improve table formatting.  
• 
An additional assessment point for vital signs was added on Day -4 and C4, D18 to 
clarify that vital will be checked twice ie, before and after Amphinex administration 
on these dates. 
• 
Additional assessment points for ECG were added on Day -4 and C4, D18 to clarify 
that ECG will be monitored thrice ie, before and approximately 30 minutes and 4 
hours after Amphinex administration (time matched with PK samples) on these 
dates. 
• 
Pregnancy test was added on ‘Day -4’ and ‘Cycle 4, Day 18’. 
• 
Added detailed sampling for assessment of fimaporfin pharmacokinetics which was 
previously provided in a separate table (Table 9 in original protocol). The PK 
sampling schedule was revised to include 2 groups; Group 1 - rich sampling and 
Group 2 - sparse sampling. Groups 3 and 4 were deleted. All patients in Arm A will 
now undergo the PK sampling schedule as follows: 
o 
Group 1: Day -4; Cycle 1, Day 1; Cycle 1, Day 8; Cycle 2, Day 8; Cycle 3, 
Day 8; Cycle 4, Day 8; Cycle 4, Day 18; Cycle 5, Day 1; Cycle 5, Day 8; 
Cycle 6, Day 8; Cycle 7, Day 8; Cycle 8, Day 8. 


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o 
Group 2: Day -4; Cycle 1, Day 1; Cycle 2, Day 8; Cycle 4, Day 8; Cycle 4, 
Day 18; Cycle 5, Day 8; Cycle 7, Day 8. 
• 
Removed footnote “c” from row heading ‘Informed consent’; information within 
footnote “c” merged into footnote “a”. 
• 
Biomarker assessments for standard tumour markers (CA-19-9/ CA-125/CEA) 
moved to ‘Laboratory Assessments’. Both rows for ‘Biomarker Assessments’ 
(exploratory biomarkers and standard tumour biomarkers) were updated as follows: 
an ‘X’ was added to Day -4 (baseline assessment) for consistency with text in the 
protocol body, and the ‘X’ included under the ‘C7, D8’ column in error was deleted 
and correctly added under the ‘C8, D1’ column. The footnote ‘p’ was added to 
standard tumour markers to clarify that they will be analysed from serum samples 
collected for clinical chemistry. The footnote ‘v’ only applied to the optional 
sampling for exploratory biomarkers analysis, and not to the sampling for the 
standard tumour markers. 
• 
Removed row containing background treatment information for Arm B patients. 
• 
Revised footnote ‘a’ to merge the former footnote ‘a’ and ‘c’: Screening evaluations 
to be performed after the patient has signed and dated the informed consent 
form and withinup to 14 days prior to randomisationDay -4. except tumour 
evaluation, stenting, and histology/cytology, which may be performed up to 28 days 
before Day 1 Tumour assessment may be performed within 28 days prior to 
randomisation. Histology/cytology is to be performed/confirmed before 
randomisation. 
• 
Footnote ‘b’ (former footnote ‘e’ moved): Patients in Arm A only Upon 
completion of all screening evaluations, eligible patients will be randomised via 
the Interactive Web Response System. 
• 
Footnote ‘c’: A second PCI treatment procedure aimed at the initiation of Cycle 
5 or, if patient-related factors demand postponement, at initiation of Cycle 6, 7, 
or 8 (Section 3.3.2). 
• 
Footnote ‘d’: Biliary stenting is to be performed on all patients according to local 
practice, however, the chosen stent must be of an exchangeable (plastic) type 
throughout the active treatment period of the study until radiological progression 
is declared. Stenting is to may be performed at any time from confirmation of 
histological/cytological diagnosis until the day of immediately after the first laser 
light application. Patients who have already undergone stenting before screening 
should be reviewed to ensure the stent is of an acceptable type, correctly positioned 
and adequate liver drainage confirmed. Stents will must be removed before for the 
laser light application, and a new plastic stents will be inserted stent must be 
placed immediately after the procedure for Arm A patients. light application. 
Stent removal, laser light application, and stent replacement will take place 
during the same ERCP procedure. 
• 
Footnote ‘h’ (former footnote ‘i’): Vital signs including pulse rate, systolic and 
diastolic blood pressure (sitting), and temperature. Vital signs will be performed 
before and after Amphinex administration on Day -4 and Cycle 4, Day 18. 


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• 
Footnote ‘i’ (former footnote ‘j’): Standard 12-lead ECG. Tracings must be 
interpreted, dated, and signed by the Investigator or his/her designee and filed with 
the patient’s source documents. The ECG will be performed after Amphinex 
administration on Day -4. On Day -4 and Cycle 4, Day 18, the ECG will be time 
matched with PK samples: For PK Group 1, ECG will be performed before, 
approximately 30 minutes after, and 4 hours after Amphinex administration, 
and for PK Group 2, ECG will be performed before Amphinex administration. 
• 
Footnote ‘k’ (former footnote ‘l’): If the second PCI treatment is delayedpostponed, 
unanticipated adverse device effects/adverse incidents recording will be done on the 
day of administration of delayedpostponed second PCI treatment (laser light 
application). 
• 
Footnote ‘l’ (former footnote ‘m’): Patients in Arm A will be asked about possible 
skin and photosensitivity reactions and their exposure to light during study visits for 
3 months following the last Amphinex administration. 
• 
Footnote ‘m’ (former footnote ‘n’): Quality of life assessments will be performed at 
selected time points during treatment and thereafter every 12 weeks, preferably 
before any other study assessments are performed. 
• 
Footnote ‘n’ (former footnote ‘o’): Radiographic tumour assessment with diagnostic 
contrast-enhanced CT or MRI scan and clinical assessment performed every 12 
weeks (±1 week) from randomisation until disease progression. Baseline (screening) 
measurement may be performed within 28 days prior to Day -4 randomisation. 
• 
Footnote ‘o’ (former footnote ‘p’): Clinical chemistry includes sodium, potassium, 
calcium, magnesium, phosphate, chloride, glucose (fasting), creatinine, total 
bilirubin, gamma-glutamyltransferase, alkaline phosphatase, aspartate 
aminotransferase, alanine aminotransferase, C-reactive protein, urea/blood urea 
nitrogen, total protein, serum amylase, serum lipase and lactate dehydrogenase. 
Haematology includes haemoglobin, haematocrit, white blood cell count, 
differentials (absolute), international normalised ratio, and platelet count. Safety 
blood samples do not need to be repeated on Day -4 prior to Amphinex 
administration, if the screening evaluation was done 1 day before. Samples taken 
within 3 days of Day 1 for any chemotherapy cycle do not need to be repeated on 
Day 1 prior to dosing. 
• 
Added footnote ‘p’: Standard tumour markers will be analysed from serum 
samples collected for clinical chemistry. 
• 
Footnote ‘q’: Urinalysis dipstick for albumin or total protein, glucose, bilirubin and 
blood (microscopy is to be done if there is more than one positive test). 
• 
Footnote ‘r’: A serum creatinine clearance at baseline is required. Creatinine 
clearance prior to treatment should be >45 mL/min ≥60 mL/min. Serum creatinine 
should be checked before each cycle of treatment based on calculation. If there is a 
>25% increase in serum creatinine compared to the baseline then the 
ethylenediamine tetraacetic acid (EDTA) clearance or equivalent method must be 
performed and cisplatin dosing modified accordingly. 


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• 
Footnote ‘s’: Coagulation tests including INR and APTT should be performed on 
Day 1 of each 21-day chemotherapy cycle except if patient is receiving warfarin, in 
which case, assessments should also be done on Day 8 of each cycle and Day 15 of 
each cycleCycle 1. Tests do not need to be repeated on Day -4 prior to Amphinex 
administration, if the pre-treatment evaluation was done 1 day before. 
• 
Footnote ‘t’: For women of childbearing potential only. A highly sensitive urine or 
serum pregnancy test is acceptable. 
• 
Footnote ‘u’: PK samples will be collected from all patients in Arm A only, please 
see Table 12 for details of sub groups and sampling time points. Group 1: the 20 
first patients randomised to Arm A; Group 2: all other patients randomised to 
Arm A. On Day -4 and Cycle 4, Day 18, the PK samples will be time matched 
with ECG: For PK Group 1, PK sampling will be performed before, 
approximately 30 minutes after, and 4 hours after Amphinex administration; 
for PK Group 2, PK sampling will be performed before Amphinex 
administration. 
• 
Footnote ‘v’: BloodPlasma and serum samples (each 5 ml20 mL) for exploratory 
biomarkers in plasma will be collected at baseline and at approximately 3-month 
intervals throughout the study. In addition, in a subset of study sites with facilities 
and resources for the purpose, sampling for the characterisation of circulating cells 
(tumour and leukocyte subsets) will be collected and analysed. 
• 
Footnote ‘w’: Laser light application procedure is to be performed 3 hours (±1 hour) 
after end of gemcitabine administration (Arm A patients only). It is expected that 
all patients will be hospitalised for one night after the ERCP/laser light 
applications on Day 1 of Cycle 1 and Day 1 of Cycle 5. 
• 
Footnote ‘y’ (‘To be recorded as long as the patient has not withdrawn the 
consent.’) was removed. 
 
 
Appendix A, Pharmacokinetic Sampling Schedule (Arm A) 
The separate table of pharmacokinetic sampling schedule for Arm A patients (Table 9 in 
original protocol) was removed and PK sampling details were incorporated into 
Table 10, Schedule of Events for the Active Treatment Period-Arm A Patients (see list 
of changes to Table 10 for details of changes above to PK sampling schedule). 
 
 
Appendix B, Table 12, Schedule of Events for the Follow-Up Period 
The following changes were made to the schedule of events:  
• Added ECG to be performed at 30 days after the end of the active treatment (end of 
treatment [Day 30]). 
• Specified that photosensitivity evaluation will be done for Arm A patients only and 
will be also performed in follow-up period (every 12 weeks ± 1 week); a new 
footnote ‘e’ was inserted: Patients in Arm A will be asked about possible skin 
photosensitivity reactions and their exposure to light during study visits for 
3 months following the last Amphinex administration. 
• Specified timing of quality of life assessments relative to other study assessments. 
New footnote ‘f’ was inserted: Quality of life assessments will be performed at 


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selected time points during treatment and thereafter every 12 weeks, preferably 
before any other study assessments are performed. 
• Row heading ‘Exploratory assessments’ was changed to ‘Exploratory biomarkers’. 
• Pregnancy testing was added at the end of the active treatment (end of treatment 
period Day 30) and follow-up period (12 weeks ± 1 week). A new footnote ‘g’ was 
inserted: For women of childbearing potential only. A highly sensitive urine or 
serum pregnancy test is acceptable. 
• 
Serious adverse event reporting was added to the survival follow-up period for 
consistency with text in the protocol body and a new footnote ‘i’ was inserted: 
Serious adverse events that occur more than 30 days after the last dose of study 
treatment do not need to be reported unless the Investigator considers them 
related to study treatment and/or procedures. 
• Due to the insertion of footnote ‘e’, ‘f’, ‘g’, and ‘i’, numbering of subsequent 
footnotes was updated. 
• Footnote ‘j’ wording was clarified: Survival status will be assessed for all patients 
(eg, in a telephone call) every 12 weeks, with a window of ±4 weeks after study 
withdrawal (either after confirmation of disease progression or, discontinuation for 
any other reason), or study withdrawal if patient has consented to be followed 
up, until death from any cause. 
• Follow-up fimaporfin pharmacokinetic sampling and time-matched ECGs for Arm A 
patients only were added to this table at 30 days (±3 days) after last dose of study 
treatment or chemotherapy and every 12 weeks (±1 week), due to the removal of the 
separate PK sampling schedule table (Table 12). New footnote ‘k’ was inserted: A 
pharmacokinetic blood sample and corresponding ECG should be taken at the 
time of the 2 tumour assessments after end of treatment. 
 
 
Section 13.3, Appendix C: RECIST 1.1 
Updated the website link for RECIST 1.1: 
http://recist.eortc.org/wp-content/uploads/2015/03/RECISTGuidelines.pdf 
https://project.eortc.org/recist/wp-
content/uploads/sites/4/2015/03/RECISTGuidelines.pdf 
 
 
Appendix D: Health-Related Quality of Life Questionnaires 
• 
Swapped the order of subheadings ‘EORTC QLQ-BIL21’ and ‘EORTC QLQ-C30’, 
and questionnaires renumbered starting from EORTC QLQ-C30.  
• 
Removed EORTC QLQ-BIL21 question: ‘Have you had pain in your shoulder?’ 
 
 
Section 13.5, Appendix E: Protocol Amendments were added. 
Version
 3.0 
Global 
Amend
ment 2 
13 Jul 
2020 
Title Page, Protocol Approval - Sponsor Signatory 
The Chief Medical Officer and Sponsor contact details were updated from Hans 
Olivecrona, MD to Amir Snapir, MD. 
The Medical Monitor details were updated. 
 
 
Summary of Changes 
An overview of rationale for the changes made as a result of Protocol Amendment 2 


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were added. 
 
 
List of Abbreviations 
 
 
 
 
 
 
 
 
List of Definitions 
PCI 
treatment 
In the present protocol, a single PCI treatment consists of IV 
administration of Amphinex solution for injection (dose 0.25 
mg/kg fimaporfin-di-olamine, equivalent to 0.22 mg/kg 
fimaporfin), followed 4 days later by gemcitabine IV infusion 
(1000 mg/m2) and bile duct intraluminal laser light application 
(light dose 30 J/cm).  
Amphinex® 
Amphinex solution for injection is a sterile solution containing 
active substance fimaporfin di-olamine; 30 mg/mL (equals 26 
mg/mL of fimaporfin), tween 80 (3.0%), tris buffer pH 8.5, and 50 
mM mannitol (2.8 %)  
Fimaporfin 
Active substance (salt form: fimaporfin di-olamine) 
DLTs 
dose-limiting toxicities 
EDR 
early discrepancy rate 
LDR 
late discrepancy rate 
NE 
not evaluable 
RP2D 
recommended Phase 2 dose 
 
 
Section 2.3, Exploratory Objectives 
2. To explore changes in standard tumour markers and exploratory biomarkers for the 
assessment of their diagnostic and prognostic relevance in the disease, and for the 
treatment itself. 
 
 
Section 3.1, Study Design 
Updated Figure 1 (Overall Study Design) to reflect the changes to the study design. 
 
 
Section 3.2, Treatment Assignment 
Patients will be stratified at randomisation according to whether they have any 
measurable disease at baseline (as assessed by the Investigator) versus no measurable 
disease, and according to presence or absence of hepatic metastases. Patients with any 
measurable disease must have at least 1 measurable lesion (bile duct or liver). It is 
expected that approximately two-thirds of patients will have measurable disease at 
baseline. 
 
 
Section 3.2.1, Arm A 
Patients randomised to Arm A will be treated with PCI, integrated into 21-day cycles of 
standard gemcitabine/cisplatin combination chemotherapy (background SoC treatment). 
as follows:  


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Patients who have started gemcitabine/cisplatin treatment before the screening 
period should continue their treatment as scheduled. PCI treatment should be 
synchronised with the schedule of the ongoing gemcitabine/cisplatin treatment. 
Study cycles will be counted from enrolment – as for all patients in the study; 
however, the number of chemotherapy cycles with gemcitabine/cisplatin will be 
counted from first treatment. For clarification, treatment with 
gemcitabine/cisplatin cannot exceed 8 treatment cycles. 
Treatment schedule as follows: 
Cycle 1: Amphinex® (fimaporfin) will be administered on Day -4 (4 days before 
gemcitabine administration), followed by gemcitabine administration and laser light 
application on Day 1, and gemcitabine/cisplatin on Day 8. Note: Cisplatin is omitted 
from Cycle 1 Day 1 treatment. ‘...’ 
Cycle 5: Gemcitabine administration and laser light application will be given on Day 1, 
and gemcitabine/cisplatin on Day 8. Note: Cisplatin is omitted from Cycle 5 Day 1 
treatment. ‘...’ 
Patient-related factors may demand postponement of the second PCI treatment to a later 
Ccycle 6, 7 or 8. Please see Section 3.3.2 for more detailed information. 
It is expected that all pPatients in Arm A willmay be admitted for overnight follow-up 
after hospitalised for one night after the endoscopic retrograde cholangio-
pancreatography (ERCP)/laser light applications and related procedures on Day 1 of 
Cycle 1 and on Day 1 of Cycle 5.  
For some patients, 1 to 3 days of hospitalisation after Amphinex administration may be 
required to ensure adequate initial protection from light. This will be at the Investigator’s 
discretion, as it could depend on factors such as time of year and weather conditions 
(risk of inadvertent exposure to sunshine or bright daylight) or the patient’s disposition 
and ability to comply with light protection guidance, travel distance, etc. 
 
 
Section 3.2.2, Arm B 
Patients randomised to Arm B (control arm) will be administered background SoC 
treatment (standard gemcitabine/cisplatin chemotherapy) only, on Days 1 and 8 of each 
21-day cycle, for up to 8 cycles. 
Patients who have started gemcitabine/cisplatin treatment before the screening 
period should continue their treatment as scheduled. Cycle 1, Day 1 visit should be 
synchronised with the schedule of the ongoing gemcitabine/cisplatin treatment. 
Study cycles will be counted from enrolment – as for all patients in the study; 
however, the number of chemotherapy cycles with gemcitabine/cisplatin will be 
counted from first treatment. For clarification, treatment with 
gemcitabine/cisplatin cannot exceed 8 treatment cycles. 


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Section 3.3.1, Stent Placement 
Biliary stenting is to be performed on all patients according to local practice; however, 
the chosen stent must be of an exchangeable (plastic) type until radiological progression. 
Stenting must be performed at the latest before first study treatment (Arm B) or 
immediately after the first laser light application (Arm A)may be performed at any 
time from confirmation of histological/cytological diagnosis until Cycle 1 Day 1 
(immediately after the first laser light application, for patients in Arm A). Patients who 
have already undergone stenting before screening should be reviewed to ensure the stent 
is of an acceptable plastic type, correctly positioned and adequate liver drainage 
confirmed; at least 50% of liver volume, or at least 2 sectors, should be drained. 
Stents must be removed for the laser light application, and a new stent must be placed 
immediately after light application. Stent removal, laser light application, and stent 
replacement will take place during the same ERCP one procedure. 
At least 50% of liver volume should be drained. Allowing for pathological changes with 
atrophy of chronically obstructed segments, this effectively means 2 of 3 sectors (ie, 
either all of the right or left liver lobe and either anterior or posterior sector of right liver 
lobe). This may require a combination of percutaneous transhepatic biliary drainage and 
endoscopic drainage but is optimally achieved by endoscopic drainage. 
 
 
Section 3.3.2, Arm A 
Patients randomised to Arm A will receive up to 2 PCI treatments, separated by at least 
3 months, together with up to 8 cycles of gemcitabine/cisplatin combination 
chemotherapy (Figure 2). ‘...’ 
This regimen replaces the standard gemcitabine/cisplatin administration of Day 1 in the 
first chemotherapy cycle. Patients will thereafter receive the remaining treatments as per 
standard SoC gemcitabine/cisplatin combination chemotherapy in Cycle 1 (Day 8) to 
Cycle 4 with cisplatin at 25 mg/m2 and gemcitabine at 1000 mg/m2, administered on Day 
1 and Day 8 of each 21-day cycle. ‘...’ 
A second PCI treatment following the same schedule will be performed at the start of 
Cycle 5 (Amphinex injection on Cycle 4, Day 18) followed by gemcitabine infusion and 
intraluminal laser light application on Cycle 5, Day 1. The second PCI treatment 
should be separated by at least 3 months from the first PCI treatment. ‘...’ 
If delays in the chemotherapy schedule have occurred or the schedule has been altered 
for any reason; or if a second PCI treatment in Cycle 5 is deemed medically 
inappropriate, temporarily unsafe, presents with an increased risk related to the 
endoscopy or PCI treatment; or if the patient strongly prefers its postponement for other 
reasons, or the patient has had chemotherapy before enrolment, the second PCI can 
be conducted in any of the later cCycles 6 to 8 at the discretion of the treating 
physician. However, the general goal should be to schedule the second PCI treatment at 
the start of Cycle 5 and avoid postponements unless an event or cause as outlined above 
is present to justify it. 
The second PCI treatment may be postponed if: 
• 
In the opinion of the Investigator, the single dose of gemcitabine cannot be given 
at the full 1000 mg/m2 dose due to residual toxicity 
• 
The Investigator determines that the patient will not tolerate a second PCI 
treatment at the scheduled time based on the patient’s poor tolerability of 
the first PCI treatment 


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• 
‘...’ 
• 
Total bilirubin >2.5 × ULN 
In contrast to postponing the second PCI, this treatment will not be given at all if any of 
the following criteria are fulfilled: 
• 
The patient experienced a PCI treatment-related schedule-limiting toxicity (SLT) 
defined as: 
o 
A clinically significant toxicity or abnormal laboratory value occurring 
after PCI treatment and during the first chemotherapy cycle, assessed as 
unrelated to the underlying disease, or concomitant medications, where 
there is a reasonable possibility that it is related to either PCI treatment 
or related to the combination of PCI treatment with the 
cisplatin/gemcitabine systemic chemotherapy and meets any of the 
following criteria, based on National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0: ‘...’ 
In patients still in theon study treatment(ie, not formally discontinued or withdrawn), 
the reason(s) for delays, postponement, or omitting of the second PCI must be 
adequately documented and recorded in the electronic case report form (eCRF). 
Patients should continue their randomised chemotherapy treatment until a maximum of 8 
systemic gemcitabine/cisplatin cycles or RECIST 1.1 defined progression or until a 
treatment discontinuation criterion is met. 
 
 
Section 3.3.3, Arm B 
Patients randomised to Arm B (control arm) will receive background SoC treatment 
only, with SoC systemic gemcitabine/cisplatin combination chemotherapy for 
nonresectable or metastatic CCA as follows: ‘...’ 
Patients should continue their randomised chemotherapy treatment until a maximum of 8 
systemic gemcitabine/cisplatin cycles or RECIST 1.1-defined progression or until a 
treatment discontinuation criterion is met. 
 
 
Section 3.4.2, Rationale for Study Endpoints 
The authors discussed that a PFS HR<0.7 observed in a randomised clinical trial of 
advanced biliary tract cancer treatment with a superiority design could translate to 
a 20% improvement in OS. 
 
 
Section 3.4.3, Clinical Precedence 
The authors discussed that a PFS HR<0.7 observed in a randomised clinical trial of 
advanced biliary tract cancer treatment with a superiority design could translate to a 20% 
improvement in OS. 
Fimaporfin has been evaluated in 3 cancer studies to date: 1 completed study and 1 
terminated study with fimaporfin-induced PCI of bleomycin, and one ongoing 
completed study with fimaporfin-induced PCI of gemcitabine. As of September 
2019June 2020, 69 patients have received fimaporfin; 46 with bleomycin and 23 with 
gemcitabine. Thirteen patients have received fimaporfin-induced PCI of gemcitabine at 
the dose level of this study, Recommended Phase 2 Dose (RP2D), established as 0.22 
mg/kg fimaporfin (equivalent to 0.25 mg/kg fimaporfin di-olamine) and 30 J/cm light 
dose. ‘...’ 
The third study, PCIA 202/12 is was a currently-ongoing Phase 1/2 study to assess the 
safety, tolerability and efficacy of fimaporfin-induced PCI of gemcitabine followed by 


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gemcitabine/cisplatin chemotherapy in patients with advanced inoperable CCA. 
Enrollment into the study has been completedA total of 23 patients were included, 20 
males and 3 females, in 5 cohorts. 
Sixteen patients have beenwere treated in the single-arm dose escalation part (Phase 1) 
of the study. Three patients have beenwere treated at a fimaporfin dose of 0.05 mg/kg 
with a light dose of 15 J/cm (Cohort 1), 3 patients at a fimaporfin dose of 0.05 mg/kg 
and a light dose of 30 J/cm (Cohort 2), 4 patients at a fimaporfin dose of 0.10 mg/kg and 
light dose of 30 J/cm (Cohort 3), and 6 patients at a fimaporfin dose of 0.22 mg/kg and a 
light dose of 30 J/cm (Cohort 4). No dose-limiting toxicities (DLTs) were reported 
and the dose of Cohort 4 was selected for future studies. 
Seven patients have beenwere enrolled in the extended Phase 1 part, with the objective 
of determining safety and tolerability of a two-dose regimen of PCI treatment at the 
selected dose from the dose escalation part. A total of 5 patients underwent the 2 PCI 
treatment procedures and completed the required 21-day safety window following the 
second procedure as per protocol. All SLT criteria were assessed and it was concluded 
that no SLTs were reported; therefore, in the 5 eligible patients who completed both 
PCI procedures. Tthe Cohort Review Committee (CRC) concluded that the procedure 
was tolerable based on the fact that no SLTs were observed in the 5 eligible patients who 
completed both PCI procedures. Study enrolment was therefore closed. 
Cholangitis is was the SAE most frequently reported SAE from the ongoing study PCIA 
202/12with fimaporfin-induced PCI of gemcitabine (16 . Fifteen patients, have 
experienced SAEs of cholangitis (4332 events). Overall, no correlation between PCI 
treatment and time to onset of cholangitis was evident. The rates of cholangitis seen 
are similar to those seen in published Bismuth III and IV hilar CCA endoscopic 
procedure studies (Pisello et al 2009; Talreja et al 2013).  
Encouraging preliminary signs of efficacy have been seen in the Phase 1 dose escalation 
part of the study. Based on evaluation of 6-month radiology data from patients treated in 
Cohorts 3 and 4, a response rate (complete response [CR] + partial response [PR]) of 
5550% has been observed in the 10 9 evaluable patients. treated in Cohorts 3 and 4 
(63% if based on the 8 patients with measurable disease at baseline) and the interim 
average In the extended Phase I part of the study, one patient had PR out of the 5 
evaluable patients (ORR of 20%). Overall, 6 out of 19 evaluable patients had a 
BOR of confirmed CR or PR (ORR of 31.6%) and 15 of the 22 evaluable patients 
(68.2%) were progression-free at their 6-month scan. The median OS of all 2316 
patients was 19.516.1 months in July 2019. 
Phase 2 of the currentThe PCIA 202/12 protocol, was designed as a proof-of-concept 
study with up to 60 patients being randomised either to an active treatment arm (PCI + 
backgroundSoC treatment with gemcitabine and cisplatin), or to a control arm 
(backgroundSoC treatment with gemcitabine and cisplatin, only). However, based on the 
encouraging preliminary efficacy and safety findings in the Phase 1 portionpart, the 
Phase 2 part of the study PCIA 202/12 is being replaced by the current study with the 
aim of this becoming a registration study. Refer to the current edition of the Amphinex 
(fimaporfin) Investigator’s Brochure (IB) for a complete summary of nonclinical and 
clinical information including safety, PK, and efficacy. 
 
 
Section 3.4.4, Rational for Dose 
In terms of safety, Amphinex has been well tolerated in doses up to the maximum 
tolerated dose of 0.87 mg/kg as established in the Phase 1 study PCI 101/06 and as 


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shown by the absence of dose-limiting toxicities in the Phase 1 dose escalation part of 
the ongoing study PCIA 202/12 in CCA. Overall, Amphinex shows a suitable safety and 
tolerability profile for the treatment of advanced CCA. Based on the limited available 
data, no clear dose dependency relationship has been observed for safety. Clear evidence 
of efficacy has been seen at several doses evaluated for efficacy so far, as manifested by 
rapid responses. 
The PCI treatment with Amphinex in combination with chemotherapeutic substances 
bleomycin and gemcitabine has been shown to be tolerated in preclinical and clinical 
studies. In the completed Phase 1 PCI 101/06 and PCI 101/06 Extension studies in 
patients with local recurrent or advanced/metastatic subcutaneous and cutaneous 
malignancies (PCI 101/06 and PCI 101/06 Extension), Amphinex was given in 
combination with a fixed dose of bleomycin and laser light. Amphinex doses between 
0.11 and 0.87 mg/kg were well tolerated, and doses between 0.22 and 1.3 mg/kg showed 
early signs of efficacy. In the Phase 2 PCIA 202/10 study of Amphinex in combination 
with bleomycin and laser light in patients with recurrent HNSCC (PCIA 202/10), an 
Amphinex dose of 0.22 mg/kg was given with a fixed dose of bleomycin and varying 
light doses. Preliminary signs of efficacy were shown in patients receiving superficial 
light application. 
The Phase 1 dose escalation part of the ongoing study PCIA 202/12 study in patients 
with advanced CCA has beenwas completed with good safety, tolerability and anti-
tumour activity at different dose levels, including the 2-administration 
schedulepromising early signs of efficacy. In total, 16 patients have been treated, 13 
males and 3 females, in 4 cohorts (see Section 3.4.3). For the PCI treatment, all patients 
received the standard gemcitabine dose of 1000 mg/m2. 
FourteenTwenty-one of the 2316 enrolled patients completed the safety evaluation 
window and no dose limiting toxicitiesDLTs, SLTs or other safety concerns were 
reported. The Amphinex dose administered in Cohorts 1 and 2 was regarded too low for 
achieving tumour effects. An evaluation of 6 months radiology data from patients treated 
in Cohorts 3 and 4 concluded that a total of 79 patients had radiologicallywere evaluable 
cancerfor BOR and 5 of these had confirmed objective tumour response., of which 2 
were CRs. Specifically, of the 3 evaluable patients in Cohort 3, the radiology evaluation 
concluded that there were 1 CR, 1 PR, and 1 stable disease (SD) at 6 months after the 
PCI treatment. In Cohort 4, there were 1 CR, 2 PR and 1 progressive disease (PD). 
A proposal to proceed to Phase 2 with the highestThe selection of the dose of 
Amphinex and light applied in Cohort 4 of the Phase 1 of PCIA 202/12, as well as the 
standard gemcitabine dose of 1000 mg/m2, is based on the observed well-tolerated 
safety profile and these early promising signs of antitumour activityresponse in the last 
dose cohorts, combined with experience from the previous clinical studies with 
Amphinex (including PCIA 202/10). In HNSCC, a higher light dose of 60 J/cm was 
associated with serious local adverse reactions, whereas, the 2 lower photochemical 
doses were regarded too low for achieving tumour effects. 
Based upon assessment ofon these cumulative safety data, athe dose of 0.22 mg/kg 
Amphinex and intraluminal light dose of 30 J/cm with the standard gemcitabine dose 
(1000 mg/m2) were selected as safe and tolerablefor further studies. 
 
 
Section 3.4.5, Rational for Treatment Regimen 
During In the extended part of Phase 1 in study PCIA 202/12, the 2-administration 
schedule will was to be considered non-tolerated if 2 or more of the first 6 evaluable 


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patients experienced an SLT. If none or 1 of the first 6 evaluable patients experienced an 
SLT (see definition in Section 3.3.2), the 2-administration schedule willwas to be 
considered tolerated. 
A total of 5 patients underwent the 2 PCI treatment procedures and completed the 
required 21-day safety window following the second procedure as per protocol. All SLT 
criteria were assessed and it was concluded that no SLTs were reported in these 5 
eligible patients who completed both PCI procedures. The CRC concluded that the 
procedure was tolerable based on the fact that no SLTs were observed in the 5 eligible 
patients. Therefore, the 2-administration schedule can be considered tolerated. ‘...’ 
Preliminary Rresults from Study PCIA 202/12 show that there is greater variation in 
half-life values, ranging from 21 to 93 days; however, as reported above, there were no 
SLTs reported in any of the 5 patients who received a second administration.  
 
 
Section 3.4.6, Benefit/Risk and Ethical Assessment 
In patients treated with lower light doses (10 J/cm, 20 J/cm, and 30 J/cm), there have 
been no reports of excessive tissue loss. In the ongoing study PCIA 202/12 in patients 
with CCA, only one light fibre iswas used for the intraluminal application. The fibre 
iswas manipulated within an ERCP catheter to ensure full coverage of the area to be 
treated, which may be longer than the cylindrical light diffuser that provides the laser 
light illumination. ‘...’ 
In the current study, a second PCI treatment is introduced at the onset of Cycle 5 of the 
combination chemotherapy regimen. The window of approximately at least 3 months 
between the PCI treatments will allow for local reactions (in terms of inflammatory 
response) to cease, and for potentially weakened, normal tissue to revert to normal or 
fibrotic tissue. ‘...’ 
Data from clinical studies (studies PCI 101-06, PCIA 202-10, and PCIA 202-12) 
showed that all photosensitivity-related AEs were mild or moderate. No severe AEs 
related to photosensitivity were reported among 41 subjects treated in those studies 
with the same dose of fimaporfin that is given in the current study. ‘...’ 
All patients in this study will be treated with current SoC for the disease, 
gemcitabine/cisplatin background treatment. In addition, patients in the active Arm A 
will be treated with fimaporfin-inducedreceive PCI of gemcitabine, and intraluminal 
laser light application will be by use of a single optical fibretreatment. No major safety 
concerns have been raised with the RP2D study dose of 0.22 mg/kg fimaporfin and 
30 J/cm intraluminal light used in study PCIA 202/12. In all clinical data sets so far, 
there has not been evidence of any significant biochemical or haematological toxicity 
solely attributed to the PCI treatment. 
In a previous clinical study (PCIA 202/12), radiological response has been observed 
in 32% of 19 patients treated with the fimaporfin dose that is given in this study. 
Fifteen of the 22 evaluable patients (68.2%) were progression-free at 6 months. The 
median OS of all 23 patients was 16.1 months. 
 
 
Section 4.1.1, Inclusion Criteria 
3. 
Cholangiocarcinoma verified as adenocarcinoma by histopathology or cytology 
(C5) with a perihilar or distal stenosis that has been stented or will require stenting, and 
that is accessible for PCI light treatment; 
6. 
If metastatic disease, metastasis must be limited to tissues other than bone or 
the central nervous systemto the liver parenchyma and/or local lymph nodes (within 


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close proximity to the hepatoduodenal ligament); 
7. 
Adequate biliary drainage (either at least 50% of the liver volume, or at least 2 
sectors), with no evidence of active uncontrolled infection (patients on antibiotics are 
eligible); 
 
 
Section 4.1.2, Exclusion Criteria 
1. 
Previously received any anti-tumour (either local or systemic) treatment for 
CCA, except for previous treatment of up to 2 cycles of gemcitabine/cisplatin; 
3. 
A history of frequently recurring septic biliary events caused by non-malignant 
strictures (primary sclerosing cholangitis [PSC], autoimmune hepatitis or advanced 
chronic liver dysfunction); 
5. 
An active second primary cancer, defined as one with a disease-free interval of 
<5 years before screening. A second primary cancer that has been treated with intent 
to cure may be allowed after consultation with the study Medical Monitor., with the 
exception of aAdequately treated basal cell carcinoma, squamous cell carcinoma or other 
non-melanomatous skin cancer, in situ carcinoma of the uterine cervix, or prostate 
cancer that is controlled by hormone therapy (patients may continue hormone therapy 
while on study) are allowed; 
10. 
Clinically significant and uncontrolled cardiac disease including unstable 
angina, acute myocardial infarction within 6 months prior to baseline, congestive heart 
failure, and arrhythmia requiring therapy, with the exception forof extra systoles or 
minor conduction abnormalities and controlled and well treated chronic atrial 
fibrillation; 
16. 
Significant hearing impairment; 
19.18. 
Male patients unwilling to use highly effective contraception, or women of 
childbearing potential (WOCBP) (see definition in Section 5.6) unwilling to use a highly 
effective form of contraception such as the following: 
o 
Combined (oestrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation2 (oral, intravaginal and transdermal) 
o 
Progestogen-only hormonal contraception associated with inhibition of 
ovulation2 (oral, injectable, or implantable) 
o 
Intrauterine devices 
o 
Intrauterine hormone-releasing system 
o 
Bilateral tubal ligation 
2 Hormonal contraception may be susceptible to interaction with the investigational 
medicinal product, which may reduce the efficacy of the contraception method. 
22.21. 
Inadequate liver function despite satisfactory endoscopic or percutaneous 
biliary tree stentingdrainage, defined as: 
o 
Serum (total) bilirubin persisting at >2.5 × the ULN for the institution 
o 
AST or ALT >3.0 × ULN (>5 × ULN if liver metastases are present) 
o 
ALP levels >5.0 × ULN; 
 
 
Section 4.2.1, Discontinuation From Study Treatment 
Study treatment will continue until a maximum of 8 gemcitabine/cisplatin chemotherapy 
cycles or objective disease progression or other criteria for discontinuation of treatment 
are met. A study patient is at any time free to discontinue study treatment prematurely at 
any time, without prejudice to further treatment. If so, the patient shall always be asked 


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about the reason(s) for treatment discontinuation, and the presence of SAEs and AEs. If 
AEs are ongoing, these will be followed up as detailed in the study plan. 
In addition, aA patient may be discontinued from study treatment in any of the following 
situations: ‘...’ 
 
 
Section 4.2.2, Withdrawal From Study 
In case of death, athe randomised patient will be considered withdrawn from the study. 
‘...’ 
Patients who choose to withdraw from the study shall always be asked about the 
reason(s) for withdrawal from study. Patients should always be asked specifically 
whether they would still allowconsent to be contacted for determination of survival 
follow-up. If patients who withdraw do not consent to survival follow-up, no further 
study procedures or follow up assessments will be performed following withdrawal, and 
no further data will be collected through patient interactions. 
For patients whose reason for withdrawal is not death, if permitted, determination of 
survival may be collected through publicly available death registry information, where 
permitted locally. 
 
 
Section 4.2.3, Handling of Discontinuations/Withdrawals 
Patients who discontinue study treatment or active participation in the study will no 
longer receive study treatment from the Sponsor. When a patient withdraws from the 
study treatment or active participation in the study, the reason(s) for withdrawal shall be 
recorded by the Investigator on the relevant page of the eCRF. Whenever possible, all 
Ppatients who discontinue study treatment prematurely will continue to be followed for 
objective radiological progression and survival. Patients who fail to return for final 
assessments will be contacted by the site (eg, 2 documented phone calls followed by 1 
registered letter) in an attempt to have them comply with the protocol. 
To achieve the goals of the study and maintain patient safety, iIt is vital to obtain 
follow-up data on any patient withdrawn from the study because of an AE or SAE. In 
every case, efforts must be made to undertake protocol-specified, safety, follow-up 
procedures. 
 
 
Section 4.2.3, Replacements 
Randomised patients who discontinue treatment or withdraw from the study will not be 
replaced. If a randomised patient is withdrawn, the patient identifier number will not be 
reused. 
All randomised patients must be included in the primary analysis under the principles of 
ITT and therefore collection of follow up data for patients who discontinue is important. 
 
 
Section 5.1, Method of Assigning Patients to Treatment Arms 
Upon completion of all screening evaluations to confirm eligibility to participate in the 
study, eligible patients will be randomised via the Interactive Web Response System 
(IWRS). The randomisation will be stratified by 2 factors: any measurable disease at 
baseline (yes versus no) and presence or absence of hepatic metastases. 
 
 
Section 5.2, Identity of Investigational Products/Background Standard of Care 
Treatment 
A single PCI treatment consists of IV administration of Amphinex solution for injection 
(dose 0.25 mg/kg fimaporfin-di-olamine, equivalent to 0.22 mg/kg fimaporfin), followed 
4 days later by gemcitabine IV infusion (1000 mg/m2) and bile duct intraluminal laser 


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light application (light dose 30 J/cm).  
Gemcitabine is currently not licensed for the treatment of patients with advanced 
inoperable CCA, but it is part of the current recognised SoC therapy. 
 
 
Section 5.2.1.1, Fimaporfin-Associated Photosensitivity 
All patients who receive Amphinex (fimaporfin) are expected to become temporarily 
photosensitive and must take precautions to protect the skin and the eyes in order to 
prevent photosensitivity reactions.  
Data from clinical studies (studies PCI 101-06, PCIA 202-10 and PCIA 202-12) 
showed that all photosensitivity-related AEs were mild or moderate. No severe AEs 
related to photosensitivity were reported among 41 subjects treated in those studies 
with the same dose of fimaporfin that is given in the current study.  
Based on non-clinical data (Gederaas et al 2017) it is expected that fimaporfin 
photoactivation properties are diminished upon exposure to light (“bleaching” 
effect) and therefore aA gradual return to normal light conditions is 
requiredrecommended to shorten the time of light sensitivity. ‘...’ 
• 
Operators and persons assisting during the treatment must wear glasses 
protecting against the laser emission wavelength 652 nm (green glasses). Patients must 
wear glasses that protect against laser emission wavelength, and all wavelength that 
activates fimaporfin, ie, ultravisible and visible light (dark glasses). The laser and 
eyewear will be provided by the Sponsor. ‘...’ 
For at least 4 weeks Ffollowing Amphinex injection, precautions must should be taken 
for at least 4 weeks to avoid exposure of skin and eyes to direct sunlight or bright 
indoor light.  
In Table 1, the following changes were made: 
Day 2-7: ‘...’ 
The type of clothes and accessories the patient must wear are: 
• 
Wide-brimmed hat: for head, neck, face, nose and ears 
• 
Scarf: for head and neck 
• 
Dark glasses with side panels: for eyes and skin around eyes  
• 
Long sleeved top: for upper body/arms 
• 
Long trousers: for lower body/legs 
• 
Gloves: for hands, wrist and fingers 
• 
Socks: for feet and ankles 
• 
Closed shoes: for feet 
• 
An umbrella/parasol can give additional protection 
Skin photosensitivity reactions are caused by visible light. Sunscreens that protect from 
ultraviolet light will not protect from visible light. Dark, tightly woven clothing should 
be worn. Very thin clothing will not protect from strong light. 
If exposed to excessive bright light, the patient may feel a burning sensation on the skin. 
The patient must move away from the light source immediately. If a photosensitivity 
reaction develops, contact the Clinical Investigator for advice (see below). 
Day 8-15: ‘...’ 
If exposed to excessive bright light, the patient may feel a burning sensation on the skin. 
The patient must move away from the light source immediately. If a photosensitivity 


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reaction develops, contact the Clinical Investigator for advice (see below). 
 
 
Section 5.2.5, Light Source 
Laser light is used to activate fimaporfin. The light source used in this study will be 
supplied by PCI Biotechthe Sponsor and is a CE marked medical laser system, emitting 
red light at 652 nm. A fibre-optic cylindrical light diffuser is connected to the laser 
system and inserted into a n ERCP or percutaneous transhepatic cholangiography 
catheter during laser light application. The cylindrical light diffuser and catheter to be 
used will be provided by the Sponsor. The monitor will verify that the laser light 
application procedure is correctly documented and recorded in the eCRF. Laser light 
source handling is performed according to the laser system Instructions for Use. 
Performance of the laser system after treatment of each patient must be adequately 
documented and recorded in the eCRF (did the laser system perform as intended? 
yes/no). Operators should adhere to safety instructions provided. ‘...’ 
Placement of the cylindrical light diffuser inside the ERCP catheter, both of which will 
be provided by the Sponsor, is described in the Procedure Manual. The entire stenosis 
should be illuminated. 
 
 
Section 5.2.6.2, Dose Modifications for Systemic Chemotherapy Cycles 
Renal toxicity: The creatinine clearance must be ≥ 60 mL/min in order to administer the 
full dose of cisplatin. Serum creatinine should be checked before each cycle of 
treatment. If there is a >25% increase of serum creatinine compared to the baseline, then 
the ethylenediamine tetraacetic acid (EDTA) clearance (or equivalent, including 
estimation of GFR, according to local practice) must be performed. 
 
 
Section 5.5.1, Permitted Treatments 
Patients will be allowed to receive supportive care therapies (including cytokine growth 
factors) concomitantly during the study. Other than the chemotherapy given during the 
course of the study, the use of any other chemotherapy, immunotherapy, radiation 
therapy, or experimental medications is prohibited during the study treatment period. 
Patients with prostate cancer that is controlled by hormone therapy may continue that 
therapy while on study. Disease progression requiring other specific anti-tumour therapy 
will be cause for discontinuation from the study treatment. ‘...’ 
Any prior, concurrent, or procedural medications or therapy given to or taken by the 
patient will be recorded in the eCRF along with the indication for its use. All 
concomitant medication taken from the time that the informed consent form (ICF) is 
signed, until 30 days after end of treatment, will be recorded in the eCRF. The date 
of first administration and reason for use will be recorded in the eCRF. Major 
changes in dose, schedule, or reason for use will also be recorded in the 
eCRF.should be recorded for up to 4 weeks following the last protocol treatment. ‘...’ 
All concomitant medication taken during the study, from the time that the informed 
consent form (ICF) is signed, until 30 days following the last dose of chemotherapy, will 
be recorded in the eCRF. The date of first administration and reason for use will be 
recorded in the eCRF. Major changes in dose, schedule, or reason for use will also be 
recorded in the eCRF. 
 
 
Section 5.5.2, Prohibited Therapies 
The following therapies are prohibited during the course of the study treatment period: 
• 
Phenytoin 
• 
Anti-cancer treatment other than the study treatments. Hormone therapy 


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for prostate cancer that started before randomisation is allowed to continue during 
the study. 
• 
Any experimental treatment other than PCI treatment. 
 
 
Section 5.6, Contraception 
Only men with pregnant or non-pregnant partners considered of childbearing potential 
will need to follow contraception requirements. A condom is also required to be used by 
vasectomised men to prevent delivery of the drug via seminal fluid. As the treatment 
includes genotoxic investigational medicinal products, the male patient should use 
condoms during treatment and until the end of relevant systemic exposure in the male 
patient (at least 9 months after last dose of Amphinex or 6 months after last dose of 
chemotherapy, whichever is the latest), plus a further 90 days. 
 
 
Section 6.1.1, Tumour Assessments 
The study will evaluate tumour responses as determined by Investigator according to 
RECIST 1.1. Efficacy assessments of PFS, ORR, DoR, and DCR will be derived using 
Investigator RECIST 1.1 assessments. The primary PFS analysis will be based on the 
local radiological assessment, which will be used to guide clinical management 
decisions. Note: iIn cases of symptomatic progression, patients will continue to be 
followed for radiological RECIST progression. ‘...’ 
The local radiological assessment will be used to guide clinical management decisions 
and will be the basis for. Tthe primary analysis of PFS and the secondary RECIST 1.1-
based endpoints will also be based on the local radiological assessment. In addition, an 
blinded independent central radiological review (BICR), blinded to the assessment of 
the local radiologist and/or oncologist, will be performed for the tumour response data. 
The data from the independent central reviewer(s) BICR will provide data for thea 
supportive analysis of PFS. For the interim analysis of ORR, the assessment made 
by the BICR will be considered the primary analysis. ‘...’ 
Additional survival contacts (ie, outside of the 12 weekly calls) may be conducted 
around the time of interim ORR analysis and final PFS analysis at data cut-off to ensure 
that the survival information is as up to date as possible for the analysis of OS. 
Determination of survival may be collected through publicly available death registry 
information, where permitted locally.  
<Other minor administrative updates were made.> 
 
 
Section 6.2, Pharmacokinetic Assessments 
Blood samples (each 5 mL) for PK analysis will be collected into EDTA collection tubes 
with sodium citrate. Plasma sSamples will be shipped to the designated bioanalytical 
laboratory for quantification of plasma fimaporfin concentrations using a validated 
analytical method. 
Details concerning handling of the PK serum plasma samples, including labelling and 
shipping instructions, will be provided in the study Laboratory Manual. 
 
 
Section 6.3, Standard Tumour Markers and Exploratory Biomarkers 
Section 6.3.1 
Standard Tumour Markers 
6.3.2 
Exploratory Biomarkers 
Blood samples (20 mL) for exploratory biomarkers in plasma will be collected at 
baseline and at approximately 3-month intervals throughout the study. Samples will be 
banked for a collective post hoc analysis, enabling an evaluation of the relative 


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importance and covariance of various biochemical changes to treatment outcome in the 2 
study arms. As described in Section 6.3.1, traditional tumour diagnostic markers may 
exhibit low sensitivity and there is an urgent need for novel, more sensitive, and easy to 
detect biomarkers which can be used in cancer diagnosis and prognosis. For example, 
cell free nucleic acids such as microRNA (a type of small non-coding RNA molecule) 
may have a potential application as specific and sensitive biomarkers for clinical 
diagnosis or prognosis. As the study is well-sized in consideration of this rare cancer 
population, an exploratory assessment of changes in known and novel biomarkers over 
time, and with treatment, is highly motivated. 
 
 
Section 6.4.1.4, Reporting Adverse Events 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs. These data will be captured as 
efficacy assessment data only. In most cases, the expected pattern of progression will be 
based on RECIST 1.1. In rare cases, the determination of clinical progression will be 
based on symptomatic deterioration. However, every effort should be made to document 
progression through the use of objective criteriaradiologically. If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported as 
an AE. 
 
 
Section 6.4.3.1, Safety Laboratory Analyses 
a 
Serum creatinine should be checked before each cycle of treatment. If there is a 
>25% increase compared to the baseline, then the ethylenediamine tetraacetic acid 
(EDTA) clearance or equivalent method, including estimation of GFR, according to 
local practice, must be performed and cisplatin dosing modified accordingly. 
Analysis of exploratory biomarkers in plasma was removed from Table 7 and the total 
blood volume updated for each arm. 
 
 
Section 6.4.6, Electrocardiograms 
After paper ECGs have been recorded, the Investigator or designated physician will 
review each of the ECGs and may refer to a local Cardiologist if appropriate. A signed 
and dated paper copy, with relevant results noted by the Investigator, should be filed in 
the patient’s medical records. If an abnormal ECG finding at screening is considered to 
be clinically significant by the Investigator, it should be reported as a concurrent 
condition. For all ECGs, details of rhythm, PR, R-R, QRS and QT intervals and an 
overall evaluation will be recorded. Corrected QT intervals will be calculated using 
Bazett’s formula (QTcB) and Fridericia’s formula (QTcF). 
The ECG on Day -4 and on Cycle 4, Day 18 must be performed before and 
approximately 30 minutes and 4 hours after Amphinex administration. 
 
 
Section 6.4.7, Photosensitivity Measurements and Skin Reactions 
In both study arms, skin reactions and photosensitivity reactions will be 
documented as AEs in the eCRF and coded using MedDRA and followed to 
adequate resolution.Patients in Arm A who receive Amphinex will be photosensitive 
and must observe precautions to avoid exposure of skin and eyes to prevent 
photosensitivity reactions (Table 1) according to the instructions in the patient guidance 
document. The written instructions must be reviewed and explained verbally to each 
patient and allow for questions and answers to ensure proper understanding of the 
instructions. Photosensitivity reactions will be documented and coded (using MedDRA) 
as AEs and followed to adequate resolution. 


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For patients in both treatment arms, skin reactions will be documented and recorded in 
the eCRF. 
 
 
Section 6.4.9, Physical Examinations 
A complete physical examination with weight and body surface area, will be performed. 
Height will be recorded at screening only. Body surface area will be calculated. 
 
 
Section 7.2.2, Best Overall Response 
The BOR is the best response recorded from the start of the treatment until disease 
progression/recurrence (using the smallest measurements recorded since the treatment 
started as reference for progressive disease). 
 
 
Section 7.2.3, Objective Response Rate 
The ORR is calculated as the proportion of patients with measurable disease at baseline 
who have at least one visit response with a CR or PR noted. 
 
 
Section 7.2.4, Duration of Response 
The DoR is defined as the time from the first documented tumour response until the first 
documentedradiological disease progression, or death in the absence of disease 
progression. 
 
 
Section 7.2.9, Quality of Life Assessments 
An evaluation and comparison of HRQoL/PRO associated with the fimaporfin-induced 
PCI of gemcitabine complemented by systemic gemcitabine/cisplatin chemotherapy 
versus gemcitabine/cisplatin alone, will be conducted by use of EORTC QLQ-30 and 
QLQ-BIL21. 
 
 
Section 7.3, Exploratory Endpoints 
The following exploratory endpoints will be evaluated in this study: 
• 
Tumour response (ORR, DCR, and PFS) by location of disease, as pre-defined 
further in the SAP, including: 
o 
Loco-regional tumour control 
o 
Metastatic lesions within the liver parenchyma 
o 
Other metastatic lesionsLocal lymph nodes 
• 
To analyse blood samples for standard tumour markers and exploratory 
biomarkers. 
 
 
Section 7.4, Sample Size Calculations 
Approximately 186 patients with inoperable CCA will be randomised in a 1:1 ratio 
(fimaporfin-induced PCI of gemcitabine complemented by gemcitabine/cisplatin 
chemotherapy versus gemcitabine/cisplatin chemotherapy alone) to this study. The 
primary (final) analysis of PFS, as assessed by local radiological review, will be 
conducted when approximately 129 progression events (69% maturity) have been 
observed. If the PFS result is statistically significant at the 43.95% (2-sided) alpha level 
(adjusted for interim analysis of ORR), ORR will be compared between the arms and 
an interim analysis of OS will then be assessed, as detailed in Section 7.7.7.  
If the true HR for the comparison of fimaporfin-induced PCI of gemcitabine 
complemented by gemcitabine/cisplatin chemotherapy versus gemcitabine/cisplatin 
chemotherapy alone is 0.6, 129 progression events will provide approximately 80% 
power to demonstrate a statistically significant difference in PFS at a 43.95% 2-sided 
significance level (this may translate to an improvement in median PFS from 7.4 to 12.3 


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months, if PFS is exponentially distributed). A minimum or critical HR of 0.697 (eg, 7.4 
to 10.76 months), if observed, would give a 2-sided p<0.03954, but there is only 50% 
power associated with the critical HR. ‘...’ 
In addition to the interim analysis of OS at the time of the final PFS analysis 
(approximately 58% of patients are predicted to have died at this point), data collection 
for OS will continue beyond the final PFS analysis and an updated OS analysis will be 
performed. The final OS analysis will occur after approximately 147 death events have 
been observed in 186 patients (>75% maturity). Assuming a true OS HR of 0.63, there 
will be 80% power to detect an improvement in median OS from 11.7 to 18.7 months 
with 2-sided p<0.04476 (O’Brien and Fleming boundary adjusted for 2 interim 
analyses of based on interim OS at approximately 103 events). A minimum or critical 
HR of 0.72 (eg, 11.7 to 16.3 months), if observed, would be statistically significant. The 
exact level of maturity will be determined based on the final PFS and interim OS results, 
in discussion with the regulatory authorities. The 147 death events are expected to occur 
at approximately 6563 to 6866 months from first patient randomised. 
 
 
Section 7.5, Analysis Sets 
The following analysis sets will be used in the statistical analyses. ‘...’ 
• 
The Evaluable for Response analysis set is a subset of the ITT analysis set that 
includes all randomised patients who have measurable disease at study entry. 
The Evaluable for Response analysis set will be used for summaries of ORR, 
DoR, and change in tumour size. 
 
 
Section 7.6, Description of Subgroups to be Analysed 
Subgroup analyses will be performed for the stratification factors used at the point of 
randomisation (measurable disease – yes versus no and presence or absence of hepatic 
metastases). Exploratory subgroup analyses will also be performed to assess key 
endpoints by loco regional tumour control, metastatic lesions and local lymph 
nodeswithin the liver parenchyma, and other metastatic lesions. Four distinct groups will 
be explored: primary; primary with liver metastases; primary with local lymph nodes; 
and primary with liver metastases and local lymph nodes. An additional subgroup 
analysis will be performed to compare patients with and without PSC at study entry. If 
there are too few events available for a meaningful analysis of a particular subgroup (it 
is not considered appropriate to present analyses where there are less than 20 events per 
level in a subgroup), the relationship between that subgroup and PFS/OS will not be 
assessed. In this case, only descriptive summaries will be provided. Further details and 
any other exploratory subgroups of interest will be provided in the SAP. 
 
 
Section 7.7.1, Analysis of Primary Endpoint 
Progression-free survival, as assessed by local radiological review, will be analysed 
using a log rank test stratified by any measurable disease at baseline (yes versus no), and 
presence or absence of hepatic metastases. If these 2 stratification factors lead to low 
numbers (eg, <510 progression events) within a single stratum, data will be pooled 
across strata in the stratified analyses one or more stratification factors may be 
removed from the statistical analysis. The criteria for removal pooling will be pre-
defined in the SAP.  
The HR will be estimated using a stratified Cox proportional hazards model using the 
Efron approach for handling ties (Efron 1977), together with the associated profile 
likelihood 95% CI for the HR based on the Wald method. ‘...’ 


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A Kaplan-Meier (KM) plot of PFS will be presented by treatment group. Median PFS 
with 95% CIs will be presented. In addition, KM landmark PFS estimates at 6 months 
and 12 months with corresponding CIs will also be presented using KM methodology. 
KM estimates may be presented for other timepoints of interest. The assumption of 
proportionality will be assessed. In the event of non-proportionality, the HR will be 
interpreted as an average HR over the observed extent of follow-up. Proportionality will 
be tested firstly by examining the plots of complementary log-log (event times) versus 
log (time) and, if necessary, a time dependent covariate will be fitted to assess the extent 
to which this represents random variation. 
 
 
Section 7.7.2.1, Overall Survival 
Data collection for OS will continue beyond the final PFS analysis and an updated OS 
analysis will be performed. 
 
 
Section 7.7.2.2, Best Overall Response 
Summaries of BOR will also be repeated using the BICR data. Furthermore, two-by-two 
tables will be produced to describe the consistency between the BICR and local 
evaluation assessment for BOR (and also the timing of PD to show how often the 
investigator declares PD at the same time, before or after the BICR). 
 
 
Section 7.7.2.3, Objective Response Rate 
The ORR will be summarised using the Evaluable for ResponseITT analysis set (ie, all 
randomised patients who have measurable disease at study entry). ORR will be 
compared between treatment arms using a Cochran-Mantel-Haenszel (CMH) test 
stratified by presence of any measurable disease at baseline (yes versus no), and 
presence/absence of metastases at baseline (1 or 0). logistic regression model with the 
covariate (stratification factor) of hepatic metastases. However, if there are <10 patients 
within a stratum, this stratification factor will be removed from the statistical analysis. 
In addition to presenting the ORR and associated exact 95% CI for each treatment 
arm, the treatment effect will be described using the CMH estimate of the common 
odds ratio together with its associated 95% CI (Emerson 1994). 
As sensitivity analyses, the ORR will be further summarised by measurable/non-
measurable disease at entry (as integrated directly from the IVRS to the eCRF) and 
compared between the arms using the CMH test stratified by presence/absence of 
metastases at baseline (1 or 0). The ORR analyses will also be repeated using the 
mITT analysis set. 
The results of the analysis will be presented in terms of an odds ratio together with its 
associated 95% profile likelihood CI. The p-value will be based on a test statistic that is 
calculated as twice the change in log-likelihood resulting from the addition of a 
treatment factor to a model that contains the covariates defined above. The test statistics 
is chi-squared distributed with 1 degree of freedom. 
 
 
Section 7.7.2.4, Duration of Response 
The DoR is calculated only for those with a documented response of CR or PR and 
is defined as the time from the date of first documented tumour response until the 
first date of radiological disease progression or death, whichever is earlier. If a 
patient does not progress following a response, then their DoR will be censored at the 
PFS censoring time. The DoR will not be defined for those patients who do not have 
documented responses. The DoR will be summarised for the ITT analysis set. 
The DoR will be summarised using the Evaluable for Response analysis set (ie, all 


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randomised patients who have measurable disease at study entry). 
 
 
Section 7.7.2.6, Change in Tumour Size 
The change in tumour size will be summarised for patients with measurable disease at 
study entrythe Evaluable for Response analysis set. Summaries and waterfall plots 
indicating best percentage change from baseline in the sum of the diameters of target 
lesions will be produced. Bars will be differentially shaded by RECIST 1.1 response. 
 
 
Section 7.7.2.7, Blinded Independent Central Review 
For each patient, the BICR will define the overall visit response (ie, the response 
obtained overall at each visit by independently assessing target lesions, non-target 
lesions and new lesion data). If a patient has had a tumour assessment that cannot 
be evaluated then the patient will be assigned a visit response of NE (unless there is 
evidence of progression in which case the response will be assigned as PD; for 
example, if the target lesions are NE but there is evidence of a new lesion).   
A BICR will be performed for the interim analysis of ORR (primary data), which 
will cover all scans up to the data cut-off for the interim analysis, and for the final 
database lock for PFS, which will cover all of the scans up to the data cut-off 
(supportive data).  
Endpoints (ORR, BOR, PFS, and DoR) will be derived programmatically using the 
visit responses provided by the BICR. 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 1.1 assessment conducted by the Investigator. 
Cross-tabulations will be produced to describe the consistency between the BICR 
and local Investigator assessment for the following: 
• 
Best overall response 
• 
Timing of PD 
o 
Early discrepancy rate (EDR): the frequency at which the local 
review declares progression early relative to the BICR in each arm 
as a proportion of the total number of locally assessed 
progressions; and 
o 
Late discrepancy rate (LDR): the frequency at which the local 
review declares progression later than the BICR in each arm as a 
proportion of the total discrepancies in each arm.  
The EDR and LDR will be calculated for each treatment arm and the differential 
discordance will be summarised as the rate on the experimental arm minus the rate 
on the control arm. If the discrepancies are similar between the arms, this suggests 
an absence of evaluation bias that favours one arm. A negative differential 
discordance for the EDR and/or positive differential discordance for the LDR may 
be indicative of bias in the local evaluation favouring the experimental arm (Amit 
et al 2011).   
Analyses of PFS by BICR will be described in the SAP. 
 
 
Section 7.7.7, Interim Analyses 
A formal interim analysis of ORR will be performed after approximately 120 patients 
(65%) have been randomised and followed to their first 12-week follow-up scan 
(estimated to be at approximately 39 months from first patient dosed). Based on an 
assumption that ~80 patients will have measurable disease, tThere will be >80% power 


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to detect an improvement in ORR from 2015% to 5745% with 2-sided p<0.0105 
(approximates an O’Brien and Fleming boundary based on 65% information). An 
minimum improvement from 2015% to 4738% will be statistically significant, if 
observed. If the comparison of the interim ORR data between the arms based on a 
CMH test is statistically significant, OS data will be formally compared between the 
arms and it will be summarised together with PFS and DoR to support a conditional 
marketing authorisation application. PFS and DoR will be summarised descriptively 
with no formal comparison of PFSSurvival data will be limited at this point and will 
be summarised descriptively. 
Three analyses of OS will be performed: at the time of the interim ORR analysis, at 
the time of the PFS assessment and at an updated (final) analysis.An interim analysis 
of OS will be performed at the time of the final PFS assessment when approximately 
103 patients are predicted to have died. A 2-sided p<0.015 will be required to 
demonstrate statistical significance. 
 
 
Section 7.7.7.1, Multiplicity and Control of Type 1 Error 
The multiple testing procedure will strongly control the Type I error probability 
(alpha) at 5% (2-sided) amongst the key efficacy endpoints (PFS, ORR, OS). Strong 
control of alpha ensures that the probability of rejecting any (ie, one or more) true 
null hypothesis, in either direction, is at most 5%, irrespective of how many and 
which null hypotheses are true or false 
At the interim and final analysis points, the key endpoints will be tested in a 
hierarchical order as shown in Figure 4. If any previous analysis in the sequence is 
not statistically significant, the alpha cannot be transferred to subsequent 
endpoints. Note: A non-statistically significant ORR result at the interim analysis 
will not preclude testing of PFS at the final analysis. 
An interim analysis of ORR will be conducted after 120 out of 186 patients have 
been randomised (65% information) and 1.05% of alpha will be spent on the 
comparison of ORR, based on an O’Brien and Fleming spending function.   
In the case both null hypotheses are true (ie, there is no true difference between the 
arms, neither for ORR nor for PFS) and assuming independence between these 2 
endpoints, the final significance level for PFS can be set at 3.95%.  
In the event that the null hypotheses for both ORR and PFS are false, alpha needs 
to be controlled at 5% over the 3 planned OS analyses; for example, assuming 55 
death events (37% information) at the first analysis, 108 death events (73% 
information) at the second analysis and 147 death events (100% information) at the 
final OS analysis, the significance levels according to a Lan and De Mets O’Brien 
and Fleming spending function (Lan and de Mets 1983) will be 0.05%, 1.73% and 
4.47%, respectively. 
The exact significance levels will be adjusted for the actual information fractions. 
In order to provide strong control of the type I error rate at the 2-sided 5% level, the 
primary endpoint of PFS and key secondary endpoints of ORR and OS will be tested in 
this sequential (hierarchical) order at the time of the primary analysis. If any previous 
analysis in the sequence is not statistically significant, the alpha cannot be transferred to 
subsequent endpoints (ie, the multiple testing procedure will recycle the test mass to the 
endpoint not yet rejected in the hierarchy outlined in Figure 4). 
The interim analysis of ORR will be conducted after approximately 120 out of 186 
patients have been randomised. Assuming 65% information at the interim, statistical 


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significance will be declared for ORR if 2-sided p<0.01, which approximates an O’Brien 
and Fleming spending function. 
The remaining 2-sided alpha of 4% will be spent at the final PFS analysis, which will be 
triggered after approximately 129 progression events. Note, a non statistically significant 
ORR result at the interim analysis will not preclude testing of PFS at the final analysis. 
If the final PFS is statistically significant at 2-sided p<0.04, the alpha will be recycled to 
ORR. If both are significant, an interim analysis of OS at the full 5% alpha will be 
performed. Statistical alpha will be shared across the interim and final assessments of 
OS using the Lan DeMets approach. Assuming 70% information (number of events at 
interim / number of events at final analysis) at the interim, statistical significance will be 
declared for interim OS if 2-sided p<0.015, based on an O’Brien and Fleming spending 
function. The exact significance levels will be adjusted for the actual information 
fractions. 
Figure 4 was updated:  
 
Abbreviations: ORR, objective response rate; OS, overall survival; PFS, progression-free survival. 
*O’Brien and Fleming boundary based on 5% alpha and approximately 70% information at 
interim (assumes 103/147 deaths at interim) 
 
 
Section 8.1, Data Management 
Clinical data management will be performed in accordance with applicable PCI 
BiotechPPD standards and data cleaning procedures to ensure the integrity of the data, 
eg, removing errors and inconsistencies in the data. 
 
 
Section 11.2.2, Protocol Deviations 
Significant protocol deviations for this study may include 1) use of prohibited 
concomitant medications during the study treatment period, 2) tumour assessments 
(RECIST) for screening not performed within 28 days prior to randomisation, 3) patients 
who received the wrong treatment, etc. 
 
 
Section 12, Reference List 
The following 4 references were added: 
Amit O, Mannino F, Stone AM, et al. Blinded independent central review of 
progression in cancer clinical trials: results from a meta-analysis. Eur J Cancer. 
2011;47(12):1772-8. 
Emerson JD. Combining estimates of the odds ratio: the state of the art. Stat 
Methods Med Res. 1994;3(2):157-78. 
Gederaas OA, Johnsson A, Berg K, et al. Photochemical internalization in bladder 
cancer – development of an orthotopic in vivo model. Photochem Photobiol Sci. 
2017;16(11):1664 76. 
Lan KKG and DeMets DL. Discrete sequential boundaries for clinical trials. 
Biometrika. 1983;70(3):659–63. 
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: 


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Hepatobiliary Cancers. Version 4. 2020 – August June 19 1, 202019. 
 
 
Appendix A, Table 10 
The following changes were made to the schedule of events:  
• 
Removed the rows for biomarker assessments and exploratory biomarkers. 
• 
“Background” was replaced with “SoC”. 
• 
A new footnote “a” was added: Patients who have started gemcitabine/cisplatin 
treatment before the screening period should continue their treatment as 
scheduled, including during the screening period. Study visits should be 
synchronised with ongoing SoC chemotherapy. Study cycles will be counted for 
all patients from first treatment after enrolment (PCI treatment No. 1). 
Chemotherapy cycles will be counted from first chemotherapy treatment and 
cannot exceed 8 cycles. 
• 
Footnote “b”: Screening evaluations are to be performed after the patient has signed 
and dated the informed consent form and within 2114 days prior to randomisation. 
Tumour assessment may be performed within 28 days prior to randomisation. 
Histology/cytology is to be performed/confirmed before randomisation. 
• 
Footnote “d”: A second PCI treatment procedure aimed at the initiation of Cycle 5 
or, if patient-related factors demand postponement, at initiation of a later cCycle 6, 
7 or 8 (Section 3.3.2). The PCI treatments must be separated by at least 3 
months. 
• 
Footnote “e”: Biliary stenting is to be performed on all patients according to local 
practice; however, the chosen stent must be of an exchangeable (plastic) type until 
radiological progression is declared. Stenting may be performed at any time from 
confirmation of histological/cytological diagnosis until immediately after the first 
laser light application. Patients who have already undergone stenting before 
screening should be reviewed to ensure the stent is of an acceptableplastic type, 
correctly positioned and adequate liver drainage confirmed. Stents must be removed 
for the laser light application, and a new stent must be placed immediately after 
light application. Stent removal, laser light application, and stent replacement will 
take place during the same ERCPone procedure. 
• 
Footnote “j”: Standard 12 lead ECG. Tracings must be interpreted, dated, and 
signed by the Investigator or his/her designee and filed with the patient’s source 
documents. On Day -4 and Cycle 4, Day 18, the ECG will be time matched with PK 
samples: For PK Group 1, ECG will be performed before, approximately 30 
minutes after, and approximately 4 hours after Amphinex administration, and for 
PK Group 2, ECG will be performed before Amphinex administration. 
• 
Footnote “s”: A creatinine clearance at baseline is required. Creatinine clearance 
prior to treatment should be ≥60 mL/min. Serum creatinine should be checked 
before each cycle of treatment. If there is a >25% increase in serum creatinine 
compared to the baseline, then the ethylenediamine tetraacetic acid (EDTA) 
clearance or equivalent, including estimation of GFR, according to local practice, 
method must be performed and cisplatin dosing modified accordingly. 
• 
Footnote “v”: PK samples will be collected from all patients in Arm A. Group 1: the 
20 first patients randomised to Arm A; Group 2: all other patients randomised to 
Arm A. On Day -4 and Cycle 4, Day 18, the PK samples will be time matched with 
ECG: For PK Group 1, PK sampling and ECG will be performed before, 


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approximately 30 minutes after, and approximately 4 hours after Amphinex 
administration; for PK Group 2, PK sampling and ECG will be performed before 
Amphinex administration, only ECG will be performed 30 minutes after and 
approximately 4 hours after Amphinex administration.  
• 
Footnote “w”: Blood samples (20 mL) for exploratory biomarkers in plasma will be 
collected at baseline and at approximately 3-month intervals throughout the study. 
• 
Footnote “x”: Laser light application procedure is to be performed 3 hours (±1 hour) 
after end of the gemcitabine administration. It is expected that all pPatients will 
may be admitted for overnight follow-up hospitalised for one night after the 
ERCP/laser light applications and related procedures on Day 1 of Cycle 1 and 
Day 1 of Cycle 5. 
 
 
Appendix A, Table 11 
The following changes were made to the schedule of events:  
• 
Removed the rows for biomarker assessments and exploratory biomarkers. 
• 
“Background” was replaced with “SoC”. 
• 
A new footnote “a” was added: Patients who have started gemcitabine/cisplatin 
treatment before the screening period should continue their treatment as 
scheduled, including during the screening period. Study visits should be 
synchronised with ongoing SoC chemotherapy. Chemotherapy cycles will be 
counted from first chemotherapy treatment and cannot exceed 8 cycles. 
• 
Footnote “b”: Screening evaluations are to be performed after the patient has signed 
and dated the informed consent form and within 2114 days prior to randomisation. 
Tumour assessments may be performed within 28 days prior to randomisation. 
Stenting and histology/cytology are to be performed/confirmed before 
randomisation. 
• 
Footnote “d”: Biliary stenting is to be performed on all patients according to local 
practice; however, the chosen stent must be of an exchangeable (plastic) type until 
radiological progression is declared. Stenting may be performed at any time from 
confirmation of histological/cytological diagnosis until immediately after the first 
laser light application. Patients who have already undergone stenting before 
screening should be reviewed to ensure the stent is of an acceptableplastic type, 
correctly positioned and adequate liver drainage confirmed.  
• 
Footnote “p”: A creatinine clearance at baseline is required. Creatinine clearance 
prior to treatment should be ≥60 mL/min. Serum creatinine should be checked 
before each cycle of treatment. If there is a >25% increase in serum creatinine 
compared to the baseline, then the ethylenediamine tetraacetic acid (EDTA) 
clearance or equivalent, including estimation of GFR, according to local 
practice, method must be performed and cisplatin dosing modified accordingly. 
• 
Footnote “s”: Blood samples (20 mL) for exploratory biomarkers in plasma will be 
collected at baseline and at approximately 3-month intervals throughout the study. 
 
 
Appendix B, Table 12 
The following changes were made to the schedule of events:  
• 
Removed the row for exploratory biomarkers 
• 
Record details of subsequent anti-cancer therapy was added to the tumour response 
follow-up of the follow-up period 


PCI Biotech AS 
Amphinex 
Protocol: PCIA 203/18 Final/3.0 (Global Amendment 2) 
13 Jul 2020 
 
Page 203 
Versio
n 
Date 
Changes 
• 
Footnote “h” was deleted: To be recorded as long as the patient has not withdrawn 
the consent.