Clinical trial NCT03694522
Conditions: Gastric Cancer
Sponsor: Five Prime Therapeutics, Inc.
Start date: 2018-09-14; Completion date: 2022-05-13
Enrollment: 155 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective of the Phase 2 part of the study is to evaluate the efficacy of bemarituzumab (FPA144), a targeted antibody, in combination with modified FOLFOX6 compared to placebo in combination with modified FOLFOX6 in participants with advanced gastrointestinal cancer.

Detailed description:
Study FPA144-004 is a phase 1/2, multicenter, global, double-blind, randomized, controlled study designed to evaluate the safety, tolerability, efficacy, and pharmacokinetics (PK) of bemarituzumab in combination with mFOLFOX6, compared with placebo in combination with mFOLFOX6, in adults with unresectable, locally advanced, or metastatic gastric cancer including cancer of the gastroesophageal junction (GEJ).

This study includes a Phase 1 safety run-in portion and a Phase 2 portion. The Phase 1 safety run-in is an open-label dose-escalation of bemarituzumab + mFOLFOX6 in patients with GI tumors (not FGFR2 selected) that is reported separately (NCT03343301).

The Phase 2 portion of the study (to follow the Phase 1 safety run-in) is described in this record.

Arms: arm 1: Participants received 15 mg/kg bemarituzumab administered every 2 weeks (Q2W) with a single additional bemarituzumab 7.5 mg/kg dose on cycle 1 day 8. Participants also received mFOLFOX6 chemotherapy administered Q2W. Treatment continued until unacceptable toxicity, disease progression, or death. arm 2: Participants received placebo for bemarituzumab administered every 2 weeks with a single additional placebo dose on cycle 1 day 8. Participants also received mFOLFOX6 chemotherapy administered Q2W. Treatment continued until unacceptable toxicity, disease progression, or death.
Interventions: intervention 1: Bemarituzumab intervention 2: Placebo intervention 3: Modified FOLFOX6
Intervention descriptions: intervention 1: Administered by intravenous infusion over approximately 30 minutes intervention 2: Administered by intravenous infusion over approximately 30 minutes intervention 3: mFOLFOX6 regimen consists of the following:

* Oxaliplatin 85 mg/m² IV infusion over 120 minutes
* Leucovorin 400 mg/m² IV infusion over 120 minutes, or 200 mg/m² levo-leucovorin if leucovorin is unavailable
* 5-fluorouracil (5-FU) 400 mg/m² bolus over approximately 5 minutes then 5-FU 2400 mg/m² as a continuous IV infusion over approximately 48 hours

Protocol documents:
Prot_000.pdf: 
FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
Page 1 of 139 
Confidential 
FIGHT: A Phase 2 Randomized, Double-Blind, Controlled Study 
Evaluating FPA144 and Modified FOLFOX6 in Patients with 
Previously Untreated Advanced Gastric and Gastroesophageal 
Cancer: Phase 2 Preceded by Dose-Finding in Phase 1 
Protocol Number: 
FPA144-004 
Investigational Product: 
FPA144 
IND Number: 
117701 
Development Phase: 
Phase 1/2 
Indication Studied: 
Advanced Gastric and Gastroesophageal Cancer 
Protocol Version: 
Amendment 4 
Date of Protocol: 
10 March 2021 
Supersedes 
Version 3, 05 June 2020 
Sponsor: 
Five Prime Therapeutics, Inc. 
111 Oyster Point Boulevard 
South San Francisco, CA 94080 
Tel: + 1 415-365-5600  
Responsible Medical 
Officer: 
, MD 
Chief Medical Officer  
Five Prime Therapeutics, Inc.  
111 Oyster Point Boulevard 
South San Francisco, CA 94080 
Confidential 
This document contains proprietary and confidential information of Five Prime Therapeutics, Inc. and may not be 
reproduced or disclosed in whole or in part without written authorization from Five Prime Therapeutics, Inc.  
NCT Number: NCT03694522
This NCT number has been applied to the document
for the purposes of posting on clinicaltrials.gov


FPA144-004 Clinical Protocol 
Amendment 4
10 Mar 2021
Page 2 of 139
Confidential 
Protocol Approval Signature Page 
Declaration of Sponsor 
FIGHT: A Phase 2 Randomized, Double-Blind, Controlled Study Evaluating 
FPA144 and Modified FOLFOX6 in Patients with Previously Untreated 
Advanced Gastric and Gastroesophageal Cancer: Phase 2 Preceded by 
Dose-Finding in Phase 1 
The study will be conducted according to the protocol and in compliance with Good Clinical 
Practice (GCP), the Declaration of Helsinki, and other applicable regulatory requirements.  
Essential study documents will be archived in accordance with applicable regulations. 
This study protocol was subjected to critical review.  The information it contains is consistent 
with current knowledge of the risks and benefits of the investigational product, as well as with 
the moral, ethical, and scientific principles governing clinical research as set out in the 
Declaration of Helsinki, 1989, and the International Conference on Harmonization (ICH) 
guidelines on GCP.  
, MD 
Chief Medical Officer 
Five Prime Therapeutics, Inc. 
Date 
10Mar2021
DocuSign Envelope ID: 20B82B7A-5340-49B0-8A1F-588EE5F9FDFE


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 3 of 139 
Confidential 
Declaration of the Investigator 
FIGHT: A Phase 2 Randomized, Double-Blind, Controlled Study Evaluating 
FPA144 and Modified FOLFOX6 in Patients with Previously Untreated 
Advanced Gastric and Gastroesophageal Cancer: Phase 2 Preceded by 
Dose-Finding in Phase 1 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence.  This documentation includes this study 
protocol, Investigator’s Brochure (IB), electronic case report forms (eCRFs), and other scientific 
data. 
The study will not be commenced without the prior written approval of a properly constituted 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC).  No changes will be 
made to the study protocol without the prior written approval of the Sponsor and the IRB or IEC, 
except as necessary to eliminate an immediate hazard to the patients. 
I confirm that I have read the above-mentioned protocol/protocol amendments and its 
attachments.  I agree to conduct the described trial in compliance with all stipulations of the 
protocol, applicable laws, regulations and ICH E6 Guideline for Good Clinical Practice (GCP). 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
Name (printed) 
 
 
 
 
 
Institution or Company Name 
 
 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 4 of 139 
Confidential 
Protocol Synopsis 
Title: 
FIGHT: A Phase 2 Randomized, Double-Blind, Controlled Study 
Evaluating FPA144 and Modified FOLFOX6 in Patients with 
Previously Untreated Advanced Gastric and Gastroesophageal 
Cancer: Phase 2 Preceded by Dose-Finding in Phase 1 
Protocol Number: FPA144-004 
Clinical Phase: 
1/2 
Sponsor: 
Five Prime Therapeutics, Inc. 
Study Centers: 
Up to approximately 190 global study centers  
Phase 1 
Objectives: 
Primary 
To determine the recommended dose (RD) of FPA144 combined with a 
fixed dose of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin 
(mFOLFOX6) (hereinafter referred to as FPA144 + mFOLFOX6) in 
patients with advanced gastrointestinal (GI) tumors 
Secondary  
• To evaluate the safety and tolerability of FPA144 + mFOLFOX6 in 
patients with GI tumors 
• To characterize the pharmacokinetic (PK) profile of FPA144 + 
mFOLFOX6 in patients with GI tumors 
• To characterize the immunogenicity of FPA144 
Exploratory 
Phase 2 
Objectives: 
Primary 
To compare investigator-assessed progression-free survival (PFS) in 
patients with fibroblast growth factor receptor 2 (FGFR2)-selected gastric 
or gastroesophageal cancer (GC) treated with FPA144 + mFOLFOX6, to 
those treated with placebo combined with mFOLFOX6 (hereafter referred 
to as placebo + mFOLFOX6) 
Secondary  
To compare the following in patients with FGFR2-selected GC treated 
with FPA144 + mFOLFOX6 to those treated with placebo + mFOLFOX6: 
• Overall survival (OS) 
• Investigator-assessed objective response rate (ORR)  
• Safety and tolerability 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 5 of 139 
Confidential 
Exploratory  
To compare the following in patients with FGFR2-selected GC treated 
with FPA144 + mFOLFOX6 to those treated with placebo + 
mFOLFOX6: 
• Duration of response (DOR)  
• Patient-reported outcomes (PROs) and quality of life (QOL) outcomes 
until investigator-assessed disease progression 
• To explore the association between FGFR2 status (in tumor tissue 
and/or blood) with clinical outcome 
• To explore the concordance between FGFR2b overexpression in tumor 
tissue and FGFR2 gene amplification in blood 
To characterize the following: 
• PK profile of FPA144 + mFOLFOX6 in patients with FGFR2-selected 
GC 
• Immunogenicity of FPA144 
Phase 1 
Endpoints: 
Primary 
The incidence of Grade 2 or higher adverse events (AEs) assessed as 
related to FPA144 by the investigator and the incidence of clinical 
laboratory abnormalities defined as dose-limiting toxicities (DLTs) 
Secondary  
• The incidence of AEs, clinical laboratory abnormalities, corneal and 
retinal findings, and electrocardiogram (ECG) abnormalities  
• PK parameters of FPA144, such as area under serum concentration-time 
curve (AUC), maximum serum concentration (Cmax), trough serum 
concentration (Ctrough), clearance (CL), terminal half-life (t1/2), volume 
of distribution, the time to achieve steady state, dose-linearity, and 
accumulation ratio 
• Incidence of treatment-emergent anti-FPA144 antibody response 
Exploratory  
Phase 2 
Endpoints: 
Primary 
Investigator-assessed progression-free survival (PFS), defined as time 
from randomization until the date of disease progression based on 
investigator assessment (using Response Evaluation Criteria in Solid 
Tumors version 1.1 [RECIST v1.1]) or death from any cause, whichever 
comes first  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 6 of 139 
Confidential 
Secondary  
• Overall survival (OS), defined as time from randomization until death 
from any cause  
• Objective response rate (ORR), defined as the proportion of patients 
with partial or complete response based on investigator assessment of 
tumor lesions per RECIST v1.1  
• Incidence of AEs, clinical laboratory abnormalities, corneal and retinal 
findings, and ECG abnormalities  
Exploratory  
• DOR limited to patients who are responders to treatment, as determined 
by the investigator per RECIST v1.1, and defined as the time of first 
response to progression or death from any cause, whichever comes first 
• Change from baseline in functional outcomes as measured by 
EuroQOL-5D-5L (EQ-5D-5L) and the European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire 
Version 3.0 (EORTC QLQ-C30) 
• The correlation between identified FGFR2 status in tumor tissue and/or 
circulating tumor DNA (ctDNA) blood assay, as determined by 
immunohistochemistry (IHC) and blood-based molecular diagnostic 
assay, with OS, PFS, and ORR per RECIST v1.1 
• The correlation between identified FGFR2b overexpression in tumor 
tissue by IHC and FGFR2 gene amplification as determined by ctDNA 
blood assay 
• Pharmacokinetic (PK) parameters, Cmax and Ctrough of FPA144 in 
combination with mFOLFOX6  
• Incidence of treatment-emergent anti-FPA144 antibody response 
Investigational 
Product 
FPA144 drug product is supplied for intravenous (IV) administration as a 
sterile, aqueous, colorless to slightly yellowish, pyrogen-free solution 
supplied in single-use glass vials.  The composition of the drug product 
contains 20 mg/mL active ingredient, 20 mM L-histidine, 270 mM 
sucrose, and 0.01% (w/v) polysorbate 20 at pH 6.0. 
mFOLFOX6: Leucovorin (or levo-leucovorin), 5-FU, and oxaliplatin 
will be obtained from Sponsor-approved commercial sources at each 
participating site.  Management (ie, handling, storage, administration, and 
disposal) of these products will be in accordance with the relevant local 
guidelines.  For countries where the Sponsor is required to provide all 
study drugs, including standard-of-care drugs, the Sponsor will provide 
leucovorin, 5-FU, and oxaliplatin from a commercial supply that is 
clinically labeled in accordance with relevant local guidelines.  For further 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 7 of 139 
Confidential 
details, refer to the manufacturer’s prescribing information for the 
respective chemotherapies and the study Pharmacy Manual. 
Placebo (only used in Phase 2) will match the FPA144 drug product.  
It will be supplied for IV administration as a sterile, aqueous, colorless to 
slightly yellowish, pyrogen-free solution supplied in single-use vials.  
The composition of matching placebo contains 20 mM L-histidine, 
270 mM sucrose, and 0.01% (w/v) polysorbate 20 at pH 6.0. 
Administration of Study Treatment is outlined below. 
Study Design 
This is a double-blind, randomized, controlled, multicenter Phase 1/2 
study to evaluate the safety, tolerability, efficacy, and PK of FPA144 + 
mFOLFOX6 versus placebo + mFOLFOX6. 
This study includes a Phase 1 safety run-in portion and a Phase 2 portion.  
Patients may enroll in either Phase 1 or Phase 2, but may not enroll in 
both phases of the study. 
The Phase 1 safety run-in is an open-label dose-escalation of FPA144 + 
mFOLFOX6 in patients with GI tumors (not FGFR2-selected). 
The Phase 2 part of this study was initially designed as a Phase 3 study in 
the front-line setting evaluating bemarituzumab (FPA144) with SOC 
chemotherapy.  The study initiated following promising monotherapy 
activity of bemarituzumab in the Phase 1 study conducted in late-line 
gastric cancer. The Phase 3 statistical design assumed the incidence of 
FGFR2b positivity in front-line gastric cancer to be ~10%.  However, 
over the conduct of the study, the true incidence has been 30%. 
Additionally 2 methods of testing for FGFR2b status, IHC and ctDNA, 
were utilized to identify eligible patients and the expectation was that the 
majority of positive tumors would be identified by both tests.  In actuality, 
the vast majority of tumors have been identified by IHC alone, leading to 
a question of adequate study power. The study design has been modified 
in consideration of these factors. 
The Phase 2 portion of the study (to follow the Phase 1 safety run-in) is 
a global, randomized, double-blind, controlled, study to evaluate the 
efficacy of FPA144 + mFOLFOX6 versus placebo + mFOLFOX6 in 
patients with FGFR2-selected GC (as determined by prospective IHC 
demonstrating FGFR2b overexpression and/or a ctDNA blood assay 
demonstrating FGFR2 gene amplification). 
FGFR2 Expression Requirements (Pre-Screening): 
• Required provision of tissue and blood sample for FGFR2 positive 
status by 1 of these testing methods for enrollment in Phase 2:  
Provision of archival (or fresh biopsy if archival tissue is not available) 
for pre-screening FGFR2b overexpression testing by IHC is required; 
provision of a blood sample is also required for pre-screening by 
ctDNA for FGFR2 amplification.  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 8 of 139 
Confidential 
• Results of the centralized FGFR2 testing may take approximately 2 
weeks; patients are permitted to receive up to 1 dose of mFOLFOX6 
during this interim time period (pre-screening) at the discretion of the 
investigator.  This 1 dose of chemotherapy is not a requirement of the 
study and is not considered part of this clinical study. 
Screening Period: 
Pre-screening allows for collection of blood and tissue to determine 
FGFR2 positivity using ctDNA and IHC assays.  Once a patient is 
confirmed to have a positive result based on central testing, the screening 
period initiates, allowing for evaluation of all other eligibility criteria.   
All study assessments are outlined in the Schedules of Assessments in 
Protocol Appendix 2 and Appendix 3. 
Phase 1 Safety 
Run-in 
Dose Escalation Design 
The Phase 1; after a maximum 28-day screening period, eligible patients 
will initiate study treatment.  
In Phase 1, dose cohorts are planned at proposed doses beginning at an 
FPA144 dose level of 6 mg/kg per dose, and enrollment will depend on 
safety and tolerability.  Phase 1 will include a standard 3+3 dose 
escalation design (Cohort 1), and rolling-6 design (Cohort 2, 1a, and 1b), 
until the RD of FPA144 to be administered in combination with 
mFOLFOX6 in Phase 2 is determined.  A minimum of 2 dosing cohorts 
of FPA144 combined with mFOLFOX6 will be included in Phase 1.  
Proposed FPA144 Dose Levels  
The proposed FPA144 dose levels for dose escalation are as follows: 
• Cohort 1: 6 mg/kg FPA144 once every 2 weeks (Q2W) 
• Cohort 2: 15 mg/kg FPA144 Q2W with 1 dose of FPA144 7.5 mg/kg 
on Day 8 (Cycle 1 only) 
• Cohort 1a (if needed, eg, if the Cohort 2 dose level or schedule is not 
tolerated): 15 mg/kg FPA144 Q2W  
• Cohort 1b (if needed, eg, if Cohort 2 and 1a dose levels or schedules are 
not tolerated):  Dose level lower than Cohort 1a, but higher than 
Cohort 1 to achieve tolerability with optimal target exposure. 
Dose-Limiting Toxicity Observation 
Patients will be observed for a 28-day DLT period, starting on the first 
day (Cycle 1 Day 1 [C1D1]) of treatment with FPA144 and mFOLFOX6, 
for safety assessments, PK, and occurrence of DLTs.  If the first dose 
cohort (6 mg/kg) clears the 28-day DLT period, the second dose cohort 
(15 mg/kg Q2W with 1 dose of 7.5 mg/kg on Day 8 [Cycle 1 only]) will 
be tested in a rolling-6 design and will enroll 6 patients to explore the 
safety and efficacy at this dose level. Subsequent cohorts will also be 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 9 of 139 
Confidential 
enrolled as a rolling 6 design and will only be enrolled if Cohort 2 is 
deemed intolerable.  
Dose-Limiting Toxicity Definitions 
DLTs during Phase 1 are defined as any of the following events 
considered by the investigator to be related to study drug: 
• Absolute neutrophil count (ANC) < 0.5 × 109/L > 5 days’ duration or 
febrile neutropenia (ie, ANC < 1.0 × 109/L with a single temperature of 
> 38.3°C, or fever ≥ 38°C for more than 1 hour).  Use of granulocyte-
colony stimulating factor (G-CSF) is permitted in accordance with 
institutional standards 
• Platelets < 25 × 109/L  
• Platelets < 50 × 109/L with bleeding requiring medical intervention 
• Platelets < 50 × 109/L (> 3 days) 
• Grade 4 anemia (ie, life-threatening consequences; urgent intervention 
indicated) 
• Any Grade 2-3 ophthalmologic AE that does not resolve within 7 days 
• Any Grade 4 ophthalmologic AE  
• Any Grade 4 laboratory value 
• Any Grade 3 laboratory values that are not of clinical significance 
according to investigator and Sponsor agreement if they do not resolve 
within 72 hours 
• Aspartate aminotransferase/alanine aminotransferase (AST/ALT) 
≥ 3× upper limit of normal (ULN) and concurrent total bilirubin 
≥ 2× ULN not related to liver involvement with cancer 
• Any non-hematological AE Grade 3 or greater (except nausea, 
vomiting, and diarrhea) 
• Grade 3 nausea, vomiting or diarrhea that does not resolve with 
supportive care in 72 hours  
• Grade 4 nausea, vomiting or diarrhea 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 10 of 139 
Confidential 
 
Algorithm for Dose Escalation Decisions  
The following algorithm will be used for dose escalation decisions in 
Phase 1: 
Number of 
Patients with DLTs 
Dose Escalation Decision 
0/3 
Open next cohort 
1/3 
Enroll 3 more patients in same cohort 
≥ 2/3 
Stop enrollment. If Cohort 1, then the study will be stopped.  
1/6 
Open next cohort 
≥ 2/6 
Stop enrollment at that level. If at Cohort 1, the study will end. 
If at Cohort 2 or Cohort 1a, then Cohorts 1a or Cohort 1b will 
open respectively and 6 patients will be enrolled. 
 
After the 28-day DLT period, mFOLFOX6 or FPA144 may be dose 
adjusted (held or reduced) based on the toxicity experienced according to 
Section 5.1.3.4 and Section 5.2.3.1.  
Determination of a Recommended Dose for Phase 2 
The RD of FPA144 for Phase 2 will be identified by the Cohort Review 
Committee (CRC) based on an evaluation of all available safety, 
tolerability, and PK data and will not exceed 15 mg/kg administered IV 
Q2W with 1 dose of 7.5 mg/kg on Day 8 of Cycle 1 only.  Based on the 
totality of the data, the chosen RD of FPA144 will be a dose that is not 
anticipated to lead to a decrease in the dose intensity of mFOLFOX6 to be 
administered.  Cohort 1a will not be opened for enrollment unless the 
Cohort 2 dose level is not tolerated.  Identifying a maximum tolerated 
dose (MTD), therefore is not a requirement of this study and the 
recommended dose (RD) may be lower than the MTD. 
The MTD is defined as the maximum dose at which < 33% of patients 
experience a DLT during the DLT period.  If a DLT is observed in 1 of 
3 patients in Cohort 1, then 3 additional patients will be enrolled at that 
dose level.  Dose escalation may continue until 2 of 3 to 6 patients treated 
at a dose level experience a DLT.  The next lower dose will then be 
considered the MTD.  
No additional doses of FPA144 or more than 2 doses of mFOLFOX6 
should be administered during the 28-day DLT period.  The doses of 
FPA144 and mFOLFOX6 on Day 1 of Cycle 2 do not need to be 
synchronized.  For example, if mFOLFOX6 is delayed due to an AE that 
is deemed related only to mFOLFOX6 and not to FPA144, FPA144 
should be administered as scheduled for Cycles 1 and 2 regardless of 
delays in the mFOLFOX6 dosing schedule. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 11 of 139 
Confidential 
Phase 2 
Phase 2 Dose 
Based on an assessment of overall safety, tolerability, and PK of FPA144 
in combination with mFOLFOX6 by the CRC, the dose of 15 mg/kg Q2W 
with an additional dose of 7.5 mg/kg on Cycle 1 Day 8 will be used for 
the Phase 2 portion of the trial. 
 
Global, Randomized, Double-Blind, Controlled Design 
Enrollment in Phase 2 will begin when an RD for FPA144 has been 
identified by the CRC, which will not exceed the highest dose level 
evaluated and tolerated in Phase 1.  Opening the Phase 2 portion of the 
study for enrollment will be at the discretion of the Sponsor.  
The Phase 2 screening period will be up to 28 days; after a maximum 
28-day screening period, eligible patients will initiate randomized study 
treatment.  
Phase 2 will include 2 treatment arms: 
• Arm 1: FPA144 combined with mFOLFOX6, administered Q2W 
• Arm 2: Placebo combined with mFOLFOX6, administered Q2W 
In Phase 2, patients must initiate first administration of study treatment 
within 3 days of enrollment. 
Dosing 
Administration of Study Treatment 
Phase 1 (Open Label, FPA144 + mFOLFOX6) 
FPA144 administration is outlined in Section 5.1.2 of the protocol; 
guidance for dose modification is provided in Section 5.1.3.  
FPA144 will be administered over approximately 30 minutes 
(± 10 minutes) Q2W (± 3 days) on Day 1 of each 2-week cycle. FPA144 
will be administered prior to mFOLFOX6 chemotherapy. Patients treated 
in Cohort 2 (only) will receive 1 additional dose of FPA144 on Day 8 of 
Cycle 1 (mFOLFOX6 will not be administered on this day).  
mFOLFOX6 administration is outlined in Section 5.2 of the protocol; 
guidance for dose modification is provided in Section 5.2.3.1.   
mFOLFOX6 will be administered Q2W beginning on C1D1 and will be 
administered at least 30 minutes after the end of the infusion of FPA144.  
Leucovorin (or levo-leucovorin), 5-FU, and oxaliplatin will be 
administered in accordance with the relevant local guidelines and 
summary of product characteristics (SmPCs).  For further details, refer to 
the manufacturer’s prescribing information for the respective 
chemotherapies and the study Pharmacy Manual. 
Instructions for mFOLFOX6 administration include the following: 
On Day 1 of each cycle (at least 30 minutes after FPA144/placebo): 
• Oxaliplatin 85 mg/m2 IV infusion over 120 minutes 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 12 of 139 
Confidential 
• Leucovorin 400 mg/m2 IV infusion over 120 minutes, can be 
administered concurrently with oxaliplatin if using a Y connector, 
(if not using a Y connector, administer drugs sequentially) 
• If leucovorin is unavailable, 200 mg/m2 levo-leucovorin may be 
used.  Study treatment may be administered without either agent 
in the event that both are unavailable.  Leucovorin (or levo-
leucovorin) may be given at either the protocol-recommended 
doses or as deemed appropriate by the investigator in accordance 
with institutional standard of care 
• Immediately after oxaliplatin and leucovorin, 5 FU 400 mg/m2 bolus 
over approximately 5 minutes 
• Immediately after the 5-FU bolus, 5-FU 2400 mg/m2 as a continuous IV 
infusion over approximately 48 hours 
Premedication for mFOLFOX6 may be used at the discretion of the 
investigator based on the local standard of care.  
Phase 2 (Double-Blind, Randomized, Controlled) 
Patients in Phase 2 will be randomized to receive FPA144 + mFOLFOX6 
(Arm 1) or placebo + mFOLFOX6 (Arm 2).  FPA144 will be prepared 
and administered as in Phase 1, and the dosing and schedule of FPA144 
will be 15 mg/kg Q2W with an additional dose of 7.5 mg/kg on Cycle 1 
Day 8 (determined in Phase 1).  
mFOLFOX6 will be administered as described for Phase 1: Q2W 
beginning at least 30 minutes after the end of the infusion of 
FPA144/placebo.  For further details, refer to the manufacturer’s 
prescribing information for the respective chemotherapies and to the study 
Pharmacy Manual. 
Dose Modification, Duration, and Discontinuation 
Dose Delays and Modifications 
In the event a cycle of mFOLFOX6 is delayed due to chemotherapy-
related toxicity during the first 3 cycles of treatment (42 days), FPA144/ 
placebo should be administered on schedule (± 3 days).  After the first 
3 cycles, FPA144/placebo may be delayed up to 7 days to be 
synchronized with administered mFOLFOX6.  
Duration of Dosing 
There is no protocol-mandated maximum number of doses for 
FPA144/placebo or mFOLFOX6. 
In Phase 1, upon completion of the DLT period (starting with Cycle 3), 
patients may continue receiving FPA144 in combination with 
mFOLFOX6.  Ongoing administration of the mFOLFOX6 regimen 
beyond the DLT period will be according to the schedule noted in 
Section 5.1.2 with any modifications as noted in Section 5.2.3.1.  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 13 of 139 
Confidential 
In both study phases, FPA144 or placebo dosing will continue Q2W until 
investigator-assessed disease progression, unacceptable toxicity, or until 
the patient meets any of the other protocol-specified withdrawal criteria 
(refer to Section 4.5). 
Discontinuation  
Patients who discontinue all study treatment (all components of FPA144 
+ mFOLFOX6 and placebo + mFOLFOX6) for any reason other than 
consent withdrawal will undergo an EOT safety follow-up visit 
approximately 28 days after the last dose of the last administered 
component of treatment (oxaliplatin, leucovorin, 5-FU, or FPA144).  
In addition, patients in Phase 2 will continue to undergo tumor 
assessments according to the protocol schedule until investigator-assessed 
disease progression or the initiation of additional anticancer therapy, at 
which point they will enter a long term follow up (LTFU) period to assess 
survival. 
Discontinuation of any component of the study treatment (mFOLFOX6, 
a component of mFOLFOX6, or FPA144/placebo) for any reason other 
than disease progression or any of the other protocol-specified withdrawal 
criteria does not mandate discontinuation of other components.  The 
exception is the permanent discontinuation of 5-FU for any reason, which 
requires discontinuation of oxaliplatin and leucovorin. 
Study Duration 
The duration of study for an individual patient includes Screening 
(up to 28 days), treatment and an EOT visit approximately 28 days after 
the last dose.  Since all patients are eligible to be treated until disease 
progression, the actual treatment duration for each individual patient will 
vary depending on the time to progression.  
In addition, patients enrolled in Phase 2 will be followed for subsequent 
anticancer therapy and survival. LTFU for survival will be performed 
approximately every 3 months (± 1 month) after the EOT visit until up to 
24 months after the last patient is enrolled in the study, or until death, loss 
to follow up, withdrawal of consent, or study termination by the Sponsor 
(whichever occurs first). 
Number of 
Patients 
The total number of patients planned for enrollment in this study is 
approximately 167.  
• Phase 1 will enroll approximately 9 to 21 patients depending on 
incidence of DLTs; this allows for evaluation of safety, PK, and 
pharmacodynamics at 1 or more dose levels. 
• Phase 2 will enroll approximately 155 patients with FGFR2b 
overexpression and/or FGFR2 gene amplification. Patients will be 
randomized 1:1 to receive FPA144 at the RD in combination with 
mFOLFOX6 versus placebo in combination with mFOLFOX6 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 14 of 139 
Confidential 
Patient Replacements  
Phase 1 
To be evaluable in Phase 1, patients must have received 2 doses of 
FPA144 (except for Cohort 2 [must have received 3 doses of FPA144]) 
and 2 doses of mFOLFOX6 (regardless of cohort).  All patients deemed 
unevaluable must be replaced, unless the reason they didn’t receive the 
required minimum amount of therapy was due to an FPA144-related 
DLT.  The replaced patient may continue on study at the investigator’s 
discretion and after discussion with the Sponsor. 
Phase 2 
Patients are not replaced.  All enrolled patients are deemed evaluable for 
the endpoint of survival. 
Eligibility 
Criteria 
Inclusion Criteria for Phase 1 and Phase 2 (criteria may not be 
sequentially numbered due to data management convention) 
Patients enrolling in either Phase 1 or Phase 2 of the study must meet all 
of the following inclusion criteria: 
1) Disease that is unresectable, locally advanced, or metastatic (not 
amenable to curative therapy) 
2) Understand and sign an Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC)-approved ICF prior to 
any study-specific evaluation 
3) Life expectancy of at least 3 months in the opinion of the investigator 
4) Eastern Cooperative Oncology Group (ECOG) performance status of 
0 to 1 
5) Age ≥ 18 years at the time the ICF is signed 
6) In sexually active patients (women of child bearing potential 
[WOCBP] and males), willingness to use 2 effective methods of 
contraception, of which 1 must be a physical barrier method (condom, 
diaphragm, or cervical/vault cap) until 6 months after the last dose of 
FPA144. Other effective forms of contraception include: 
• Permanent sterilization (hysterectomy and/or bilateral 
oophorectomy, or bilateral tubal ligation with surgery, or 
vasectomy) at least 6 months prior to screening 
• WOCBP who are on stable oral contraceptive therapy or 
intrauterine or implant device for at least 90 days prior to the 
study, or abstain from sexual intercourse as a way of living 
7) Adequate hematological and biological function, confirmed by the 
following laboratory values within 96 hours prior to enrollment: 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 15 of 139 
Confidential 
Bone Marrow Function  
• 
ANC ≥ 1.5 × 109/L 
• 
Platelets ≥ 100 × 109/L 
• 
Hemoglobin ≥ 9 g/dL 
Hepatic Function 
• 
AST and ALT < 3 × ULN; if liver metastases, then < 5 × ULN 
• 
Bilirubin < 1.5 × ULN except in patients with Gilbert’s disease 
Renal Function 
• Calculated creatinine clearance (CrCl) using Cockcroft Gault 
formula ≥ 50 mL/min or estimated glomerular filtrate rate (eGFR) 
using the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) formula ≥ 50 mL/min (refer to Appendix 1) 
8) International normalized ratio (INR), or prothrombin time (PT) 
< 1.5 × the ULN except for patients receiving anticoagulation therapy 
who must be on a stable dose of warfarin for 6 weeks prior to 
enrollment 
9) Measurable or non-measurable, but evaluable disease using RECIST 
v1.1 
 
Additional Inclusion Criteria for Phase 1 Only 
Patients enrolling in Phase 1 of the study must also meet the following 
inclusion criteria: 
10) Histologically or cytologically confirmed GI malignancy for which 
mFOLFOX6 is considered an appropriate treatment (eg, GC, 
colorectal carcinoma, pancreatic adenocarcinoma) 
11) Patient must be a candidate to receive at least 2 doses of mFOLFOX6 
chemotherapy  
Additional Inclusion Criteria for Phase 2 Only 
Patients enrolling in Phase 2 of the study must also meet the following 
inclusion criteria: 
14) Histologically documented gastric or gastroesophageal junction 
adenocarcinoma (not amenable to curative therapy) 
15) Radiographic imaging of the chest, abdomen and pelvis (computed 
tomography [CT] preferred, magnetic resonance imaging [MRI] 
acceptable) performed within 28 days (+3 days) of treatment (C1D1) 
16) FGFR2b overexpression as determined by a centrally performed IHC 
tissue test and/or FGFR2 gene amplification as determined by a 
centrally performed ctDNA blood-based assay 
17) Patient must be a candidate for mFOLFOX6 chemotherapy 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 16 of 139 
Confidential 
18) No prior chemotherapy for metastatic or unresectable disease (except a 
maximum of 1 dose of mFOLFOX6 administered while waiting for 
results of FGFR2 testing during the pre-screening period) 
19) If prior adjuvant or neo-adjuvant therapy (chemotherapy and/or 
chemoradiation) has been received, more than 6 months must have 
elapsed between the end of adjuvant therapy and the confirmation of 
radiographic disease progression 
 
Exclusion Criteria for Phase 1 and Phase 2 
Patients enrolling in either Phase 1 or Phase 2 will be excluded if any of 
the following criteria apply: 
1) Untreated or symptomatic central nervous system (CNS) metastases 
(CNS imaging not required).  Patients with asymptomatic CNS 
metastases are eligible provided they have been clinically stable for at 
least 4 weeks and do not require intervention such as surgery, 
radiation, or any corticosteroid therapy for management of symptoms 
related to CNS disease 
2) Impaired cardiac function or clinically significant cardiac disease, 
including any of the following (Criteria a through g): 
a) Unstable angina pectoris ≤ 6 months prior to enrollment 
b) Acute myocardial infarction ≤ 6 months prior to enrollment 
c) New York Heart Association class II-IV congestive heart failure 
d) Uncontrolled hypertension (as defined as ≥ 160/90 despite optimal 
medical management) 
e) Uncontrolled cardiac arrhythmias requiring anti-arrhythmic 
therapy other than beta blockers or digoxin  
f) Active coronary artery disease 
g) Fridericia’s correction formula (QTcF) ≥ 480 
3) Peripheral sensory neuropathy ≥ Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 2 
4) Active infection requiring systemic treatment or any uncontrolled 
infection ≤ 14 days prior to enrollment 
5) Known human immunodeficiency virus (HIV) or acquired 
immunodeficiency syndrome (AIDS)-related illness, or known active 
or chronic hepatitis B or C infection 
6) History of interstitial lung disease (eg, pneumonitis or pulmonary 
fibrosis) 
7) Evidence or history of bleeding diathesis or coagulopathy 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 17 of 139 
Confidential 
8) Radiotherapy ≤ 28 days of enrollment.  Patients must be recovered 
from all acute radiotherapy-related toxicities.  No 
radiopharmaceuticals (strontium, samarium) within 8 weeks of 
enrollment 
9) Prior treatment with any selective inhibitor (eg, AZD4547, BGJ398, 
JNJ-42756493, BAY1179470) of the FGF-FGFR pathway 
10) Ongoing adverse effects from prior systemic treatment > NCI CTCAE 
Grade 1 (with the exception of Grade 2 alopecia and anemia) 
11) Participation in another therapeutic clinical study or receiving any 
investigational agent within 28 days of enrollment or during this 
clinical study 
12) Corneal defects, corneal ulcerations, keratitis, keratoconus, history of 
corneal transplant, or other known abnormalities of the cornea that 
may pose an increased risk of developing a corneal ulcer 
13) Known positivity for human epidermal growth factor receptor 2 
(HER2) (as defined by a positive IHC test of 3+ or IHC of 2+ with 
positive FISH)  
14) Major surgical procedures not permitted ≤ 28 days prior to enrollment.  
Surgery requiring local/epidural anesthesia must be completed at least 
72 hours before enrollment.  In all cases, the patient must be 
sufficiently recovered and stable before treatment administration. 
15) Women who are pregnant or breastfeeding (unless the patient is 
willing to interrupt breastfeeding during study treatment 
administration and then resume 6 months after study discontinuation); 
WOCBP must not consider getting pregnant during the study 
16) Presence of any serious or unstable concomitant systemic disorder 
incompatible with the clinical study (e.g., substance abuse, psychiatric 
disturbance, or uncontrolled intercurrent illness including arterial 
thrombosis, and symptomatic pulmonary embolism) 
17) Presence of any other condition that may increase the risk associated 
with study participation, or may interfere with the interpretation of 
study results, and, in the opinion of the investigator, would make the 
patient inappropriate for entry in the study 
18) Known allergy, hypersensitivity or contraindication to components of 
the FPA144 formulation including polysorbate or to platinum-
containing medications, 5-FU, or leucovorin 
19) History of prior malignancy, except (Criteria a through f): 
a) Curatively treated non-melanoma skin malignancy  
b) Cervical cancer in situ 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 18 of 139 
Confidential 
c) Curatively treated Stage I uterine cancer 
d) Curatively treated ductal or lobular breast carcinoma in situ and 
not currently receiving any systemic therapy 
e) Localized prostate cancer that has been treated surgically with 
curative intent and presumed cured 
f) Solid tumor treated curatively more than 5 years previously 
without evidence of recurrence 
No waivers of these inclusion or exclusion criteria will be granted. 
Pharmacokinetic 
Assessments: 
Blood samples will be collected to measure serum levels of FPA144 at the 
time points outlined in Appendix 6 for Phase 1.  Blood samples will be 
collected to measure levels of FPA144 at the time points outlined in 
Appendix 7 for Phase 2.  PK parameters will be estimated using 
non-compartmental analysis, though compartmental analysis may be 
employed if appropriate. Serum concentration-time data from 
FPA144-004 will be pooled with data from other studies for integrated 
population PK analysis and exposure-response relationship assessment. 
Immunogenicity 
Assessments: 
For all enrolled patients in Phase 1 and Phase 2, blood samples will be 
collected for anti-FPA144 antibodies at the time points specified in 
Appendix 6 and Appendix 7, respectively. 
Immunogenicity, defined as an immune response to FPA144, will be 
assessed by measurement of total anti-FPA144 antibodies from all 
patients.  Immunogenicity testing will consist of screening, confirmation, 
and determination of the antidrug antibody (ADA) concentration.  
Additional characterization of a confirmed anti-FPA144 antibody 
response will be conducted.  
Efficacy 
Assessments: 
During Phase 2, tumor response assessment will be performed by the 
investigator per RECIST v1.1 guidelines.  All radiology images will be 
analyzed by the investigator and this assessment will be used in the 
determination of progression.  
Efficacy measures will include tumor assessments consisting of clinical 
examination and appropriate imaging techniques, preferably CT scans of 
the chest, abdomen, and pelvis with appropriate slice thickness per 
RECIST v1.1 guidelines.  Alternatively, MRI is also acceptable at the 
discretion of the investigator.  Scans will be done during the screening 
window (within 28 +3 days of C1D1).  A scan performed prior to 
Screening as part of standard of care, performed no greater than 28 days 
(+3 days) prior to treatment (C1D1) is acceptable.  Scans will be 
performed every 8 weeks (± 7 days) from C1D1 until 12 months from 
C1D1 and then every 12 weeks (± 14 days) thereafter. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 19 of 139 
Confidential 
Safety 
Assessments: 
Safety measures will include AEs, hematology, clinical chemistry, 
urinalysis, vital signs, body weight, concomitant medications/procedures, 
ECOG performance status, targeted physical examinations, ECGs, and 
ophthalmology examinations in both Phase 1 and Phase 2.  Safety 
measures will also include evaluation for DLTs in Phase 1 only. 
In Phase 2, an independent Data Monitoring Committee (DMC) will 
evaluate safety including AEs and serious adverse events (SAEs) on a 
regular basis throughout the treatment phase. 
Pharmaco-
dynamic 
Assessments: 
Phase 1 
Tumor tissue provided for evaluation of FGFR2 status, if available, will 
be retrospectively analysed for FGFR2b overexpression using IHC. 
Blood samples provided for evaluation of FGFR2 status will be collected 
prior to the first dose of study treatment and analysed retrospectively for 
FGFR2 gene amplification using a ctDNA blood assay. 
 
 will be collected longitudinally according to  
Appendix 5. 
No pharmacodynamic assessments will be performed during Phase 2. 
Statistical 
Procedures: 
Power and Sample Size 
This Phase 2 study is designed to assess the hazard ratio (HR) of PFS for 
FPA144 + mFOLFOX6 compared with placebo + mFOLFOX6. It is 
planned to observe 84 PFS events in order to achieve 71% power to detect 
an HR of 0.67 for PFS, at the 1-sided alpha of 0.1. Assuming an 
exponential distribution, this corresponds approximately to an 50% 
increase in median PFS (e.g. from 5 months to 7.5 months).  Statistical 
significance (at 1-sided alpha of 0.1) for PFS will occur with an observed 
HR=0.756, corresponding approximately to a 32.3% increase in observed 
median PFS (e.g. from 5 months to 6.6 months). 
One hundred fifty-five patients have been randomized (1:1) during 
13 months of accrual. It is projected to observe 84 PFS events with 
approximately 11 additional months of follow-up. 
There is no planned interim analysis for this study.Statistical Methods 
In Phase 1, all analyses will be descriptive and will be presented by dose 
cohort and cumulative as appropriate.  Descriptive statistics will include 
number of observations, mean, standard deviation, median, range, and 
inter-quartile range for continuous variables, and the number and percent 
for categorical variables; 95% confidence intervals (CIs) will be presented 
where appropriate.  Additionally, incidence of treatment-emergent adverse 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 20 of 139 
Confidential 
events (TEAEs) leading to dosing reductions or dose discontinuation will 
be tabulated and summarized. 
In Phase 2, efficacy and tolerability will be evaluated and presented by 
treatment arm (Arm 1, FPA144 + mFOLFOX6; Arm 2, placebo + 
mFOLFOX6). 
Eligible patients will be stratified by: 
• Geographic region 
• Prior treatment status (de novo versus adjuvant/neo-adjuvant)  
• Administration of a single dose of mFOLFOX6 prior to enrollment 
(yes or no) 
In Phase 2, the primary efficacy analysis is the comparison of PFS 
between the treatment arms.  The primary endpoint, PFS, is defined as 
time from randomization until the date of radiological disease progression 
based on investigator assessment (using Response Evaluation Criteria in 
Solid Tumors version 1.1 [RECIST v1.1]) or death from any cause, 
whichever comes first.  The secondary efficacy endpoints include OS and 
ORR.  
The analysis of PFS will be performed using the intent-to-treat (ITT) 
population and will be conducted using a stratified log-rank test.  The 
stratification factors will be the same used to stratify the randomization 
schedule as documented in the interactive voice and web response system 
(IXRS).  
The median PFS and the associated 95% CI for each treatment arm will be 
estimated using the Kaplan-Meier method.  The hazard ratio (HR= 
λFPA144+mFOLFOX6/ λplacebo+mFOLFOX6) will be estimated using a Cox 
regression model with treatment group as the only main effect and 
stratifying by the same stratification factors as were used for the stratified 
log-rank test.  An unstratified HR will also be presented. 
Analyses of secondary endpoints OS and ORR will be conducted 
hierarchically.  The formal hypotheses regarding effects on OS and ORR 
will be tested hierarchically at a one-sided level of 0.1.  The OS will be 
tested first and if it is significant, the ORR will be tested next.  The 
family-wise type I error rate of testing primary and secondary endpoints 
will be in a control by employing this gate-keeping testing procedure at a 
one-sided level of 0.1.  
Overall survival will be analyzed in a similar manner as for PFS. 
The analysis of ORR will be performed based on the ITT population.  
In the analysis of ORR, patients without postbaseline adequate tumor 
assessments will be counted as non-responders.  Formal hypothesis testing 
of ORR will be performed using the stratified Cochran-Mantel-Haenszel 
test at a one-sided level of 0.1.  The stratification factors will be the same 
used to stratify the randomization schedule as documented in the IXRS. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 21 of 139 
Confidential 
Safety Analysis  
All AEs will be coded using the Medical Dictionary for Regulatory 
Activities Version 20.1 (MedDRA v 20.1).  The investigator will classify 
the severity of AEs using the CTCAE v 4.03 in Phase 1 and v 5.0 in Phase 
2.  A TEAE is defined as any event with an onset date on or after date of 
first dose of study treatment, or any event present before treatment that 
worsens after treatment.  
Clinical laboratory data will be summarized by the type of laboratory test.  
The number and percentage of patients who experience abnormal 
(ie, outside of reference ranges) and/or clinically significant abnormal 
laboratories after study treatment administration will be presented for each 
clinical laboratory measurement.  For each clinical laboratory 
measurement, descriptive statistics will be provided for baseline and all 
subsequent posttreatment scheduled visits.  Changes from baseline to the 
posttreatment visits will also be provided.  Descriptive statistics of vital 
signs will also be provided in a similar manner.  In addition, shift from 
baseline in CTCAE grade (where applicable) and by high/low flags 
(where CTCAE grades are not defined) will be presented in a similar 
manner. 
Safety Analyses in Phase 1 
Safety analyses will be performed for patients included in the safety 
population.  The incidence of DLTs, incidence of TEAEs, clinical 
laboratory abnormalities (eg, shift table), vital signs, corneal and retinal 
findings, and ECGs will be tabulated and summarized by dose level.  
Additionally, incidence of TEAEs leading to dosing reduction or dose 
discontinuation of FPA144 or any component of mFOLFOX6 will be 
tabulated and summarized. 
Safety Analyses in Phase 2 
The analyses of safety will include all patients who receive any study 
treatment (FPA144 + mFOLFOX6 or placebo + mFOLFOX6) throughout 
the study and will provide posttreatment safety information.  The 
incidence of TEAEs, clinical laboratory abnormalities, vital signs, corneal 
and retinal findings, and ECGs will be tabulated and summarized by 
treatment group.  
No formal comparisons of safety endpoints are planned. 
PK Analysis and Immunogenicity 
Individual and mean (± SD) serum FPA144 concentration-time data will 
be tabulated and plotted by dose level.  PK parameters will be tabulated 
and summarized by dose level when appropriate and applicable.  The 
impact of immunogenicity on FPA144 exposure will be assessed, 
tabulated, and summarized by dose level as data allow.  Integrated 
population PK analysis and exposure-response relationship assessment 
will be presented in a separate report. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 22 of 139 
Confidential 
List of Key Study Personnel 
 
Sponsor: 
 
 
 
 
 
Responsible Medical 
Officers: 
 
Five Prime Therapeutics, Inc. 
111 Oyster Point Boulevard 
South San Francisco, CA 94080 
+ 1 415-365-5600 (main) 
+ 1 415-365-5601 (fax)  
 
, MD, PhD 
Five Prime Therapeutics, Inc. 
111 Oyster Point Boulevard 
South San Francisco, CA 94080 
 
, MD 
Five Prime Therapeutics, Inc. 
111 Oyster Point Boulevard 
South San Francisco, CA 94080 
 
 
 
 
Contract Research 
Organization: 
 
ICON Clinical Research Limited 
South County Business Park 
Leopardstown, Dublin 18, Ireland 
+1 647-632-6537 (mobile) 
+1 215-616-6990 (office) 
 
Serious Adverse Event 
Reporting: 
 
ICON Medical and Safety Services 
Fax number: 
 
SAE Hotline: 
  
Email: 
 
 
 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 23 of 139 
Confidential 
TABLE OF CONTENTS 
PROTOCOL APPROVAL SIGNATURE PAGE ...........................................................................2 
DECLARATION OF THE INVESTIGATOR ................................................................................3 
PROTOCOL SYNOPSIS.................................................................................................................4 
LIST OF KEY STUDY PERSONNEL .........................................................................................22 
TABLE OF CONTENTS ...............................................................................................................23 
LIST OF TABLES .........................................................................................................................28 
LIST OF FIGURES .......................................................................................................................28 
LIST OF APPENDICES ................................................................................................................28 
LIST OF ABBREVIATIONS AND DEFINITIONS ....................................................................29 
1.0 
INTRODUCTION .............................................................................................................33 
1.1 
General Gastric Cancer ..........................................................................................33 
1.2 
Targeted Agents .....................................................................................................33 
1.3 
FPA144 ..................................................................................................................34 
1.3.1 
Background ...........................................................................................34 
1.3.2 
FPA144, an Fibroblast Growth Factor Receptor 2-Specific 
Antibody ................................................................................................35 
1.3.3 
Nonclinical Studies with FPA144 .........................................................36 
1.3.3.1 
In Vivo Pharmacology ...................................................................36 
1.3.3.2 
Analysis of Immune Effector Functions of FPA144 .....................37 
1.3.3.3 
FPA144 Exposure Efficacy Relationships .....................................39 
1.3.4 
Toxicology ............................................................................................40 
1.3.5 
Clinical Experience with FPA144 .........................................................41 
1.4 
Rationale for mFOLFOX6 .....................................................................................44 
1.5 
Rationale for Combination Therapy: FPA144 and mFOLFOX6 ..........................45 
1.6 
FPA144 and mFOLFOX6 Starting Dose Justification ..........................................46 
1.7 
Risk-Benefit Assessment of FPA144 and mFOLFOX6 ........................................47 
1.8 
Rationale for Phase 2 Pre-Screening ......................................................................49 
1.9 
Rationale for Tumor Tissue and Blood Assessments ............................................50 
2.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................51 
2.1 
Phase 1 Objectives .................................................................................................51 
2.1.1 
Primary ..................................................................................................51 
2.1.2 
Secondary ..............................................................................................51 
2.1.3 
Exploratory ............................................................................................51 
2.2 
Phase 2 Objectives .................................................................................................51 
2.2.1 
Primary ..................................................................................................51 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 24 of 139 
Confidential 
2.2.2 
Secondary ..............................................................................................51 
2.2.3 
Exploratory ............................................................................................51 
2.3 
Phase 1 Endpoints ..................................................................................................52 
2.3.1 
Primary ..................................................................................................52 
2.3.2 
Secondary ..............................................................................................52 
2.3.3 
Exploratory ............................................................................................52 
2.4 
Phase 2 Endpoints ..................................................................................................52 
2.4.1 
Primary ..................................................................................................52 
2.4.2 
Secondary ..............................................................................................52 
2.4.3 
Exploratory ............................................................................................53 
3.0 
STUDY DESIGN...............................................................................................................54 
3.1 
Study Overview .....................................................................................................54 
3.2 
Phase 1 ...................................................................................................................55 
3.2.1 
Dose Escalation .....................................................................................55 
3.2.2 
Definition of Dose-Limiting Toxicity ...................................................56 
3.2.3 
Observation of Dose-Limiting Toxicity (the DLT Period) ...................57 
3.2.4 
Determination of Maximum Tolerated Dose and Recommended 
Dose ......................................................................................................58 
3.2.5 
Phase 2 Dose of FPA144 ......................................................................59 
3.2.6 
Patient Replacement ..............................................................................59 
3.2.7 
Number of Doses ..................................................................................59 
3.3 
Phase 2 ...................................................................................................................60 
3.3.1 
Treatment Arms ....................................................................................60 
3.4 
Study Schemas .......................................................................................................62 
3.5 
Rationale for the Study Design ..............................................................................63 
3.5.1 
Rationale for Selection of Patients for FGFR2 .....................................63 
3.6 
Rationale for Stratification .....................................................................................64 
3.6.1 
Geographic Region ...............................................................................64 
3.6.2 
Prior Therapy ........................................................................................64 
3.6.3 
Administration of mFOLFOX6 Prior to Enrollment ............................64 
4.0 
STUDY ELIGIBILITY AND WITHDRAWAL CRITERIA ............................................65 
4.1 
Planned Number of Patients and Study Centers ....................................................65 
4.2 
Inclusion Criteria for Phase 1 and Phase 2 ............................................................65 
4.3 
Exclusion Criteria for Phase 1 and Phase 2 ...........................................................67 
4.4 
Patient Identification and Enrollment ....................................................................69 
4.5 
Patient Withdrawal and Replacement ....................................................................69 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 25 of 139 
Confidential 
5.0 
STUDY TREATMENT .....................................................................................................71 
5.1 
FPA144 ..................................................................................................................71 
5.1.1 
Identity, Packaging, Storage .................................................................71 
5.1.2 
Administration (Phase 1 and Phase 2) ..................................................71 
5.1.3 
FPA144 Dose Modifications .................................................................72 
5.1.3.1 
Dose Escalation ..............................................................................72 
5.1.3.2 
Weight ............................................................................................72 
5.1.3.3 
Infusion or Hypersensitivity Reactions ..........................................72 
5.1.3.4 
Toxicity: FPA144 Dose Modification Guidelines .........................73 
5.2 
mFOLFOX6 ...........................................................................................................75 
5.2.1 
Identity, Packaging, Storage .................................................................75 
5.2.2 
Administration (Phase 1 and Phase 2) ..................................................75 
5.2.3 
mFOLFOX6 Dose Modifications .........................................................76 
5.2.3.1 
Toxicity: mFOLFOX6 Dose Modifications Guidelines ................76 
5.3 
Placebo ...................................................................................................................79 
5.4 
Unblinding Treatment Assignment ........................................................................79 
5.5 
Drug Accountability...............................................................................................79 
5.6 
Investigational Product Compliance ......................................................................80 
5.7 
Concomitant Medication and Treatment ...............................................................80 
5.8 
Prohibited Therapy .................................................................................................80 
6.0 
STUDY ASSESSMENTS AND PROCEDURES .............................................................81 
6.1 
Tumor Tissue Collection: Analysis for FGFR2b Overexpression for Patient 
Selection .................................................................................................................81 
6.1.1 
Phase 1 ..................................................................................................81 
6.1.2 
Phase 2 ..................................................................................................81 
6.2 
Informed Consent Requirements ...........................................................................82 
6.3 
Screening................................................................................................................82 
6.3.1 
Phase 1 ..................................................................................................82 
6.3.2 
Phase 2 ..................................................................................................83 
6.4 
Study Enrollment ...................................................................................................83 
6.4.1 
Phase 1 ..................................................................................................83 
6.4.2 
Phase 2 ..................................................................................................84 
6.4.3 
Blinding .................................................................................................84 
6.5 
Medical/Oncology History and Demographics .....................................................84 
6.6 
Safety Assessments ................................................................................................85 
6.6.1 
Vital Signs .............................................................................................85 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 26 of 139 
Confidential 
6.6.2 
Physical Examinations, Height, and Weight .........................................85 
6.6.3 
Ophthalmologic Examinations ..............................................................85 
6.6.4 
Electrocardiograms ...............................................................................86 
6.6.5 
Eastern Cooperative Oncology Group Performance Status ..................86 
6.7 
Clinical Laboratory Parameters .............................................................................87 
6.8 
Urinalysis ...............................................................................................................87 
6.9 
Pregnancy ...............................................................................................................87 
6.10 
Tumor Assessments ...............................................................................................88 
6.11 
Pharmacokinetic Assessment .................................................................................89 
6.12 
Pharmacodynamic Biomarker Analysis Using Blood ...........................................89 
6.13 
Immunogenicity .....................................................................................................90 
6.14 
Immunohistochemistry ..........................................................................................90 
6.15 
Circulating Tumor DNA Blood Assay ..................................................................90 
6.16 
Patient Reported Outcomes / Quality of Life Scales .............................................90 
6.17 
Adverse Events ......................................................................................................91 
6.17.1 
Collection of Adverse Events................................................................91 
6.17.2 
Definitions .............................................................................................92 
6.17.3 
Assessment of Adverse Events .............................................................92 
6.17.3.1 
Seriousness .....................................................................................93 
6.17.3.2 
Causality ........................................................................................94 
6.17.3.3 
Outcome and Action Taken ...........................................................95 
6.17.4 
Reporting Serious Adverse Events .......................................................96 
6.17.5 
Follow-up of Adverse Events................................................................97 
6.18 
End of Treatment ...................................................................................................98 
6.19 
Long Term Follow Up (Phase 2) ...........................................................................98 
6.19.1 
Additional Follow-up for Patients without Progression at the End 
of Treatment Visit (Phase 2) (Scan Follow-up) ....................................98 
7.0 
STATISTICAL METHODS ..............................................................................................99 
7.1 
Analysis Populations ..............................................................................................99 
7.2 
General Considerations ..........................................................................................99 
7.3 
Power and Sample Size in Phase 2 ........................................................................99 
7.4 
Efficacy Analyses ................................................................................................100 
7.4.1 
Analysis of Primary Efficacy Endpoint ..............................................100 
7.4.2 
Analysis of Secondary Efficacy Endpoints .........................................101 
7.4.3 
Analysis of Exploratory Endpoints .....................................................102 
7.4.3.1 
Efficacy ........................................................................................102 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 27 of 139 
Confidential 
7.4.3.2 
Quality of Life..............................................................................102 
7.5 
Safety Analyses ....................................................................................................102 
7.5.1 
Safety Analyses in Phase 1 .................................................................103 
7.5.2 
Safety Analyses in Phase 2 .................................................................103 
7.6 
Pharmacokinetic Analyses ...................................................................................103 
7.7 
Changes in the Planned Analyses ........................................................................104 
8.0 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS .........................................105 
8.1 
Data Quality Assurance .......................................................................................105 
8.2 
Data Protection.....................................................................................................105 
8.3 
Electronic Case Report Forms and Source Documentation .................................106 
8.4 
Access to Source Data .........................................................................................106 
8.5 
Data Processing ....................................................................................................107 
8.6 
Archiving Study Records .....................................................................................107 
8.7 
Good Clinical Practice .........................................................................................107 
8.8 
Informed Consent.................................................................................................108 
8.9 
Protocol Approval and Amendment ....................................................................108 
8.10 
Study Committee and Central Review .................................................................108 
8.10.1 
Cohort Review Committee ..................................................................108 
8.10.2 
Data Monitoring Committee ...............................................................109 
8.11 
Premature Termination of the Study ....................................................................109 
8.12 
Confidentiality .....................................................................................................109 
8.13 
Other Ethical and Regulatory Issues ....................................................................110 
9.0 
REFERENCES ................................................................................................................111 
10.0 
APPENDICES .................................................................................................................117 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 28 of 139 
Confidential 
LIST OF TABLES 
Table 1:  
Phase 1 Proposed Dose Levels by Cohort .............................................................56 
Table 2:  
Phase 1 Dose Escalation Algorithm .......................................................................58 
Table 3:  
Phase 2 Treatment Arms ........................................................................................61 
Table 4: 
Eligibility Based on FGFR2 Status ........................................................................69 
Table 5: 
Phase 2 FPA144 Dose Levels for Dose Reductions ..............................................73 
Table 6:  
Dose Modification Guidelines for FPA144 Related Adverse Events (Any 
Noncorneal, Noninfusion Toxicity1) ......................................................................74 
Table 7: 
Dose Modification Guidelines for FPA144 (Any Related Corneal 
Toxicity1) ...............................................................................................................74 
Table 8: 
Dose Reductions and Delays for mFOLFOX6 Chemotherapy ..............................78 
 
LIST OF FIGURES 
Figure 1:  
Tumor Growth Inhibition in OCUM-2 Gastric Cancer Cell Line .........................36 
Figure 2:  
In Vitro ADCC Activity of FPA144 ......................................................................38 
Figure 3:  
FPA144, but not an ADCC-Deficient FGFR2b Antibody Leads to Tumor 
Suppression in a Syngeneic Tumor Model with Modest FGFR2b Expression .....39 
Figure 4:  
Phase 1/2 Study Schema ........................................................................................62 
Figure 5:  
Phase 1 Patient Timeline ........................................................................................62 
Figure 6:  
Phase 2 Patient Timeline ........................................................................................63 
 
LIST OF APPENDICES 
Appendix 1: 
Formulas to Calculate Renal Function .................................................................118 
Appendix 2: 
Schedule of Assessments: Dose-Escalation Safety Run-in (Phase 1) .................119 
Appendix 3: 
Schedule of Assessments: Randomized, Placebo-Controlled Portion 
(Phase 2)...............................................................................................................123 
Appendix 4: 
Laboratory Evaluations ........................................................................................128 
Appendix 5: 
Clinical Fixed Time Point Assessments ..............................................................129 
Appendix 6: 
Study Flowchart for Pharmacokinetic, Immunogenicity, and 
 
 for Phase 1 ................131 
Appendix 7: 
Study Flowchart for FPA144 Pharmacokinetic and Immunogenicity Blood 
Sample Collections for Phase 2 ...........................................................................133 
Appendix 8: 
ECOG Performance Status ..................................................................................134 
Appendix 9: 
Fluorescein Stain Grading Systems .....................................................................135 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 29 of 139 
Confidential 
List of Abbreviations and Definitions 
Abbreviation 
Definition 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
ADA 
antidrug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
AIDS 
acquired immunodeficiency syndrome  
ALT 
alanine aminotransferase  
ANC 
absolute neutrophil count  
AST 
aspartate aminotransferase  
AUC 
area under serum concentration-time curve  
AUCτ 
AUC over the dose interval τ 
β-hCG 
β-human chorionic gonadotropin  
BP 
blood pressure 
C1D1 
Cycle 1 Day 1 
CDC 
complement-dependent cytotoxicity 
CFR 
Code of Federal Regulations 
CHO 
Chinese hamster ovary  
CI 
confidence interval 
CL 
total clearance  
Cmax 
maximum observed serum concentration  
CNS 
central nervous system  
CRC 
Cohort Review Committee  
CrCl 
creatinine clearance 
CRO 
contract research organization 
CT 
computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events  
ctDNA 
circulating tumor DNA  
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee  
DNA 
deoxyribonucleic acid 
DOR 
duration of response  
ECG 
electrocardiogram  
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic case report forms  
ELISA 
enzyme linked immunosorbent assay  
EORTC 
European Organization for Research and Treatment of Cancer  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 30 of 139 
Confidential 
Abbreviation 
Definition 
EOS 
end of study 
EOT 
end of treatment 
EQ-5D-5L 
EuroQOL-5D-5L 
EU 
European Union 
5-FU 
5-fluorouracil 
FDA 
Food and Drug Administration 
FGF 
fibroblast growth factor  
FGFR 
fibroblast growth factor receptor  
FISH 
fluorescent in situ hybridization  
FP 
5-FU/cisplatin 
FRS2 
FGF receptor substrate-2  
GC 
gastric or gastroesophageal cancer 
GCP 
Good Clinical Practices  
G-CSF 
granulocyte-colony stimulating factor 
GEJ 
gastroesophageal junction  
GI 
gastrointestinal  
GLP 
GLP Good Laboratory Practices 
HER2 
human epidermal growth factor receptor 2 also known as ERBB2 
hFc-G1 
Fc fragment of human IgG1 
HIV 
human immunodeficiency virus  
HNSTD 
highest, non-severely toxic dose  
HR 
hazard ratio  
HR 
heart rate 
HR 
hazard ratio  
IB 
Investigator’s Brochure  
ICF 
informed consent form  
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee  
IgG1 
humanized monoclonal antibody 
IHC 
immunohistochemistry 
IND 
investigational new drug (application) 
INR 
international normalized ratio  
IOP 
intra-ocular pressure 
IRB 
Institutional Review Board  
ITT 
intent-to-treat  
IV 
intravenous 
IXRS 
interactive voice and Web response system  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 31 of 139 
Confidential 
Abbreviation 
Definition 
LTFU 
long term follow up 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFOLFOX6 
modified FOLFOX (infusional 5-FU, leucovorin, and oxaliplatin) 
mOS 
median OS 
mPFS 
median progression free survival  
MRI 
magnetic resonance imaging  
MTD 
maximum tolerated dose  
NCBI 
National Center for Biotechnology Information 
NCI 
National Cancer Institute 
NK 
natural killer 
OCT 
ocular coherence tomography  
ORR 
objective response rate  
OS 
overall survival  
PBMC 
peripheral blood mononuclear cell(s) 
PFS 
progression-free survival  
PK 
pharmacokinetic(s)  
PRO 
patient reported outcomes  
Q2W 
once every 2 weeks 
QLQ 
quality of life questionnaire  
QLQ-C30 
Quality of Life Questionnaire Version 3.0 
QOL 
quality of life  
QTcF 
Fridericia’s correction formula 
RD 
recommended dose  
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROW 
Rest of World 
RPE 
retinal pigment epithelium  
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan  
SD 
standard deviation  
SEM  
standard error of the mean 
SmPCs 
summaries of product characteristics 
t1/2 
terminal half-life  
TEAE 
treatment-emergent adverse event 
TKI 
tyrosine kinase inhibitor  
ULN 
upper limit of normal  
US  
United States 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 32 of 139 
Confidential 
Abbreviation 
Definition 
VAS 
visual analogue scale  
VEGF 
vascular endothelial growth factor 
WOCBP 
women of childbearing potential 
 
 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 33 of 139 
Confidential 
1.0 
INTRODUCTION 
1.1 
General Gastric Cancer 
Gastric or gastroesophageal cancer (GC), including gastroesophageal junction (GEJ) cancer, 
represents the fourth most common cancer worldwide (Kamangar 2006) and is a highly lethal 
disease, with 5-year overall survival (OS) rates below 30% in the United States (US) regardless 
of stage (National Cancer Institute 2015).  Though intensive multimodal therapy for locoregional 
disease improves survival (The GASTRIC Group 2010, Waddell 2014) it does not cure most 
patients and chemotherapy for metastatic disease provides only short-term benefits (Wagner 
2006, Waddell 2014).  First-line chemotherapy used in patients with metastatic or recurrent 
disease consists of a fluoropyrimidine (5-fluorouracil [5-FU] or capecitabine) with a platinum 
agent (usually oxaliplatin or cisplatin) (Al-Batran 2008, Kang 2009).  This treatment prolongs 
survival by 6 months compared to best supportive care (Wagner 2006), but the benefits are only 
short-term with a median OS (mOS) of 9 to 10 months and a progression-free survival (PFS) of 
5 to 5.6 months (Kang 2009, Waddell 2014).  
1.2 
Targeted Agents 
It is important to identify new treatments with acceptable toxicities for this patient population. 
Recent studies have identified important pathways involved in GC development.  The 
availability of targeted agents has led to the development of strategies incorporating these agents 
in the therapy for patients with such a poor prognosis.  Recently ramucirumab (a monoclonal 
antibody targeting the vascular endothelial growth factor [VEGF] pathway) was approved for 
treatment in patients with GC who progressed following first line treatment (Wilke 2014).  OS 
for patients treated with ramucirumab with paclitaxel was 9.6 months compared to 7.4 months 
with paclitaxel and placebo. 
One well established pathway is the human epithelial growth factor receptor 2 (HER-2 also 
known as ERBB2) (Gravalos 2008, Hofmann 2008).  HER-2 overexpression has been identified 
in 9 to 38% of GCs depending on histology and tumor location (Gravalos 2008).  The 
availability of trastuzumab, a monoclonal antibody targeting HER-2, led to the development of a 
randomized trial in newly diagnosed GC patients whose tumors overexpressed HER-2.  About 
22% of screened patients were HER-2 positive and the combination of standard chemotherapy 
with trastuzumab resulted in a median OS of 13.8 months compared to 11.1 months for patients 
treated with standard chemotherapy (Bang 2010).  Based on these results, this has become 
standard care for patients overexpressing HER-2.  
In spite of these improvements, the majority of GC patients succumb to their disease, and there 
are few treatment options following progression after first-line chemotherapy.  Recently anti-
PD1 therapies have been approved for treatment of later line GC in Japan and the United States.  
In September 2017, Japanese Ministry of Health, Labor and Welfare approved the PD1 inhibitor 
nivolumab (Opdivo®) for the treatment of unresectable advanced or recurrent gastric cancer 
which has progressed after chemotherapy.  This approval was based on the Phase 3 study 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 34 of 139 
Confidential 
ATTRACTION-2 (ONO-4538-12), in which Opdivo® significantly reduced patients’ risk of 
death by 37% (HR 0.63 [95% CI: 0.51-0.78, p<0.0001]) when compared to placebo (Kang 2017).  
Additionally, in September 2017, the United States Food and Drug Administration (FDA) 
granted accelerated approval to pembrolizumab (KEYTRUDA®) (Fuchs 2017) for patients with 
recurrent locally advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma 
whose tumors express PD-L1.  Patients must have had disease progression on or after 2 or more 
prior systemic therapies, including fluoropyrimidine- and platinum-containing chemotherapy 
and, if appropriate, HER2/neu-targeted therapy.  Pembrolizumab approval was based on data 
from 143 patients with tumors expressing PD-L1 and who were either microsatellite stable 
(MSS) or had unknown microsatellite instable (MSI) or mismatch repair deficient (dMMR) 
status, who demonstrated an objective response rate (ORR) of 13.3% (95% CI: 8.2, 20.0) and a 
duration of response (DOR) ranging from 2.8+ to 19.4+ months.  The majority of patients, 
however, do not respond to anti-PD1 therapy and other late line therapies such as ramucirumab 
with or without paclitaxel, and irinotecan improve the mPFS by less than 2 months (Thuss-
Patience 2011, Ford 2014, Fuchs 2014).  Therefore, continued evaluation of agents that can 
target the mutations present in GC is imperative. 
Amplification of fibroblast growth factor receptor 2 (FGFR2) has recently been identified as 
having prognostic importance in patients with GC (Jung 2012, Matsumoto 2012, Su 2014, 
Seo 2016).  Patients with FGFR2 gene amplification appear to have a worse prognosis (Su 2014, 
Seo 2016), suggesting that inhibition of FGFR2 may be an important target (Jung 2012, 
Matsumoto 2012).  FPA144 is a humanized monoclonal antibody specific to the human FGFR2b 
receptor that blocks fibroblast growth factor (FGF) binding to the receptor.  Evaluation of this 
agent in patients with GC whose tumors have alterations of FGFR2 would be an important 
strategy to improve the prognosis for these patients.  
1.3 
FPA144 
1.3.1 
Background 
The role of the FGFR pathway in cancer is well known.  FGFs can stimulate the transformation 
and proliferation of tumor cells and stimulate angiogenesis.  There are 22 known human FGFs 
with the expression of individual FGFs generally restricted to specific tissues, cell types, and/or 
developmental stage.  FGF signaling is mediated by a family of transmembrane tyrosine kinase 
receptors encoded by 4 distinct genes producing FGF receptor subtypes termed FGFR1–4 
(Turner 2010).  
The FGFR2 has 2 splicing variants, b and c.  In general, FGFR2b is expressed in tissues of 
epithelial origin (eg, stomach, skin) (Miki 1992).  The major ligands signaling through FGFR2b 
are FGF7, FGF10 and FGF22.  Alteration in signaling in the FGF/FGFR2 pathway 
(eg, overexpression of FGFR2 protein or amplification of FGFR2 gene) has been associated with 
gastric, breast, and other cancers, and appears to portend a worse prognosis (Turner 2010, 
Wu 2013).  As early as 1990, subsets of patients with GC (approximately 3 to 9%) and breast 
cancer (1 to 2%) were noted to have amplification of the FGFR2 gene, which resides on 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 35 of 139 
Confidential 
chromosome 10q26 (Hattori 1990, Turner 2010).  In GC, FGFR2 gene amplification leads to 
high-level expression of the FGFR2b receptor on the surface of the cells. 
1.3.2 
FPA144, an Fibroblast Growth Factor Receptor 2-Specific Antibody 
FPA144 is a humanized monoclonal antibody (IgG1 isotype) specific to the human FGFR2b 
receptor (National Cancer Institute 2015) that blocks FGF ligand binding to the receptor.  
FPA144 is directed against the third Ig region of the FGFR2b receptor isoform, the region that is 
alternatively spliced and regulates ligand specificity.  This antibody is glycosylated but is 
produced in a Chinese hamster ovary (CHO) cell line that lacks the FUT8 gene 
(α1,6-Fucosyltransferase) and therefore lacks a core fucose in the polysaccharide portion of the 
antibody.  The absence of the core fucose results in higher affinity for the Fc receptor FcγRIIIa 
compared to the fucosylated molecule and potentially enhances immune cell-mediated tumor cell 
killing (Shinkawa 2003).  The antibody has thus been glycoengineered for enhanced 
antibody-dependent cell-mediated cytotoxicity (ADCC) (Gemo 2014).  FPA144 inhibits FGF 
ligand-stimulated FGFR2b phosphorylation and cell proliferation in cell culture in FGFR2b 
overexpressing gastric and breast cancer cell lines.  FPA144 also inhibits tumor growth in 
FGFR2b overexpressing gastric and breast xenograft models.  The 3 potential mechanisms of 
action of FPA144 thus include blocking ligand binding and downstream signaling, decreasing 
expression of the FGFR2b driver protein, and enhancing ADCC.  
FPA144 can produce complete and durable tumor growth inhibition in FGFR2b-overexpressing 
and FGFR2 gene-amplified GC xenografts in immune-compromised mice where FGFR2b is 
considered a driver of tumor growth (Gemo 2014).  In addition, FPA144 demonstrates 
recruitment of natural killer (NK) cells and concomitant tumor growth inhibition in the 4T1 
syngeneic tumor model with modest expression of FGFR2b (Powers 2016).  These data suggest 
that ADCC may be efficacious in patients without FGFR2 gene amplification with moderate 
FGFR2b overexpression, and that ADCC activity may be a major contributor to the mechanism 
of action in these patients. 
Additionally, since FPA144 is specific for the FGFR2b receptor, it does not interfere with 
signaling of the other FGFs/ FGFRs, including FGFR2c.  In contrast to the FGFR tyrosine kinase 
inhibitors (TKIs), FPA144 does not inhibit FGF23 signaling.  FGF23 is a ligand involved in 
calcium/phosphate metabolism.  Thus, treatment with FPA144 is not expected to cause the 
dose-limiting hyperphosphatemia associated with the FGFR TKIs (Brown 2005, Andre 2013, 
Dienstmann 2014, Sequist 2014).  
As FPA144 is a targeted biologic, the clinical development of FPA144 will ultimately be in 
selected patients with alterations in the FGFR2 pathway that are most likely to respond to this 
novel agent.  The tumor types most relevant to date include gastric, bladder, and possibly 
cholangiocarcinoma.  Each of these cancers needs new therapeutic options.  The FPA144-004 
study is designed to evaluate the efficacy, safety, and PK of FPA144 in combination with 
modified FOLFOX (infusional 5-FU, leucovorin, and oxaliplatin) (mFOLFOX6) chemotherapy 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 36 of 139 
Confidential 
treatment.  Patients with gastrointestinal (GI) tumors will be enrolled in a Phase 1 safety run in, 
while the Phase 2 will enroll GC patients specifically selected for FGFR2 expression and/or 
FGFR2 gene amplification (FGFR2 selected) who are eligible for first-line mFOLFOX6 
chemotherapy. 
1.3.3 
Nonclinical Studies with FPA144 
The 3 mechanisms of action of FPA144 described above have been explored both in vitro and 
in vivo. 
1.3.3.1 
In Vivo Pharmacology 
FPA144 has been studied in a series of mouse xenograft models using human gastric and breast 
tumor cell lines that contain the FGFR2 amplicon.  These FGFR2 amplified lines all express 
high levels of the FGFR2b protein and respond to FPA144 in a dose-dependent fashion.  A dose 
response study (twice weekly dosing) was performed with the most sensitive model, a GC line, 
OCUM-2 (Figure 1).  Mice were treated at the indicated concentrations of FPA144, and the 
tumor growth was compared to mice treated with albumin alone.  Statistically significant tumor 
growth inhibition was seen at 0.3 mg/kg, but not at 0.1 mg/kg, and tumor regression was seen at 
1 mg/kg with complete tumor regression starting at doses of 1.5 mg/kg (2/15 animals), 2 mg/kg 
(1/15 animals), 3 mg/kg (5/15 animals), and 5 mg/kg (8/15 animals).  In the SNU-16 GC model, 
tumor growth inhibition was seen at 1 mg/kg, while in the MFM-223 tumor-bearing mice, 
5 mg/kg led to tumor stasis.  
Figure 1:  
Tumor Growth Inhibition in OCUM-2 Gastric Cancer Cell Line 
 
Cl) i' 
ew 
-=~ 
O"' 
> E 
o E 
EC 
::I «I 
I- ~ -
1000 
800 
600 
400 
200 
0 
0 
.....,. Albumin 
+- FPA144 1 mg/kg 
-+- FPA144 1.5 mg/kg 
...... FPA144 2 mg/kg 
...... FPA144 3 mg/kg 
-& FPA144 5 mg/kg 
10 
20 
30 
40 
50 
Days Post Tumor Implantation 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 37 of 139 
Confidential 
These tumor models require immunodeficient mice for tumor engraftment.  Because these mice 
lack a fully functioning immune system, and because the mouse Fcγ receptor (the receptor on 
immune cells required for ADCC) has lower affinity for human antibodies than the human 
Fcγ receptor, ADCC is impaired in these models of FPA144 mediated tumor growth inhibition.  
Thus, in patients with FGFR2 overexpressing tumors, ADCC may further contribute to antitumor 
activity in the clinical setting.  To understand the contribution of Fc receptor engagement and 
ADCC on FPA144 antitumor efficacy, a mutant antibody was engineered that cannot bind Fc 
receptors, thereby rendering it incapable of promoting ADCC.  The syngeneic 4T1 model of 
breast cancer was employed in immune competent mice that express FGFR2b, but to a lesser 
degree than amplified or overexpressed FGFR2b xenografts, such as OCUM-2M or SNU-16 
xenograft tumors.  4T1 tumors were grown to a volume of approximately 100 mm3, sorted into 
groups of equivalent tumor volume, then treated bi-weekly with FPA144, the ADCC-deficient 
FGFR2b antibody, or the Fc fragment of human IgG1 (hFc-G1) as control. FPA144 decreased 
tumor burden by 30% versus hFc-G1 control (p=0.001) while the mutant antibody showed no 
effect.  These data support a role for ADCC activity through Fc receptor binding as a required 
mechanism for FPA144 efficacy in a model that expresses modest amounts of FGFR2b protein. 
Mechanistically, FPA144 blocks FGFR2b phosphorylation, downregulates the receptor and 
inhibits downstream signaling.  The effect on downstream signaling was measured by examing 
phosphorylation of a protein that is directly phosphorylated by the FGFR2 protein, FGF receptor 
substrate-2 (FRS2).  This has been demonstrated in the SNU-16 FGFR2-amplified GC xenograft 
model.  In this experiment, mice were treated twice weekly with 10 mg/kg FPA144.  When 
tumors had reached approximately 500 mm3, the animals were sacrificed and protein levels in 
tumors were measured via Western Blotting.  FPA144 treatment resulted in decreased FGFR 
phosphorylation, total receptor expression, and phosphorylation of the downstream signal 
transduction molecule, FRS2. 
In contrast to the results with FGFR2-amplified GC models, FPA144 has minimal impact on 
xenograft models that are not FGFR2 amplified or do not express the FGFR2b protein.  Mice 
bearing NCI-87 gastric tumors, which do not express FGFR2b, were dosed intraperitoneally 
twice a week with FPA144 once the tumors reached approximately 100 mm3.  The tumor growth 
rate was indistinguishable between animals treated with either FPA144 (5 mg/kg) or control 
animals administered albumin.  
1.3.3.2 
Analysis of Immune Effector Functions of FPA144 
Some therapeutic antibodies containing IgG1 Fc are capable of recruiting immune effector 
function, specifically ADCC and complement-dependent cellular toxicity.  Once antibodies of 
the IgG1 isotype bind to their target on tumor cells, immune cells which express the Fc gamma 
receptor IIIa (FcγRIIIa), especially NK cells and macrophages, are recruited to the tumor cells 
and promote cell death in a process known as ADCC.  FPA144 is specifically engineered for 
enhanced ADCC.  This antibody lacks a core fucose in the polysaccharide portion of the 
antibody, and the lack of fucose results in higher affinity of FPA144 for FcγRIIIa compared to 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 38 of 139 
Confidential 
the fucosylated molecule and potentially enhanced immune cell mediated tumor cell killing.  In 
some in vitro studies, including ADCC assays, and in vivo studies, including toxicology studies, 
the fucosylated form of FPA144 (FPA144-F) was compared to the afucosylated form (FPA144).  
FPA144 was compared to FPA144-F for in vitro ADCC activity.  The target cell in the assay was 
an engineered cell line that expresses the full-length human FGFR2b described as Ba/F3 
FGFR2b, and the effector cells were peripheral blood mononuclear cells (PBMCs) obtained fresh 
from individual human donors.  As a negative control, FPA144 was also tested using a target cell 
line that was engineered to express the FGFR2c variant of the receptor (Ba/F3 FGFR2c cells), to 
which FPA144 does not bind.  The data are shown in Figure 2.  FPA144 and FPA144-F both 
showed ADCC activity, but the degree to which FPA144 killed the target cells was substantially 
greater than what was measured for FPA144-F.  As expected, FPA144 showed no ADCC 
activity in the negative control.  
Figure 2:  
In Vitro ADCC Activity of FPA144 
 
Abbreviations: ADCC = antibody-dependent cell-mediated cytotoxicity; FGFR = fibroblast growth factor receptor; 
No Ab = no antibody. 
The ability of FPA144 to mediate complement-dependent cytotoxicity (CDC) of 4 gastric cell 
lines with high FGFR2b was tested using previously published methods (Li 2009, Zhao 2010). 
No CDC was observed under any conditions tested, although positive controls (rituximab tested 
with RAMOS and RAJI cells) did induce CDC (these data not shown). 
0.01
0.1
1
10
0
50
100
FPA144-F /  FGFR2b
FPA144 / FGFR2b
No Ab
FPA144 / FGFR2c
FPA144 (µg/mL)
% Specific Lysis
........ 
-1::r-
........ 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 39 of 139 
Confidential 
1.3.3.2.1 
In vivo Antibody-Dependent Cell-Mediated Cytotoxicity Activity of FPA144  
To understand the contribution of ADCC on FPA144 antitumor efficacy, a mutant antibody, 
FPA144 N297Q, which cannot bind Fc receptors, was compared to FPA144 in the syngeneic 
4T1 model that expresses FGFR2b, but to a lesser degree than amplified or overexpressed 
FGFR2b xenografts, such as OCUM-2M or SNU-16 xenograft tumors. 4T1 tumors were grown 
to a volume of approximately 100 mm3, then treated with FPA144, FPA144 N297Q, or the 
hFc-IgG1 as control.  FPA144 decreased tumor burden versus hFc-IgG1 control while FPA144 
N297Q showed no effect (Figure 3).  These data support a role for ADCC activity through Fc 
receptor binding as a required mechanism for FPA144 efficacy in a model that expresses modest 
amounts of FGFR2b protein. 
Figure 3:  
FPA144, but not an ADCC-Deficient FGFR2b Antibody Leads to Tumor 
Suppression in a Syngeneic Tumor Model with Modest FGFR2b Expression 
 
1.3.3.3 
FPA144 Exposure Efficacy Relationships 
To translate the efficacy results in animal models to cancer patients, the relationship between 
FPA144 trough concentrations and efficacy in animal models was examined.  Intraperitoneal 
FPA144 doses of 1 mg/kg twice weekly were associated with tumor growth inhibition while 
greater efficacy depicted by tumor regression was noted at doses ≥ 3 mg/kg.  A dose of 1 mg/kg 
in the mouse xenograft model led to steady state trough plasma concentrations of about 1 µg/ml, 
while 3 mg/kg resulted in significant tumor regression and trough plasma concentrations of 67 to 
109 µg/mL.  
700 
-600 
~ 
~ ~ 500 
::, g M; 400 
o E 300 
E c: 
::, 8J 200 
I-
~ 
-100 
Orthotopic 4T1 
Tumor Volume 
..,. hFc-G1 
-+- FPA144 
......,. FPA144 N297Q 
0 -t--..... -.-~-i'----r-~-.-~-...-..-, 
10 
12 
14 
16 
18 
Days Post Implantation 
• 
Dosing 
20 
22 
a, 
E 
::, 
0"' 
> E 
0 E 
E 
::, 
I-
Individual Tumor Volumes 
Day 21 
1000 
-
800 + , 
600 
400 
200 
0 
0" 
~ 
~o 
,;,• 
?-" 
~ 
J 
<,_<I. 
~~ 
?-" 
<,,<I. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 40 of 139 
Confidential 
1.3.4 
Toxicology 
Toxicology studies with FPA144 have been performed in rat and cynomolgus monkey.  
The studies performed have included pilot single dose PK/tolerability and repeat-dose studies as 
well as Good Laboratory Practices (GLP) repeat-dose studies.  The longest of these studies 
involved intravenous (IV) administration of 13 weekly doses in rats and monkeys. 
In pilot repeat-dose toxicology studies, rats and cynomolgus monkeys received 4 weekly IV 
doses of FPA144 up to 150 mg/kg.  There were no changes in clinical signs and symptoms or 
clinical chemistry.  The most significant findings from these repeat-dose pilot studies were 
microscopic findings in corneal epithelium.  FPA144-treated animals displayed a dose-dependent 
thinning that represents both attenuation and reduction in the number of cells present in the 
corneal epithelium.  In addition, microscopic changes in the retinal pigment epithelium (RPE) in 
rat were noted that included RPE atrophy in 1 high-dose animal that received 4 weekly 
150 mg/kg doses.  Retinal changes were not observed in the 13-week GLP toxicology studies 
with a high dose of 100 mg/kg. 
In the 13-week repeat-dose GLP toxicology studies, FPA144 was administered by IV at dose 
levels of 1, 5, or 100 mg/kg/dose to both rats and monkeys for 13 weekly doses. 
In the rat, FPA144 resulted in adverse findings including: tooth (incisor) abnormalities (clinical, 
macroscopic, and microscopic findings) and body weight loss/lack of weight gain, which were 
most likely secondary to the tooth findings that necessitated early euthanasia at the 
100 mg/kg/dose, ocular findings (ophthalmic and microscopic findings), and macroscopic and/or 
microscopic findings in the Harderian gland (not present in humans) and oral mucosa (hard 
palate) at 5 and 100 mg/kg/dose, and macroscopic and/or microscopic findings in the tongue at 
all dose levels.  FGFR2 pathway signaling is known to play a critical role in maintaining the 
health of rat incisors, but has not been found to be relevant in human dentition.  FPA144-related, 
but non-adverse microscopic findings, were also noted in the mammary gland of animals at all 
dose levels.  Administration of FPA144 also resulted in exacerbation of background microscopic 
findings in the prostate gland of males given 1, 5, and 100 mg/kg, the non-glandular stomach of 
animals given 5 and 100 mg/kg/dose, and the lung of animals given 100 mg/kg/dose.  With the 
exception of FPA144-related effects on incisor teeth, some degree of recovery up to total 
recovery was evident for all findings at the end of recovery.  The absence of FPA144-related 
findings in the eye (ophthalmic or microscopic findings), Harderian gland, mammary gland, and 
prostate gland at the end of the recovery period indicated complete reversibility of the findings in 
these tissues.  Since all findings in the 1 mg/kg/dose group were minimal, without clinical 
consequences, and recoverable, the highest, non-severely toxic dose (HNSTD) in rats was 
determined to be 1 mg/kg/dose when given weekly for 13 weeks.  The lowest dose of 
1 mg/kg/dose level was associated with mean maximum observed serum concentration (Cmax) 
and area under serum concentration-time curve (AUC) over the dose interval τ (AUCτ) 
(τ=168 hours) of 27.7 µg/mL and 789 h*μg/mL, respectively, for combined sexes on Day 85 of 
the dosing phase. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 41 of 139 
Confidential 
In the 13-week repeat-dose GLP toxicology study performed in cynomolgus monkeys, FPA144 
was generally well tolerated.  FPA144-related effects were limited to microscopic findings of 
corneal atrophy (slight to moderate) in animals given 5 and 100 mg/kg/dose and mammary gland 
atrophy (moderate to marked severity) in females from all dose groups.  These findings in the 
cornea and mammary gland were not associated with clinical sequelae and were not observed at 
the end of the recovery phase, indicating complete recovery.  Therefore, based on the lack of 
correlative clinical findings or changes (eg, ophthalmic findings or clinical observations) and 
the demonstrated reversal during a recovery period, neither finding was considered adverse.  
The 100-mg/kg/dose level is considered below the severely toxic dose level in monkeys for the 
study.  This represents a > 300-fold safety factor over the proposed starting dose of 0.3 mg/kg.  
The highest dose of 100 mg/kg was associated with mean Cmax and AUCτ (τ=168 hours) values 
of 3,266 µg/mL and 252,787 h*μg/mL, respectively, for combined sexes on Day 85 of the dosing 
phase. 
In addition to in vivo toxicology studies, a GLP-compliant tissue cross reactivity study has been 
performed to compare the binding of FPA144 to a panel of 36 tissues from rat, cynomolgus 
monkey, and human.  In general, the binding pattern of FPA144 was similar among the 3 species 
and agreed with literature reports on the expression of FGFR2b being epithelial-based. 
Additional details of the nonclinical program for FPA144 are provided in the Investigator’s 
Brochure (IB), which contains comprehensive information on the investigational product. 
1.3.5 
Clinical Experience with FPA144 
Please refer to the bemarituzumab Investigator’s Brochure for updated results of the clinical 
experience with FPA144.  
FPA144 underwent evaluation in 2 Phase 1 dose escalation studies.  The first Phase 1, first-in-
human study, FPA144-001, entitled “A Phase 1 Open-Label, Dose-Finding Study Evaluating 
Safety and Pharmacokinetics of FPA144 in Patients with Advanced Solid Tumors” started in 
December 2014 and was conducted in the US, South Korea, and Taiwan.  This open-label study 
assessed the safety, pharmacokinetics (PK), and preliminary efficacy of FPA144 monotherapy in 
patients with solid tumors.  The study was comprised of 3 parts: a dose escalation portion in 
unselected solid tumor patients (Part 1A), a dose escalation portion in GC patients (Part 1B), and 
a dose expansion portion for patients with FGFR2b-selected tumors including FGFR2b-selected 
GC, and FGFR2b-selected bladder cancer (Part 2).  
Two parallel dose escalations were performed: Part 1A enrolled patients with solid tumors 
(19 patients), and Part 1B enrolled patients with GC (8 patients) to evaluate early evidence of 
efficacy and PKs to support the RD for the dose expansion cohort.  FPA144 was well tolerated in 
doses up to 15 mg/kg administered every 2 weeks (Q2W) in patients with advanced solid tumors.  
There were no dose-limiting toxicities (DLTs) observed during dose-escalation and a maximum 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 42 of 139 
Confidential 
tolerated dose (MTD) was not reached.  Based on an assessment of safety, tolerability, and PK, 
an RD of 15 mg/kg administered Q2W was selected. 
As of 20 March 2017, a total of 64 patients across the dose escalation (Parts 1A and 1B: 
27 patients) and the dose expansion (Part 2: 37 patients) enrolled in the study and 60 received at 
least 1 dose of FPA144.  Of these 64 patients, 41 patients had GC and 21 of those were identified 
as having GC with strong FGFR2b overexpression (or FGFR2b+ high, defined as IHC 3+ 
intensity in ≥ 10% of tumor cells).  Of those 21 patients, 6 patients were enrolled in the Part 1B 
dose escalation and 15 patients in the Part 2 dose expansion (Cohort A).  In addition, 4 GC 
patients with low FGFR2b overexpression (or FGFR2b+ low, defined as IHC 2+ intensity in 
< 10% of tumor cells or any immunohistochemistry (IHC) 1+ staining) have been enrolled in 
Cohort E and 10 GC patients (IHC 0–2) have been enrolled in Cohort C in Part 2 (dose 
expansion). 
Safety and tolerability of FPA144 is supported by a total of 64 patients from the Phase 1 study 
(FPA144-001) who have received at least 1 dose of FPA144.  
Safety data from 64 patients enrolled in FPA144-001 including 37 patients treated at 15 mg/kg 
administered Q2W (expansion dose) are described here.  Adverse events (AEs) have been 
reported in 58 of 64 patients (90.6%).  Thirty-two of the 64 patients reported an AE that was 
deemed by the investigator to be drug related. Of the drug-related AEs, none were Grade 4 or 5.  
There were 6 Grade 3 events: an infusion reaction in 1 patient, an aspartate aminotransferase 
(AST) elevation and alkaline phosphatase increase in 1 patient, nausea in 2 patients and a 
transient decrease in neutrophil count (which resolved without dose interruption or modification) 
in 1 patient.  Three patients discontinued treatment due to an AE.  One for E. coli sepsis, a 
second for cancer pain, both considered unrelated to study treatment and a third patient (post data 
cut) with limbic stem cell deficiency after approximately 14 months of therapy, considered 
related to study treatment also discontinued treatment.  All other patients discontinued treatment 
as a result of disease progression.  Treatment-related serious adverse events (SAEs) were 
reported in 3 patients: 1 patient (15 mg/kg) with the Grade 3 infusion reaction, 1 patient 
(15 mg/kg) with the Grade 2 corneal ulcer, and 1 patient (10 mg/kg) with the Grade 2 limbic 
stem cell deficiency (post data cut). In all 3 patients with treatment-related SAEs, the events 
resolved.  The patient with the infusion reaction resumed drug administration after premedication 
and a reduced dose.  The patient with the Grade 2 corneal ulcer temporarily interrupted FPA144 
and received ophthalmic drugs with resolution of the event.  The patient with the Grade 2 limbic 
stem cell deficiency discontinued study treatment and her symptoms and signs resolved after 
approximately 3 months. 
Additional development of FPA144 for the treatment of GC includes an ex-US, non-US 
investigational new drug (IND) study, FPA144-002, entitled “A Phase 1 Open-Label, Dose-
Finding Study of FPA144 in Japanese Patients with Advanced Gastric or Gastroesophageal 
Cancer.”  This dose escalation study was designed to assess the PK and safety of single agent 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 43 of 139 
Confidential 
FPA144 and identified the RD for single agent FPA144 in Japanese patients.  No DLTs were 
reported in the FPA144-004 study. 
Please reference the bemarituzumab investigator’s brochure for an updated review of the ocular 
events that have occurred in clinical studies with FPA144. As discussed in Section 1.3.4, 
preclinical animal toxicity studies support a need for comprehensive ophthalmologic 
examinations.  The comprehensive ophthalmologic examinations in the Phase 1 study (FPA144-
001) includedd fundoscopic and slit lamp examination, ocular coherence tomography (OCT), 
visual acuity, and review of ocular and visual symptoms at screening, prior to the third dose, and 
at the end of treatment (EOT) visit.  Slit lamp examinations (with completion of fluorescein 
staining score form), were conducted at regular intervals for all patients.   
Twenty-three of 79 (29%) patients treated with FPA144 monotherapy in study FPA144-001 
reported ocular adverse events.  The most common ocular events (> 5%) were dry eye 
(14 patients [18%]) and increased lacrimation (5 patients [6%]). Among these patients, 3 events, 
a Grade 2 ulcerative keratitis, a Grade 2 limbic stem cell deficiency, and a Grade 2 corneal 
dystrophy, required treatment and follow-up from an ophthalmologist.   
In the phase 1 part of study FPA144-004, two events of punctate keratitis and one each of 
corneal abrasion, corneal disorder and limbal stem cell deficiency were reported. As of 
October 29, 2019, 18 of 134 (13%) patients treated in the phase 2 part of the FPA144-004 study 
had reported ocular adverse events involving the cornea or retina.  Eight patients experienced 
keratitis (grade 1 (1); grade 2 (5), grade 3 (2)), three patients experienced punctate keratitis 
(grade 1; grade 2; grade 3 (1 each)), two experienced limbal stem cell deficiency (grade 3), two 
patients experienced retinal hemorrhage (grade 1), two patients experienced ulcerative keratitis 
(grade 2 (1); grade 3 (1)),one patient each experienced corneal erosion (grade 1), corneal 
infiltrate (grade 1) and xerophthalmia (grade 2). The retinal hemorrhages were asymptomatic 
incidental findings during comprehensive ophthalmologic evaluation and did not preclude 
ongoing treatment with FPA144/placebo. The study drug/placebo was withdrawn in eight 
patients (2 patients with keratitis, 1 patient each with corneal infiltrates, corneal ulcer, eye 
disorder, dry eye, ulcerative keratitis, xerophthalmia) and was delayed in four patients (2 cases of 
keratitis, and one patient each with superficial punctate lentitis both eyes and punctate epithelial 
erosion).  
Evidence of early efficacy in the FGFR2b+ high gastric and GEJ cancer patient population is 
supported by a confirmed response rate (using Response Evaluation Criteria in Solid Tumors 
version 1.1 [RECIST v1.1]) of 19.0% [5.4-41.9%]) in 21 patients in the target patient population 
with a duration of response (DOR) of 15.4 weeks (95% confidence interval [CI] 9.1, 19.1 weeks) 
and a median PFS of 11 weeks (95% CI 5.7, 20.6 weeks). 
FPA144 serum concentration was measured by a validated enzyme linked immunosorbent assay 
(ELISA) (refer to the FPA144 IB).  FPA144 demonstrated nonlinear clearance (CL) from 
0.3 mg/kg to 1 mg/kg and close to linear CL from 1 mg/kg to 15 mg/kg in patients with solid 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 44 of 139 
Confidential 
tumors including GCs tested in Parts 1A and 1B, suggesting target-mediated CL.  The estimated 
half-life (t1/2) ranged from 6.01 to 11.7 days across cohorts, which supports every 2-week dosing.  
As derived from the mouse efficacy study using the OCUM2 FGFR2-amplified GC xenograft 
model, 60 µg/ml was selected as target trough serum concentration at steady state (Ctrough ss).  
Based on the PK data in combination with safety data and evidence of efficacious activity from 
Part 1 of the clinical study, the 15 mg/kg Q2W dose was selected to test in the Part 2 expansion 
cohorts as this dose level was expected to achieve target Ctrough ss of ≥ 60 µg/mL.  Limited PK 
data in Part 2 from a total of 18 GC patients dosed at 15 mg/kg Q2W, including 8 patients with 
high FGFR2b overexpression (Cohort A) and 10 patients without FGFR2b overexpression 
defined as IHC 0 (Cohort C), suggested that a dose of 15 mg/kg Q2W will achieve Ctrough ss target 
of ≥ 60 µg/mL (refer to the FPA144 IB) in approximately 70% of patients at Day 28.  PK 
modeling suggests that the addition of a single dose of 7.5 mg/kg administered on Day 8 of the 
first cycle allows at least 90% of patients to achieve the target trough of ≥ 60 ug/ml at Day 15, 
without significantly increasing the Cmax. 
1.4 
Rationale for mFOLFOX6 
Chemotherapy for advanced GC prolongs survival and improves symptoms (Wagner 2006, Al-
Batran 2008, Kang 2009, Okines 2009, Waddell 2014).  The combination of a platinum agent 
with a fluoropyrimidine has become a frequently used combination (Kang 2009) and in a recent 
meta-analysis has been identified as superior to single agent treatment and best supportive care 
(Wagner 2006).  Although there is no single standard globally accepted first line reference 
chemotherapeutic regimen for advanced GC, the combination of a fluoropyrimidine (5-FU, 
capecitabine or S1) and a platinum agent (cisplatin or oxaliplatin) is an accepted standard of care 
in both Western and Asian countries (Wagner 2006, Al-Batran 2008, Keam 2008, Kang 2009, 
Okines 2009). 
The antitumor treatment effect of fluorouracil derivatives (5FU, capecitabine) are believed to 
result from inhibiting the enzyme thymidylate synthase (TS). (Ulrich 2000, Pullarkat 2001, 
Chen 2003).  Leucovorin, also known as folinic acid, causes a biochemical modulation of 5-FU 
enhances the treatment effect of 5-FU in patients with GC (Kim 2003). 
Oxaliplatin is a cisplatin analog that functions through its ability to form DACH-platinum 
adducts and block deoxyribonucleic acid (DNA) replications.  Oxaliplatin exhibits additive or 
synergistic properties when combined with 5-FU and has proven to be effective even when 
treating 5-FU resistant cell lines or cell lines resistant to cisplatin (Kim 2003, Keam 2008).  
In a randomized Phase 3 trial comparing 5-FU/LV/oxaliplatin with 5-FU/LV/cisplatin (FLP) in 
the treatment of 220 patients with GC reported a statistically insignificant improved time-to-
progression; however, the oxaliplatin based regimen was associated with meaningful reductions 
in Grade 3–4 AEs, including anemia, nausea, vomiting and renal toxicity, but with more 
neuropathy (Al-Batran 2008).  Subsequent studies have supported the safety and efficacy of 
mFOLFOX6 as the first line of treatment for advanced GC (Keam 2008). 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 45 of 139 
Confidential 
Accordingly, mFOLFOX6 is used as standard therapy in advanced/metastatic GC patients in the 
US, Europe, and Asia. 
1.5 
Rationale for Combination Therapy: FPA144 and mFOLFOX6 
Since advanced GC is not cured with the currently available chemotherapy regimens, there is a 
continued need to provide improvement to available treatments.  The FGFR pathway has been 
shown to play an important role in the transformation and proliferation of tumor cells, and 
inhibiting FGF ligand-stimulated FGFR2b phosphorylation and cell proliferation has been shown 
to reduce tumor growth in both FGFR2b overexpressing gastric and breast cell lines and 
xenograft models.  
FPA144 as monotherapy has demonstrated objective tumor responses in preclinical studies, 
blocking ligand binding and downstream signaling, decreasing expression of the FGFR2b driver 
protein and enhancing ADCC.  Preliminary data from the first-in-human study of FPA144 
indicate that FPA144 monotherapy has activity in patients with heavily pretreated 
FGFR2b-selected GC.  The safety profile has been tolerable, with no DLTs encountered to date. 
The combination of FPA144 and paclitaxel demonstrated enhanced activity in both the 
OCUM-2M and HSC-39 xenograft models of GC compared to monotherapy of either agent at 
the doses tested (Gemo 2014).  Using a more aggressive chemotherapy regimen in these same 
models, such as cisplatin and 5-FU or oxaliplatin and 5-FU chemotherapy, provided near 
complete growth suppression in the HSC-39 model and therefore no additional benefit was 
observed with the addition of FPA144.  Alternatively, the OCUM-2M FGFR2-amplified model, 
demonstrated near complete tumor suppression with FPA144 at the doses tested, and therefore 
no additional benefit was observed in combination with cisplatin + 5-FU or oxaliplatin + 5-FU 
chemotherapy.  Importantly, the addition of FPA144 to any of these chemotherapy regimens did 
not increase the toxicity associated with chemotherapy as measured by weight loss in mice. 
Advanced stage GC has been demonstrated to be heterogeneous, and the development of 
additional heterogeneity is hypothesized to be induced by standard front line chemotherapy 
(Smyth 2016).  Specifically, GC metastases are more likely to overexpress FGFR2b compared to 
the primary tumor, suggesting that emergence of an FGFR2b overexpressing tumor is a later 
stage event (Ahn 2016), and may even be induced by prior systemic chemotherapy.  Sequential 
biopsies and circulating tumor DNA (ctDNA) testing have demonstrated that subclones of 
tumors with different phenotype emerge after targeted therapy treatment (Smyth 2016, 
Catenacci 2017).  The hypothesis that chemotherapy and FPA144 target different subclones of 
GC is supported by the ability of FPA144 or mFOLFOX6 to drive complete growth suppression 
of GC tumors in distinct xenograft models (Gemo 2014).  
Further, the hypothesis that adding a targeted biologic agent to standard chemotherapy in GC 
may be beneficial in selected patients is further supported by the demonstration of the clinical 
benefit (PFS and OS) of adding trastuzumab to chemotherapy in patients with GC whose tumors 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 46 of 139 
Confidential 
overexpress HER2 (Bang 2010) and the addition of ramucirumab to paclitaxel in patients who 
progressed after front-line therapy (Wilke 2014).  
1.6 
FPA144 and mFOLFOX6 Starting Dose Justification 
In study FPA144-001, no DLTs were reported at doses tested from 0.3 mg/kg to 15 mg/kg 
administered Q2W and no MTD of FPA144 was identified.  Therefore, the RD for expansion 
was based on the observation of clinical efficacy and tolerability in the human FPA144-001 
Phase 1 study, combined with preclinical data from the OCUM2 FGFR2-amplified GC xenograft 
mouse model, which identified 60 µg/mL as the target trough serum concentration to achieve 
maximum efficacy.  Supporting the hypothesis that ≥ 60 µg/mL should be the target minimum 
trough serum concentration (Ctrough), all patients who demonstrated a partial response in the 
ongoing FPA144-001 study achieved the target Ctrough ss of ≥ 60 µg/mL.  Patients receiving a 
lower dose of 10 mg/kg Q2W also achieved a target trough of ≥60 µg/mL, but not until steady 
state approximately 3 months after the initiation of FPA144.  At the earlier time point of 28 days, 
only 3 of 6 patients dosed at the 10 mg/kg dose achieved the target Ctrough of ≥ 60 µg/mL 
compared to 21 of 29 patients dosed at 15 mg/kg Q2W based on data as of 20 March 2017. 
To safely minimize the time needed to reach the target FPA144 target trough concentration while 
increasing the potential for earlier efficacy in this rapidly progressing cancer, a dose of 
7.5 mg/kg FPA144 will be administered on Day 8 of Cycle 1 for patients enrolled in Cohort 2. 
PK modeling suggests that the schedule of 15 mg/kg Q2W with 1 dose of 7.5 mg/kg on Day 8 
(Cycle 1 only) will allow at least 90% of patients to achieve the biologically active target trough 
concentration by Day 15 instead of by Day 28.  Achieving the target trough concentration earlier 
is clinically important in this patient population with rapidly progressive disease. 
No drug-drug interactions are expected between FPA144 and mFOLFOX6 based on known 
mechanisms of CL.  However, based on FGFR2b expression in tissues of epithelial origin 
(eg, stomach and skin), and the AEs reported in the ongoing FPA144-001 study, FGFR2 
inhibition could increase the rate of mucositis, nausea, vomiting and diarrhea observed with 
mFOLFOX6 alone.  
The Phase 1 portion of this study will initiate FPA144 combined with mFOLFOX6 a dose of 
6 mg/kg administered Q2W.  Assuming the dose of 6 mg/kg is demonstrated to be safe, 
tolerable, and without clinical or pharmacologic evidence of a drug interaction, the second dose 
to be tested will be 15 mg/kg Q2W with 1 dose of 7.5 mg/kg on Day 8 (Cycle 1 only).  If 
Cohort 1 (6 mg/kg Q2W) clears the 28 day DLT period, but ≥ 2 DLTs are observed in Cohort 2 
(15 mg/kg Q2W with 1 dose of 7.5 mg/kg on Day 8 of Cycle 1 only), based on observed safety, 
tolerability and PK, a dose level between Cohorts 1 and 2 (this new cohort will be Cohort 1a, 
proposed to be 15 mg/kg Q2W) may be evaluated in a rolling 6 design.  If ≥ 2 DLTs are 
observed in Cohort 1a, then the Cohort Review Committee (CRC) may decide to evaluate a dose 
between the dose levels tested in Cohort 1a and Cohort 1 (this new cohort will be Cohort 1b) to 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 47 of 139 
Confidential 
achieve tolerability with optimal target exposure.  At least 6 patients will be evaluated for safety, 
tolerability and PK at the final RD prior to initiating the Phase 2 portion of the study.  
1.7 
Risk-Benefit Assessment of FPA144 and mFOLFOX6 
This overview is not intended to replace the complete information presented in the FPA144 IB. 
Please consult the IB for more detailed information.  
GC is a highly lethal disease, the treatment of which depends significantly on the stage of the 
disease.  Intensive multimodal therapy for locoregional disease fails to cure most patients and 
standard chemotherapy for metastatic disease provides only short-term benefits.  First-line 
chemotherapy used in metastatic or recurrent disease generally consists of a fluoropyrimidine 
(5-FU, S1 or capecitabine) with a platinum agent (usually oxaliplatin or cisplatin) and the mOS 
is 9 to 11 months with a median PFS of 5 to 7.4 months (Kang 2009).  Patients with GC and 
FGFR2 gene amplification (Seo 2016) or FGFR2b overexpression (Ahn 2016) have a worse 
prognosis (Hattori 1996, Gemo 2014) thus warranting evaluation of a new targeted agent against 
FGFR2+ GC . 
mFOLFOX6 chemotherapy is associated with myelosuppression, most frequently Grade 3-4 
neutropenia reported in about 40–50% of patients, peripheral neuropathy (> Grade 2) reported in 
about 70% of patients, diarrhea (> Grade 2) reported in about 25% of patients, and 
nausea/vomiting reported in about 3% of patients each (Tournigand 2004, van Hazel 2016).  
Vomiting and mucositis were not observed in FPA144 toxicology studies, however, 20.4% of 
patients in the ongoing FPA144-001 study with monotherapy FPA144 reported nausea and/or 
vomiting, with 3.1% reporting Grade 3 (no Grade 4 or higher was reported).  Although no 
mucositis or diarrhea has been reported (n=64), based on mechanism of action, inhibition of 
FGFR2 may increase this risk.  In patients with underlying metastatic GC receiving mFOLFOX6 
chemotherapy, an increase in the incidence of any of these GI symptoms could be clinically 
meaningful.  
The protocol includes standard anti-emetic therapy, close clinical monitoring and drug 
modifications and discontinuation.  Additionally, an independent data monitoring committee 
(DMC) will monitor safety and toxicity on the study (refer to Section 8.10.2). 
The individual agents used in the FOLFOX regimen (5-FU, oxaliplatin and leucovorin) are also 
associated with risks. Refer to local prescribing information for complete details. 
The risks associated with fluorouracil include: myelosuppression, diarrhea, nausea and vomiting, 
mucositis, anorexia, palmar-plantar erythrodysthesia, alopecia, cardiac toxicity, neurotoxicity 
and hyperammonemic encephalopathy.  Due to a potential drug-drug interaction between 5-FU 
and warfarin, there is a risk of an elevated international normalized ratio (INR) for patients on 
warfarin who also receive 5-FU (Teva Pharmaceuticals USA Inc 2016). 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 48 of 139 
Confidential 
The risks associated with oxaliplatin include allergic reactions, neuropathy, pulmonary toxicity, 
hepatotoxicity, cardiovascular toxicity, rhabdomyolysis, nausea/vomiting, diarrhea, mucositis, 
myelosuppression, fatigue.  
As of November 2017, no drug has been approved in the US, EU, or Asia specifically for the 
subset of patients with FGFR2-selected GC.  Based on the emerging data from the Phase 1 
FPA144-001 trial, FPA144 may provide a meaningful clinical benefit with an acceptable 
tolerability profile in heavily pretreated patients with GC whose tumors overexpressed FGFR2.  
FGF signaling pathways appear to be a valid target for clinical investigation in human cancer 
based on preclinical models as well as ongoing clinical trials with other molecules that broadly 
target FGF signaling (Taiho Oncology Inc 2015, Hall 2016, GlaxoSmithKline 2017). 
As detailed in Section 1.5, the addition of FPA144 to current standard of care first-line treatment 
for advanced GC with mFOLFOX6 is anticipated to improve PFS compared to chemotherapy 
alone.  Preliminary data from the first-in-human study of FPA144 indicate that FPA144 
monotherapy has activity in patients with FGFR2b-selected gastric and bladder cancer.  The 
safety profile has been tolerable, with no DLTs reported.  
In addition to the study design (dose escalation) and eligibility criteria that exclude patients with 
significant organ dysfunction, the following precautions will be taken in this study: 
• Based on non-clinical toxicology, FPA144 has an expected on-target effect leading to corneal 
thinning which may increase the risk of developing a corneal ulcer or a secondary corneal 
infection.  Based on the aggregate clinical data, keratitis has been identified as an adverse 
drug reaction to bemarituzumab treatment. Accordingly, patients who at baseline have a 
history of corneal disease such as keratitis or corneal transplant will be excluded.  Patients 
found to have ocular abnormalities involving the cornea during screening will also be 
excluded, including corneal defects, corneal ulcerations, keratoconus, or other abnormalities 
that can pose an increased risk of developing a corneal ulcer.  Ophthalmology examinations 
will be performed at baseline and at regular protocol required intervals during the study to 
monitor potential ocular effects (described in Section 6.6.2). 
• Based on non-clinical data, FPA144 may have on-target effects on the epithelium of the 
oropharynx, although redundancy in the FGF pathway in these organs may limit and the 
toxicity beyond what is anticipated from mFOLFX6 alone.  To date, 1 event of Grade 1 dry 
mouth has been reported in a patient during Cycle 6 of FPA144 given at 3 mg/kg. 
Fluoropyrimidines have a known toxicity of mucositis (Teva Parenteral Medicines Inc 2016). 
Patients will undergo physical examination approximately every 2 weeks, including 
examination of the oropharynx.  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 49 of 139 
Confidential 
• Patients will be closely monitored for infusion-related reactions which are known potential 
toxicities of both oxaliplatin and FPA144.  The FPA144 infusion rate may be reduced at the 
investigator’s discretion based on occurrence of infusion-related reactions, such as changes in 
vital signs, nausea, vomiting, or other constitutional symptoms or allergic reactions occurring 
during infusion or up to 2 hours after cessation of the infusion.  
• Routine premedication is not generally administered for the initial FPA144 dose; patients 
who develop infusion-related AEs may be premedicated prior to subsequent infusions of 
FPA144 at the discretion of the investigator.  Pre-medication for mFOLFOX6 should be 
at the discretion of the investigator, administered according to the institution’s standard 
practice, and captured on the patient’s electronic case report form (eCRF).  
• Epinephrine for subcutaneous injection, diphenhydramine (or equivalent) for IV 
injection, and any other medications and resuscitation equipment for emergency 
management of anaphylactic reactions must be available in the room where the infusions 
are being performed.  
1.8 
Rationale for Phase 2 Pre-Screening 
FPA144 is an antibody designed to recognize the FGFR2 receptor when expressed on gastric 
tumors.  The current hypothesis is that the presence of FGFR2 will be an important predictor of 
how patients with FGFR2-selected GC will respond to treatment with FPA144.  This is based on 
the preclinical observation that only tumors that overexpressed FGFR2b responded to FPA144 
treatment in xenograft studies, as well as early results from the ongoing first-in-human study 
demonstrating objective responses in patients with FGFR2b overexpression. 
Eligibility for enrollment in the Phase 2 portion is based on FGFR2b overexpression and/or 
FGFR2 gene amplification as determined by a centrally performed, validated IHC or ctDNA 
blood assay.  Patients are required to provide both a tissue sample and a blood sample to test for 
FGFR2 and patients unable to provide both samples will not be eligible for this trial.  Patients 
who are positive for FGFR2b overexpression and/or FGFR2 gene amplification are referred to in 
this protocol as FGFR2-selected.  Positivity based on only 1 assay is adequate to meet eligibility 
requirements (eg, positive by ctDNA blood assay, but negative by IHC) (refer to Section 4.2).  
Pre-screening allows for collection of blood and tissue to determine FGFR2 positivity using 
ctDNA and IHC assays.  Once a patient is confirmed to have a positive result based on central 
testing, the screening period initiates, allowing for evaluation of all other eligibility criteria (refer 
to Section 4.2).  
Eligible patients for the Phase 2 portion must be naïve to prior chemotherapy for metastatic or 
unresectable disease, with the exception that patients may have received prior adjuvant or 
neo-adjuvant therapy (chemotherapy and/or chemoradiation) greater than 6 months prior to 
enrollment.  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 50 of 139 
Confidential 
Since the IHC and ctDNA blood results may require approximately 2 weeks to complete, 
patients eligible for entering Phase 2 of this study are permitted to receive 1 dose of mFOLFOX6 
during this interim time period (pre-screening period) at the discretion of the investigator.  This 
1 dose of chemotherapy is not a requirement of the study and is not considered part of this 
clinical study.  
1.9 
Rationale for Tumor Tissue and Blood Assessments 
Patients who do not demonstrate either FGFR2b overexpression using IHC or FGFR2 gene 
amplification using a ctDNA blood assay will not be eligible for enrollment.  Positivity based on 
either 1 or both assays is adequate to meet the eligibility requirements (eg, positive by ctDNA 
blood assay, but negative by IHC).  The blood test will reveal DNA amplification of FGFR2, 
while the IHC test will show the extent of protein expression.  Five Prime has developed an 
anti-FGFR2 antibody for nonclinical use, whose sensitivity and specificity to detect FGFR2 by 
IHC has been optimized (Deshpande 2014). 
In studies evaluating GC samples, FGFR2 gene amplification has been uniformly associated 
with significant FGFR2b surface expression, as detected by IHC (Gemo 2014).  The antitumor 
effect of FPA144 that was observed in preclinical testing was predicated upon the 
overexpression of FGFR2b in the tumor cell lines.  Patients without overexpression of FGFR2 
are unlikely to see a significant benefit from treatment with FPA144 in combination with 
mFOLFOX6. 
The selection of patients with FGFR2-positive tumors for treatment with FPA144 is supported 
by data from the ongoing Phase 1, first-in-human study of FPA144-001.  Confirmed responses 
have only been reported in patients having tumors with FGFR2b overexpression, validating the 
strategy of selecting these patients for treatment with FPA144 based on FGFR2 status.  
Additionally, since GC is heterogeneous, the use of ctDNA has been incorporated to identify 
tumors that shed FGFR2 into the blood stream, but whose tumors do not overexpress FGFR2b 
(due to tissue sampling error).  Allowing patients to enroll who either test positive for FGFR2b 
by tissue or positive for FGFR2 by blood will maximize the inclusion of patients with FGFR2 
amplified tumors in the trial. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 51 of 139 
Confidential 
2.0 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Phase 1 Objectives 
2.1.1 
Primary 
To determine the RD of FPA144 combined with a fixed dose of mFOLFOX6 (hereinafter 
referred to as FPA144 + mFOLFOX6) in patients with advanced GI tumors  
2.1.2 
Secondary  
• To evaluate the safety and tolerability of FPA144 + mFOLFOX6 in patients with GI tumors 
• To characterize the PK profile of FPA144 + mFOLFOX6 in patients with GI tumors 
• To characterize the immunogenicity of FPA144 
2.1.3 
Exploratory 
To characterize the pharmacodynamic profile of FPA144 + mFOLFOX6 in patients with GI 
tumors 
2.2 
Phase 2 Objectives 
2.2.1 
Primary 
To compare investigator-assessed PFS in patients with FGFR2-selected GC treated with FPA144 
+ mFOLFOX6 to those treated with placebo combined with mFOLFOX6 (hereafter referred to 
as placebo + mFOLFOX6)  
2.2.2 
Secondary  
To compare the following in patients with FGFR2-selected GC treated with FPA144 + 
mFOLFOX6 to those treated with placebo + mFOLFOX6: 
• Overall survival (OS) 
• Investigator-assessed ORR 
• Safety and tolerability 
2.2.3 
Exploratory 
To compare the following in patients with FGFR2-selected GC treated with FPA144 + 
mFOLFOX6 to those treated with placebo + mFOLFOX6: 
• DOR 
• Patient-reported outcomes (PROs) and quality of life (QOL) outcomes until investigator-
assessed disease progression 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 52 of 139 
Confidential 
• To explore the association between FGFR2 status (in tumor tissue and/or blood) with clinical 
outcome 
• To explore the concordance between FGFR2b overexpression in tumor tissue and FGFR2 
gene amplification in blood 
To characterize the following: 
• PK profile of FPA144 + mFOLFOX6 in patients with FGFR2-selected GC 
• Immunogenicty of FPA144 
2.3 
Phase 1 Endpoints 
2.3.1 
Primary 
• The incidence of Grade 2 or higher AEs assessed as related to FPA144 by the investigator 
and the incidence of clinical laboratory abnormalities defined as DLTs 
2.3.2 
Secondary  
• The incidence of AEs, clinical laboratory abnormalities, corneal and retinal findings, and 
electrocardiogram (ECG) abnormalities  
• PK parameters of FPA144, such AUC, Cmax, Ctrough, CL, t1/2, volume of distribution, the time 
to achieve steady state, dose-linearity, and accumulation ratio 
• Incidence of treatment-emergent anti-FPA144 antibody response 
2.3.3 
Exploratory 
2.4 
Phase 2 Endpoints 
2.4.1 
Primary 
PFS, defined as time from randomization until the date of disease progression based on 
investigator assessment per RECIST v1.1 or death from any cause, whichever comes first 
2.4.2 
Secondary 
• OS, defined as time from randomization until death from any cause 
• ORR, defined as the proportion of patients with partial or complete response in all enrolled 
patients based on investigator assessment of tumor lesions per RECIST v1.1 
• Incidence of AEs, clinical laboratory abnormalities, corneal and retinal findings, and ECG 
abnormalities  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 53 of 139 
Confidential 
2.4.3 
Exploratory 
• DOR limited to patients who are responders to treatment, as determined by the investigator 
per RECIST v1.1, and defined as the time of first response to progression or death from any 
cause, whichever comes first 
• Change from baseline in functional outcomes as measured by EuroQOL-5D-5L (EQ-5D-5L) 
and the European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Version 3.0 (EORTC QLQ-C30) 
• The correlation between identified FGFR2 status in tumor tissue and/or ctDNA blood assay, 
as determined by IHC and blood-based molecular diagnostic assay, with OS, PFS, and 
objective response per RECIST v1.1 
• The correlation between identified FGFR2b overexpression in tumor tissue by IHC and 
FGFR2 gene amplification as determined by ctDNA blood assay  
• PK parameters, Cmax and Ctrough of FPA144 in combination with mFOLFOX6  
• Incidence of treatment-emergent anti-FPA144 antibody response 
 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
Page 54 of 139 
Confidential 
3.0 
STUDY DESIGN 
3.1 
Study Overview 
The Phase 2 portion of this study was initially designed as a Phase 3 with overall survival as the 
primary endpoint. The study design has been changed considering the findings of a higher 
proportion of FGFR2 positive tumors in patients in the front-line gastric cancer setting than 
expected (~ 30% vs the expected rate of 10%)  and that the vast majority of tumors are positive 
via IHC analysis for FGFR2b overexpression rather than by ctDNA analysis of FGFR2 
amplification. The randomized, double-blind study design will be maintained through the 
primary analysis of the Phase 2 study. 
This is a double-blind, randomized, controlled, multicenter Phase 1/2 study to evaluate the 
safety, tolerability, efficacy, and PK of FPA144 + mFOLFOX6 versus placebo + mFOLFOX6.  
Patients may enroll into either Phase 1 or Phase 2 but may not enroll in both phases of the study. 
This study includes a Phase 1 safety run-in portion and a Phase 2 portion.  The Phase 1 safety 
run-in is an open-label dose-escalation of FPA144 + mFOLFOX6 in patients with GI tumors 
(not FGFR2 selected).  Provision of tissue for retrospective FGFR2b overexpression testing by 
IHC, and blood for FGFR2 gene amplification by ctDNA, are not required for enrollment in 
Phase 1, but will be tested retrospectively if available (refer to Section 6.1). 
The Phase 2 portion of the study (to follow the Phase 1 safety run-in) is a global, randomized, 
double-blind, controlled, study to evaluate the efficacy of FPA144 + mFOLFOX6 versus placebo 
+ mFOLFOX6 in patients with FGFR2-selected GC.  FGFR2b overexpression will be
determined by prospective IHC analysis and/or a ctDNA blood assay demonstrating FGFR2 gene
amplification.  The duration of the study is expected to be approximately 43 months to complete;
this includes Phase 1 (6 months for completion) and Phase 2 (13 months for accrual and
24 months of long term follow up (LTFU) from the last patient enrolled).
In Phase 1, the starting dose level of FPA144 is 6 mg/kg per dose. Subsequent dose escalations 
between cohorts in Phase 1 are described in Section 3.2.1.  The dose of FPA144 for Phase 2 will 
be determined by evaluation of the data from Phase 1 of the study, as described in Sections 3.2.3 
and 3.2.4. 
Additional study design details are provided below for each study phase.  The study schemas are 
provided in Section 3.4.  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 55 of 139 
Confidential 
3.2 
Phase 1 
3.2.1 
Dose Escalation 
In Phase 1, dose cohorts are planned at proposed doses beginning at an FPA144 dose level of 
6 mg/kg per dose Q2W, and enrollment will depend on safety and tolerability.  Phase 1 includes 
a 3+3 and rolling 6 design until the RD of FPA144 to be administered in combination with 
mFOLFOX6 in Phase 2 is determined.  A minimum of 2 dosing cohorts of FPA144 + 
mFOLFOX6 will be included in Phase 1 to determine the RD of FPA144 in combination with 
mFOLFOX6. 
Patients enrolled in Phase 1 will be treated with escalating doses of FPA144 in combination with 
a fixed-dose chemotherapy regimen of mFOLFOX6 in 2-week cycles, as outlined in Table 1.  
Intra-patient dose escalation will not be permitted. 
Additional details regarding dose escalation and the DLT period are provided in Section 3.2.3.  
Proposed dose levels are outlined in Table 1 and also in Section 5.1.2 and Section 5.2 of the 
protocol; guidance for dose modification is provided in Section 5.1.3.4.  
Decisions on how to next proceed will be based on safety, tolerability, and PK data, and will be 
determined by the CRC. 
Administration of FPA144 will be over approximately 30 minutes (± 10 minutes) Q2W ± 3 days 
on Day 1 of each 2-week cycle. FPA144 will be administered prior to mFOLFOX6 
chemotherapy.  Patients treated in Cohort 2 (only) will receive 1 additional dose of FPA144 on 
Day 8 of Cycle 1 (mFOLFOX6 will not be administered on this day).  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 56 of 139 
Confidential 
Table 1:  
Phase 1 Proposed Dose Levels by Cohort 
Cohort 
FPA144 
mFOLFOX6 
(mFOLFOX6 will be administered at a fixed dose to all 
FPA144 dose cohorts) 
Cohort 1 
6 mg/kg Q2W beginning on 
C1D1 
Q2W beginning on C1D1, at least 30 minutes after the end of 
infusion of FPA144: 
• 
Oxaliplatin 85 mg/m2 IV infusion over 120 minutes 
• 
Leucovorin 400 mg/m2 IV infusion over 120 minutes, can be 
administered concurrently with oxaliplatin if using a 
Y connector, (if not using a Y connector, administer drugs 
sequentially) 
− 
If leucovorin is unavailable, 200 mg/m2 levo-leucovorin 
may be used. Study treatment may be administered 
without either agent in the event that both are 
unavailable.  Leucovorin (or levo-leucovorin) may be 
given at either the protocol-recommended doses or as 
deemed appropriate by the investigator in accordance 
with institutional standard of care 
• 
Immediately after oxaliplatin and leucovorin, 5 FU 
400 mg/m2 bolus over approximately 5 minutes 
• 
Immediately after the 5-FU bolus, 5-FU 2400 mg/m2 as a 
continuous IV infusion over approximately 48 hours 
For further details, refer to the manufacturer’s prescribing 
information for the respective chemotherapies and the study 
Pharmacy Manual. 
Cohort 2 
15 mg/kg Q2W beginning on 
C1D1, plus 1 dose of 
7.5 mg/kg on Day 8 (Cycle 1 
only) 
Cohort 1a 
(if needed, eg, if the Cohort 2 
dose level or schedule is not 
tolerated) 
15 mg/kg Q2W beginning on 
C1D1 
Cohort 1b 
(if needed, eg, if the Cohort 2 
and 1a dose levels or 
schedules are not tolerated) 
Dose level lower than Cohort 
1a, but higher than Cohort 1 to 
achieve tolerability with 
optimal target exposure 
Abbreviations: C1D1 = Cycle 1 Day 1; IV = intravenous; Q2W = every 2 weeks. 
Note: If leucovorin is unavailable, 200 mg/m2 levofolinic acid may be used. Study treatment may be administered 
without either agent in the event that both are unavailable.  Folinic acid (or levofolinic acid) may be given at either 
the protocol-recommended doses or as deemed appropriate by the investigator in accordance with institutional 
standard of care. 
3.2.2 
Definition of Dose-Limiting Toxicity 
DLTs are defined as any of the following events that occur during the first 28 days of treatment 
and are assessed by the CRC as related to FPA144.  As applicable, events will be classified 
according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) (Version 4.03). 
• Absolute neutrophil count (ANC) < 0.5 × 109/L > 5 days’ duration or febrile neutropenia 
(ie, ANC < 1.0 × 109/L with a single temperature of > 38.3°C, or fever ≥ 38 °C for more than 
1 hour).  Use of granulocyte-colony stimulating factor (G-CSF) is permitted in accordance 
with institutional standards 
• Platelets < 25 × 109/L  
• Platelets < 50 × 109/L with bleeding requiring medical intervention 
• Platelets < 50 × 109/L (> 3 days)  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 57 of 139 
Confidential 
• Grade 4 anemia (ie, life-threatening consequences, urgent intervention indicated) 
• Any Grade 2–3 ophthalmologic AE that does not resolve within 7 days 
• Any Grade 4 ophthalmologic AE  
• Any Grade 4 laboratory value 
• Any Grade 3 laboratory values that are not of clinical significance according to investigator 
and Sponsor agreement that do not resolve within 72 hours 
• AST/ alanine aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN) and concurrent 
total bilirubin ≥ 2 × ULN not related to liver involvement with cancer 
• Any non-hematological AE Grade 3 or greater (except nausea, vomiting, and diarrhea) 
• Grade 3 nausea, vomiting, or diarrhea that does not resolve with supportive care in 72 hours  
• Grade 4 nausea, vomiting, or diarrhea 
3.2.3 
Observation of Dose-Limiting Toxicity (the DLT Period) 
Beginning on the first day (Cycle 1 Day 1 [C1D1]) of treatment with FPA144 and mFOLFOX6, 
each patient will be observed for 28 days (the DLT period) for safety, PK, and occurrence of 
DLTs. DLTs are defined in Section 3.2.2. 
FPA144 dose escalation will occur as follows (refer to Table 2 for the dose escalation 
algorithm): 
• Cohort 1 begins with a FPA144 dose of 6 mg/kg per dose in a 3+3 design. 
• If Cohort 1 at 6 mg/kg (3+3 design) clears the 28-day DLT period, then Cohort 2 at 15 mg/kg 
Q2W with 1 dose of 7.5 mg/kg on Day 8 (Cycle 1 only) will be tested in a rolling 6 design 
and enroll 6 patients. 
• Upon initiation of enrollment in Cohort 2, 6 patients will be enrolled to explore the safety, 
tolerability and PK at this dose level. 
• If ≥ 2 DLTs are observed in Cohort 2, then a dose level between Cohorts 1 and 2 may be 
evaluated in a rolling 6 design (this cohort will be Cohort 1a 15 mg/kg Q2W).  
• If ≥ 2 DLTs are observed in Cohort 1a, then a dose level lower than Cohort 1a, but higher 
than Cohort 1 may be evaluated in a rolling 6 design (this cohort will be Cohort 1b at a dose 
to be determined). 
Dose escalation decisions will be agreed upon by the CRC, consisting of the Sponsor and 
investigators.  Dose escalation decisions will be based on an assessment of DLTs, overall safety, 
and tolerability, and will be made after the last patient enrolled in each cohort has completed the 
28-day DLT period (completion of 2 treatment cycles of FPA144 and mFOLFOX6).  Review of 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 58 of 139 
Confidential 
safety and PK parameters may inform decisions to add cohorts with alternative dose levels to 
reach an optimal target exposure.  
No additional doses of FPA144 or more than 2 doses of mFOLFOX6 should be administered 
during the 28-day DLT period.  The doses of FPA144 and mFOLFOX6 on Day 1 of Cycle 2 do 
not need to be synchronized.  For example, if mFOLFOX6 is delayed due to an AE that is 
deemed related only to mFOLFOX6 and not to FPA144, FPA144 should be administered as 
described in Section 5.1 for Cycles 1 and 2 regardless of delays in the mFOLFOX6 dosing 
schedule.  
DLTs are defined in detail in Section 3.2.2.  The algorithm shown in Table 2 will be used for 
Phase 1 dose escalation decisions. 
Table 2:  
Phase 1 Dose Escalation Algorithm 
Number of Patients 
with DLTs 
Action 
  0/3 
Open next cohort 
  1/3 
Enroll 3 more patients in same cohort 
≥ 2/3 
Stop enrollment. If Cohort 1, then the study will end.  
  1/6 
Open next cohort 
≥ 2/6 
Stop enrollment at that level.  If at Cohort 1, the study will end.  If at Cohort 2 or 
Cohort 1a, then Cohort 1a or Cohort 1b will open respectively and 6 patients will be 
enrolled. 
Abbreviations: DLT = dose-limiting toxicity. 
Upon completion of the DLT period (starting with Cycle 3), patients may continue to receive 
FPA144 + mFOLFOX6.  Additional doses may be administered Q2W (1 cycle) until disease 
progression, unacceptable toxicity, or until the patient meets any of the other protocol-specified 
withdrawal criteria (refer to Section 4.0).  There is no maximum number of doses of FPA144.  
Ongoing administration of the mFOLFOX6 regimen beyond the DLT period will be according to 
local standard of care. 
3.2.4 
Determination of Maximum Tolerated Dose and Recommended Dose 
The RD of FPA144 for Phase 2 will be identified by the CRC based on an evaluation of the 
overall safety, tolerability, and PK and will not exceed 15 mg/kg administered IV Q2W with 
1 dose of 7.5 mg/kg on Day 8 of Cycle 1 only.  In determining the RD, the CRC will consider 
toxicities observed during the DLT evaluation period, any toxicities observed beyond the DLT 
evaluation period, as well as dose reductions and discontinuations of mFOLFOX6 or FPA144 
due to toxicities that do not meet the DLT criteria.  Based on the totality of the data, the chosen 
RD of FPA144 will be a dose that is not anticipated to lead to a decrease in the dose intensity of 
mFOLFOX6 to be administered.  The RD, therefore, may or may not be the same as the 
identified MTD.  For example, if the MTD is not reached, or if data from subsequent cycles of 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 59 of 139 
Confidential 
treatment from Phase 1 provide additional insight on the safety profile, then the RD may be a 
different, though not higher, dose than the MTD. 
The MTD is defined as the maximum dose at which < 33% of patients experience a DLT during 
the DLT period.  If a DLT is observed in 1 of 3 patients in Cohort 1, then 3 additional patients 
will be enrolled at that same dose level.  Dose escalation may continue until 2 of 3 to 6 patients 
treated at a dose level experience a DLT (dose level not to exceed the highest dose level tolerated 
in Phase 1).  The next lower dose will then be considered the MTD. 
3.2.5 
Phase 2 Dose of FPA144 
There were no DLTs observed during the Phase 1 safety run-in and an MTD was not reached. 
Based on an assessment of overall safety, tolerability, and PK of FPA144 in combination with 
mFOLFOX6 by the CRC, the dose of 15 mg/kg Q2W with an additional dose of 7.5 mg/kg on 
Cycle 1 Day 8 will be used for the Phase 2 portion of the trial. 
3.2.6 
Patient Replacement 
Any patient who does not receive the total number of doses of FPA144 defined by the cohort or 
2 complete doses of mFOLFOX6 during the DLT period due to a reason that is not a DLT or an 
AE related to FPA144, will be considered unevaluable and the patient will be replaced.  The 
replaced patient may continue on study at the investigator’s discretion and after discussion with 
the Sponsor.  
3.2.7 
Number of Doses 
There is no protocol-mandated maximum number of doses for FPA144 or mFOLFOX6.  
Ongoing administration of the mFOLFOX6 regimen beyond the DLT period will be according to 
Section 3.2 or 5.2 with dose adjustments as detailed in Section 5.2.3.1.  Initiation of a new cycle 
of mFOLFOX6 following a dosing delay may be synchronized with administration of an 
FPA144 infusion but is not a study requirement.  In the Phase 1 portion of the study, if FPA144 
is permanently discontinued for any reason the patient will undergo an EOT visit approximately 
28 days after the last dose of FPA144 or mFOLFOX6.  For these patients, the end of FPA144 
treatment is the end of study (EOS) and no further follow-up will be conducted. 
If mFOLFOX6 is discontinued for any reason other than investigator-assessed disease 
progression, or any of the other protocol-specified withdrawal criteria, FPA144 may be 
continued as a single agent therapy at the investigator’s discretion, and administered Q2W until 
investigator-assessed disease progression, unacceptable toxicity, or until the patient meets any of 
the other protocol-specified withdrawal criteria. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 60 of 139 
Confidential 
In the event a cycle of mFOLFOX6 is delayed beyond the next scheduled administration due to 
chemotherapy-related toxicity during the first 3 cycles of treatment, FPA144 should be 
administered on schedule (± 3 days).  After the first 3 cycles, FPA144 may be delayed up to 
7 days to be synchronized with administered mFOLFOX6. 
3.3 
Phase 2  
Enrollment in Phase 2 will begin when an RD for FPA144 has been identified by the CRC which 
does not exceed the highest dose level evaluated and tolerated in Phase 1. Opening Phase2 for 
enrollment will be at the discretion of the Sponsor. 
Provision of archival (or fresh biopsy if archival tissue is not available) for pre-screening 
FGFR2b overexpression testing by IHC is required (refer to Section 6.1); a blood sample is also 
required for pre-screening by ctDNA for FGFR2 amplification.  FGFR2 positive status by 1 of 
these testing methods is required for enrollment in Phase 2.  The results of the centralized 
FGFR2 testing may take approximately 2 weeks; patients are permitted to receive up to 1 dose of 
mFOLFOX6 during this interim time period (pre-screening) at the discretion of the investigator.  
This 1 dose of chemotherapy is not a requirement of the study and is not considered part of this 
clinical study. 
In the Phase 2, a patient is considered enrolled when he/she is randomized.  The enrollment date 
is the same as randomization date.  Phase 2 patients must initiate the first administration of study 
treatment within 3 days of enrollment. 
FPA144 will be prepared and administered as in Phase 1 (Section 5.1), and the dosing and 
schedule of FPA144 will be at the RD as determined in Phase 1.  
3.3.1 
Treatment Arms 
Phase 2 will be randomized 1:1 to 1 of 2 treatment arms, as outlined in Table 3. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 61 of 139 
Confidential 
Table 3:  
Phase 2 Treatment Arms 
Arm 1 
FPA144 + 
mFOLFOX6 
FPA144 
15 mg/kg Q2W with an 
additional dose of 7.5 mg/kg on 
Cycle 1 Day 8  
mFOLFOX6 will be administered at a fixed dose to both 
Phase 2 treatment arms:  
Q2W beginning on C1D1, at least 30 minutes after the end of 
infusion of FPA144: 
• 
Oxaliplatin 85 mg/m2 IV infusion over 120 minutes 
• 
Leucovorin 400 mg/m2 IV infusion over 120 minutes, can 
be administered concurrently with oxaliplatin if using a 
Y connector, (if not using a Y connector, administer 
drugs sequentially) 
 
If leucovorin is unavailable, 200 mg/m2 levo-leucovorin 
may be used. Study treatment may be administered 
without either agent in the event that both are unavailable. 
Leucovorin (or levo-leucovorin) may be given at either 
the protocol-recommended doses or as deemed 
appropriate by the investigator in accordance with 
institutional standard of care 
• 
Immediately after oxaliplatin and leucovorin, 5 FU 
400 mg/m2 bolus over approximately 5 minutes 
• 
Immediately after the 5-FU bolus, 5-FU 2400 mg/m2 as a 
continuous IV infusion over approximately 48 hours 
For further details, refer to the manufacturer’s prescribing 
information for the respective chemotherapies and the study 
Pharmacy Manual. 
Arm 2 
Placebo + 
mFOLFOX6 
Placebo 
Abbreviations: C1D1 = Cycle 1 Day 1; IV = intravenous; Q2W = every 2 weeks; RD = recommended dose. 
Note: If leucovorin is unavailable, 200 mg/m2 levofolinic acid may be used. Study treatment may be administered 
without either agent in the event that both are unavailable.  Folinic acid (or levofolinic acid) may be given at either 
the protocol-recommended doses or as deemed appropriate by the investigator in accordance with institutional 
standard of care. 
Enrolled patients may continue treatment in 2-week cycles of mFOLFOX6 with or without 
FPA144 until investigator-assessed disease progression, unacceptable toxicity, or the patient 
meets any of the other protocol-specified withdrawal criteria.  There is no protocol-mandated 
maximum number of doses for FPA144 or mFOLFOX6. 
Discontinuation of any component of the study (mFOLFOX6, a component of mFOLFOX6, 
or FPA144) for any reason other than disease progression, does not necessarily mandate 
discontinuation of the other components.  An exception is the permanent discontinuation of 5-FU 
for any reason, which requires concurrent discontinuation of oxaliplatin and leucovorin. 
The first 3 cycles of FPA144 should be administered as scheduled (± 3 days) regardless of delays 
in mFOLFOX6 treatment.  After the first 3 cycles, FPA144 may be delayed up to 7 days to be 
synchronized with administered mFOLFOX6.  However, synchronization of FPA144 and 
mFOLFOX6 is not a protocol requirement.  If after 7 days, the patient is still unable to receive 
mFOLFOX6, FPA144 should continue as monotherapy Q2W. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 62 of 139 
Confidential 
Patients who discontinue study treatment (FPA144 and/or mFOLFOX6) for reasons other than 
disease progression or withdrawal of consent will continue to undergo tumor assessments 
according to the protocol schedule until disease progression or the initiation of additional 
anticancer therapy, at which point they would undergo LTFU for survival. 
3.4 
Study Schemas 
The study schema (Phase 1/2) is shown in Figure 4.  Patient timelines are shown in both Figure 5 
(Phase 1) and Figure 6 (Phase 2). 
Figure 4:  
Phase 1/2 Study Schema 
 
Abbreviations: Q2W = every 2 weeks. 
Figure 5:  
Phase 1 Patient Timeline 
  
Abbreviations: DLT = dose-limiting toxicity; Q2W = every 2 weeks. 
Cohort 2 
FPA144 15mg/kg Q2W 
with one dose of 7 .5 mg/kg 
on Day 8 of Cycle 1 only 
+ mFOLFOX6 
FPA144 Recommended 
FPA144 + 
Dose: 15 mg/kg Q2W 
~ 
~-m_F_O_L_FO_ X6 _ 
_J 
with one dose of 7.5 •I 
Randomization 
I~ 
mg/kg on Day 8 of Cycle 
L _______ 
__J_ 
~-----
1 only + mFOLFOX6 
Placebo+ 
mFOLFOX6 
Cohort 1 
FPA144 6 mg/kg Q2W 
+ mFOLFOX6 
i---Cohort 1a (if needed) ---: 
: FPA144 15mg/kg Q2W + : 
i ___________ mFOLFOX_6 ___________ : 
,, 
' ,, 
~.! 
i---- Cohort 1 b (if ~~~d~~;;-----: 
I 
: FPA144 Intermediate Dose : 
i 
+ mFOLFOX6 
i 
'------------------------------ ,--------- ' 
L_ 
r 
Phase 1 Open Label, Dose Escalation 
(Advanced) Gastrointestinal Cancer (GI) 
Phase 2 Double-Blind, Randomized, Controlled 
FGFR2+ Selected Advanced Gastric or 
Gastroesophageal Cancer (GC) 
Cycles 3+ 
__J 
Advanced 
Gastrointestinal 
Cancer(GI) 
FPA144 + 
~ 
mFOLFOX6 
End of 
. 
DLT • 
FPA144 
+ • 
Tumor 
Q2W 
---,, 
Period 
I 
I 
-28 days 
Cycle 1 Day 1 
Study Day 28, 
l ___ l ... -----'' , ___ 
____., 
I 
Screen'ing Period 
DLTPeliiod 
(maximum 2,8 daysl, 
2,8 days 
mFOLFOX6 
Progression 
Q2W 
Study Day 29 
(± 3 days) 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 63 of 139 
Confidential 
Figure 6:  
Phase 2 Patient Timeline  
 
Abbreviations: CT = computed tomography; ctDNA = circulating tumor DNA; EOT = end of treatment; 
FGFR2 = fibroblast growth factor receptor 2; LTFU = long term follow up; Q2W = every 2 weeks. 
3.5 
Rationale for the Study Design 
The aim of this study is to compare efficacy and safety of FPA144 versus placebo in 
combination with an accepted standard therapy, mFOLFOX6, in previously untreated patients 
with metastatic GC that is classified as both HER2 negative and FGFR2 positive.  A placebo 
control will be administered with the chemotherapy to avoid any observational or other potential 
bias in the assessment of both efficacy and safety of the study treatment.  This control group will 
be instrumental in assessing the relative benefit or risk of adding FPA144 to chemotherapy. 
3.5.1 
Rationale for Selection of Patients for FGFR2  
Selecting patients for FGFR2 gene amplification and overexpression targets patients that are 
most likely to obtain a clinical benefit from FPA144. It is hypothesized that the presence of 
FGFR2 will be an important predictor of how patients with FGFR2-selected gastric or 
gastroesophageal cancer will respond.  This is based on the preclinical observation that only 
tumors that overexpressed FGFR2b responded to FPA144 treatment in xenograft studies, as well 
as early results from the ongoing first-in-human study (FPA144-001) demonstrating objective 
responses in patients with FGFR2b overexpression.  To be eligible, patients must demonstrate 
either FGFR2b overexpression using IHC or FGFR2 gene amplification using a ctDNA blood 
assay.  Positivity based on either 1 or both assays is adequate to meet the eligibility requirements.  
The blood test will reveal DNA amplification of FGFR2, while the IHC test will show the extent 
of protein expression.  In studies evaluating GC samples, FGFR2 gene amplification has been 
uniformly associated with significant FGFR2b surface overexpression, as detected by IHC 
(Gemo 2014).  Patients without overexpression of FGFR2 are unlikely to see a significant benefit 
from treatment with FPA144 and mFOLFOX6. 
FGFR2+ 
FPA144 + 
overexpression 
Treatment 
Advanced Gastric 
by IHC tissue 
~ 
mFOLFOX6 
~ 
Q2W 
until tumor 
or .. 
assay and/or .. 
Randomization/ 
progression: 
Gastroesophageal 
FGFR2gene 
Enrollment 
CT scans 
Cancer(GC) 
amplification by 
._ 
Placebo+ 
~ every8 
ctDNA blood 
mFOLFOX6 
weeks 
assay 
Q2W 
-21days 
Study Day 0 
Cycle 1 Day 1 
(3 days from Study Day 0) 
,.__ ____ ___,/l,_ ____ _,/\ .... ____ ___,/I._ ____ ___, 
f 
l 
f 
l 
Pre-Screening 
Period 
Screening Period 
(maximum 28 days) 
Enrollment 
Treabnent Period 
(maximum 3 days) 
LTFU: 
Patient contact 
every 3 months 
after EOT until 
24 months after 
last patient 
enrolled 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 64 of 139 
Confidential 
3.6 
Rationale for Stratification  
To balance the disease-related risk factors across the treatment arms, patients will be stratified at 
study entry.  A permuted-block randomization scheme will be used to ensure an approximately 
equal sample size and a similar distribution of stratification factors for the two treatment arms.  
Patients will be stratified as outlined in Sections 3.6.1, 3.6.2, and 3.6.3. 
3.6.1 
Geographic Region 
Although GC is a global disease, there is significant heterogeneity with respect to survival 
outcomes between Eastern and Western populations, with better OS reported in Asian 
populations and in particular Japanese patients (Ohtsu 2011, Davidson 2016).  The cause of the 
different outcomes is unknown, but has been hypothesized to be driven by variation in initial 
staging, biology or subsequent treatment (Ohtsu 2006).  Historically, large global trials have not 
included a significant proportion of patients from China, so it is unknown if the outcome is more 
similar to US and EU or the rest of Asia (Davidson 2016).  As it is anticipated that 
approximately half the enrollment in this clinical trial will be from China, China will be a 
separate geographic region from the rest of Asia and accordingly, stratification will be by 
4 geographic areas: 
• Region 1: including US, Europe, and Australia  
• Region 2: China 
• Region 3: Rest of Asia including Japan, South Korea, Taiwan, and Thailand 
• Region 4: Rest of World 
3.6.2 
Prior Therapy 
Patients will be stratified based on history of prior chemotherapy administered for neo-adjuvant 
or adjuvant therapy.  This stratification is included because this has been shown to be a 
prognostic factor associated with longer OS in some studies (Bang 2010, Ohtsu 2011, 
Sawaki 2011). 
3.6.3 
Administration of mFOLFOX6 Prior to Enrollment 
Patients will be stratified based on whether they have received a single dose of mFOLFOX6 
chemotherapy for advanced stage disease prior to enrollment.  Although it is anticipated that a 
low proportion of patients will receive this single dose of mFOLFOX6 prior to enrollment, 
patients who receive a prior dose of chemotherapy are likely have characteristics that would be 
associated with a different prognosis than patients who do not receive this single dose of 
mFOLFOX6.  Specifically, their extent of disease is likely to be greater or the rate of progression 
of the disease in these patients is likely to be greater than patients who can wait until results for 
FGFR2 testing is available.  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 65 of 139 
Confidential 
4.0 
STUDY ELIGIBILITY AND WITHDRAWAL CRITERIA 
4.1 
Planned Number of Patients and Study Centers 
In the dose escalation Phase 1, at least 2 dose cohorts of FPA144 are anticipated using a 3+3 
design for patients enrolled in Cohort 1 and a minimum of 2 patients enrolled in subsequent 
cohorts, which will enroll using a rolling 6 design.  The total enrollment for Phase 1 will 
therefore be approximately 9 to 21 patients.  
In Phase 2, approximately 155 FGFR2-selected GC patients will be randomized 1:1 to be treated 
with FPA144 + mFOLFOX6 or placebo + mFOLFOX6 in 2-week cycles at an RD selected after 
assessment of data obtained in Phase 1.  Opening of Phase 2 for enrollment will be at the 
discretion of the Sponsor. 
The total enrollment planned for this study is approximately 167 patients. 
The Phase 1 study will be conducted only in the US, while the Phase 2 study will be conducted at 
up to approximately 190 global study centers. 
4.2 
Inclusion Criteria for Phase 1 and Phase 2 
Patients enrolling in either Phase 1 or Phase 2 of the study must meet all of the following 
inclusion criteria: 
1) Disease that is unresectable, locally advanced, or metastatic (not amenable to curative 
therapy) 
2) Understand and sign an Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)-approved ICF prior to any study-specific evaluation 
3) Life expectancy of at least 3 months in the opinion of the investigator 
4) Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 
5) Age ≥ 18 years at the time the ICF is signed 
6) In sexually active patients (women of child bearing potential [WOCBP] and males), 
willingness to use 2 effective methods of contraception, of which 1 must be a physical barrier 
method (condom, diaphragm, or cervical/vault cap) until 6 months after the last dose of 
FPA144. Other effective forms of contraception include: 
• Permanent sterilization (hysterectomy and/or bilateral oophorectomy, or bilateral tubal 
ligation with surgery, or vasectomy) at least 6 months prior to screening 
• WOCBP who are on stable oral contraceptive therapy or intrauterine or implant device 
for at least 90 days prior to the study, or abstain from sexual intercourse as a way of 
living 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 66 of 139 
Confidential 
7) Adequate hematological and biological function, confirmed by the following laboratory 
values within 96 hours prior to enrollment:  
Bone Marrow Function 
• ANC ≥ 1.5 × 109/L 
• Platelets ≥ 100 × 109/L 
• Hemoglobin ≥ 9 g/dL 
Hepatic Function 
• AST and ALT < 3 × ULN; if liver metastases, then < 5 × ULN 
• Bilirubin < 1.5 × ULN except in patients with Gilbert’s disease 
Renal Function 
• Calculated CrCl using Cockcroft Gault formula ≥ 50 mL/min or estimated glomerular 
filtrate rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) formula ≥ 50 mL/min (refer to Appendix 1) 
8) INR or prothrombin time (PT) < 1.5 × the ULN except for patients receiving anticoagulation, 
who must be on a stable dose of warfarin for 6 weeks prior to enrollment  
9) Measurable or non-measurable, but evaluable disease using RECIST v1.1 
Additional Inclusion Criteria for Phase 1 Only 
Patients enrolling in Phase 1 of the study must also meet the following inclusion criteria: 
10) Histologically or cytologically confirmed GI malignancy for which mFOLFOX6 is 
considered an appropriate treatment (eg, GC, colorectal carcinoma, pancreatic 
adenocarcinoma) 
11) Patient must be a candidate to receive at least 2 doses of mFOLFOX6 chemotherapy 
(according to Section 3.2 of the protocol) 
Additional Inclusion Criteria for Phase 2 Only 
Patients enrolling in Phase 2 of the study must also meet the following inclusion criteria: 
14) Histologically documented gastric or gastroesophageal junction (GEJ) adenocarcinoma 
(not amenable to curative therapy) 
15) Radiographic imaging of the chest, abdomen and pelvis (computed tomography [CT] 
preferred, magnetic resonance imaging [MRI] acceptable) performed within 28 days 
(+3 days) of treatment (C1D1) 
16) FGFR2b overexpression as determined by a centrally performed IHC tissue test and/or 
FGFR2 gene amplification as determined by a centrally performed ctDNA blood based assay  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 67 of 139 
Confidential 
17) Patient must be a candidate for mFOLFOX6 chemotherapy  
18) No prior chemotherapy for metastatic or unresectable disease (except a maximum of 1 dose 
of mFOLFOX6 administered while waiting for results of FGFR2 testing during the 
pre-screening period)  
19) If prior adjuvant or neo-adjuvant therapy (chemotherapy and/or chemoradiation) has been 
received, more than 6 months must have elapsed between the end of adjuvant therapy and the 
confirmation of radiographic disease progression 
4.3 
Exclusion Criteria for Phase 1 and Phase 2 
Patients enrolling in either Phase 1 or Phase 2 will be excluded if any of the following criteria 
apply: 
1) Untreated or symptomatic central nervous system (CNS) metastases (CNS imaging not 
required).  Patients with asymptomatic CNS metastases are eligible provided they have been 
clinically stable for at least 4 weeks and do not require intervention such as surgery, 
radiation, or any corticosteroid therapy for management of symptoms related to CNS disease 
2) Impaired cardiac function or clinically significant cardiac disease, including any of the 
following (Criteria a through g): 
a) Unstable angina pectoris ≤ 6 months prior to enrollment 
b) Acute myocardial infarction ≤ 6 months prior to enrollment 
c) New York Heart Association Class II-IV congestive heart failure 
d) Uncontrolled hypertension (as defined as ≥ 160/90 despite optimal medical management) 
e) Uncontrolled cardiac arrhythmias requiring anti-arrhythmic therapy other than beta 
blockers or digoxin 
f) Active coronary artery disease 
g) Fridericia’s correction formula (QTcF) ≥ 480 
3) Peripheral sensory neuropathy ≥ CTCAE Grade 2 
4) Active infection requiring systemic treatment or any uncontrolled infection ≤ 14 days prior to 
enrollment 
5) Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS)-related illness, or known active or chronic hepatitis B or C infection 
6) History of interstitial lung disease (eg, pneumonitis or pulmonary fibrosis)  
7) Evidence or history of bleeding diathesis or coagulopathy 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 68 of 139 
Confidential 
8) Radiotherapy ≤ 28 days of enrollment. Patients must be recovered from all acute 
radiotherapy-related toxicities.  No radiopharmaceuticals (strontium, samarium) within 
8 weeks of enrollment 
9) Prior treatment with any selective inhibitor (eg, AZD4547, BGJ398, JNJ-42756493, 
BAY1179470) of the FGF-FGFR pathway 
10) Ongoing adverse effects from prior systemic treatment > NCI CTCAE Grade 1 (with the 
exception of Grade 2 alopecia and anemia) 
11) Participation in another therapeutic clinical study or receiving any investigational agent 
within 28 days of enrollment or during this clinical study 
12) Corneal defects, corneal ulcerations, keratitis, keratoconus, history of corneal transplant, or 
other known abnormalities of the cornea that may pose an increased risk of developing a 
corneal ulcer 
13) Known positivity for HER2 (as defined by a positive IHC test of 3+ or IHC of 2+ with 
fluorescent in situ hybridization [FISH]) 
14) Major surgical procedures not permitted ≤ 28 days prior to enrollment.  Surgery requiring 
local/epidural anesthesia must be completed at least 72 hours before enrollment.  In all 
cases, the patient must be sufficiently recovered and stable before treatment administration 
15) Women who are pregnant or breastfeeding (unless the patient is willing to interrupt 
breastfeeding during study treatment administration and then resume 6 months after study 
discontinuation); WOCBP must not consider getting pregnant during the study 
16) Presence of any serious or unstable concomitant systemic disorder incompatible with the 
clinical study (eg, substance abuse, psychiatric disturbance, uncontrolled intercurrent illness 
including arterial thrombosis, or symptomatic pulmonary embolism) 
17) Presence of any other condition that may increase the risk associated with study 
participation, or may interfere with the interpretation of study results, and, in the opinion of 
the investigator, would make the patient inappropriate for entry in the study 
18) Known allergy, hypersensitivity or contraindication to components of the FPA144 
formulation including polysorbate or to platinum-containing medications, 5-FU, or 
leucovorin  
19) History of prior malignancy, except (Criteria a through f): 
a) Curatively treated non-melanoma skin malignancy 
b) Cervical cancer in situ 
c) Curatively treated Stage I uterine cancer  
d) Curatively treated ductal or lobular breast carcinoma in situ and not currently receiving 
any systemic therapy 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 69 of 139 
Confidential 
e) Localized prostate cancer that has been treated surgically with curative intent and 
presumed cured  
f) Solid tumor treated curatively more than 5 years previously without evidence of 
recurrence 
No waivers of these inclusion or exclusion criteria will be granted. 
4.4 
Patient Identification and Enrollment 
Patients must be able to provide written informed consent and meet all eligibility criteria prior to 
enrollment.  Patients who qualify for Phase 1 of the study will be enrolled in the first available 
cohort.  A patient may be enrolled in either Phase 1 or Phase 2 of the study, but not both. 
In Phase 2, patients first undergo pre-screening in which both a tissue test and a ctDNA blood 
assay are required.  Tissue may be archival or fresh and if archival must be fresh section (cannot 
be previously cut slides).  Patients who are determined to be FGFR2 positive by either test may 
immediately enter the screening period and be evaluated for eligibility for the Phase 2 study 
(refer to Section 3.3). 
Table 4: 
Eligibility Based on FGFR2 Status 
FGFR2 Gene Amplification1 
(using a ctDNA blood assay)2 
FGFR2b Overexpression1 
(using a tissue-based IHC assay)3 
Eligibility 
Blood (+) 
IHC (+) 
Eligible 
Blood (-) 
IHC (+) 
Eligible 
Blood (+) 
IHC (-) 
Eligible 
Blood (-) 
IHC (-) 
Ineligible 
Abbreviations: ctDNA = circulating tumor DNA; FGFR2 = fibroblast growth factor receptor 2; 
IHC = immunohistochemistry. 
Note: Patients must be FGFR2-positive by 1 of the 2 methods to be enrolled in the trial. 
1 
Both tests will be carried out at central laboratories 
2 
Requires 2 × 10 mL  
3 
Minimum of 5 slides required 
In both Phase 1 and 3, the investigator may repeat qualifying laboratory tests and vital 
signs/ECGs during the screening period one time prior to enrollment if a non-qualifying finding 
is considered an error or an acute finding is likely to meet eligibility criteria on repeat testing. 
4.5 
Patient Withdrawal and Replacement 
A patient must be discontinued from protocol-prescribed therapy if any of the following apply: 
• Consent withdrawal at the request of the patient or their legally authorized representative 
• Progression of patient’s disease as assessed by the investigator per RECIST v1.1 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 70 of 139 
Confidential 
• Any event that would pose an unacceptable safety risk to the patient 
• A concurrent illness that would affect assessments of the clinical status to a significant 
degree  
• Pregnancy at any time during the study 
• At the specific request of the Sponsor or its authorized representative (eg, if the study is 
terminated for reasons of patient safety) 
Patient replacement will be as follows: 
• Patients in the Phase 1 safety run-in will be replaced if they are unevaluable for DLT 
(according to Section 3.2.6)  
• Patients in the Phase 2 study will not be replaced 
 
 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 71 of 139 
Confidential 
5.0 
STUDY TREATMENT 
5.1 
FPA144  
5.1.1 
Identity, Packaging, Storage 
FPA144 drug product is supplied for IV administration as a sterile, aqueous, colorless to slightly 
yellowish, pyrogen-free solution supplied in single-use glass vials.  The composition of the drug 
product contains 20 mg/mL active ingredient, 20 mM L-histidine, 270 mM sucrose, and 0.01% 
(w/v) polysorbate 20 at pH 6.0.  The final drug product will be provided as 2° to 8°C refrigerated 
liquid protected from light which is diluted for administration according to instructions provided 
in a separate Pharmacy Manual. 
FPA144 will be supplied in a sterile vial for dilution in an IV bag for administration by the study 
center. 
5.1.2 
Administration (Phase 1 and Phase 2)  
The FPA144 proposed doses were outlined above in Table 1.  In Phase 1 the starting dose level 
of FPA144 is 6 mg/kg per dose in combination with a fixed dose chemotherapy regimen of 
mFOLFOX6 (Section 5.2).  In Phase 2, the dose of FPA144 in combination with a fixed dose 
chemotherapy regimen of mFOLFOX6 will be determined by evaluation of the data from Phase 
1 of the study. 
FPA144 will be administered only to patients in this study using procedures described in this 
protocol.  The dose of FPA144 is based on body weight at C1D1 and should be recalculated only 
if the weight changes > 10% from the C1D1 weight.  If the dose is recalculated due to a >10% 
weight change from C1D1, the weight used for the recalculated dose should function as the new 
baseline for subsequent evaluation of dose recalculations.  Doses should be rounded to the 
nearest 10 mg. 
A pharmacist (or other responsible person) will prepare FPA144 for administration.  After 
calculating the number of vials based on the patient’s weight, FPA144 will be diluted in a 0.9% 
sodium chloride solution.  Prepared FPA144 should be administered ≤ 8 hours after preparation 
(ambient temperature).  FPA144 will be administered under medical supervision over 
approximately 30-minute (± 10 minutes) IV infusion via a peripheral vein or central venous 
catheter.  The IV administration set for FPA144 infusion must contain a 0.22 µm in-line filter or 
a 0.22 µm syringe filter. 
Infusion of FPA144 must be stopped, reduced, interrupted, or discontinued according to 
Sections 3.2.2 and 5.1.3.4.  If a patient experiences an infusion reaction, the patient’s vital signs 
(temperature, blood pressure [BP], heart rate [HR], and respiration rate [RR]) should be 
monitored during the infusion as well as every 30 minutes after the infusion for a minimum of 
2 hours and until resolution of the infusion reaction. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 72 of 139 
Confidential 
Patients may continue receiving FPA144 administered in 2-week cycles until investigator-
assessed disease progression (Phase 2 only), unacceptable toxicity, or until the patient meets any 
of the other protocol-specified withdrawal criteria.  There is no maximum number of doses of 
FPA144. 
Further instructions on drug preparation and administration are provided in the Pharmacy 
Manual. 
5.1.3 
FPA144 Dose Modifications 
Dose modifications discussed in this section include intrapatient dose modifications. Dose 
escalations/modifications between cohorts in Phase 1 are described in Section 3.2.1.  The dose of 
FPA144 for Phase 2 was determined by evaluation of the data from Phase 1 of the study, as 
described in Sections 3.2.3 and 3.2.4. 
5.1.3.1 
Dose Escalation  
In Phase 1, intrapatient dose escalation will not be permitted.  In Phase 2, patients will be treated 
at the MTD and/or RD as determined from Phase 1. 
5.1.3.2 
Weight  
A complete physical examination including height and weight will be performed at Screening.  
The dose of FPA144 will be based on body weight at C1D1 and should be recalculated only if 
the weight changes > 10% from the C1D1 weight.  If the dose is recalculated due to a >10% 
weight change from C1D1, the weight used for the recalculated dose should function as the new 
baseline for subsequent evaluation of dose recalculations.   
5.1.3.3 
Infusion or Hypersensitivity Reactions  
If a patient experiences a Grade 3 or higher infusion or hypersensitivity reaction prior to 
completion of FPA144 infusion, the infusion must be stopped, and the patient promptly managed 
and monitored according to signs, symptoms, and local standard protocol until complete 
resolution of the event.  Signs and symptoms of infusion or hypersensitivity reactions may 
include, but are not limited to fever, chills, rigors, urticaria, hypotension or hypertension, 
headache, wheezing, shortness of breath, hypoxia, and pulmonary infiltrates.  Appropriate 
interventions include, but are not limited to antihistamines, corticosteroids, bronchodilators, 
and/or IV fluids. 
If a patient experiences an infusion reaction, the patient’s vital signs (temperature, BP, HR, and 
RR) should be monitored every 30 minutes after the infusion has been discontinued for a 
minimum of 2 hours or resolution of the infusion reaction, whichever takes longer. 
At the investigator’s discretion, the infusion of FPA144 may also be stopped if a less severe AE 
(Grade 1 or 2) occurs during the infusion. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 73 of 139 
Confidential 
If the infusion reaction resolves, at investigator discretion the infusion may be restarted at half 
the previous infusion rate.  If, despite appropriate premedication, signs or symptoms of a 
hypersensitivity/infusion reaction recur, the infusion should be discontinued, and no further 
dosing of FPA144 will occur without consultation with the Sponsor or Sponsor’s designee. 
After experiencing a Grade 3 or higher infusion or hypersensitivity reaction, all subsequent 
infusions of FPA144 for the patient should be administered at the reduced rate (over 60 minutes) 
with premedication.  Pre-medication may include medications such as corticosteroids, 
antihistamine and/or acetaminophen in accordance with local standard of care. 
5.1.3.4 
Toxicity: FPA144 Dose Modification Guidelines  
Dose reductions for FPA144 may be permitted for patients on treatment beyond the DLT period 
in Phase 1 or any patient in Phase 2 and are based on local laboratories and clinical assessment.  
If a patient in Phase 1 requires a dose reduction or is unable to receive FPA144 during the DLT 
period, their reported toxicity is considered a DLT and be permanently discontinued from 
FPA144.  Doses may be held or reduced for FPA144-related AEs following the guidelines 
outlined in Table 5 (Phase 2 FPA144 dose levels for dose reductions), Table 6 (non-corneal 
toxicities), and Table 7 (corneal toxicities).  
Any patient with a corneal event which occurs within 100 days of last receiving a dose of 
FPA144, regardless if deemed related or not related to FPA144 should be evaluated by an 
ophthalmologist.  Any patient with FPA144-related retinal toxicity should permanently 
discontinue FPA144.  If dose reductions or interruptions that do not fall within these guidelines 
are being considered by the investigator, these will require discussion with and approval by the 
Sponsor or designee. Patients may resume the FPA144 if the event returns to baseline or ≤ Grade 
1 in accordance with the guidelines outlined in Table 6, and Table 7. 
Patients who require FPA144 dose reductions will receive the reduced dose for the remainder of 
the study. Cycles may be delayed to manage toxicity.  Cycle delays of longer than 28 days 
should be discussed with the medical monitor prior to reinitiation.  
Table 5: 
Phase 2 FPA144 Dose Levels for Dose Reductions  
Dose Level 
FPA144 Dose 
0 
15 mg/kg Q2W + 7.5mg/kg D81 
-1 
6 mg/kg Q2W 
1 For patients who require dose reduction prior to C1D8, the C1D8 dose should be skipped, continuing with 
15mg/kg Q2W 
 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 74 of 139 
Confidential 
Table 6:  
Dose Modification Guidelines for FPA144 Related Adverse Events (Any 
Noncorneal, Noninfusion Toxicity1) 
FPA144-Related  
Toxicity Grade 
Dose Schedule 
New FPA144 Dose 
Grade 1 or 2 
No delay or missed dose required 
100% of dose 
Grade 3  
(first occurrence) 
Delay or miss dose until recovery to 
baseline or Grade 1  
If recovery to baseline or Grade 1 within 
28 days, may resume at 100% of starting 
dose or 1 dose lower2  
Grade 3  
(second occurrence) 
Delay or miss dose until recovery to 
baseline or Grade 1  
If recovery to baseline or Grade 1 within 
28 days, may resume at 1 dose level 
lower2 than previous dose or discontinue  
Grade 3 (third occurrence) 
Grade 3 which does not 
recover to baseline or Grade 1 
within 28-day of onset event 
Any Grade 4 
Permanently Discontinue 
N/A 
Abbreviations: N/A = not applicable. 
1 
mFOLFOX6 dosing in case of FPA144 toxicity may continue regardless of FPA144 dose modifications. 
2 
See Table 5 for dose levels for dose reductions in Phase 2. 
Any patient who reports pain or irritation of the eye or change in vision should be evaluated by 
an ophthalmologist.  
Table 7: 
Dose Modification Guidelines for FPA144 (Any Related Corneal Toxicity1) 
FPA144/IMP-related Toxicity 
Grade 
Dose Schedule 
New FPA144 Dose 
Grade 1  
No Delay 
100%  
Grade 2 and  
Grade 3  
Delay dosing, see ophthalmologist 
and treat with topical 
(ophthalmologic) antibiotics  
If recovery to baseline or Grade 1 
within 28 days, may resume at 
100% dose  
Grade 2 or Grade 3 which does not 
return to baseline within 28 days 
since last dose 
Any Grade 4 
Permanently discontinue dosing of 
FPA144 
N/A 
Abbreviations: N/A = not applicable. 
1 
mFOLFOX6 dosing may continue regardless of FPA144 dose modifications. 
There is a ± 3-day window for the first 3 cycles (42 days) of FPA144 dosing regardless of delays 
in mFOLFOX6 in Phase 2 only.  After the first 3 cycles, FPA144 can be delayed up to a 
maximum of 7 days to synchronize with mFOLFOX6 chemotherapy infusion.  However, 
synchronization of administration of FPA144/placebo and mFOLFOX6 is not a protocol 
requirement.  Vital signs and clinical laboratory tests must be performed within 72 hours prior to 
either FPA144 or mFOLFOX6 administration.  Patients should only have 2 consecutive doses of 
FPA144 within 7 days during Cycle 1 of treatment if enrolled in Cohort 2 (Phase 1) or if the RD 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 75 of 139 
Confidential 
of FPA144 is the dose used in Cohort 2 (Phase 2).  In subsequent cycles, FPA144 is administered 
Q2W.  The first dose of each cycle is considered Day 1 of each cycle.  Cycles will repeat every 
2 weeks unless there is a treatment delay.  Intrapatient dose escalation above the starting dose for 
each patient will not be permitted.  Any patient whose dose of FPA144 is decreased cannot be 
subsequently increased. 
5.2 
mFOLFOX6 
Leucovorin (or levo-leucovorin), 5-FU, and oxaliplatin will be obtained from commercial 
sources at each participating site.  Management (ie, handling, storage, administration, and 
disposal) of these products will be in accordance with the relevant local guidelines.  For 
countries where the Sponsor is required to provide all study drugs, including standard-of-care 
drugs, the Sponsor designee will provide leucovorin, 5-FU, and oxaliplatin from a commercial 
supply that is clinically labelled in accordance with relevant local guidelines. For further details, 
refer to the manufacturer’s prescribing information for the respective chemotherapies and the 
study Pharmacy Manual. 
5.2.1 
Identity, Packaging, Storage 
Refer to the most current package insert for packaging, labeling, and storage information of 
mFOLFOX6. 
FPA144 will be packaged and labeled as a 20 mL fill in ISO 20R vials by the Sponsor 
(or designee).  
All FPA144 vials must be stored refrigerated at 2° to 8°C in accordance with the manufacturer’s 
instructions as provided in the Pharmacy Manual.  Until dispensed to patients, FPA144 will be 
stored in a securely locked area, accessible to authorized personnel only. 
5.2.2 
Administration (Phase 1 and Phase 2)  
mFOLFOX6 will be administered Q2W beginning on C1D1, and will be administered at least 
30 minutes after the end of the infusion of FPA144.  
For further prescribing information, refer to the manufacturer’s prescribing information for the 
respective chemotherapies and the study Pharmacy Manual. Oxaliplatin, 5-FU, and leucovorin 
will be administered by each site as detailed below (and as was outlined above in Table 1).  
The mFOLFOX6 regimen will be administered Q2W (± 3 days) until investigator-assessed 
disease progression (Phase 2 only), clinical disease progression, unacceptable toxicity, or the 
patient meets any of the other protocol-specified withdrawal criteria. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 76 of 139 
Confidential 
Instructions for mFOLFOX6 administration include the following: 
On Day 1 of each cycle (at least 30 minutes after FPA144/placebo): 
• Oxaliplatin 85 mg/m2 IV infusion over 120 minutes 
• Leucovorin 400 mg/m2 IV infusion over 120 minutes, can be administered concurrently with 
oxaliplatin if using a Y connector, (if not using a Y connector, administer drugs sequentially) 
− If leucovorin is unavailable, 200 mg/m2 levo-leucovorin may be used.  Study treatment 
may be administered without either agent in the event that both are unavailable.  
Leucovorin (or levo-leucovorin) may be given at either the protocol-recommended doses 
or as deemed appropriate by the investigator in accordance with institutional standard of 
care 
• Immediately after oxaliplatin and leucovorin, 5 FU 400 mg/m2 bolus over approximately 
5 minutes 
• Immediately after the 5-FU bolus, 5-FU 2400 mg/m2 as a continuous IV infusion over 
approximately 48 hours 
Premedication may be used at the discretion of the investigator based on the local standard of 
care.  
5.2.3 
mFOLFOX6 Dose Modifications 
Guidelines for dose interruptions, delays, and modifications due to toxicity are outlined in 
Section 5.2.3.1.  If mFOLFOX6 is delayed due to toxicity, vital signs and clinical laboratory tests 
need to be performed within 72 hours of its administration.  
In the event that oxaliplatin administration is discontinued for any reason prior to disease 
progression, 5-FU/leucovorin therapy may continue on a Q2W schedule until disease 
progression, unacceptable toxicity, or other cause for study withdrawal.  In the case 
5-FU/leucovorin therapy is permanently discontinued then oxaliplatin must be discontinued. 
5.2.3.1 
Toxicity: mFOLFOX6 Dose Modifications Guidelines  
Patients should be closely monitored for mFOLFOX6 toxicity.  In Phase 1, any patient who does 
not receive 2 complete doses of mFOLFOX6 during the DLT period due to a reason that is not a 
DLT or an AE related to FPA144, will be considered unevaluable and the patient will be 
replaced.  Beyond the DLT period in Phase 1, or at any time in Phase 2, dose adjustments for any 
component of mFOLFOX6 are permitted according to the guidelines outlined below. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 77 of 139 
Confidential 
The dose of mFOLFOX6 is based on body weight at C1D1 and should be recalculated only if the 
weight changes > 10% from the C1D1 weight. If the dose is recalculated due to a >10% weight 
change from C1D1, the weight used for the recalculated dose should function as the new baseline 
for subsequent evaluation of dose recalculations.    
Patients should be counseled to avoid exposure to cold weather during and for approximately 
72 hours after each infusion. 
Correct hypokalemia and hypomagnesemia prior to initiating oxaliplatin. 
Evaluation for dihydropyrimidine dehydrogenase deficiency should be considered if the 
following events occur after 5-FU: severe diarrhea, mucositis, and myelosuppression. 
The leucovorin dose is given for d, l-racemic mixture.  Use half the dose for levo-leucovorin 
(l-leucovorin).  Leucovorin will stay at a fixed dose of (400 mg/m2 and or as deemed appropriate 
by the investigator) will be given prior to each 5-FU dose.  If 5-FU is delayed, leucovorin will be 
delayed.  If leucovorin is not available, levo-leucovorin (200 mg/m2 or as deemed appropriate by 
the investigator) may be administered.  Leucovorin or levo-leucovorin may be omitted from 
study treatment in the event that they are both unavailable. 
Patients who require chemotherapy dose reductions will receive the reduced dose for the 
remainder of the study.  The only exception to this practice will be in the case of nausea/ 
vomiting.  If nausea and/or vomiting occur despite antiemetic therapy, the chemotherapy dose 
should be reduced by 25% for the next dose.  If tolerated, an increase back to a 100% dose may 
be allowed at the investigator’s discretion.  Any patient who required 2 dose reductions and 
experienced persistent toxicity with a third dose reduction will be discontinued from all 
chemotherapy.  Chemotherapy cycles may be delayed to manage toxicity.  Cycle delays of 
longer than 28 days should be discussed with the medical monitor prior to reinitiation of 
treatment.  
Dose adjustments at the start of each 14-day cycle will be based on nadir hematologic counts or 
maximum non-hematologic toxicity from the preceding cycle of therapy. 
Dose adjustments of each agent may be made independently based on the specific types of 
toxicities observed. 
Recommended dose adjustments for mFOLFOX6 toxicity are shown in Table 8. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 78 of 139 
Confidential 
Table 8: 
Dose Reductions and Delays for mFOLFOX6 Chemotherapy 
Toxicity  
Grade 
Oxaliplatin 
5-FU 
Neurotoxicity 
Persistent (≥14 days) Grade 2 
neurotoxicity 
Decrease from 85 mg/m2 
to 65 mg/m2 a 
No change 
Transient (> 7 days and 
≤ 14 days) Grade 3 neurotoxicity 
Decrease from 85 mg/m2 
to 65 mg/m2 a 
No change 
Persistent (> 14 days)  
≥ Grade 3 neurotoxicity or any 
Grade 4 neurotoxicity 
Permanent 
Discontinuation 
No change 
Gastrointestinal 
> Grade 3 (after prophylaxis) 
Hold until toxicity is 
≤ Grade 1, decrease from 
85 mg/m2 to 65 mg/m2 a 
Hold until toxicity is  
≤ Grade 1, decrease by 
20% a 
Hematologic 
≥ Grade 3 platelets 
Hold until platelets are 
≥ 75,000 then decrease 
from 85 mg/m2 to 
65 mg/m2 a 
Reduce by 20% a 
≥ Grade 3 neutropenia 
Hold until ANC is ≥ 1500, 
then decrease from 
85 mg/m2 to 65 mg/m2 a 
Reduce by 20% a 
Skin 
≥ Grade 3 hand/foot syndrome 
Hold until 5-FU resumes, 
then no change 
Hold until ≤ Grade 1, 
then decrease by 20% a 
Other 
≥ Grade 3 
Hold until ≤ Grade 1, then 
decrease from 85 mg/m2 
to 65 mg/m2 a 
Hold until ≤ Grade 1, 
then reduce by 20% a 
Pharyngolaryngeal 
dysesthesia 
Any 
Stop infusion, then 
consider increase duration 
of infusion up to 6 hours 
No change 
Pneumonitis 
Any 
Hold, investigate; discontinue permanently if 
confirmed 
Hepatic Impairment 
Bilirubin 1–2× ULN 
No change 
No change, consider 
decrease by 20%a 
Bilirubin > 2–4× ULN and/or 
AST/ALT is 2–4× ULN 
No change 
No change, consider 
decrease by 20% 
Bilirubin > 4× ULN and/or 
AST/ALT is > 4× ULN 
Discontinue 
Discontinue 
Renal Impairment 
(Creatinine 
Clearance) 
> 50 mL/min 
No change 
No change 
30 to < 50 mL/min 
No change, consider 
decrease to 65 mg/m2a 
No change 
< 30 mL/min 
Discontinue 
Decrease dose by 20%a 
a 
If toxicity recurs at the same grade level after dose reduction; consider permanent discontinuation. Note that if 
5-FU is permanently discontinued, oxaliplatin and leucovorin should be permanently discontinued. 
Adapted from (Cheeseman 2002, Hochster 2008, Teva Pharmaceuticals USA 2012, Teva Parenteral Medicines Inc 
2014, Teva Parenteral Medicines Inc 2016) 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 79 of 139 
Confidential 
If a patient experiences Grade 1 or 2 allergic reaction to oxaliplatin, premedication should be 
given according to institutional practice prior to subsequent further study drug administration. 
If Grade 1–2 allergic reaction persists into the next cycle, escalating the appropriate 
premedication should be given according to institutional practice prior to administration of 
oxaliplatin. 
For patients experiencing Grade 3-4 allergic reactions, treatment with oxaliplatin should be 
discontinued. 
5.3 
Placebo 
Placebo product (only used in Phase 2) will match the FPA144 drug product.  It will be supplied 
for IV administration as a sterile, aqueous, colorless to slightly yellowish, pyrogen-free solution 
supplied in single-use vials.  The composition of matching placebo contains 20 mM L-histidine, 
270 mM sucrose, and 0.01% (w/v) polysorbate 20 at pH 6.0. Placebo will be administered in a 
method that matches the administration of FPA144 to maintain blinding. 
5.4 
Unblinding Treatment Assignment 
The Phase 2 portion of this study is double-blind.  Placebo will be matched to FPA144. 
Treatment codes should not be broken except in emergency situations.  With the exception of 
unblinding for the analysis (to be defined in the Statistical Analysis Plan [SAP]), all individuals 
involved in the conduct of the study (eg, all site staff and participants, monitoring personnel, 
Sponsor personnel) will be blinded to randomized treatment assignment.  The decision and 
ability to unblind the treatment code in emergency situations resides with the investigator.   
The investigator should document and provide an explanation for any premature unblinding 
(eg, accidental unblinding or unblinding because of a serious adverse event). 
5.5 
Drug Accountability 
The investigator or appropriately qualified staff is responsible for maintaining accurate study 
treatment accountability records throughout the study. 
The investigator is responsible for destroying or returning all unused study treatment to the 
Sponsor (or designee), and must verify that no remaining supplies are in the investigator’s 
possession.  The study site is permitted to destroy unused, used or partially used study treatment 
vials according to the site policy once Sponsor (or designee) approval of their documented 
destruction procedure has been obtained.  On completion of the study, the number of FPA144 
vials shipped, destroyed, and returned must be reconciled. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 80 of 139 
Confidential 
5.6 
Investigational Product Compliance 
Only qualified trained study center personnel may administer FPA144.  Pharmacy personnel 
trained in the study requirements will monitor compliance with the treatment assignments. 
Records of study medication administered (date, time, and dose administered relative to time of 
preparation) will be recorded on the patient’s eCRF. 
5.7 
Concomitant Medication and Treatment 
Supportive care (eg, antiemetics, analgesics for pain control) may be used at the investigator’s 
discretion and in accordance with institutional procedures.  Patients should receive antiemetic 
and other prophylactic treatments according to the local standard of care and manufacturer’s 
instruction.  Patients should receive full supportive care, transfusions of blood and blood 
products, antibiotics, antiemetics, etc., when appropriate.  Hematopoietic stimulating agents may 
be used if indicated.  Concomitant anticancer therapies of any kind are not permitted. 
Patients receiving oxaliplatin should not receive oral cryotherapy as this may exacerbate 
laryngopharyngeal dysesthesia caused by oxaliplatin.  For patients on anticoagulant therapy, 
close monitoring of coagulation parameters is recommended. 
5.8 
Prohibited Therapy 
Vaccination with a live vaccine should be avoided in patients receiving 5-FU because of the 
potential for serious or fatal infections. 
 
 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 81 of 139 
Confidential 
6.0 
STUDY ASSESSMENTS AND PROCEDURES  
Unless otherwise specified, all assessments and procedures must be conducted in accordance 
with the Schedule of Assessments (Appendix 2 and Appendix 3).  
Descriptions of assessments are provided in Sections 6.1 through 6.19 below. 
Additional guidance for study assessments and procedures is provided in the following 
appendices: 
• Schedule of Assessments for Phase 1: Appendix 2 
• Schedule of Assessments for Phase 2: Appendix 3 
• List of safety laboratory assessments for Phase 1 and Phase 2: Appendix 4 
• Clinical Fixed Time Point Assessments: Appendix 5 
• Instructions for the collection time points of PK, immunogenicity, and 
 
 for Phase 1 are provided in Appendix 6  
• Instructions for the collection time points of PK and immunogenicity samples for Phase 2 
are provided in Appendix 7 
6.1 
Tumor Tissue Collection: Analysis for FGFR2b Overexpression for Patient 
Selection 
6.1.1 
Phase 1 
Provision of tissue for retrospective FGFR2b overexpression testing by IHC, and blood for 
FGFR2 amplification by ctDNA, are not required for enrollment in Phase 1, but will be tested 
retrospectively if available. 
Patients eligible for Phase 1 have unselected GI cancer (with or without FGFR2 positive status) 
with unresectable, locally advanced, or metastatic disease, and are candidates to receive both 
FPA144 and mFOLFOX6 chemotherapy.  FGFR2b overexpression will be determined 
retrospectively using central assessment by IHC and FGFR2 gene amplification will be 
determined retrospectively by using central assessment by a ctDNA blood assay.  
6.1.2 
Phase 2 
Provision of archival (or fresh biopsy if archival tissue is not available) for Pre-Screening 
FGFR2b overexpression testing by IHC is required; a blood sample is also required for 
Pre-Screening by ctDNA for FGFR2 gene amplification.  FGFR2 positive status by one of these 
testing methods is required for enrollment in Phase 2.  Results of the centralized FGFR2 testing 
may take approximately 2 weeks; patients are permitted to receive up to 1 dose of mFOLFOX6 
during this interim time period (pre-screening) at the discretion of the investigator.  This 1 dose 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 82 of 139 
Confidential 
of chemotherapy is not a requirement of the study and is not considered part of this clinical 
study. 
Patients in Phase 2 of this study must consent to tumor tissue analysis and blood sample analysis.  
Patients will be selected for enrollment based on FGFR2b overexpression and/or FGFR2 gene 
amplification, as determined by a validated IHC or ctDNA blood assay, respectively, using the 
central laboratory.  Patients who do not demonstrate either FGFR2b overexpression using IHC or 
FGFR2 gene amplification using a ctDNA blood assay will not be eligible for enrollment.  
However, positivity based on 1 or both of the assays is adequate to meet eligibility requirements 
(eg, positive by ctDNA blood assay, but negative by IHC, and vice versa) (refer to Table 4).  It is 
the responsibility of each investigator to obtain an adequate tumor specimen for analysis of 
FGFR2 positivity for enrollment.  A minimum of 5 slides are required.  Tumor slide or tumor 
block specimen processing, labeling, and shipping instructions are detailed in the Laboratory 
Manual that will be distributed with the specimen collection kit.  
Central laboratories will perform the FGFR2b overexpression and FGFR2 gene amplification 
analysis using a validated IHC test and ctDNA blood assay.  
For Phase 2, once tumor and blood specimens are received, analysis will be performed as 
efficiently as possible, and results will be communicated back to the investigator or designee.  
6.2 
Informed Consent Requirements 
Written, signed informed consent must be collected prior to any study-specific procedures 
(including pre-screening).  Patients who have fully consented to participation in the main study 
will undergo screening assessments within 28 days prior to administration of the first infusion of 
study treatment.  
6.3 
Screening 
Unless otherwise specified, all Screening assessments must be completed prior to enrollment in 
accordance with the Schedule of Assessments (Appendix 2).  During the screening period, the 
patient will undergo protocol-specified screening procedures to ensure all eligibility criteria are 
met.  
6.3.1 
Phase 1 
For Phase 1, all patients will undergo screening assessments within 28 days (as outlined in 
Appendix 2).  After a maximum 28-day screening period, eligible patients will initiate study 
treatment as described in Section 5.0.  Patients who screen fail may undergo repeat screening 
procedures one time, but all procedures must be done within the 28-day screening window, 
inclusive of informed consent. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 83 of 139 
Confidential 
Patients may have initiated or received mFOLFOX6 chemotherapy prior to enrollment in Phase 
1, but eligibility requires that the patient be a candidate to receive at least 2 additional doses of 
mFOLFOX6 chemotherapy (there is no upper limit on the number of previous mFOLFOX6 
doses that patients may have received, nor is there a requirement for prior treatment with 
mFOLFOX6 in Phase 1). 
Patients should have tumor tissue collected from archival material (if available) for analysis of 
FGFR2b overexpression by IHC retrospectively. 
6.3.2 
Phase 2 
For Phase 2, all patients will undergo screening assessments within 28 days.  After a maximum 
28-day screening period, eligible patients will initiate randomized study treatment as described 
below.  Patients who screen fail for Phase 2 may repeat screening procedures one time (not 
applicable to pre-screening when tissue or blood sample is determined to be evaluable and 
FGFR2 negative), but all procedures must be done within the 28-day screening window, 
inclusive of informed consent. 
The description of testing for FGFR2 positivity is described in Section 3.3.  Eligibility for 
Phase 2 will be evaluated in 2 steps:  
• Step 1: Patients will provide informed consent to allow testing for FGFR2b overexpression 
by archival or fresh tissue with IHC and a blood sample for FGFR2 amplification by ctDNA.  
The time between providing informed consent and site notification of the result of the test is 
considered the pre-screening period (refer to Section 3.3).  
• Step 2: Pre-screening allows for collection of blood and tissue to determine FGFR2 positivity 
using ctDNA and IHC assays.  Once a patient is confirmed to have a positive result based on 
central testing, the screening period initiates, allowing for evaluation of all other eligibility 
criteria (refer to Section 4.2).  Patients who test negative for FGFR2b overexpression or 
FGFR2 amplification will be considered pre-screen failed.  Patients who test positive and 
enter the screening period, but do not enroll, will be considered screen failed. 
6.4 
Study Enrollment 
6.4.1 
Phase 1 
Phase 1 is an open-label dose-escalation safety run-in.  There is no randomization in this phase. 
Patients who are determined to be eligible will be enrolled sequentially.  For patients 
participating in Phase 1, the date of enrollment is the date of first administration of study 
treatment.  
FGFR2 status is not a requirement for enrollment in Phase 1. FGFR2b overexpression will be 
tested retrospectively by IHC (if tissue is available) and FGFR2 gene amplification will be tested 
retrospectively by ctDNA blood assay.  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 84 of 139 
Confidential 
6.4.2 
Phase 2 
In Phase 2, patients who meet eligibility will be randomized 1:1 to FPA144 + mFOLFOX6 or 
placebo + mFOLFOX6.  The date of enrollment is the date of randomization.  Patients must 
initiate the first administration of study treatment within 3 days of enrollment.  The date of first 
administration of study treatment is C1D1 or Study Day 1.  
Enrollment in Phase 2 will begin when an RD for FPA144 has been identified by the CRC, 
which will not exceed the highest dose level evaluated and tolerated in Phase 1; based on the 
Phase 1 results, the Phase 2 dose of FPA144 is 15 mg/kg Q2W with an additional dose of 
7.5 mg/kg on Cycle 1 Day 8.  Patients may enroll in either Phase 1 or Phase 2, but may not enroll 
in both phases of the study.  Opening the Phase 2 portion of the study for enrollment will be at 
the discretion of the Sponsor.  A patient is considered enrolled when he/she is randomized. 
In Phase2, FGFR2b overexpression will be determined by prospective IHC analysis and/or a 
ctDNA blood assay demonstrating FGFR2 gene amplification.  
Eligible patients whose tumors have FGFR2b overexpression by IHC and/or FGFR2 gene 
amplification by blood may consent to study participation and subsequently undergo Screening 
procedures, including a comprehensive ophthalmologic examination, to ensure the eligibility 
criteria are met.  
Baseline radiographic imaging is also a study requirement.  Imaging performed as standard of 
care that includes imaging of chest, abdomen and pelvis may be used if it has been performed 
within 28 days (+3 days) of treatment (C1D1).  
6.4.3 
Blinding  
The Phase 1 part of this study will be open label. 
For Phase 2, all individuals involved in the conduct of the study (ie, site staff and patients, CRO 
personnel, Sponsor personnel) will be blinded to randomized treatment assignment.  
To facilitate the Phase 2 analysis, certain Sponsor representatives and Sponsor designees will be 
unblinded to treatment assignments prior to and during the analysis (including the biostatistician 
and external groups for bioanalytical PK/pharmacodynamic, and PRO analyses).  Additional 
details of the analyses and unblinding will be provided in the SAP. 
6.5 
Medical/Oncology History and Demographics 
In both Phase 1 and Phase 2, patient medical and surgical history recorded during the Screening 
visit includes a thorough review of significant past medical and surgical history, current 
conditions, concomitant therapies, alcohol and smoking history, and smoking status. At C1D1, 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 85 of 139 
Confidential 
the medical, disease, and medication history should be updated to capture any changes from 
Screening. 
Demographics including age, gender, race, and ethnicity will be recorded. 
6.6 
Safety Assessments 
Safety measures will include AEs, hematology, clinical chemistry, urinalysis, vital signs, body 
weight, concomitant medications/procedures, ECOG performance status, targeted physical 
examinations, ECGs, and ophthalmology examinations.  Safety measures are to be collected in 
both Phase 1 and Phase 2 in accordance with the Schedules of Assessments (Appendix 2, 
Appendix 3, and Appendix 4). 
Safety measures will also include evaluation for DLTs in Phase 1 only (refer to Section 3.2.3). 
An independent DMC will evaluate safety study data (AEs and SAEs) on a regular basis 
throughout the entire treatment phase (as prescribed in the DMC Charter) in Phase 2 (refer to 
Section 8.10.2). 
6.6.1 
Vital Signs 
Vital signs (BP, HR, RR, and temperature) are to be measured in both Phase 1 and Phase 2 in 
accordance with the Schedules of Assessments (Appendix 2, Appendix 3, Appendix 5). 
6.6.2 
Physical Examinations, Height, and Weight 
A complete physical examination including height and weight will be performed at Screening.  
Limited physical examinations (eg, symptom-directed examination of specific organ 
systems/body area) should be conducted in both Phase 1 and Phase 2 in accordance with the 
Schedules of Assessments (Appendix 2, Appendix 3) and include weight and examination of the 
oropharynx. 
The dose of FPA144 and mFOLFOX6 is based on body weight at C1D1 and should be 
recalculated only if the weight changes > 10% from the C1D1 weight.  If the dose is recalculated 
due to a > 10% weight change from C1D1, the weight used for the recalculated dose should 
function as the new baseline for subsequent evaluation of dose recalculations.   
6.6.3 
Ophthalmologic Examinations 
Ophthalmologic examinations, including comprehensive ophthalmologic examinations and slit 
lamp examinations with fluorescein score, will be performed in both Phase 1 and Phase 2 
according to Appendix 2, Appendix 3, Appendix 5.  Any abnormal OCT examinations reports 
should be provided to the Sponsor.  In addition, if a patient has any persistent ophthalmologic 
findings, the ophthalmologic assessments should continue every 8 weeks until resolution of 
findings, withdrawal of consent, death, or loss to follow up. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 86 of 139 
Confidential 
Comprehensive ophthalmologic examinations include fundoscopic and slit lamp examination, 
OCT, visual acuity, completion of fluorescein staining score form (Appendix 9), determination 
of intraocular pressure (IOP), and review of ocular/visual symptoms. When performing the 
ocular examination by the ophthalmologist, the following should be noted: 
• IOP can be measured by tonometer or applanation, but should be done before dilation 
• Confrontation visual fields is adequate 
• OCT should include the macula: Any abnormal OCT examinations identified during the 
study should be provided to the Sponsor.  
• Corneal staining and scoring should be done before dilation and before the IOP check as both 
may disrupt corneal integrity 
During Phase 1, comprehensive ophthalmologic examinations will be performed during 
Screening, at approximately 4 weeks from C1D1, at approximately 8 weeks from C1D1, at the 
EOT visit (± 7 days), and at any time there are ophthalmologic symptoms up to 100 days after 
the last dose of FPA144.  In addition to the comprehensive ophthalmologic exams, slit lamp 
examinations with completion of fluorescein staining score will be performed starting at 
Week 16 (± 7 days) from C1D1 and continue every 8 weeks until study completion.  
During Phase 2, comprehensive ophthalmologic examinations will be conducted at Screening, at 
8 weeks from C1D1 (± 7 days), at the EOT visit (± 7 days), and at any time there are 
ophthalmologic symptoms up to 100 days after the last dose of FPA144.  In addition to the 
comprehensive ophthalmologic examinations, slit lamp examinations with completion of 
fluorescein staining score form will be performed starting at 16 weeks (± 7 days) from C1D1 and 
then every 8 weeks (± 7 days) until study completion. 
In both Phase 1 and Phase 2, after the EOT visit, if the patient has any persistent corneal 
findings, the assessments should continue every 8 weeks until resolution of findings, withdrawal 
of consent, death, or loss to follow up. 
6.6.4 
Electrocardiograms  
Twelve-lead ECGs will be performed in both Phase 1 and Phase 2 in accordance with the 
Schedules of Assessments (Appendix 2, Appendix 3), and Table of Clinical Fixed Time Point 
Assessments (Appendix 5).  The investigator must review the ECG, document this review in the 
source documents, and record any clinically significant changes that occur during the study as an 
AE in the eCRF. 
6.6.5 
Eastern Cooperative Oncology Group Performance Status 
ECOG performance status will be assessed in all patients in both Phase 1 and Phase 2 at the time 
points outlined in Appendix 2 and Appendix 3.  The ECOG performance status is a scale used to 
assess how a patient's disease is progressing, assess how the disease affects the daily living 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 87 of 139 
Confidential 
abilities of the patient, and determine appropriate treatment and prognosis. The ECOG scale is 
shown in Appendix 8. 
6.7 
Clinical Laboratory Parameters 
Laboratory assessments (listed in Appendix 4) will be performed locally in both Phase 1 and 
Phase 2 at each study center’s laboratory by means of their established methods.  Before starting 
the study, the investigator will provide the Sponsor (or designee) with a list of the normal ranges 
and units of measurement.  Local hematology and blood chemistry test results must be obtained 
within 96 hours prior to enrollment.  On subsequent dosing days for both FPA144 and 
mFOLFOX6 (Phase 1) or FPA144/placebo and mFOLFOX6 (Phase 2), hematology and blood 
chemistry results must be obtained within 72 hours prior to dosing.  Coagulation results need to 
be obtained at baseline, at Day 1 of Cycles 1 through 4 within 72 hours prior to dosing with 
FPA144, and whenever clinically indicated. Ongoing evaluation of INR or PT should be 
continued for patients who are receiving therapeutic anticoagulation according to the local 
standard of care. 
Blood samples should be taken using standard venipuncture techniques. Laboratory assessments 
will be performed in both Phase 1 and Phase 2 in accordance with the Schedule of Assessments 
(Appendix 2, Appendix 3).  Abnormal laboratory results that lead to a change in patient 
treatment management (eg, dose delay, requirement for additional medication or monitoring) are 
considered clinically significant for the purposes of this study and will be recorded on the AE 
page of the eCRF.  Values meeting SAE criteria must be reported as SAEs. Refer to 
Section 6.17.2 for details around the reporting of abnormal laboratory findings as AEs.  
6.8 
Urinalysis 
Urinalysis will be performed in both Phase 1 and Phase 2 in accordance with the Schedule of 
Assessments (Appendix 2, Appendix 3).  Urinalysis includes protein, glucose, blood, pH, and 
ketones on Day 1 for both FPA144 and mFOLFOX6 of odd cycles (every other cycle).  If 
findings clinically significant, a microscopic evaluation will be performed per institutional 
standard. 
6.9 
Pregnancy 
Pregnancy is an exclusion criterion and WOCBP must not be considering getting pregnant 
during the study. Serum beta-human chorionic gonadotropin (ß-hCG) (evaluated by local 
laboratories) and urine pregnancy tests will be performed only on WOCBP.  A serum pregnancy 
test in WOCBP obtained within 96 hours prior to enrollment is mandatory in both Phase 1 and 
Phase 2.  Subsequent pregnancy tests should be performed in accordance with the Schedule of 
Assessments (Appendix 2, Appendix 3). 
In the event of suspected pregnancy, a serum pregnancy test should be repeated.  Patients who 
become pregnant during the study must discontinue study treatment immediately. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 88 of 139 
Confidential 
The Sponsor must be notified of any patient who becomes pregnant while participating in this 
study.  Although pregnancy is not an AE, all pregnancies must be followed to conclusion to 
determine their outcome.  Male patients should immediately inform the investigator if their 
partner becomes pregnant during the study or within 6 months after the last dose of study 
medication.  It is the responsibility of the investigator or designee to report any pregnancy in a 
patient that occurs during the study by completing the Pregnancy Reporting Form.  Please 
contact the study monitor to receive the Pregnancy Reporting Form upon learning of a 
pregnancy. 
Notification of the pregnancy including the anticipated date of birth should be provided on a 
Pregnancy Reporting Form within 24 hours of awareness and reported using the same procedure 
as described for reporting SAEs (Section 6.17.4).  If the pregnancy is to be terminated, the 
anticipated date of termination should be provided.  A pregnancy report form should also be 
completed by the investigator within 24 hours after learning of the pregnancy in the partner of a 
male patient during the study or within 6 months after the last dose of study medication using the 
procedure for SAE reporting (Section 6.17.4).  An investigator who is contacted by the male 
patient or his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the treating 
physician and/or obstetrician. 
The patient will be asked to provide information on the outcome of the pregnancy, including 
premature termination should the case arise.  Spontaneous miscarriages, premature termination 
of the pregnancy, congenital abnormalities and any other abnormalities in the mother or 
fetus/newborn will be reported as SAEs.  Information on the status of the mother and child will 
be forwarded to the Sponsor.  Attempts should also be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient exposed to drug.  The 
pregnant partner will need to sign and Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up of the pregnancy.  Once the authorization has been signed the 
investigator will update the Pregnancy Report reform with additional information on the course 
and outcome of the pregnancy.  Generally, follow-up will be in accordance with regulatory 
guidance and at least 6 to 8 weeks after the estimated delivery date.  
Pregnancies that occur during the first 6 months of the Follow-up Period should be reported to 
the Sponsor and followed as described above. 
6.10 
Tumor Assessments 
Tumor assessments will be performed in Phase 2 only.  Tumor assessments should consist of 
clinical examination and appropriate imaging techniques (preferably CT scans with appropriate 
slice thickness per RECIST v1.1; MRIs are acceptable).  The same methods used to detect 
lesions at baseline are to be used to follow the same lesions throughout the clinical study.  
Tumor response assessment will be performed by the investigator per RECIST v1.1 guidelines.  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 89 of 139 
Confidential 
Tumor scans will be performed at Screening (within 28 days +3 days) of treatment [C1D1] and 
then every 8 weeks (± 7 days) from C1D1 until 12 months and then every 12 weeks (± 14 days) 
thereafter.  Scans should be obtained per schedule regardless of drug interruption or 
discontinuation.  
Patients who discontinue study treatment (the last administered dose of FPA144/placebo and 
mFOLFOX6) for reasons other than disease progression or withdrawal of consent, radiographic 
tumor assessments will continue according to the protocol (approximately every 8 weeks ± 
7 days) until 12 months and then every 12 weeks ± 14 days thereafter) until either the patient 
initiates additional anticancer therapy or experiences disease progression. 
6.11 
Pharmacokinetic Assessment 
Blood samples to determine serum FPA144 concentration will be acquired from each patient as 
outlined in the Study Flowchart for PK, Immunogenicity, and 
 
 for Phase 1 (Appendix 6) and in the Study Flowchart for PK and 
Immunogenicity Blood Samples Collections for Phase 2 (Appendix 7).  These samples will be 
collected and processed according to the instructions provided in a separate Laboratory Manual. 
PK parameters will be estimated using noncompartmental analysis, though compartment analysis 
may be employed if appropriate.  Serum concentration-time data from FPA144-004 will be 
pooled with data from other studies for integrated population PK analysis and exposure-response 
relationship assessment. 
6.12 
Pharmacodynamic Biomarker Analysis Using Blood 
Pharmacodynamic assessments will only be conducted in Phase 1. 
Pharmacodynamic samples will be collected at the time points specified in Appendix 6.  Tumor 
tissue provided for evaluation of FGFR2 status, if available, will be retrospectively analysed for 
FGFR2b overexpression using IHC. 
Blood samples provided for evaluation of FGFR2 status will be collected prior to the first dose of 
study treatment and analysed retrospectively for FGFR2 gene amplification using a ctDNA 
blood assay. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 90 of 139 
Confidential 
6.13 
Immunogenicity 
Immunogenicity, defined as an immune response to FPA144, will be assessed by measurement 
of total anti-FPA144 antibodies from all patients.  Immunogenicity testing will consist of 
screening, confirmation, and ADA concentration.  Additional characterization of a confirmed 
anti-FPA144 antibody response may be conducted.  
Samples for immunogenicity, anti-drug antibody (ADA) assessment will be drawn in both 
Phase 1 and Phase 2 from each patient at the time points outlined in Appendix 6 and Appendix 7.  
Samples for immunogenicity testing will be collected and processed at central laboratory 
according to the instruction provided in the Laboratory Manual. 
6.14 
Immunohistochemistry 
In Phase 1 collection of samples is optional for FGFR2b overexpression using IHC (archival 
sample with fresh cuts).   
Phase 2 requires collection of samples for FGFR2b overexpression using IHC (archival sample 
with fresh cuts or a fresh biopsy).  Patients whose samples show FGFR2b overexpression will be 
considered positive.   For patients in Phase 1, results of the IHC do not need to be available prior 
to enrollment and dosing.  For patients participating in the Phase 2 portion of the trial, a blood 
sample for ctDNA testing is required prior to consent and enrollment.  Patients may be enrolled 
on Phase 2 based on positive IHC or ctDNA (refer to Section 6.15). 
6.15 
Circulating Tumor DNA Blood Assay  
In both phases of the study, samples for ctDNA blood assay will be collected prior to the first 
dose of study treatment (C1D1) and analyzed for FGFR2 gene amplification in the central 
laboratory.  For patients in Phase 1, results of the ctDNA do not need to be available prior to 
enrollment and dosing.  For patients participating in the Phase 2 portion of the trial, a blood 
sample for ctDNA testing is required prior to consent and enrollment.  Patients may be enrolled 
based on a positive ctDNA or IHC test.   
6.16 
Patient Reported Outcomes / Quality of Life Scales 
In Phase 2, the EQ-5D-5L QOL questionnaire and the EORTC QLQ-C30 will be administered in 
accordance with Appendix 3.  
The EQ-5D-5L questionnaire was developed by the EuroQol Group, which is a standardized 
measure to provide utilities for clinical and economic appraisal.  It uses a descriptive system and 
a visual analogue scale (VAS).  The descriptive system has 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression, and each dimension has 5 levels 
consisting of no problems, slight problems, moderate problems, severe problems, and extreme 
problems.  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 91 of 139 
Confidential 
The EORTC QLQ is an integrated system for assessing the health-related quality of life of 
cancer patients participating in international clinical trials.  The EORTC uses a modular 
approach to QOL assessment, consisting of a core questionnaire (EORTC QLQ-C30) to be 
administered, if necessary with a module specific to tumor site, treatment modality or a QOL 
dimension (eg, GC-specific module is QLQ-STO22). 
6.17 
Adverse Events  
Assessment of AEs will follow the guidelines provided in the NCI CTCAE version 4.03 in Phase 
1 and version 5.0 in Phase 2.  AEs will be assessed as outlined in Section 6.17.3.  Abnormal 
laboratory results that lead to a change in patient treatment management (eg, dose delay, 
requirement for additional medication or monitoring) are considered clinically significant for the 
purposes of this study and will be recorded on the AE page of the eCRF.  Events meeting SAE 
criteria must be reported as SAEs (Section 6.17.3.1).  
6.17.1 
Collection of Adverse Events 
In Phase 1, any new symptoms, injury, or worsening of symptoms that occur during the 
screening period (ie, following signing of the ICF, but prior to first infusion [C1D1]), will be 
considered pretreatment events and reported on the Medical History page of the eCRF, unless 
they directly correlate to a study-related procedure in which case they will be reported on the AE 
eCRF page.  Otherwise, AE reporting will begin at the time of infusion of C1D1 (day of first 
infusion) and continue until completion of the EOT visit or 4 weeks (28 days) after the last dose 
of FPA144.  
In Phase 2, AEs should not be reported during the pre-screening period unless they are related to 
a pre-screening procedure, as patients are not yet enrolled on the study at that time.  The worst 
grade of AEs occurring during the screening period should be reported as described above for the 
Phase 1 screening period.  AE reporting will continue until the EOT visit. SAE reporting will 
initiate at study enrollment unless the event is related to a study procedure.  Symptomatic corneal 
and all retinal events are considered of special interest and should be reported up to 100 days 
from the last dose of FPA144. 
Since the IHC and ctDNA blood results may require up to 2 weeks to complete, patients eligible 
for entering Phase 2 of this study may not be able to delay start of standard chemotherapy while 
waiting to receive the IHC or ctDNA blood result.  Therefore, patients are permitted to receive 
1 dose of mFOLFOX6 prior to enrolling in this clinical trial, while waiting for FGFR2 status to 
be confirmed. AEs due to this single dose of therapy that are ongoing on Study Day 1 will be 
captured on the medical history eCRF. 
SAEs occurring after the EOT visit should be reported to the Sponsor by the investigator only if 
the investigator considers them related to FPA144 or mFOLFOX6. SAEs should always be 
recorded on the AE eCRF and reported to the Sponsor using the SAE report form. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 92 of 139 
Confidential 
6.17.2 
Definitions 
An AE is any untoward medical occurrence that occurs in a patient administered a 
pharmaceutical product, and which does not necessarily have to have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the product.  Abnormal laboratory 
findings that are not considered clinically significant will be recorded only on the laboratory 
eCRF pages and not on the AE pages.  Abnormal laboratory results that are considered clinically 
significant in the investigator’s opinion are also to be recorded on the AE eCRF.  Relationship 
(reasonable causal relationship) to drug therapy and counter measures undertaken will be noted 
on the eCRF. 
All AEs including intercurrent illnesses that occur during the study, from the time of 
administration of study treatment, will be documented on the AE eCRF.  Concomitant illnesses, 
which existed prior to the day of the first study infusion, will not be considered AEs unless they 
worsen by at least 1 grade during the treatment period.  Intensity (severity) grade will be defined 
according to the NCI-CTCAE, version 4.03 in Phase 1 and version 5.0 in Phase 2.  Pre-existing 
conditions will be recorded on the Medical History eCRF. 
A treatment-emergent AE will be defined as an AE that begins or worsens in severity after at 
least 1 dose of study treatment (FPA144 and/or mFOLFOX6) has been administered. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, will not be 
reported as an AE, but the procedure and/or therapeutic treatment should be recorded on the 
appropriate eCRF.  The medical condition for which the procedure was performed must be 
reported as an AE (or as part of the patient’s medical history, if the procedure precedes the 
initiation of study-prescribed treatment).  Signs and symptoms associated with disease 
progression itself should not be reported as an AE or SAE if the diagnosis is available. 
Disease progression itself is an endpoint and not an AE or SAE. 
6.17.3 
Assessment of Adverse Events 
Each AE will be assessed by the investigator with regard to seriousness, intensity (severity), 
causality, and the outcome and action taken.  All AEs, regardless of the relationship to study 
treatment, will be recorded on the AE eCRF.  This includes potential end-organ toxicity, eg, 
renal (proteinuria), hepatic, and cardiovascular (increased BP) effects, and effects on wound 
healing.  All AE reports should contain a brief description of the event, date of onset, ongoing or 
date of resolution, intensity, treatment required, relationship to study treatment, action taken with 
the study treatment, outcome, and whether the event is classified as serious as described below. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 93 of 139 
Confidential 
6.17.3.1 
Seriousness 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death. Death may occur as a result of the underlying disease process.  All events 
other than progression of underlying disease that result in death during the reporting period 
up to 28 days following the last dose of study treatment must be treated as an SAE and 
reported as such 
• Is life-threatening (patient is at immediate risk of death from the event as it occurred) 
• Requires inpatient hospitalization (formal admission to a hospital for medical reasons) or 
prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
Medically significant events that may not result in death, are not life-threatening, or do not 
require hospitalization may be considered SAEs when, based on appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse. 
Medical and scientific judgment should be exercised in deciding whether a case is considered 
medically significant or serious and whether expedited reporting is appropriate. 
Hospitalization for an event solely related to disease progression is not considered an SAE.  
Hospitalization for an elective or planned procedure to treat a pre-existing condition is not 
considered an SAE unless it results in one of the outcomes listed above. 
6.17.3.1.1 
Adverse Events of Special Interest (AESI) 
An AESI (serious or non-serious) is an event of medical concern considered potentially 
associated to the investigational product or disease under study, for which ongoing monitoring 
and rapid communication by the investigator to the Sponsor is necessary.  Ocular events 
associated with symptomatic corneal involvement and symptomatic and asymptomatic retinal 
involvement are considered events of special interest in this study.  Such events might warrant 
further investigation in order to characterize the safety profile of the product.  Depending on the 
nature of these events, rapid communication by FivePrime to other parties (eg, regulators) might 
also be warranted. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 94 of 139 
Confidential 
6.17.3.1.2 
Intensity (Severity) 
Investigators need to assess the severity of AEs according to the guidelines provided in 
NCI-CTCAE, version 4.03 in Phase 1 and version 5.0 in Phase 2. 
CTCAE v 4.03 and v 5.0 Severity Grades are: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated; mild AE 
• Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living; moderate AE 
• Grade 3: Severe or medically significant, but non-immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living; severe AE 
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Fatal AE 
If the AE is not specified in the CTCAE or the study protocol, the grading of severity will be 
assessed as mild (Grade 1), moderate (Grade 2), severe (Grade 3), life-threatening (Grade 4), 
or death due to the AE (Grade 5) using the following definitions: 
• Mild: The patient is aware of the event or symptom, but the event or symptom is easily 
tolerated. 
• Moderate: The patient experiences sufficient discomfort to interfere with or reduce his or her 
usual level of activity. 
• Severe: Significant impairment of functioning: the patient is unable to carry out usual 
activities. 
• Very severe (life-threatening): The patient’s life is at risk from the event. 
6.17.3.2 
Causality 
The investigator will assess the causality/relationship between the study treatment and the AE 
and record that assessment on the eCRF. 
The most likely cause of an SAE (eg, disease under treatment, concomitant disease, concomitant 
medication, other) will be indicated on the eCRF with details of the concomitant disease or 
medication or other cause. 
The causal relationship of the AE to study treatment will be assessed by means of a question: 
‘Is there a reasonable possibility that the AE may have been caused by the study treatment?’ 
Answer Yes or No. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 95 of 139 
Confidential 
The description below provides guiding principles for the investigator to make casualty 
assessments. 
• Yes, there is a reasonable possibility that the AE may have been caused by the study 
treatment: 
• Follows a reasonable temporal sequence from administration of the study treatment 
• Could not be reasonably explained by the patient’s clinical state, environmental or toxic 
factors, or other therapies administered to the patient 
• Disappears or decreases on cessation or reduction in dose of the study treatment 
• Follows a known pattern of response to the study treatment 
• Reappears or worsens on re-challenge 
• No, there is no reasonable possibility that the AE may have been caused by the study 
treatment: 
• Does not follow a reasonable temporal sequence from administration of the study 
treatment 
• Could be reasonably explained by the patient’s clinical state, environmental or toxic 
factors, or other therapies administered to the patient 
• Does not follow a known pattern of response to the study treatment 
• Does not reappear or worsen on re-challenge 
The relatedness for SAEs will also be assessed and documented on the AE eCRF. 
If the causality of the AE requiring discontinuation is confirmed to be due to one of the study 
treatments in the combination therapy, the other drug may be continued according to the protocol 
schedule under the following scenarios: 
• Timely resolution of the AE based on the treatment modification table 
• Clinical benefit is shown by the patient based on investigator assessment 
6.17.3.3 
Outcome and Action Taken 
The investigator will record the action taken and outcome for each AE according to the 
following criteria: 
• Action Taken 
• Dose Not Changed 
• Drug Interrupted 
• Drug Withdrawn 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 96 of 139 
Confidential 
• Drug Delayed 
• Dose Increased 
• Dose Reduced 
• Not Applicable 
• Unknown 
• Outcome 
• Fatal 
• Not Recovered/Not Resolved 
• Recovered/Resolved 
• Recovered/Resolved with Sequelae 
• Recovering/Resolving 
6.17.4 
Reporting Serious Adverse Events 
Any SAEs, whether or not considered related to treatment with FPA144 or mFOLFOX6, must be 
reported by the investigator to the Sponsor or Sponsor’s designee within 24 hours of the 
investigator becoming aware of the event and must be recorded on both the SAE form and AE 
eCRF.  Additional SAE information including medications or other therapeutic measures used to 
treat the event, action taken with the study treatment due to the event, and outcome/resolution of 
the event will be recorded on the SAE form.  Forms for reporting SAEs will also be provided to 
the study centers. 
A copy of the SAE forms must be faxed or electronically communicated within 24 hours to the 
attention of the ICON Pharmacovigilance Safety Specialist: 
ICON Medical and Safety Services 
Fax number: +1-866-955-7492 
SAE Hotline: +1-888-723-9952  
Email: icon-mads@iconplc.com 
The investigator should not wait to receive additional information to fully document the event 
before notification of a SAE, though additional information may be requested.  The minimum 
information that is required for an initial SAE report is as follows: 
• Patient study number 
• Investigator name and study center number 
• Event term 
• Event onset date 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 97 of 139 
Confidential 
• Serious criteria 
• Relationship to study treatment(s) 
As applicable, information from relevant laboratory results, hospital case records, and autopsy 
reports should be obtained. 
Serious AEs occurring after the EOT visit should be reported to the Sponsor by the investigator 
if the investigator considers the event related to the study treatment.  Events of special interest 
(symptomatic corneal and all retinal events) should be reported to the Sponsor up to 100 days 
from last dose of FPA144.  
The investigator and Sponsor will review each SAE report and evaluate the seriousness and 
causal relationship of the event to study treatment. In the event of a disagreement about 
causality, the most conservative assessment will be used.  In addition, the Sponsor will evaluate 
the expectedness according to the FPA144 IB.  Based on the investigator and Sponsor’s 
assessment of the event, a decision will be made concerning the need for further action. 
The Sponsor or its designee is responsible for submitting reports of AEs associated with the use 
of the drug that are both serious and unexpected the Food and Drug Administration (FDA), 
according to 21 Code of Federal Regulations (CFR) 312.32, and to other regulatory authorities, 
according to national law and/or local regulations.  All investigators participating in ongoing 
clinical studies with the study medication will receive copies of these reports for prompt 
submission to their IRB or IEC. 
The Sponsor or its designee will submit all safety updates and periodic reports to the regulatory 
authorities as required by applicable regulatory requirements. 
6.17.5 
Follow-up of Adverse Events 
All treatment-related SAEs experienced by a study patient, will be monitored until the event has 
resolved or stabilized, any abnormal laboratory values have returned to baseline or stabilized at a 
level acceptable to the investigator and Sponsor, there is a satisfactory explanation for the 
changes observed, or the patient is lost to follow-up. 
All unresolved related AEs should be followed by the investigator until the events are resolved, 
the patient is lost to follow-up, or the AE is otherwise explained.  The investigator should notify 
the study Sponsor of any death or AE occurring at any time after a patient has discontinued or 
terminated study participation that may reasonably be related to this study.  Follow-up of events 
of special interest (symptomatic corneal and all retinal events) will be determined on a case by 
case basis depending on the prognostic resolution of the event.  The Sponsor should also be 
notified if the investigator should become aware of the development of cancer or of a congenital 
anomaly in a subsequently conceived offspring of a patient that has participated in this study.  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 98 of 139 
Confidential 
6.18 
End of Treatment 
EOT assessments are outlined in Appendix 2 and in Appendix 3 for Phase 1 and Phase 2, 
respectively.  All patients should return to the clinic approximately 28 days after their last dose 
of study treatment (ie, the last administered dose of FPA144 or any component of mFOLFOX6), 
or in the event that a patient discontinues prematurely from the study, for EOT follow-up 
assessments.  
In Phase 2, after discontinuation of study treatment for reasons other than disease progression or 
withdrawal of consent, tumor assessments will continue until the patient initiates additional 
anticancer therapy or progresses. 
Symptomatic corneal and all retinal events are considered of special interest and should be 
reported up to 100 days from the last dose of FPA144. 
6.19 
Long Term Follow Up (Phase 2) 
LTFU assessments are outlined in Appendix 3 for Phase 2 only.  In Phase 2, LTFU assessments 
for survival consist of clinic visits, telephone calls, or patient registries (in line with national 
legislation and prevailing data protection laws) approximately every 3 months (± 1 month) after 
the EOT visit until up to 24 months after the last patient is enrolled in the study, or until death, 
loss to follow-up, withdrawal of consent, or study termination by the Sponsor (whichever occurs 
first), which will be considered the EOS.  During the Follow-up Period, if the patient undergoes 
anticancer therapy, this should be documented. 
During the first 6 months of the LTFU Period (for patients in Phase 2), and for the first 6 months 
after the EOT visit (for patients in Phase 1), any known pregnancy that occurs should be reported 
to the Sponsor and followed as described in Section 6.9. 
Serious AEs occurring after the EOT visit should be reported to the Sponsor by the investigator 
if the investigator considers there is a causal relationship with the study treatment (refer to 
Section 6.17.3.2). 
6.19.1 
Additional Follow-up for Patients without Progression at the End of Treatment 
Visit (Phase 2) (Scan Follow-up) 
Scan Follow-Up assessments are outlined in Appendix 3 for Phase 2 only.  If a patient 
discontinues study treatment (FPA144 and/or mFOLFOX6) for reasons other than disease 
progression or withdrawal of consent, they will have follow-up visits and continue to undergo 
tumor assessments until disease progression or the initiation of additional anticancer therapy.  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 99 of 139 
Confidential 
7.0 
STATISTICAL METHODS 
Before database lock, a SAP will be finalized, providing detailed methods for the analyses 
including the summary of conduct of study and comparability of treatment group in Phase 2.  
Any deviations from the planned analyses will be described and justified in the final clinical 
study report. 
7.1 
Analysis Populations 
The following analysis populations are defined for the study: 
• Safety Population: all enrolled patients who have received any portion of at least 1 dose of 
study treatment (FPA144 + mFOLFOX6 or placebo + mFOLFOX6).  
• DLT-evaluable Population: all patients enrolled in Phase 1 of the study who received at least 
2 doses of FPA144 (except for Cohort 2 [must have received 3 doses of FPA144]) and 
mFOLFOX6 and completed Cycles 1 and 2 of treatment, or who experienced a DLT in 
Cycle 1 or Cycle 2.  
• PK-evaluable Population: all patients who have received at least 1 dose of FPA144 and have 
had adequate PK assessments drawn for determination of the FPA144 concentration.  
Adequacy will be determined on a case-by-case basis and will be assessed prior to analysis of 
the blood samples.  
• Intent-to-treat (ITT) Population: all randomized patients (Phase 2).  
• Efficacy-evaluable Population: all patients who met eligibility criteria, received at least 
1 dose of study treatment (FPA144 + mFOLFOX6 or placebo + mFOLFOX6), and have at 
least 1 postbaseline disease assessment and no major protocol deviation that could introduce 
bias in any efficacy assessment. 
7.2 
General Considerations 
The total enrollment planned for this study is approximately 167 patients.  12 patients evaluable 
for DLT were enrolled into Phase 1. 
For Phase 2, efficacy and tolerability will be examined by enrollment of approximately 
155 patients with FGFR2-selected GC, randomized 1:1 to receive FPA144 + mFOLFOX6 or 
placebo + mFOLFOX6.  Eligible patients will be stratified according to geographic region, prior 
treatment status (de novo versus adjuvant/neo-adjuvant), and administration of a single dose of 
mFOLFOX6 prior to enrollment (yes or no). 
7.3 
Power and Sample Size in Phase 2 
This Phase 2 study is designed to assess the hazard ratio (HR) of PFS for FPA144 + mFOLFOX6 
compared with placebo + mFOLFOX6. It is planned to observe 84 PFS events in order to 
achieve 71% power to detect an HR of 0.67 for PFS, at the 1-sided alpha of 0.1. Assuming an 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 100 of 139 
Confidential 
exponential distribution, this corresponds approximately to an 50% increase in median PFS (e.g. 
from 5 months to 7.5 months).  Statistical significance (at 1-sided alpha of 0.1) for PFS will 
occur with an observed HR=0.756, corresponding approximately to a 32.3% increase in observed 
median PFS (e.g. from 5 months to 6.6 months). 
One hundred fifty-five patients have been randomized (1:1) during 13 months of accrual. It is 
projected to observe 84 PFS events with approximately 11 additional months of follow-up. 
There is no planned interim analysis for this study. 
Statistical significance for PFS will occur with an estimated HR= 0.756 at the final analysis, 
corresponding approximately to an increase of 32.3% in median progression-free survival of 
from 5 months to 6.61 months.  
Approximately 155 patients will be randomized (1:1) during 13 months of accrual, with 
approximately 12 additional months of follow-up in order to achieve the targeted number of 
primary events with 15% dropout. 
Power and sample size estimates were estimated using EAST®(V6.4). 
7.4 
Efficacy Analyses  
7.4.1 
Analysis of Primary Efficacy Endpoint 
In Phase 2, the primary efficacy analysis is the comparison of PFS in patients treated with 
FPA144 + mFOLFOX6 versus placebo + mFOLFOX6.  
The primary endpoint, PFS, is defined as time from randomization until the date of radiological 
disease progression based on investigator assessment (using RECIST v1.1) or death from any 
cause, whichever comes first.  A clinical deterioration determined by an investigator will not be 
considered as a progression event. Data will be censored at the date of last adequate tumor 
assessment for subjects: 
• who do not have documented progression or die, or 
• who start new anticancer therapy before documented progression or death without 
documented progression, or 
• who have ≥ 2 consecutive missing tumor assessments before documented progression or 
death without documented progression 
If a subject does not have a baseline tumor assessment, then PFS will be censored at the date of 
randomization, regardless of whether or not radiographic progression or death has been 
observed.   


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 101 of 139 
Confidential 
The analyses of PFS will be performed using the ITT population, and will be conducted using a 
stratified log-rank test.  The stratification factors will be the same used to stratify the 
randomization schedule as documented in the interactive voice and web response system (IXRS).  
The median PFS and the associated 95% CI for each treatment arm will be estimated using the 
Kaplan-Meier method.  The hazard ratio (HR= λFPA144+ mFOLFOX6/ λplacebo+mFOLFOX6) will be 
estimated using a Cox regression model with treatment group as the only main effect and 
stratifying by the same stratification factors as were used for the stratified log-rank test.  
An unstratified HR will also be presented.  
The detailed sensitivity analyses of PFS based upon different definitions of progression events 
and censoring rules will be provided in a SAP to address the following: 
• To correct for potential ascertainment bias in follow-up schedules between the 2 treatment 
groups; 
• To evaluate PFS based upon investigator claims: progression events will include investigator 
assessment of disease progression and initiation of subsequent anticancer therapy 
7.4.2 
Analysis of Secondary Efficacy Endpoints 
Analyses of secondary endpoints OS and ORR will be conducted hierarchically.  The formal 
hypotheses regarding effects on OS and ORR will be tested hierarchically at a one-sided level of 
0.1.  The OS will be tested first and if it is significant, the ORR will be tested next.  The family-
wise type I error rate of testing primary and secondary endpoints will be in a control by 
employing this gate-keeping testing procedure at a one-sided level of 0.1.  
Overall survival is defined as time from randomization until death from any cause. Subjects who 
are lost to follow-up or do not have a date of death at the time of data cutoff will be censored at 
the last date that they were known to be alive. Overall survival will be analyzed in the similar 
manner as for PFS. 
The analysis of ORR will be performed based on the ITT population.  In the analysis of ORR, 
patients who don’t have any postbaseline adequate tumor assessments will be counted as non-
responders.  Formal hypothesis testing of ORR will be performed using the stratified Cochran-
Mantel-Haenszel test at a one-sided level of 0.1.  The stratification factors will be the same used 
to stratify the randomization schedule as documented in the IXRS.  In addition, the analysis of 
ORR will be performed based on Efficacy-evaluable Population as sensitivity analysis. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 102 of 139 
Confidential 
7.4.3 
Analysis of Exploratory Endpoints 
7.4.3.1 
Efficacy  
Duration of response (DOR) is defined, for patients with an objective response, as the time from 
onset of radiographic documentation of objective response to disease progression evaluated by 
investigator using RECIST v1.1 or death due to any cause.  Patients who have not experienced 
disease progression or death at the time of analysis will be censored at the time of the last 
adequate tumor assessment.  Median duration of response and its associated 95% CI will be 
estimated, by treatment group, using Kaplan-Meier methods.  
The detailed analyses of exploring correlation between identified FGFR2 status in tumor tissue 
and/or ctDNA blood assay, as determined by IHC and blood-based molecular diagnostic assay, 
with PFS, OS, and objective response per RECIST v1.1 will be provided in the SAP. 
7.4.3.2 
Quality of Life 
The analysis of PROs (assessed using the EORTC QLQ-C30 questionnaires) will be performed 
according to the EORTC Scoring and Reference Values Manual.  The details of the analyses will 
be specified in the Statistical Analysis Plan.  The respective subscales from the EORTC 
QLQ-C30 will be used to evaluate and compare the time to deterioration in abdominal pain, 
reflux, eating restrictions (premature safety), weight loss, appetite loss, and fatigue between 
treatment arms.  All scores and subscales will be assessed through descriptive summary 
statistics. 
7.5 
Safety Analyses 
All AEs will be coded using the Medical Dictionary for Regulatory Activities Version 20.1 
(MedDRA v 20.1).  The investigator will classify the severity of AEs using the CTCAE v 4.03 in 
Phase 1 and version 5.0 in Phase 2. A treatment-emergent adverse event (TEAE) is defined as 
any event with an onset date on or after date of first dose of study treatment, or any event present 
before treatment that worsens after treatment.  Only TEAEs with an onset date prior to 28 days 
after the date of last dose will be tabulated in summary tables.  The exceptions are symptomatic 
corneal events or any retinal events which will be captured within 100 days of the last dose of 
FPA144. 
Clinical laboratory data will be summarized by the type of laboratory test.  The number and 
percentage of patients who experience abnormal (ie, outside of reference ranges) and/or 
clinically significant abnormal laboratories after study treatment administration will be presented 
for each clinical laboratory measurement.  For each clinical laboratory measurement, descriptive 
statistics will be provided for baseline and all subsequent posttreatment scheduled visits.  
Changes from baseline to the posttreatment visits will also be provided.  Descriptive statistics of 
vital signs will also be provided in a similar manner.  In addition, shift from baseline in CTCAE 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 103 of 139 
Confidential 
grade (where applicable) and by high/low flags (where CTCAE grades are not defined) will be 
presented in a similar manner.  
7.5.1 
Safety Analyses in Phase 1 
Safety analyses will be performed for patients included in the safety population.  The incidence 
of DLTs, incidence of TEAEs, clinical laboratory abnormality (eg, shift table), vital signs, 
corneal and retinal findings, and ECGs will be tabulated and summarized by dose level.  
Additionally, incidence of TEAEs leading to dosing reduction or dose discontinuation will be 
tabulated and summarized  
7.5.2 
Safety Analyses in Phase 2 
The analyses of safety will include all patients who receive any study treatment (FPA144 + 
mFOLFOX6, or placebo + mFOLFOX6) throughout the study and provide any posttreatment 
safety information.  The incidence of TEAEs, clinical laboratory abnormality (eg, shift table), 
vital signs, corneal and retinal findings, and ECGs will be tabulated and summarized by 
treatment group.  
No formal comparisons of safety endpoints are planned. 
7.6 
Pharmacokinetic Analyses  
PK blood samples will be collected to measure the concentration of FPA144 in serum. 
Immunogenicity blood samples will be collected to measure the level of anti-FPA144 antibodies 
in serum. Samples for PK and immunogenicity assessment will be drawn from each patient at the 
time points outlined in Appendix 6 (for Phase 1) and Appendix 7 (for Phase 2).  These samples 
will be collected and processed according to the instructions provided in a separate Laboratory 
Manual. 
Individual and mean (± SD) serum FPA144 concentration-time data will be tabulated and plotted 
by dose level.  FPA144 PK parameters will be estimated from the serum FPA144 concentration-
time data from Phase 1 using a non-compartmental analysis method with IV infusion input.  
Alternative methods may be considered.  The Cmax and Ctrough of FPA144 will be estimated from 
the serum concentration-time data for Phase 2.  The time to achieve steady state, dose linearity, 
and accumulation ratio will be evaluated as data allow.  Estimated individual and mean (± SD) 
PK parameters will be tabulated and summarized by dose level.  Other descriptive statistics 
might be reported for serum FPA144 concentration-time data and estimated PK parameters.  
The impact of immunogenicity on FPA144 exposure will be assessed, tabulated, and summarized 
by dose level as appropriate and applicable. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 104 of 139 
Confidential 
Serum concentration-time data from FPA144-004 will be pooled with data from other studies for 
integrated population PK analysis and exposure-response relationship assessment, which will be 
presented in a separate report. 
7.7 
Changes in the Planned Analyses 
If discrepancies exist between the text of the statistical analysis as planned in the protocol and 
the final SAP, a protocol amendment will not be issued, and the SAP will prevail. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 105 of 139 
Confidential 
8.0 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
8.1 
Data Quality Assurance 
The Sponsor (or designee) may conduct a site visit prior to study initiation at a site to verify the 
qualifications of each investigator, inspect the site facilities, and inform the investigator of 
responsibilities and for ensuring study compliance and procedures for adequate and correct 
documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other pertinent data for each study patient.  All 
information recorded on the eCRFs for this study must be consistent with the patients’ source 
documentation (ie, medical records). 
8.2 
Data Protection 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other pertinent data for each study patient.  All 
information recorded in the case histories or eCRFs for this study must be consistent with the 
patients’ source documentation (ie, medical records). 
Investigator and study center must maintain the anonymity of participating patients.  Each patient 
will be assigned a unique patient identifier by the Sponsor that may consist of one or more of the 
following: the patient’s patient number, initials, and/or birth date.  Investigator and study center 
will include only such patient identifier on any eCRFs or other patient records, datasets or other 
documents that are transferred or submitted to the Sponsor or Sponsor’s designee during the 
course of the study and will redact patient’s name and all other personally-identifiable patient 
information from such documents.  In addition, investigator must maintain in confidence any 
documents that include personally-identifiable patient information (e.g., the signed ICF) and take 
all reasonable precautions to prevent the disclosure of any personally identifiable patient 
information by any employee or agent of the study center to any third party or otherwise into the 
public domain.  
The investigator or study center must inform study patients that their personal study-related data 
will be used by the Sponsor in accordance with local data protection law and must explain the 
level of disclosure to patients.  In addition, each patient must be informed that his/her medical 
records may be examined by Clinical Quality Assurance auditors or other authorized personnel 
appointed by the Sponsor, by IRB/IEC members of the study center, and by inspectors from 
regulatory authorities. 
The Sponsor (or designee) may conduct a site visit prior to study initiation at a site to verify the 
qualifications of each investigator, inspect the site facilities, and inform the investigator of 
investigator’s responsibilities for ensuring study compliance and procedures for preparing and 
maintaining adequate and correct eCRFs.  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 106 of 139 
Confidential 
8.3 
Electronic Case Report Forms and Source Documentation 
All data obtained during this study should be entered in the eCRFs promptly.  All source 
documents from which eCRF entries are derived should be placed in the patient’s medical 
records.  eCRF fields for which source documents will typically be needed include laboratory 
assessments, physical examination reports, nursing notes, ECG recordings, hospital records, 
CT scans, and/or MRI) reports.  
The eCRFs for each patient will be checked against source documents at the study site by the site 
monitor.  
Instances of missing or uninterpretable data will be discussed with the investigator for resolution. 
8.4 
Access to Source Data 
During the study, a monitor will perform routine site visits to review protocol compliance, 
compare eCRFs and individual patient’s medical records, assess drug accountability, and ensure 
that the study is being conducted according to pertinent regulatory requirements.  eCRF entries 
will be verified with source documentation.  The review of medical records will be performed in 
a manner to ensure that patient confidentiality is maintained. 
In accordance with ICH Good Clinical Practices (GCP) guidelines, the investigator must ensure 
provision of sufficient time, reasonable space, and adequate qualified personnel for the 
monitoring visits.  The purpose of the visits is verifying adherence to the study protocol and the 
completeness, consistency, and accuracy of data entered on the eCRF and other documents.  
Moreover, regulatory authorities, IRBs, IECs, and/or the Sponsor’s Quality Assurance group 
may wish to carry out such source data checks and/or on-site audit inspections.  Direct access to 
source data will be required for these inspections and audits; they will be carried out giving due 
consideration to data protection and medical confidentiality.  The investigator must assure that 
the Sponsor and/or Sponsor’s designee will receive the necessary support to complete these 
activities. 
All participating centers should take particular care in ensuring that original imaging source data 
(e.g., CT images, MRI images, echo images, etc.) are maintained and accessible for monitoring, 
and that these original source data are then archived on a long-term basis in compliance with 
ICH GCP Section 8.  These images must be stored in a secure location until the Sponsor or 
Sponsor’s designee authorizes their destruction and must be retrievable by study patient number 
in the event of an audit. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 107 of 139 
Confidential 
8.5 
Data Processing 
The Data Management Plan, to be developed during the initiation phase of the study, will include 
specifications for consistency and plausibility checks on data and will also include data-handling 
rules for obvious data errors.  All processes for data processing and query handling will be 
described in the Data Management Plan. 
8.6 
Archiving Study Records 
Each study site will maintain a study file, which should contain, at minimum, the IB, the protocol 
and any amendments, the protocol for tissue sampling, drug accountability records, 
correspondence with the IEC/IRB and the Sponsor (or designee), and other study-related 
documents. 
The investigator agrees to keep records and those documents that include (but are not limited to) 
the identification of all participating patients, medical records, study-specific source documents, 
source worksheets, all original signed and dated ICFs, copies of all eCRFs, query responses, and 
detailed records of drug disposition to enable evaluations or audits from regulatory authorities 
and the Sponsor or its designees.  
The investigator shall retain records required to be maintained for a period of 5 years following 
the date a marketing application in an ICH region is approved for the drug for the indication for 
which it is being investigated or, if no application is to be filed or if the application is not 
approved for such indication, until at least 5 years after the investigation is discontinued.  
However, these documents should be retained for a longer period if required by the applicable 
regulatory requirement(s) or if needed by the Sponsor. In addition, the investigator must make 
provision for the patients’ medical records to be kept for the same period of time. 
No data should be destroyed without the agreement of the Sponsor.  Should the investigator wish 
to assign the study records to another party or move them to another location, the Sponsor must 
be notified in writing of the new responsible person and/or the new location, as applicable.  
Patients’ medical records and other original data will be archived in accordance with the 
archiving regulations or facilities of the investigational site. 
8.7 
Good Clinical Practice 
The procedures set out in this study protocol are designed to ensure that the Sponsor and 
investigator abide by GCP guidelines of the ICH and the Declaration of Helsinki (1989).  
The study also will be carried out in compliance with local legal requirements. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 108 of 139 
Confidential 
8.8 
Informed Consent 
All information about the clinical study, including the patient information and the ICFs, is 
prepared and used for the protection of the human rights of the patient according to ICH GCP 
guidelines and the Declaration of Helsinki. 
The ICF, prepared by the investigator with the assistance of the Sponsor, must be approved along 
with the study protocol by the IEC/IRB and be acceptable to the Sponsor before any patient is 
enrolled on the study.  Written informed consent will be obtained from each patient according to 
applicable regulatory and legal requirements.  Copies of the signed ICFs will be retained by the 
patient and the original will be filed in the investigator’s study center file, unless otherwise 
agreed by the Sponsor the the study center.  The investigator will not undertake any investigation 
specifically required only for the clinical study until valid consent has been obtained.  The terms 
of the consent and when it was obtained must be documented in the source documents and in the 
eCRF. 
If a protocol amendment is required, the ICFs may need to be revised to reflect the changes to 
the protocol.  If the ICF is revised, it must be reviewed and approved by the appropriate IRB/IEC 
and the revised version signed by all patients subsequently enrolled in the study as well as those 
currently enrolled in the study. 
8.9 
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IRB/IEC, in accordance with local legal requirements.  The Sponsor, Sponsor’s agents, 
and investigator must ensure that all ethical and legal requirements have been met before the first 
patient is enrolled in the study. 
This protocol is to be followed exactly.  To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC approval prior to 
implementation (if appropriate).  Following approval, the protocol amendment will be submitted 
to the IND application under which the study is being conducted. 
8.10 
Study Committee and Central Review 
8.10.1 
Cohort Review Committee  
The Phase 1 safety run-in for this study will have a CRC consisting of representatives from the 
Sponsor, the Medical Monitors and 1 or more investigators from actively participating sites. 
The CRC will assess the safety of the dose escalation (Phase 1) on a regular basis.  All dose 
escalation decisions will be based on assessment of DLTs, overall safety and tolerability, and 
will be made after the last patient enrolled in each cohort has completed the first 2 treatment 
cycles.  In addition, when selecting the dose(s) to be developed further, consideration will be 
made of toxicities observed both during and beyond the DLT evaluation period and assessment 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 109 of 139 
Confidential 
of the proportion of patients who receive planned doses at various dose levels and the percentage 
of patients that required dose reductions and dose discontinuations for toxicity.  
8.10.2 
Data Monitoring Committee 
The study will have a DMC that will operate independently from the Sponsor and the clinical 
investigators.  The primary responsibilities of the DMC are to review the accumulating safety 
data from the Phase 2 study on a regular and ad hoc basis.  In addition, the DMC will review the 
unblinded results of the OS interim analysis along with safety data to balance risk and benefit, 
and make recommendations to the Sponsor based on the data totality.  Safety data from the 
Phase 2 study will be provided at regular intervals to the DMC in the form of unblinded 
summary reports and/or data listings from an independent statistical center designated by the 
Sponsor. 
The first meeting of the DMC is planned to occur after a minimum number of patients 
(ie, 50 patients) have had the opportunity to complete a cycle of study treatment.  Subsequent 
meetings are planned to occur periodically (eg, quarterly) and ad hoc at the request of the DMC 
members or the Sponsor.  Details regarding DMC membership, schedule and format of meetings, 
format for presentation of data, access to interim data, method and timing of providing interim 
reports to the DMC, and other issues relevant to committee operations will be described in the 
DMC charter. 
8.11 
Premature Termination of the Study 
If the investigator, Sponsor, or Medical Monitor becomes aware of conditions or events that 
suggest a possible hazard to patients if the study continues, the study may be terminated. 
The study may also be terminated early at the Sponsor’s discretion in the absence of such a 
finding. 
Conditions that may warrant termination include, but are not limited to: 
• Discovery of an unexpected, significant, or unacceptable risk to the patients enrolled in the 
study 
• Failure to enroll patients at an acceptable rate 
• Decision on the part of the Sponsor to suspend or discontinue development of the drug 
8.12 
Confidentiality 
All study findings and documents will be regarded as confidential.  The investigator and 
members of his/her research team must not disclose such information without prior written 
approval from the Sponsor. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 110 of 139 
Confidential 
The anonymity of participating patients must be maintained.  Patients will be identified on 
eCRFs and other documents submitted to the Sponsor or Sponsor’s designee by their patient 
number, initials, and/or birth date.  Study patients are not to be identified by name, and any 
information sent to the Sponsor or Sponsor’s designee should have patient identifiers redacted 
and replaced with patient numbers.  Documents that include the name of the patient (e.g., the 
signed informed consent) must be maintained in confidence by the investigator.  The investigator 
will take all reasonable precautions to prevent the disclosure by any employee or agent of the 
study center to any third party or otherwise into the public domain. 
8.13 
Other Ethical and Regulatory Issues 
If a significant safety issue is identified, either from an individual case report or review of 
aggregate data, then the Sponsor will issue prompt notification to applicable regulatory 
authorities and investigators.  Investigators will then notify local IRB/IECs as deemed 
appropriate based on individual IRB/IEC policy. 
A significant safety issue is one that has a significant impact on the course of the clinical trial or 
program (including the potential for suspension of the trial program or amendments to protocols) 
or warrants immediate update of informed consent. 
 
 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 111 of 139 
Confidential 
9.0 
REFERENCES  
Ahn, S., J. Lee, M. Hong, et al. (2016). "FGFR2 in Gastric Cancer: Protein Overexpression 
Predicts Gene Amplification and High H-Index Predicts Poor Survival." Modern 
Pathology: 1-9. 
Al-Batran, S.-E., J. T. Hartmann, R. Hofheinz, et al. (2008). "Biweekly Fluorouracil, 
Leucovorin, Oxaliplation. and Docetaxel (FLOT) for Patients with Metastatic 
Adenocarcinoma of the Stomach or Esophagogastric Junction: A Phase II Trial of the 
Arbeitsgemeinschaft Internistische Onkologie " Annals of Oncology 19: 1882-1887. 
Andre, F., M. Ranson, E. Dean, et al. (2013). Abstract LB-145: Results of a Phase I Study of 
AZD4547, an Inhibitor of Fibroblast Growth Factor Receptor (FGFR), in Patients with 
Advanced Solid Tumors. AACR 104th Annual Meeting 2013, Washington, DC, 
American Association of Cancer Research. 
Bang, Y., E. Cutsem, A. Feyereislova, et al. (2010). "Trastuzumab in Combination with 
Chemotherapy Versus Chemotherapy Alone for Treatment of HER2-Positive Advanced 
Gastric or Gastro-Oesophageal Junction Cancer (ToGA): A Phase 3, Open-Label, 
Randomised Controlled Trial." The Lancet 376: 687-697. 
Bron, A., V. Evans and J. Smith (2003). "Grading of Corneal and Conjuctival Staining in the 
Context of Other Dry Eye Tests." Cornea 22(7): 640-650. 
Brown, A. P., C. L. Courtney, L. M. King, et al. (2005). "Cartilage Dysplasia and Tissue 
Mineralization in the Rat Following Administration of a FGF Receptor Tyrosine Kinase 
Inhibitor." Toxicologic Pathology 33: 449-455. 
Catenacci, D., S. Rha, Y.-J. Bang, et al. (2017). "Updated AntiTumor Activity and Safety of 
FPA144, and ADCC-Enhanced Isoform-Specific Monoclonal Antibody, in Patients with 
FGFR2b+ Gastric Cancer." Journal of Clinical Oncology 35(15): 4067. 
Cheeseman, S., S. Joel, J. Chester, et al. (2002). "A 'Modified de Gramont' Regimen of 
Fluorouracil, Alone and With Oxaliplatin, for Advanced Colorectal Cancer." British 
Journal of Cancer 87: 393-399. 
Chen, J., D. Hunter, M. Stampfer, et al. (2003). "Polymorphism in the Thymidylate Synthase 
Promoter Enhancer Region Modifies the Risk and Survival of Colorectal Cancer." Cancer 
Epidemiology, Biomarkers & Prevention 12: 958-962. 
Davidson, M. and I. Chau (2016). "Variations in Outcome for Advanced Gastric Cancer Between 
Japanese and Western Patients: A Subgroup Analysis of the RAINBOW Trial." Transl 
Gastroenterol Hepatol 1(46): 1-4. 
Deshpande, A. M., S. Palencia, D. I. Bellovin, et al. (2014). Expression of FGFR2b in Gastric 
Cancer as Measured by Immunohistochemistry With a Highly Specific Monoclonal 
Antibody. American Association for Cancer Research, San Diego, CA, Five Prime 
Therapeutics, Inc. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 112 of 139 
Confidential 
 
Dienstmann, R., R. Bahleda, A. Barbara, et al. (2014). First in human study of JNJ-42756493, a 
potent pan fibroblast growth factor receptor (FGFR) inhibitor in patients with advanced 
solid tumors. AACR 105th Annual Meeting, San Diego, CA. 
Ford, H., A. Marshall, J. Bridgewater, et al. (2014). "Docetaxel Versus Active Symptom Control 
for Refractory Oesophagogastric Adenocarcinoma (COUGAR-02): An Open-Label, 
Phase 3 Randomised Controlled Trial." Lancet Oncology 15: 78-86. 
Fuchs, C., T. Doi, R. Jang, et al. (2017). "KEYNOTE-059 Cohort 1: Efficacy and Safety of 
Pembrolizumab (Pembro) Monotherapy in Patients with Previously Treated Advanced 
Gastric Cancer." Journal of Clinical Oncology 35(15): 4003. 
Fuchs, C., J. Tomasek, C. Yong, et al. (2014). "Ramucirumab Monotherapy for Previously 
Treated Advanced Gastric or Gastro-Oesophageal Junction Adenocarcinoma 
(REGARD): an International, Randomised, Multicentre, Placebo-Controlled, Phase 3 
Trial." Lancet Oncology 383: 31-39. 
Gemo, A., A. Deshpande, S. Palencia, et al. (2014). FPA144: A Therapeutic Antibody for 
Treating Ptients with Gastric Cancers Bearing FGFR2 Gene Amplification. AACR 105th 
Annual Meeting 2014, San Diego California. 
GlaxoSmithKline (2017). "Study to Evaluate GSK3052230 in Combination with Paclitaxel and 
Carboplatin, or Docetaxel or as Single Agent in Subjects with Solid Malignancies and 
Deregulated Fibroblast Growth Factor (FGF) Pathway Signaling ". from 
https://clinicaltrials.gov/ct2/show/NCT01868022?term=NCT01868022&rank=1. 
Gravalos, C. and A. Jimeno (2008). "HER2 in Gastric Cancer: A New Prognostic Factor and a 
Novel Therapeutic Target." Annals of Oncology 19: 1523-1529. 
Hall, T., Y. Yu, S. Eathiraj, et al. (2016). "Preclinical Activity of ARQ 087, a Novel Inhibitor 
Targeting FGFR Dysregulation." PLoS ONE 11(9): 1-19. 
Hattori, Y., H. Itoh, S. Uchino, et al. (1996). "Immunohistochemical Detection of K-sam Protein 
in Stomach Cancer." Clinical Cancer Research 2: 1373-1381. 
Hattori, Y., H. Odagiri, H. Nakatani, et al. (1990). "K-sam, an Amplified Gene in Stomach 
Cancer, is a Member of the Heparin-Binding Growth Factor Receptor Genes." 
Proceedings of the National Academy of Sciences (PNAS) 87: 5983-5987. 
Hochster, H., L. Hart, R. K. Ramanathan, et al. (2008). "Safety and Efficacy of Oxaliplatin and 
Fluoropyrimidine Regimens with or without Bevacizumab As First-Line Treatment of 
Metastatic Colorectal Cancer: Results of the TREE Study." Journal of Clinical Oncology 
26(21). 
Hofmann, M., O. Stoss, D. Shi, et al. (2008). "Assessment of a HER2 Scoring System for Gastric 
Cancer: Results from a Validation Study." Histopathology 52: 797-805. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 113 of 139 
Confidential 
Jung, E., E. Jung , S. Min, et al. (2012). "Fibroblast Growth Factor Receptor 2 Gene 
Amplification Status and its Clinicopathologic Significance in Gastric Carcinoma." 
Human Pathology 43(10): 1559-1566. 
Kamangar, F., G. Dores and W. Anderson (2006). "Patterns of Cancer Incidence, Mortality, and 
Prevalence Across Five Continents: Defining Priorities to Reduce Cancer Disparities in 
Different Geographic Regions of the World." Journal of Clinical Oncology 24(14): 2137-
2150. 
Kang, Y.-K., W.-K. Kang, D.-B. Shin, et al. (2009). "Capecitabine/Cisplatin Versus 5-
Fluorouracil/Cisplatin as First-Line Therapy in Patients with Advanced Gastric Cancer: A 
Randomised Phase III Noninferiority Trial." Annals of Oncology 20: 666-673. 
Kang, Y., N. Boku, T. Satoh, et al. (2017). "Nivolumab in Patients with Advanced Gastric or 
Gastro-Oesophageal Junction Cancer Refractory to or Intolerant of, at Least Two 
Previous Chemotherapy Regimens (ONO-4538-12, ATTRACTION-2): A Randomised, 
Double-Blind, Placebo-Controlled, Phase 3 Trial." The Lancet 390: 2461-2471. 
Keam, B., S.-A. Im, S.-W. Han, et al. (2008). "Modified FOLFOX-6 Chemotherapy in 
Advanced Gastric Cancer: Results of Phase II Study and Comprehensive Analysis of 
Polymorphisms as A Predictive and Prognostic Cancer." BMC Cancer 8(148): 1-10. 
Kim, D., J. Kim, S.-H. Lee, et al. (2003). "Phase II Study of Oxaliplatin, 5- Fluorouracil and 
Leucovorin in Previously Platinum-Treated Patients with Advanced Gastric Cancer." 
Annals of Oncology 14: 383-387. 
Li, B., L. Zhao, H. Guo, et al. (2009). "Characterization of a Rituximab Variant with Potent 
Antitumor Activity Against Rituximab-Resistant B-Cell Lymphoma." Blood 114(24): 
5007-5015. 
Matsumoto, K., T. Arao, T. Hamaguchi, et al. (2012). "FGFR2 Gene Amplification and 
Clinicopathological Features in Gastric Cancer " British Journal of Cancer 106(4): 727-
732. 
Miki, T., D. P. Bottaro, T. P. Fleming, et al. (1992). "Determination of Ligand-Binding 
Specificity by Alternative Splicing: Two Distinct Growth Factor Receptors Encoded by a 
Single Gene." Proceedings of the National Academy of Sciences 69: 246-250. 
National Cancer Institute (2015). "SEER Stat Fact Sheets: Stomach Cancer." Retrieved February 
25, 2016, from http://seer.cancer.gov/statfacts/html/stomach.html. 
Ohtsu, A., M. Shah, E. Van Cutsem, et al. (2011). "Bevacizumab in Combination with 
Chemotherapy As First-Line Therapy in Advanced Gastric Cancer: A Randomized, 
Double-Blind, Placebo-Controlled Phase III Study." Journal of Clinical Oncology 29(30): 
3968-3976. 
Ohtsu, A., S. Yoshida and N. Saijo (2006). "Disparities in Gastric Cancer Chemotherapy 
Between the East and West " Journal of Clinical Oncology 24(14): 2188-2196. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 114 of 139 
Confidential 
Okines, A., A. Norman, P. McCloud, et al. (2009). "Meta-Analysis of the REAL-2 and 
ML17032 Trials: Evaluating Capecitabine-Based Combination Chemotherapy and 
Infused 5-Fluorouracil-Based Combination Chemotherapy for the Treatment of 
Advanced Oesphago- Gastric Cancer." Annals of Oncology 20(9): 1529-1534. 
Powers, J., S. Palencia, S. Foy, et al. (2016). "FPA144, A Therapeutic Monoclonal Antibody 
Targeting the FGFR2b Receptor, Promotes Antibody Dependent Cell-Mediated 
Cytotoxicity and Stimulates Sensitivity to PD-1 Blockade in the 4T1 Syngeneic Tumor 
Model in Mice." 1. 
Pullarkat, S., J. Stoehlmacher, V. Ghaderi, et al. (2001). "Thymidylate Synthase Gene 
Polymorphism Determines Response and Toxicity of 5-FU Chemotherapy." The 
Pharmacogenics Journal 1: 65-70. 
Sawaki, A., Y. Ohashi, Y. Omuro, et al. (2011). "Efficacy of Trastuzumab in Japanese Patients 
with HER2-Positive Advanced Gastric or Gastroesophageal Junction Cancer: A 
Subgroup Analysis of the Trastuzumab for Gastric Cancer (ToGA) Study." Gastric 
Cancer 15: 313-322. 
Seo, S., S. Park, M. Ryu, et al. (2016). "Prognostic Impact of Fibroblast Growth Factor Receptor 
2 Gene Amplification in Patients Receiving Fluoropyrimidine and Platinum 
Chemotherapy for Metastatic and Locally Advanced Unresectable Gastric Cancers." 
Oncotarget: 1-11. 
Sequist, L. V., P. Cassier, A. Varga, et al. (2014). Phase I Study of BGJ398, a Selective Pan-
FGFR Inhibitor in Genetically Preselected Advanced Solid Tumors. AACR 2014 Annual 
Meeting, San Diego, CA. 
Shinkawa, T., K. Nakamura, N. Yamane, et al. (2003). "The Absence of Fucose but Not the 
Presence of Galactose or Bisecting N-Acetylglucosamine of Human IgG1 Complex-type 
Oligosaccharides Shows the Critical Role of Enhancing Antibody-dependent Cellular 
Cytotoxicity." THe Journal of Biological CHemisty 278(5): 3466-3473. 
Smyth, E., M. Verheij, W. Allum, et al. (2016). "Gastric Cancer: ESMO Clinical Practice 
Guidelines for Diagnosis, Treatment, and Follow-up " Annals of Oncology 27(5): v38-
v49. 
Su, X., P. Zhan, P. Gavine, et al. (2014). "FGFR2 Amplification has Prognostic Significance in 
Gastric Cancer: Results From a Large International MultiCentre Study " British Journal 
of Cancer 110: 967-975. 
Taiho Oncology Inc (2015). "A Dose Finding Study Followed by a Safety and Efficacy Study in 
Patients with Advanced Solid Tumors or Multiple Myeloma with FGF/FGFR-Related 
Abnormalities." from 
https://clinicaltrials.gov/ct2/show/NCT02052778?term=NCT02052778&rank=1. 
Teva Parenteral Medicines Inc (2014). "Leucovorin Calcium for Injection Package Insert." 1-13. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 115 of 139 
Confidential 
Teva Parenteral Medicines Inc (2016). "ADRUCIL- Highlights of Prescribing Information." 1-
12. 
Teva Pharmaceuticals USA (2012). "Oxaliplatin: Highlights of Prescribing Information." 1-43. 
Teva Pharmaceuticals USA Inc (2016). "Warfarin Sodium Highlights of Prescribing 
Information." 1-51. 
The GASTRIC Group (2010). "Benefit of Adjuvant Chemotherapy for Resectable Gastric 
Cancer." JAMA 303(1729-1737): 1729. 
Thuss-Patience, P., A. Kretzschmar, D. Bichev, et al. (2011). "Survival Advantage for Irinotecan 
Versus Best Supportive Care as Second-Line Chemotherapy in Gastric Cancer- A 
Randosmied Phase III Study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)." 
European Journal of Cancer 47: 2306-2314. 
Tournigand, C., T. Andre, E. Achille, et al. (2004). "FOLFIRI Followed by FOLFOX6 or the 
Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study." 
Journal of Clinical Oncology 22(2): 229-237. 
Turner, N. and R. Grose (2010). "Fibroblast Growth Factor Signalling: From Development to 
Cancer." Nature 10: 116-129. 
Ulrich, C., J. Bigler, C. Velicer, et al. (2000). "Searching Expressed Sequence Tag Databases: 
Discovery and Confirmation of a Common Polymorphism in the Thymidylate Synthase 
Gene." Cancer Epidemiology, Biomarkers & Prevention 9: 1381-1385. 
van Hazel, G., V. Heinemann, N. Sharma, et al. (2016). "SIRFLOX: Randomized Phase III Trial 
Comparing First-Line mFOLFOX6 (Plus or Minus Bevacizumab) Versus mFOLFOX6 
(Plus or Minus Bevacizumab) Plus Selective Internal Radiation Therapy in Patients with 
Metastatic Colorectal Cancer." Journal of Clinical Oncology 34(15): 1723-1731. 
Waddell, T., M. Verheij, W. Allum, et al. (2014). "Gastric Cancer: ESMO-ESSO-ESTRO 
Clinical Practice Guidelines for Diagnosis, Treatment, and Follow-up " Radiotherapy and 
Oncology 110: 189-194. 
Wagner, A., W. Grothe, J. Haerting, et al. (2006). "Chemotherapy in Advanced Gastric Cancer: 
A Systematic Review and Meta-Analysis Based on Aggregrate Date." Journal of Clinical 
Oncology 24(18): 2903-2909. 
Wilke, H., K. Muro, E. Custem, et al. (2014). "Ramucirumab Plus Paclitaxel Versus Placebo 
Plus Paclitaxel in Patients with Previously Treated Advanced Gastric or Gastro-
Oesophageal Junction Adenocarcinoma (RAINBOW): A Double-Blind, Randomised 
Phase 3 Trial." Lancet Oncology 15: 1224-1235. 
Wu, Y.-M., F. Su, S. Kalyana-Sundaram, et al. (2013). "Identifi cation of Targetable FGFR Gene 
Fusions in Diverse Cancers." Cancer Discovery 3(6): 636-647. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 116 of 139 
Confidential 
Zhao, X., S. Singh, C. Pardoux, et al. (2010). "Targeting C-type Lectin-Like Molecule-1 for 
Antibody-Mediated Immunotherapy in Acute Myeloid Leukemia." Haematologica 95(1): 
71-78. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 117 of 139 
Confidential 
10.0 
APPENDICES 
Appendix 1: 
Formulas to Calculate Renal Function .................................................................118 
Appendix 2: 
Schedule of Assessments: Dose-Escalation Safety Run-in (Phase 1) .................119 
Appendix 3: 
Schedule of Assessments: Randomized, Placebo-Controlled Portion 
(Phase 2)...............................................................................................................123 
Appendix 4: 
Laboratory Evaluations ........................................................................................128 
Appendix 5: 
Clinical Fixed Time Point Assessments ..............................................................129 
Appendix 6: 
Study Flowchart for Pharmacokinetic, Immunogenicity, and 
 
 for Phase 1 ................131 
Appendix 7: 
Study Flowchart for FPA144 Pharmacokinetic and Immunogenicity Blood 
Sample Collections for Phase 2 ...........................................................................133 
Appendix 8: 
ECOG Performance Status ..................................................................................134 
Appendix 9: 
Fluorescein Stain Grading Systems .....................................................................135 
 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 118 of 139 
Confidential 
APPENDIX 1: 
FORMULAS TO CALCULATE RENAL FUNCTION  
Renal function should be determined using either the Cockcroft Gault formula or the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) formula.  
Cockcroft Gault formula:  
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶=
(140−𝑎𝑎𝑎𝑎𝑎𝑎)∗𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡
72∗𝑆𝑆𝑆𝑆𝑆𝑆
(∗0.85 𝑖𝑖𝑖𝑖 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓) 
Abbreviations/Units: age in years; weight in kg; SCr = serum creatinine in mg/dL.  
  
CKD-EPI formula: 
eGFR = 141 x min(SCr/κ, 1)α x max(SCr /κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 
[if Black] 
Abbreviations/Units: eGFR (estimated glomerular filtration rate) = mL/min/1.73 m2; SCr = standardized 
serum creatinine in mg/dL; κ = 0.7 (females) or 0.9 (males); α = -0.329 (females) or -0.411 (males); 
min = indicates the minimum of SCr. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 119 of 139 
Confidential 
APPENDIX 2: 
SCHEDULE OF ASSESSMENTS: DOSE-ESCALATION SAFETY RUN-IN (PHASE 1)  
Procedurea 
Screening 
Study Treatment Period: 
Cycles 1 and 2 
Study Treatment Period: 
Cycle 3, Cycle 4 and Subsequent Cycles 
Day --28 to 
Day 0 
Cycle 1 
Day 1 
Cycle 1 
Day 3 
Cycle 1 
Day 8 
Cycle 2 
Day 1 
Cycle 2 
Day 3 
Cycle 3b 
Day 1 
Cycle 4c 
Day 1 
Clinical Fixed 
Time Point 
Assessmentsd 
As 
Clinically 
Indicated 
Other 
Time 
Points 
EOTe,f 
Week 0 
Week 1 Week 1 Week 2 Week 3 Week 3 
≥Week 4 
Archival Tissue Provided for 
IHC (if available)g 
X 
 
 
 
 
 
 
 
 
 
 
 
Sample for ctDNA Blood 
Assayh 
 
X 
 
 
 
 
 
 
 
 
 
 
Informed Consenti 
X 
 
 
 
 
 
 
 
 
 
 
 
Review/Confirm Eligibility 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/Oncology and 
Medication History 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demography/Baseline 
Characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationj,k  
Xj 
X 
 
X 
X 
 
X 
X 
 
 
 
X 
ECOG Performance Statusl 
X 
 
 
 
 
 
Xl 
 
 
 
Xl 
X 
Vital Signsm 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
12-lead ECGn 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Comprehensive 
Ophthalmologic Examination 
(including Slit Lamp)o  
X 
 
 
 
 
 
 
 
Xd,o 
X 
Xo 
X 
Slit Lamp Examinationp  
 
 
 
 
 
 
 
 
Xd,p 
 
Xp 
 
Clinical Safety Laboratory 
Samplingq 
Xq 
Xq 
 
X 
Xq 
 
Xq 
Xq 
 
X 
 
X 
Pregnancy Testr 
Xr 
Xr 
 
 
 
 
Xr 
 
 
X 
Xr 
X 
Urinalysiss 
X 
X 
 
 
 
 
Xs 
 
 
X 
Xs 
X 
PK Samplest 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
Immunogenicity Samplingu 
 
X 
 
 
X 
 
X 
 
 
 
X 
X 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 120 of 139 
Confidential 
APPENDIX 2: 
SCHEDULE OF ASSESSMENTS: DOSE-ESCALATION SAFETY RUN-IN (PHASE 1) (CONTD) 
Procedurea 
Screening 
Study Treatment Period: 
Cycles 1 and 2 
Study Treatment Period: 
Cycle 3, Cycle 4 and Subsequent Cycles 
Day --28 to 
Day 0 
Cycle 1 
Day 1 
Cycle 1 
Day 3 
Cycle 1 
Day 8 
Cycle 2 
Day 1 
Cycle 2 
Day 3 
Cycle 3b 
Day 1 
Cycle 4c 
Day 1 
Clinical Fixed 
Time Point 
Assessmentsd 
As 
Clinically 
Indicated 
Other 
Time 
Points 
EOTe,f 
Week 0 
Week 1 Week 1 Week 2 Week 3 Week 3 
≥Week 4 
FPA144 Administrationj,w,x 
 
X 
 
Xx 
X 
 
X 
X 
 
 
 
 
mFOLFOX6 Administrationy 
 
X 
 
 
X 
 
X 
X 
 
 
 
 
Adverse Eventsz 
Xz 
X ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– X 
Concomitant Medications 
X 
X ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– X 
Note: A cycle of treatment is 2 weeks. 
a 
Unless specified, procedure is to be completed within ± 72 hours of scheduled time point and to be synchronized with the study treatment administration day. 
b 
And subsequent odd cycles beyond Cycle 3 (except for PK, immunogenicity, and pharmacodynamic blood sample collections, which are described in 
Appendix 6). 
c 
And subsequent even cycles beyond Cycle 4 (except for PK, immunogenicity, and pharmacodynamic blood sample collections, which are described in 
Appendix 6).  
d 
Clinical Fixed Time Point Assessments should be completed as originally scheduled from C1D1 regardless of dosing days or dose delays. Refer to 
Appendix 5 for collection days. 
e 
EOT assessments should be performed approximately 28 (+3) days following the last study treatment administration 
f 
For the first 6 months after the EOT visit, any pregnancy that occurs should be reported to the Sponsor. 
g 
Tumor tissue collection from archival material (if available) for retrospective IHC analysis of FGFR2b overexpression by IHC upon eligibility confirmation. 
h 
Sample for ctDNA blood assay will be collected prior to the first dose of study treatment (Cycle 1 Day 1; C1D1) and analyzed retrospectively for FGFR2 
gene amplification.  
i 
Written, signed informed consent must be collected prior to any study-specific procedures.  The most recent IRB/EC approved ICF must be signed. 
j 
Complete physical examination including height and weight will be measured at Screening only.  Limited physical examinations should be conducted, 
including weight and examination of the oropharynx, thereafter. 
k 
After Cycle 1, the FPA144 should be recalculated only if the weight changes > 10% from the C1D1 weight. If the dose is recalculated due to a >10% weight 
change from C1D1, the weight used for the recalculated dose should function as the new baseline for subsequent evaluation of dose recalculations.  Doses 
should be rounded to the nearest 10 mg. 
l 
ECOG Performance Status will be assessed at Cycle3 Day 1 and Day 1 of every other subsequent cycle (odd cycles) until the EOT visit. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 121 of 139 
Confidential 
m 
Vital signs (blood pressure, heart rate, respiration, and temperature [°C]) are to be measured after 5 minutes of rest, at one time at the Screening visit and 
Cycle 1 Day 3, Cycle 2 Day 3, EOT and as clinically indicated.  On C1D1 (all cohorts), and Cycle 1 Day 8 (Cohort 2 only) vital sign measurements should be 
at the following time points: Predose, and 0.5, 1, 2, and 4 hours from the start of the FPA144 infusion.  On subsequent dosing days, vital sign measurements 
should be predose and at 0.5, 1, and 2 hours from the start of FPA144 infusion.  
n 
12-lead ECG after patient rests for 5 minutes prior to recording. 
o 
Comprehensive ophthalmologic examinations (conducted at Screening, at 4 weeks from C1D1, at 8 weeks from C1D1, and at the EOT visit only, ±7 days) 
include fundoscopic and slit lamp examination (with fluorescein staining score form), ocular coherence tomography (OCT), visual acuity, completion of 
fluorescein staining score form, determination of intraocular pressure, and review of ocular/visual symptoms.  The comprehensive ophthalmologic 
examination will be repeated at any time if clinically indicated when changes in visual acuity or visual symptoms are reported by patients up to 100 days after 
the last dose of FPA144. After the EOT visit if the patient has any persistent ophthalmologic findings, the assessments should continue every 8 weeks until 
resolution of findings, withdrawal of consent, death, or loss to follow up.  All abnormal OCT examinations should be submitted to the Sponsor. 
p 
Slit lamp examinations alone, (with completion of fluorescein staining score form), should be conducted for all patients starting at approximately week 16 and 
then every 8 weeks through EOT visit and at any time if clinically indicated including after the EOT visit.  After the EOT visit if the patient has any persistent 
corneal findings, the assessments should continue every 8 weeks until resolution of findings, withdrawal of consent, death, or loss to follow up.  
q 
Blood tests (evaluated by local laboratories) are listed in Appendix 4.  Baseline hematology and blood chemistry test results must be obtained within 96 hours 
prior to enrollment.  On subsequent dosing days, for both FPA144 or mFOLFOX6, hematology and blood chemistry results must be obtained within 72 hours 
prior to the start of dosing.  Coagulation results need to be obtained at baseline, at Day 1 of Cycles 1 through 4 within 72 hours prior to dosing with FPA144, 
and at any time clinically indicated (eg, patients on anticoagulant therapy requiring close monitoring).  Hematology, blood chemistry and coagulation samples 
are collected at the EOT visit. 
r 
Serum ß-hCG (evaluated by local laboratories) will be performed on all women of childbearing potential at Screening within 96 hours prior to enrollment and 
when clinically indicated.  If serum B-hCG test is performed at Screening and is not within 96 hours prior to enrollment, the test must be repeated to confirm 
the patient is not pregnant.  Urine pregnancy tests and results are required on Day 1 for subsequent odd cycles (every other cycle) for both FPA144 and 
mFOLFOX6 prior to dosing.  Urine pregnancy tests are also required at EOT. 
s 
Includes protein, glucose, blood, pH, and ketones on Day 1 for both FPA144 and mFOLFOX6 of odd cycles (every other cycle).  If findings are clinically 
significant, a microscopic evaluation will be performed per institutional standard. 
t 
Blood samples for PK analysis. Refer to Appendix 6 for collection times.  
u 
Blood samples for anti-FPA144 antibodies. Refer to Appendix 6 for collection times. 
v 
w 
FPA144 is administered Q2W as a 30-minute infusion starting C1D1.  The first 3 doses (cycles) of FPA144 should be administered Q2W (±3 days) regardless 
of delays in mFOLFOX6 treatment.  After the first 3 doses, FPA144 may be delayed up to 7 days to be synchronized with administered mFOLFOX6.  
x 
FPA144 is administered only for Cohort 2 at Cycle 1 Day 8; subsequent cycles for Cohort 2 do not receive Day 8 study treatment.  No other dose levels 
receive a Cycle 1 Day 8 FPA144 administration. 
y 
mFOLFOX6 is administered Q2W at least 30 minutes after FPA144 as a continuous IV infusion over approximately 48 hours, starting on Day 1 and 
completing on Day 3. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 122 of 139 
Confidential 
z 
AE collection begins after signing of the ICF for Screening.  Events reported prior to the first on-study infusion will be considered pretreatment events and 
reported on the Medical History page of the eCRF, unless they directly correlate to a study-related procedure.  Adverse event reporting will continue until 
completion of the EOT visit or 28 days after the last dose of study treatment.  SAE reporting will initiate at study enrollment unless the event is related to a 
study procedure.  All treatment-related SAEs will be monitored until the event has resolved or stabilized, any abnormal laboratory values have returned to 
baseline or stabilized at a level acceptable to the investigator and Sponsor, there is a satisfactory explanation for the changes observed, or the patient is lost to 
follow-up.  Serious AEs occurring after the EOT visit and ophthalmological events of any grade occurring up to 100 days after EOT visit should be reported 
to the Sponsor if the investigator considers there is a causal relationship with the study treatment. 
 
 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 123 of 139 
Confidential 
APPENDIX 3: 
SCHEDULE OF ASSESSMENTS: RANDOMIZED, PLACEBO-CONTROLLED PORTION (PHASE 2) 
Procedurea 
Pre-
Screening 
Screening 
Study Treatment: 
Cycles 1 and 2 
Study Treatment: 
Cycle 3, Cycle 4 and Subsequent Cycles 
EOTe 
Follow-up 
Scans 
Follow-upff 
Long 
Term 
Follow 
Upg 
Day 
-28 to Day 0 
Cycle 1 
Day 1 
Cycle 1 
Day 8 
Cycle 2 
Day 1 
Cycle 3b 
Day 1 
Cycle 4c 
Day 1 
Clinical Fixed 
Time Points 
Assessmentsd 
As 
Clinically 
Indicated 
Other 
Time 
Points 
Week 0 
Week 1 
Week 2 
Week 3 
≥Week 4 
 
 
 
 
 
 
 
Pre-Screening Informed 
Consenth 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IHC Analysis of FGFR2b 
Overexpressioni 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Sample for Blood-Based 
(ctDNA) Assayj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consentk 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Review/Confirm 
Eligibility Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/Oncology and 
Medication History 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demography/Baseline 
Characteristics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationl 
 
Xl 
X 
X 
X 
X 
X 
 
 
 
X 
X 
 
ECOG Performance 
Statusn 
 
X 
 
 
 
Xn 
 
 
 
Xn 
X 
 
 
Patient-Reported 
Outcomes (EQ-5D-5L and 
the EORTC QLQ-C30)o 
 
X 
 
 
 
 
Xo 
 
 
Xo 
X 
 
 
Vital Signsp 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
12-lead ECGq 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
Comprehensive 
Ophthalmologic 
Examination (including 
Slit Lamp) r 
 
X 
 
 
 
 
 
Xd,r 
X 
Xr 
X 
 
 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 124 of 139 
Confidential 
APPENDIX 3: 
SCHEDULE OF ASSESSMENTS: RANDOMIZED, PLACEBO-CONTROLLED PORTION (PHASE 2) 
(CONTD) 
Procedurea 
Pre-
Screening 
Screening 
Study Treatment: 
Cycles 1 and 2 
Study Treatment: 
Cycle 3, Cycle 4 and Subsequent Cycles 
EOTe 
Follow-up 
Scans 
Follow-upff 
Long 
Term 
Follow 
Upg 
Day 
-28 to Day 0 
Cycle 1 
Day 1 
Cycle 1 
Day 8 
Cycle 2 
Day 1 
Cycle 3b 
Day 1 
Cycle 4c 
Day 1 
Clinical Fixed 
Time Points 
Assessmentsd 
As 
Clinically 
Indicated 
Other 
Time 
Points 
Week 0 
Week 1 
Week 2 
Week 3 
≥Week 4 
 
 
 
 
 
 
 
Slit Lamp Examinationt  
 
 
 
 
 
 
 
Xd,t 
 
Xt 
 
 
 
Clinical Safety Laboratory 
Samplingu 
 
X 
Xu 
X 
Xu 
Xu 
Xu 
 
X 
 
X 
 
 
Pregnancy Testv 
 
Xv 
Xv 
 
 
Xv 
 
 
X 
Xv 
X 
 
 
Urinalysisw 
 
X 
X 
 
 
Xw 
 
 
X 
Xw 
X 
 
 
Radiological/Tumor 
Assessmentx 
 
X 
 
 
 
 
 
Xff 
 
Xx 
Xs 
X 
 
Randomizationy 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Survival Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Immunogenicity 
Samplingz 
 
 
X 
 
 
X 
 
 
 
Xz 
X 
 
 
PK Samplesaa 
 
 
X 
 
 
X 
 
 
 
Xaa 
X 
 
 
mFOLFOX6 
Administrationbb 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
FPA144  
Administrationm,y,cc 
 
 
X 
Xf 
X 
X 
X 
 
 
 
 
 
 
Adverse Eventsdd 
 
Xdd 
Xdd 
   X –––––––––––––––––––-----––––––––––––––––––––––––––– X 
Xdd 
Xdd 
Concomitant 
Medicationsee 
 
X 
X 
   X–––––––––––––––––––––––––––––––––––––––––––––––––––X  
X 
Xee 
A cycle of treatment is 2 weeks 
a 
Unless specified, procedure is to be completed within ± 72 hours of scheduled time point and to be synchronized with the study treatment administration day. 
b 
And subsequent odd cycles from Cycle 3 (except for PK, immunogenicity, and pharmacodynamic blood sample collections, which are described in Appendix 7). 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 125 of 139 
Confidential 
c 
And subsequent even cycles from Cycle 4 (except for PK, immunogenicity, and pharmacodynamic blood sample collections, which are described in Appendix 7). 
d 
Clinical Fixed Time Point Assessments should be completed as originally scheduled from C1D1 regardless of dosing days or dose delays. Refer to Appendix 5 
for collection days. 
e 
EOT assessments should be performed 28 (+14) days following the last study treatment administration.  In Phase 2, after discontinuation of study treatment for 
reasons other than disease progression or withdrawal of consent, tumor assessments will continue until the patient initiates additional anticancer therapy or 
progresses. 
f 
One dose of FPA144 is administered at 7.5 mg/kg on Cycle 1 Day 8 only; subsequent cycles do not receive Day 8 study treatment.  For all other dose levels, no 
FPA144 administration on Cycle 1 Day 8. 
g 
Patients will complete LTFU for survival approximately every 3 months ± 1 month after the EOT visit until up to 24 months after the last patient is enrolled in the 
study, or until death, loss to follow-up, withdrawal of consent or study termination by the Sponsor (whichever occurs first) (refer to Section 6.19).  
h 
Informed consent must be obtained prior to obtaining blood for ctDNA and provision of tumor sample (refer to Section 1.8) 
i 
Provision of archival tissue (or fresh biopsy if archival tissue is not available) for pre-screening FGFR2b overexpression testing by IHC is required. FGFR2 
positive status by IHC or ctDNA testing methods is required for enrollment in Phase 2. 
j 
Sample for blood-based biopsy (ctDNA) assay at Pre-Screening for prospective analysis of FGFR2 gene amplification (refer to Appendix 7).  FGFR2 positive 
status by IHC or ctDNA testing methods is required for enrollment in Phase 2.   
k 
Written, signed informed consent must be collected prior to study related screening procedures.  The most recent IRB/EC approved ICF must be signed.  Patients 
who have fully consented to participation in the study will undergo screening assessments within 28 days prior to enrollment. 
l 
Complete physical examination including height and weight will be measured at screening only.  Limited physical examinations should be conducted, including 
weight and examination of the oropharynx, thereafter. 
m 
After Cycle 1, the FPA144 dose should be recalculated only if the weight changes > 10% from the C1D1 weight.  If the dose is recalculated due to a >10% weight 
change from C1D1, the weight used for the recalculated dose should function as the new baseline for subsequent evaluation of dose recalculations.  Doses should 
be rounded to the nearest 10 mg. 
n 
ECOG Performance Status will be assessed at Screening, Cycle 3 Day 1 and Day 1 of every other subsequent cycle (odd cycles), and at the EOT visit. 
o 
The EQ-5D-5L and the EORTC QLQ-C30 will be collected at Screening (within 28 days of C1D1), prior to dosing on Cycle 4 Day 1, every 8 weeks until EOT, 
and at the EOT visit.  
p 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature) are to be measured, after 5 minutes of rest, at one time at the Screening visit, EOT and as 
clinically indicated.  On C1D1, vital sign measurements should be at the following time points: Pre-dose, and 0.5, 1, 2, and 4 hours from the start of FPA144 
infusion.  On subsequent dosing days, vital sign measurements should be measured at the following time points: Predose and at 0.5, 1, and 2 hours from the start 
of FPA144 infusion. 
q 
12-lead ECG after patient rests for 5 minutes prior to recording. 
r 
Comprehensive ophthalmologic examinations (conducted at Screening, at 8 weeks from C1D1 (±7 days), and at the EOT visit only (±7 days), include 
fundoscopic and slit lamp examination (with fluorescein staining score form), ocular coherence tomography (OCT), visual acuity, completion of fluorescein 
staining score form, determination of intraocular pressure, and review of ocular/visual symptoms.  The comprehensive ophthalmologic examination will be 
repeated at any point if clinically indicated when changes in visual acuity or visual symptoms are reported by patients up to 100 days after the last dose of 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 126 of 139 
Confidential 
FPA144.  After the EOT visit if the patient has any persistent ophthalmologic findings, the assessments should continue every 8 weeks until resolution of 
findings, withdrawal of consent, death, or loss to follow up.  All abnormal OCT examinations should be submitted to the Sponsor. 
s 
This scan can be omitted if the last scan was performed < 8 weeks prior to EOT visit or if tumor progression was previously determined.  
t 
Slit lamp examinations (with completion of fluorescein staining score form), should be conducted for all patients starting at Week 16 from C1D1 then every 
8 weeks through EOT visit and at any time if clinically indicated including after the EOT visit.   After the EOT visit if the patient has any persistent corneal 
findings, the assessments should continue every 8 weeks until resolution of findings, withdrawal of consent, death, or loss to follow up. 
u 
Blood tests (evaluated by local laboratories) are listed in Appendix 4.  Screening hematology and blood chemistry test results must be obtained within 96 hours of 
enrollment.  On dosing days for both FPA144/placebo and mFOLFOX6, hematology and blood chemistry results must be obtained within 72 hours prior to 
dosing.  Coagulation results need to be obtained at Screening, at Day 1 of Cycles 1 through 4 within 72 hours prior to dosing with FPA144, and at any time 
clinically indicated (eg, patients on anticoagulant therapy requiring close monitoring).  Hematology, blood chemistry and coagulation samples are collected at 
EOT. 
v 
Serum ß-hCG (evaluated by local laboratories) will be performed on all women of childbearing potential at Screening within 96 hours prior to enrollment and 
when clinically indicated.  If serum B-hCG test is performed at Screening and is not within 96 hours prior to enrollment, the test must be repeated to confirm the 
patient is not pregnant.  Urine pregnancy tests and results are required on Day 1 for subsequent odd cycles (every other cycle) for both FPA144/placebo and 
mFOLFOX6 prior to dosing.  Urine pregnancy tests are also required at EOT. 
w 
Includes protein, glucose, blood, pH, and ketones on Screening, C1D1, dosing days of odd cycles (every other cycle), and EOT.  If findings are clinically 
significant, a microscopic evaluation will be performed per institutional standard.  
x 
Radiological/tumor assessments will be performed within 28 days (+3 days) prior to start of treatment (C1D1) and including clinical examination and appropriate 
imaging techniques (preferably CT scans with appropriate slice thickness per RECIST v1.1; MRIs are acceptable); imaging performed as standard of care that 
includes imaging of chest, abdomen and pelvis may be used if it has been performed within 28 days (+3 days) of treatment (C1D1).  Tumor scans will be 
performed at Screening (within 28 days [+3 days] of Cycle 1 Day 1), then every 8 weeks from Cycle 1 Day 1 (± 7 days) until 12 months and then every 12 weeks 
(± 14 days) thereafter.  In Phase 2, after discontinuation of study treatment for reasons other than disease progression or withdrawal of consent, tumor assessments 
will continue until radiographic progression or the initiation of additional anticancer therapy. 
y 
Patients must initiate the first administration of study treatment within 3 days of enrollment. 
z 
Blood samples for anti-FPA144 antibodies. Refer to Appendix 7 for collection times  
aa Blood samples for PK analysis. Refer to Appendix 7 for specific collection times.  
bb mFOLFOX6 is administered Q2W as a continuous IV infusion over approximately 48 hours, starting on Day 1 and completing on Day 3 (if mFOLFOX6 is 
delayed secondary to toxicity, vital signs and clinical laboratory tests need to be performed within 72 hours of its administration). 
cc C1D1 of FPA144 administered by IV infusion over 30 minutes (± 10 minutes) must occur within 3 days of being enrolled.  FPA144 is administered Q2W starting 
C1D1.  The first 3 doses (cycles) of FPA144 should be administered every 14 days (±3 days) regardless of delays in mFOLFOX6 treatment.  After the first 
3 doses, FPA144 may be delayed up to 7 days to be synchronized with administered mFOLFOX6.  


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 127 of 139 
Confidential 
dd AEs should not be reported during the pre-screening period unless they are related to a study procedure, as patients are not yet enrolled on the study at that time.  
AE collection begins following signing of the ICF for Screening.  Events reported prior to the first on-study infusion will be considered pretreatment events and 
reported on the Medical History page of the eCRF, unless they directly correlate to a study-related procedure.  Adverse event reporting will continue until 
completion of the EOT visit or 28 days after the last dose of study treatment.  SAE reporting will initiate at study enrollment unless the event is related to a study 
procedure.  All treatment-related SAEs experienced by a study patient will be monitored until the event has resolved or stabilized, any abnormal laboratory values 
have returned to baseline or stabilized at a level acceptable to the investigator and Sponsor, there is a satisfactory explanation for the changes observed, or the 
patient is lost to follow-up.  SAEs occurring after the EOT visit and ophthalmological events of any grade occurring up to 100 days after EOT visit should be 
reported to the Sponsor by the investigator if the investigator considers there is a causal relationship with the study treatment. 
ee For long term follow up, the only concomitant medication that needs to be collected is anticancer medication. 
ff 
If a patient discontinues study treatment (FPA144 and/or mFOLFOX6) for reasons other than disease progression or withdrawal of consent, they will have follow-
up visits and continue to undergo tumor assessments according to the protocol schedule until radiographic progression or the initiation of additional anticancer 
therapy (at which point the patient would begin the long term follow up for survival). 
 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 128 of 139 
Confidential 
APPENDIX 4: 
LABORATORY EVALUATIONS 
The following laboratory parameters will be determined in accordance with the Schedule of 
Assessments and can be performed locally: 
Hematology: 
 
Complete blood cell (CBC) with differential: 
 
 
white blood cells (WBC) 
platelets  
 
absolute neutrophil count (ANC) 
hemoglobin 
 
neutrophils (%) 
hematocrit 
 
eosinophils (%) 
red blood cells (RBC) 
 
basophils (%)                                                   
 
lymphocytes (%) 
 
monocytes (%) 
Urinalysis: 
 
Appearance, color, pH, specific gravity, ketones, protein, glucose, bilirubin, nitrite, urobilinogen, and occult 
blood 
 
If findings are clinically significant, a microscopic evaluation will be performed per institutional standard. 
Clinical chemistry: 
 
 
albumin                                                                  lactate dehydrogenase (LDH) 
 
alkaline phosphatase 
magnesium 
ALT (SGPT) 
phosphate 
AST (SGOT) 
potassium  
blood urea nitrogen (BUN) or urea 
sodium  
calcium 
total bilirubin 
chloride 
total cholesterol  
creatinine 
total protein 
direct bilirubin 
glucose  
uric acid 
Coagulation: 
 
international normalized ratio (INR) 
 activated partial thromboplastin time (APTT) 
Serum and urine pregnancy testing: 
 
In women of childbearing potential only. 
 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 129 of 139 
Confidential 
APPENDIX 5: 
CLINICAL FIXED TIME POINT ASSESSMENTS 
Clinical Fixed Time Point Assessments should be completed as originally scheduled from 
Cycle 1 Day 1 (C1D1), regardless of dosing days or dose delays.  Cycles are 2 weeks in length. 
Collection days are as follows: 
Procedure:  
Study Treatment Period: 
Cycle 3, Cycle 4 and Subsequent Cycles 
Comprehensive Ophthalmologic 
Examination (including Slit Lamp) 
Should be conducted at: 
Phase 1: 
• 
At Screening (within 28 days of C1D1) 
• 
At 4 weeks from C1D1 
• 
At 8 weeks from C1D1 ±7 days thereafter 
• 
At the EOT visit ±7 days 
Phase 2: 
• 
At Screening (within 28 days of C1D1) 
• 
At 8 weeks from C1D1 ±7 days 
• 
At the EOT visit ±7 days 
For both Phase 1 and Phase 2, should include fundoscopic and slit lamp 
examination (with fluorescein staining score form), ocular coherence 
tomography (OCT), visual acuity, completion of fluorescein staining 
score form, determination of intraocular pressure, and review of 
ocular/visual symptoms.  
The comprehensive ophthalmologic examination should be repeated at 
any time if clinically indicated when changes in visual acuity or visual 
symptoms are reported by patients up to 100 days after the last dose of 
FPA144.  After the EOT visit if the patient has any persistent 
ophthalmologic findings, the assessments should continue every 8 weeks 
until resolution of findings, withdrawal of consent, death, or loss to follow 
up. All abnormal OCT examinations should be submitted to the Sponsor. 
Slit Lamp Examination 
Phase 1 and Phase 2: 
Should be conducted at: 
• 
Week 16 and then every 8 weeks through EOT visit  
• at any time if clinically indicated, including after the EOT visit 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 130 of 139 
Confidential 
APPENDIX 5: 
CLINICAL FIXED TIME POINT ASSESSMENTS (CONTD) 
Procedure:  
Study Treatment Period: 
Cycle 3, Cycle 4 and Subsequent Cycles 
Radiological/Tumor Assessment 
Phase 2 only: 
Should be conducted at: 
• 
At Screening (within 28 days +3 days of treatment C1D1) 
• 
Every 8 weeks from C1D1 ±7 days until 12 months and then every 
12 weeks ±14 days thereafter.  Scans should be obtained per 
schedule regardless of drug interruption or discontinuation. 
• At the EOT visit ±7 days (this scan can be omitted if the last scan 
was performed < 8 weeks prior to EOT visit or if tumor progression 
was previously determined) 
• 
*Scan follow-up visits, if applicable  
Tumor assessments will be performed within 28 days (+3 days) prior to 
start of treatment (C1D1) and including clinical examination and 
appropriate imaging techniques (preferably CT scans with appropriate 
slice thickness per RECIST v1.1; MRIs are acceptable); imaging 
performed as standard of care that includes imaging of chest, abdomen 
and pelvis may be used if it has been performed within 28 days +3 days of 
treatment (C1D1).  
• 
*After discontinuation of study treatment for reasons other than 
disease progression or withdrawal of consent, tumor assessments 
will continue until radiographic progression or the initiation of 
additional anticancer therapy. 
 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 131 of 139 
Confidential 
APPENDIX 6: 
STUDY FLOWCHART FOR PHARMACOKINETIC, 
IMMUNOGENICITY, AND
 
 
OR PHASE 1 
Study Cycle 
Study Day 
Time Point 
Type of Sample 
Cycle 1 
Day 1 
≤ 4 hours prior to infusion 
(predose) 
ctDNA blood assay sample  
FPA144 PK (serum) 
ADA (serum) 
 
 
  
15 (±10) minutes after end of 
infusion 
FPA144 PK (serum) 
4 hours (±60 minutes) after 
end of infusion 
FPA144 PK (serum) 
Day 3 
48 hours (±6 hours) after end 
of infusion 
FPA144 PK (serum) 
 
 
 
Day 8 
168 hours (±1 day) after end 
of infusion 
FPA144 PK (serum) 
Day 8* (Cohort 2 patients 
only)  
≤ 4 hours prior to infusion 
(predose) 
FPA144 PK (serum) 
 
15 (±10) minutes after end of 
infusion 
FPA144 PK (serum) 
 
4 hours (±60 minutes) after 
end of infusion 
FPA144 PK (serum) 
Cycle 2  
Day 1 
≤ 4 hours prior to infusion 
(predose) 
FPA144 PK (serum) 
ADA (serum) 
15 (±10) minutes after end of 
infusion  
FPA144 PK (serum) 
Day 3 
48 hours (±6 hours) after end 
of infusion 
FPA144 PK (serum) 
Cycle 3  
Day 1 
≤ 4 hours prior to infusion 
(predose) 
FPA144 PK (serum) 
ADA (serum)  
 
 
y 
15 (±10) minutes after end of 
infusion 
FPA144 PK (serum) 
 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 132 of 139 
Confidential 
APPENDIX 6: 
STUDY FLOWCHART FOR PHARMACOKINETIC, 
IMMUNOGENICITY, AND
 
 
OR PHASE 1 (CONTD) 
Study Cycle 
Study Day 
Time Point 
Type of Sample 
Cycle 4 
Day 1 
≤ 4 hours prior to infusion 
(predose) 
FPA144 PK (serum) 
15 (±10) minutes after end of 
infusion 
 
 
 
FPA144 PK (serum) 
Cycle 5, 7, 9, 11 
Day 1 
≤ 4 hours prior to infusion 
(predose) 
FPA144 PK (serum) 
ADA (serum) (Cycle 7) 
 
 
  
15 (±10) minutes after end of 
infusion 
FPA144 PK (serum) 
Cycle 10 
Day 1 
15 (±10) minutes after end of 
infusion 
FPA144 PK (serum) 
Day 3 
48 hours (± 6 hours)  
FPA144 PK (serum) 
 
 
 
Day 1 
≤ 4 hours prior to infusion 
(predose) 
FPA144 PK (serum) 
ADA (serum)  
Every 8 Cycles 
Starting from 
Cycle 15 
  
 
 
 
End of Treatment 
Follow-up 
Visit date 
Single time point 
FPA144 PK (serum) 
ADA (serum)  
 
 
 
* For Cohort 2 patients only 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 133 of 139 
Confidential 
APPENDIX 7: 
STUDY FLOWCHART FOR FPA144 PHARMACOKINETIC AND 
IMMUNOGENICITY BLOOD SAMPLE COLLECTIONS FOR 
PHASE 2 
Study Cycle 
Study Day 
Time Point 
Type of Sample 
Cycle 1 
Day 1 
≤ 4 hours prior to infusion 
(predose) 
FPA144 PK (serum) 
ADA (serum) 
15 (±10) minutes after end of 
infusion 
FPA144 PK (serum) 
Cycle 3 
Day 1 
≤ 4 hours prior to infusion 
(predose) 
FPA144 PK (serum) 
ADA (serum) 
15 (±10) minutes after end of 
infusion 
FPA144 PK (serum) 
Cycles 5, 9, and 17 
Day 1 
≤ 4 hours prior to infusion 
(predose) 
FPA144 PK (serum) 
ADA (serum) 
End of Treatment Follow-up 
Visit date 
Single time point 
FPA144 PK (serum) 
ADA (serum) 
 
 
 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 134 of 139 
Confidential 
APPENDIX 8: 
ECOG PERFORMANCE STATUS 
Grade 
 
Performance Status Criteria 
0 
 
Fully active, able to carry on all predisease activities without restriction. 
1 
 
Restricted in physically strenuous activity, but ambulatory and able to carry 
out work of a light sedentary nature (light housework, office work). 
2 
 
Ambulatory and capable of all 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 any self-care. Totally confined to bed or 
chair. 
 
 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 135 of 139 
Confidential 
APPENDIX 9: 
FLUORESCEIN STAIN GRADING SYSTEMS 
 
DEWS 
DRY EYE: DIAGNOSTIC TEST TEMPLATE 
RAPPORTEUR 
A.I.Bron 
21 't Oct 2004 
TEST 
Grading staining: Oxford Schema 
TO 
The scheme is used to estimate surface damage in dry eye. 
REFERENCES 
DIAGNOSE 
VERSION of 
[ V 1 l 
TEST 
DESCRIPTION 
Surface damage to the exposed eye, assessed by staining, is 
graded against standard charts. 
NATURE of 
N.A. 
STUDY 
CONDUCT of 
Grading Schema: 
Bron Evans Smith 
TESTS 
Staining is represented by punctate dots on a series of panels 
2003. 
(A-E). Staining ranges from 0-5 for each panel and 0-15 for 
the total exposed inter-palpebral conjunctiva and cornea. The 
dots are ordered on a log scale 
PANEL 
GRADE 
CRITERIA 
A<OI> 
0 
Equal to or less 
than panel A 
B<OI> 
Equal to or less 
I 
than panel B, 
... 
greater than A 
c~}E> 
Equal to or less 
II 
than panel C, 
greater than B 
D~j> 
Equal to or less 
Ill 
than panel D, 
greater than C 
E 
Equal to or less 
IV 
than panel E, 
greater than D 
>E 
V 
Greater than 
panelE 
Conduct of Test: 
• 
Dye is instilled . 
• 
Slit-lamp is set (eg.16 magnification with xl0 
oculars with Haag-Streit). 
• 
Cornea: The upper eyelid is lifted slightly to grade 
the whole corneal surface, 
• 
Conjunctiva: To grade the temporal zone, the 
subject looks nasally; to grade the nasal zone the 
subject looks temporally. 
• 
(The uooer and lower coniuncti va can also be 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 136 of 139 
Confidential 
APPENDIX 9: 
FLUORESCEIN STAIN GRADING SYSTEMS (CONTD) 
 
graded). 
Selection of dyes: 
A list dyes and filters can be found in the original paper. 
With fluorescein, staining must be graded as quickly as 
possible after instillation, since the dye then diffuses rapidly 
into the tissue and its high luminosity blurring the stain 
margin. 
Staining after rose bengal or lissamine green, persists at high 
contrast and may therefore be observed for a considerable 
period. This is convenient for both grading and photography. 
Fluorescein sodium 
1. Quantified drop instillation 
eg 2 µI of 2 % sterile fluorescein instilled into each 
conjunctiva! sac with a micro-pipette (using a sterile tip). In 
very dry eye, larger 
volumes risk the possibility of 
inadequate dilution into the fluorescent range. 
2. Unquantified instillation - impregnated paper strips 
This is a convenient approach in the clinic using the 
following method of application: 
• 
A single drop of unit dose saline is instilled onto a 
fl uorescein-impregnated strip. 
• 
When the drop has saturated the impregnated tip, the 
excess is shaken into a waste bin with a sharp flick. 
• 
The right lower lid is then pulled down and the strip 
is tapped onto the lower tarsal conjunctiva. A 
similar procedure is carried out on the left. 
If too large a volume is delivered then the concentration in 
the tear film will be too high, and the tear film and staining 
pattern will be non-fluorescent. 
3.Timing 
The fluorescein break-up time (FBUT) is usually performed 
prior to grading. Since fluorescein diffuses rapidly into 
tissues, punctate staining blurs after a short period. It is 
therefore essential to assess staining rapidly, in sequence, in 
the right and then the left eye, so that the staining patterns 
observed are equally crisp. 
If it is intended to photograph the staining pattern for 
grading, then photography should follow immediately after 
each instillation. 
Exciter and Barrier Filters 
The absorption peak of fluorescein sodium occurs between 
465 - 490 nm and the emission peak between 520 - 530 nm 
A suggested filter pair for detection of fluorescein staining is 
a yellow, Kodak Wratten 12 barrier filter (transmitting above 
495 nm) or an orange Wratten 15 filter (transmitting above 
510 nm) in combination with a blue Wratten 4 7 or 4 7 A 
exciter filter. The 4 7 A shows greater transmittance than the 
Wratten 47 over the absorption range. The 'cobalt' filter of 
many slit-lamps is suitable to use with a Wratten 12 or 15 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 137 of 139 
Confidential 
APPENDIX 9: 
FLUORESCEIN STAIN GRADING SYSTEMS (CONTD) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
banier. 
Where more light is required for photographic purposes, 
narrow band-pass, inte1ference filters can be used. 
The use of both exciter and banier filters allows both the 
cornea and conjunctiva to be assessed using a single stain. 
This is a major advantage in clinical trials where it is 
otherwise customary to employ fluorescein to grade corneal 
staining and rose bengal or lissamine green t.o grade 
conjuncti val staining. 
Disadvantages of Fluorescein Staining 
Blurred pattern if reading is delayed. Delay in photographing 
fluorescein staining results in blw-red images of the staining 
pattern. 
Rose Bengal 
The intensity of rose bengal staining is dose dependent. If 
drop size or concentration is reduced to minimize stinging, 
the amount of staining is also reduced. Use of impregnated 
sllips will give weaker staining than use of a full drop of 1 % 
solution. Best results are achieved with, eg. 25 ~ti I%, 
instilled into the conjunctiva! sac. Because rose bengal stings, 
instillation is best preceded by a topical anesthetic. 
Instillation Technique 
I) eg. A drop of Proxymelacaine 
is instilled into the 
conjunctiva\ sac followed, after recove,y, by; 
2) A drop of rose bengal 1.0%. This is instilled onto the 
upper bulbar conjunctiva with the upper lid retracted and 
the patient looking down. 
3) Since both anaesthetic and drop may stimulate reflex 
tearing, the test should follow measurement of the FB UT 
and of the Schirmer test. (Conjunctiva! staining due to 
insertion of the Schirmer paper can usually be 
distinguished from that due lo dry eye disease). 
Both eyes may be stained prior to grading, since U,ere is no 
1isk of the staining pattern in the first eye being obscured by 
the time the second eye is graded. 
The cited paper gives advice about avoidance of overspill. 
Visibility 
Rose bengal staining on the conjunctiva shows up well 
against the sclera and may be enhanced using a red-free 
(green) light. source. Corneal staining may show up well 
against a blue iris, but is difficult to see against a dark brown 
iris. 
Phototoxicity 
Photo-activation of rose bengal by sunlight increases post-
instillation symptoms, especially in severe dry eye with 
heavy staining. This post-instillation pain can be minimised 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 138 of 139 
Confidential 
APPENDIX 9: 
FLUORESCEIN STAIN GRADING SYSTEMS (CONTD) 
 
by liberal irrigation with normal saline at the end of the test. 
Lissamine green stains the eye in a similar manner to rose 
bengal but is as well tolerated as fluorescein. Visibility and 
dose-dependency are the same as rose bengal and staining is 
persistant so that photography need not be performed 
immediately after instillation. 
Lissamine green is available as impregnated strips or may be 
ordered as a pre-prepared solution. A 25 µI 1 % drop will give 
more intense staining. Because the drop is well tolerated, no 
anaesthetic is required. 
Visibility 
As with rose bengal, lissamine green staining is easily visible 
on the conjunctiva. On the cornea, staining is seen well 
against a light blue iris background but is poorly visible 
against a dark brown iris background. For both rose bengal 
and lissamine green, because the dyes are poorly seen within 
the tear film, the dye in the tear film does not obscure the 
staining pattern. Also, since both dyes do not diffuse into the 
substantia propria of the conjunctiva, the staining pattern is 
retained for longer. 
Visibility of staining may be enhanced using a white light 
source and a red barrier filter, to give a black pattern on a red 
ground. A suitable filter is a Hoya 25A, or a Kodak Wratten 
92. 
Web Video 
Not available 
Materials: 
Oxford Grading Charts - available from A J Bron 
anthony.bron@eye.ox.ac.uk 
Standardization 
Nil additional 
Variations 
of 
technique 
Diagnostic 
No stats supplied. 
value 
Repeatability 
A small intra-interobserver study was carried out in 1986 and 
Hardman Lea et al. 
was presented but not published: 
1986 AER 
abstract. 
Intra-observer study: This study asked two trained 
ophthalmologists to grade a series of standard slides, showing 
corneal and conjunctiva! fluorescein staining, on 2 separate 
occasions. [note: -this study is only relevant to grading 
photographic records not patients.] 
Intra-observer K for grading photographs of staining, using 
the Oxford scheme. Two observers. 
Cornea 
Conjunctiva 
Observer 1 
0.86 
0.69 
Observer 2 
0.65 
0.83 
Not that values are in the good to excellent range. 
Inter-observer study: In this study, the same 2 observers 


FPA144-004 Clinical Protocol 
Amendment 4 
10 Mar 2021 
 
Page 139 of 139 
Confidential 
APPENDIX 9: 
FLUORESCEIN STAIN GRADING SYSTEMS (CONTD) 
 
(Bron 2003) 
 
graded fluorescein staining (blue exciter; yellow filter) in 13 
dry eye patients at an interval within 2-3 weeks. 
Inter-observer K for grading patients with dry eye, using 
the Oxford scheme. Two observers. Fluorescein; bengal 
rose 
Observer 1 v 2 
Cornea 
Conjunctiva 
Fluorescein 
0.88 
0.48 
Bengal rose 
0.87 
0.54 
It is of interest that observations are in the excellent category 
for cornea, with either stain and in the fair category for 
conjunctiva. 
Sensitivity 
(true positives) 
[ - l 
Specificity 
(100 - false positives) 
[ - l 
References: 
Bron A, Evans VE, Smith JA. (2003). Grading of corneal and conjunctiva! staining in the context of other 
dry eye tests. Cornea 22(7): 640-50. 


FPA144-004 Clinical Protocol 
Amendment 4 
10 March 2021 
 
1 of 1 
Confidential 
Summary of Changes Protocol FPA144-004 
 
FIGHT: A Phase 2 Randomized, Double-Blind, Controlled Study Evaluating FPA144 and Modified 
FOLFOX6 in Patients with Previously Untreated Advanced Gastric and Gastroesophageal Cancer: Phase 2 
Preceded by Dose-Finding in Phase 1  
 
Protocol Version: 
Amendment 4 
Date of Protocol Amendment: 10 Mar 2021 
Supersedes: 
Amendment 3 –dated 05June 2020 
 
Protocol Section 
Change 
Rationale 
Protocol Synopsis, 
Protocol Sections 3.1, 3.4 
(Figure 6), 6.19, 
Appendix 3 
Extended duration of LTFU 
visits from 12 to 24 months.  
 In the analysis performed on results as of 23 Sep 2020, fewer than 
50% of subjects in the treatment arm had an event evaluable for overall 
survival. The study long-term follow-up duration is being extended by 
12 months to more fully evaluate the secondary endpoint of overall 
survival (OS). 
Global 
Minor administrative changes updating version number and accompanying date have been made 
throughout the document.  
 


1 of 2 
Confidential 
Summary of Changes Protocol FPA144-004 
FIGHT: A Phase 2 Randomized, Double-Blind, Controlled Study Evaluating FPA144 and Modified 
FOLFOX6 in Patients with Previously Untreated Advanced Gastric and Gastroesophageal Cancer: Phase 2 
Preceded by Dose-Finding in Phase 1  
Protocol Version: 
Amendment 3 
Date of Protocol Amendment: 05 June 2020 
Supersedes: 
Amendment 2 –dated 19 November 2018 
Protocol Section 
Change 
Rationale 
Global 
Changed study design from Phase 3 to Phase 2. 
Study remains double-blind, placebo-controlled. 
No further enrollment is planned. 
•
The Phase 3 study in the front-line setting with SOC chemotherapy
initiated from promising monotherapy activity of bemarituzumab
(FPA144) in a Phase 1 study in late-line gastric cancer.
•
The Phase 3 statistical design assumed incidence of FGFR2b
positivity in front-line gastric cancer to be ~10%.  Over the conduct
of the study, the true incidence has been 30%.
•
Two methods of testing for FGFR2b status were utilized to capture
eligible patients: IHC and ctDNA.  Although the expectation was
that majority of positive tumors would be identified by both tests,
the vast majority of tumors have been identified by IHC alone,
resulting in a question of adequate study power.
Protocol Synopsis, 
Protocol Sections 2.2.1, 
2.2.2, 2.4.1, 2.4.2, 3.1, 3.4, 
4.1, 6.19, 7.3, 7.4.1, 7.4.2, 
Appendix 3 
Primary endpoint of study changed to investigator-
assessed progression-free survival. No interim 
analysis is planned. Overall survival is changed to 
a secondary endpoint. Sample size changed to 155 
patients.  Study duration is now 31 months to 
reflect current completion of enrollment and 
minimum of 12 months follow-up after last patient 
enrolled. 
Modifications accommodate the change to a Phase 2 design with PFS 
rather than OS as the primary endpoint. 


FPA144-004 Clinical Protocol 
Amendment 3 
05 June 2020 
2 of 2 
Confidential 
Protocol Section 
Change 
Rationale 
Protocol Synopsis 
Characterization of PK profile of FPA144 
+mFOLFOX6 in patients with FGFR2-selected GC
and immunogenicity of FPA144 changed to
exploratory endpoint
To align with change in study design
Protocol Synopsis, Protocol 
Sections 3.2.7, Appendix 2, 
Appendix 3 
After the first 3 cycles, FPA144/placebo may be 
delayed up to +7 days to be synchronized with 
administered mFOLFOX6.  
Clarified language regarding synchronization of  FPA144/placebo with 
mFOLFOX6 administration  
Protocol Sections 1.3.5, 1.7 
Updated safety information from current IB and to 
include identification of keratitis as an adverse 
drug reaction of IP. 
To provide updated safety information in the protocol consistent with 
revised safety language in the bemarituzumab Investigator’s Brochure 
(version 7) 
Protocol Section 6.15, 
Appendix 3 
Global 
Minor administrative changes and clarifications involving grammar, diction, punctuation, and other editorial changes that do 
not affect study design have been made throughout the document.  


 
Five Prime Therapeutics 
1 of 11 
Confidential 
SUMMARY OF CHANGES PROTOCOL FPA144-004 
 
FIGHT: A Phase 3 Randomized, Double-Blind, Controlled Study Evaluating FPA144 and Modified FOLFOX6 in Patients with Previously 
Untreated Advanced Gastric and Gastroesophageal Cancer: Phase 3 Preceded by Dose-Finding in Phase 1  
 
Protocol Version: 
Amendment 2 
Date of Protocol Amendment: 
19 November 2018 
Supersedes: 
Amendment 1 –dated 04 January 2018 
 
Protocol Section 
Change 
Rationale 
Protocol Synopsis, Protocol 
Section 6.2 
Removed language regarding informed consent 
requirements in Protocol Synopsis and removed 
Sections 6.2.1. and 6.2.2, instead addressing this in 
Section 6.2.   
Language has been clarified to avoid inconsistency as applies to informed 
consent process introduced by regional and/or site requirements. Informed 
consent framework for pre-screening and screening is unchanged. 
Protocol Synopsis 
 
Screening Period 
The time between signing the study ICF (for 
enrollment/participation) and enrollment in the study is 
considered the Screening Period. During the Screening 
Period, the patient will undergo protocol-specified 
Screening procedures to ensure all eligibility criteria are 
met.  
Additional details are provided below for each study 
portion under Phase 1 Safety Run-in and Phase 3. Pre-
screening allows for collection of blood and tissue to 
determine FGFR2 positivity using ctDNA and IHC 
assays.  Once a patient is confirmed to have a positive 
result based on central testing, the screening period 
initiates, allowing for evaluation of all other eligibility 
criteria.  
Simplification of language explaining distinction between pre-screening 
and screening periods. 
 


FPA144-004 Clinical Protocol 
Amendment 2 
19 November 2018 
Five Prime Therapeutics 
2 of 11 
Confidential 
 
Protocol Section 
Change 
Rationale 
Protocol Synopsis, Protocol 
Sections 3.2.5, 3.3.1, 3.4, and 
6.4.2  
Added the Phase 3 Recommended Dose 
To include the Phase 3 dose that was identified in Phase 1 in the protocol 
text.  
Protocol Synopsis, Protocol 
Section 4.2  
Added the CKD-EPI formula as an additional method 
for measurement of CrCl to inclusion criterion #7.  
The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation may provide a more accurate representation of kidney function for 
patients anticipating platinum-containing chemotherapy globally. To ensure 
that the most appropriate gastric cancer population is eligible for and 
treated in the FPA144-004 study the Sponsor is allowing for inclusion of 
patients with adequate renal function per either the Cockcroft-Gault or 
CKD-EPI calculations. 
Protocol Synopsis, Protocol 
Section 4.2 
Added an exception for anemia to exclusion criterion 
#10.  
Addresses inconsistency with inclusion criterion for hemoglobin for 
assessment of patient eligibility.  
Protocol Synopsis, Protocol 
Sections 4.2, 6.4.2, 6.10, 
Appendix 3, and Appendix 5 
Revised window for baseline radiographic imaging to be 
within 28 days (+3 days) in inclusion criterion #13 and 
other corresponding sections.   
Clarified that intent of prior language was to allow for baseline 
radiographic assessment within the screening window (ie, within 28+3 days 
of enrollment), not within 3 days of Day -28.  
Protocol Synopsis 
If the testing for OS is significant, then The analysis of 
PFS will be performed using a stratified log-rank test at 
a one-sided level of 0.025. This analysis will be based 
on 350 PFS events. Statistical significance for PFS at 
one-sided p=0.025 will occur with an estimated 
HR=0.81, corresponding approximately to an 
improvement of 23.4% in median PFS from 6 months to 
7.41 months. The final analysis of PFS will be 
conducted using a stratified log-rank test. The 
stratification factors will be the same used to stratify the 
randomization schedule as documented in the IXRS. 
Clarified language with regards to secondary endpoint of PFS to be 
consistent with prior regulatory feedback. 


FPA144-004 Clinical Protocol 
Amendment 2 
19 November 2018 
Five Prime Therapeutics 
3 of 11 
Confidential 
 
Protocol Section 
Change 
Rationale 
Protocol Synopsis 
A TEAE is defined as any event with an onset date on or 
after date of first dose of study treatment, or any event 
present before treatment that worsens after treatment. 
Only TEAEs with an onset date prior to 28 days after 
the date of the last dose will be tabulated in summary 
tables. The exceptions are symptomatic corneal events 
or any retinal events which should be captured within 
100 days of the last dose of FPA144. 
Simplified language in synopsis to be more concise. Details removed here 
are already stated in Section 7.5.  
Protocol Sections 1.8 and 
6.3.2 
Patients must sign the Pre- Screening informed consent 
form (ICF) Pre-screening allows for collection of blood 
and tissue to determine FGFR2 positivity using ctDNA 
and IHC assays. Only patients determined to be FGFR2-
selected are eligible to sign the Screening ICF and enter 
Once a patient is confirmed to have a positive result 
based on central testing, the screening period initiates, 
allowing for evaluation of. Enrollment in the study 
requires achieving all other eligibility criteria (refer to 
Section 4.2). 
Simplified language to make distinction and transition between pre-
screening and screening periods clear. Informed consent is already 
addressed in Section 6.2. 
Protocol Section 3.2.7 
In the Phase 1 portion of the study, if FPA144 is 
permanently discontinued for any reason the patient will 
undergo an EOT follow-up visit approximately 28 days 
after the last dose of FPA144 or mFOLFOX6. 
Clarified that the EOT follow-up visit is done approximately 28 days after 
the last dose of all study treatment. 
 
 


FPA144-004 Clinical Protocol 
Amendment 2 
19 November 2018 
Five Prime Therapeutics 
4 of 11 
Confidential 
 
Protocol Section 
Change 
Rationale 
Protocol Sections 5.1.2, 
5.1.3.2, Appendix 2, and 
Appendix 3 
FPA144 will be administered only to patients in this 
study using procedures described in this protocol. The 
dose of FPA144 is based on body weight at C1D1 and 
adjusted if the patient’s weight changes > 10% from 
either C1D1 or from the time of the most recent dose of 
FPA144, whichever change in dose is greater. The dose 
of FPA144 is based on body weight at C1D1 and 
should be recalculated only if the weight changes 
> 10% from the C1D1 weight. If the dose is 
recalculated due to a >10% weight change from 
C1D1, the weight used for the recalculated dose 
should function as the new baseline for subsequent 
evaluation of dose recalculations.  
Clarified when and how dose recalculations for FPA144 should be 
performed to be consistent with general consensus in the weight-based 
administration of cancer therapy.  
 
Protocol Section  
5.1.3.4  
Patients who require chemotherapy FPA144 dose 
reductions will receive the reduced dose for the 
remainder of the study. The only exception to this 
practice will be in the case of nausea/ vomiting. If 
nausea and/or vomiting occur despite antiemetic 
therapy, the chemotherapy dose should be reduced by 
25% for the next dose. If tolerated, an increase back to a 
100% dose may be allowed at the investigator’s 
discretion. Any patient who required 2 dose reductions 
and experienced persistent toxicity with a third dose 
reduction will be discontinued from all chemotherapy. 
Chemotherapy Cycles may be delayed to manage 
toxicity. Cycle delays of up to longer than 28 days are 
permitted should be discussed with the medical 
monitor prior to reinitiation. Any delay longer than 28 
days will require permanent discontinuation of all 
chemotherapy. 
Simplified language to avoid duplication as this information is already 
contained within Protocol Section 5.2.3.1. 
 
Additionally, modified language around study drug discontinuation to 
incorporate flexibility to be consistent with global variation in standard-of-
care management in front-line therapy for gastric cancer.  


FPA144-004 Clinical Protocol 
Amendment 2 
19 November 2018 
Five Prime Therapeutics 
5 of 11 
Confidential 
 
Protocol Section 
Change 
Rationale 
Protocol Section 5.1.3.4  
Added Table 5 to address dose levels for dose 
reductions in Phase 3.  
 
Inclusion of explicit statement of dose levels for dose reductions in Phase 3 
following determination of Phase 3 dose.  
 
Protocol Section 5.2.3 
Removed rounding convention for oxaliplatin and 5-FU.  Rounding will be addressed in the study pharmacy manual and be 
consistent with general consensus in the weight-based administration of 
cancer therapy. 
Protocol Section  
5.2.3.1 
Patients should be closely monitored for mFOLFOX6 
toxicity. In Phase 1, any patient who does not receive 
2 complete doses of mFOLFOX6 during the DLT 
Period due to a reason that is not a DLT or an AE 
related to FPA144, will be considered unevaluable 
and the patient will be replaced. In Phase 1, dose 
adjustments for mFOLFOX6 are permitted, but patients 
who require dose adjustments or delay of any 
component of mFOLFOX6 during the DLT period will 
not be considered evaluable unless the dose adjustment 
or delay is due to an AE deemed related to FPA144, in 
which case the AE will be considered a DLT (refer to 
Section 3.2.2 for DLT definitions).  
To address an inconsistency with the dose limiting toxicity (DLT) language 
in Section 3.2.5. This change was previously communicated in a Protocol 
Clarification Memo dated 30 April 2018. 
Protocol Section  
5.2.3.1 
If there is a change in body weight of >10% compared 
to baseline or to the weight at the time of the most 
recent dose, doses should be recalculated. The dose of 
mFOLFOX6 is based on body weight at C1D1 and 
should be recalculated only if the weight changes 
> 10% from the C1D1 weight. If the dose is 
recalculated due to a >10% weight change from 
C1D1, the weight used for the recalculated dose 
should function as the new baseline for subsequent 
evaluation of dose recalculations 
Clarified when and how dose recalculations for mFOLFOX6 should be 
performed to be consistent with general consensus in the weight-based 
administration of cancer therapy.  
 


FPA144-004 Clinical Protocol 
Amendment 2 
19 November 2018 
Five Prime Therapeutics 
6 of 11 
Confidential 
 
Protocol Section 
Change 
Rationale 
Protocol Section 5.2.3.1 
In the event that oxaliplatin administration is 
discontinued for any reason prior to disease progression, 
5-FU/leucovorin therapy may continue on an every 2-
week schedule until disease progression, unacceptable 
toxicity, or other cause for study withdrawal. In the case 
5-FU/leucovorin therapy is permanently discontinued 
then oxaliplatin must be discontinued. 
Patients who require chemotherapy dose reductions will 
receive the reduced dose for the remainder of the study. 
The only exception to this practice will be in the case of 
nausea/ vomiting. If nausea and/or vomiting occur 
despite antiemetic therapy, the chemotherapy dose 
should be reduced by 25% for the next dose. If tolerated, 
an increase back to a 100% dose may be allowed at the 
investigator’s discretion. Any patient who required 2 
dose reductions and experienced persistent toxicity with 
a third dose reduction will be discontinued from all 
chemotherapy. Chemotherapy cycles may be delayed to 
manage toxicity. Cycle delays of up to longer than 28 
days are permitted should be discussed with the 
medical monitor prior to reinitiation of treatment. 
Any delay longer than 28 days will require permanent 
discontinuation of all chemotherapy. 
Removed redundant language on oxaliplatin discontinuation as it is 
included in Section 5.2.3.  
Additionally, modified language around study drug discontinuation to 
incorporate flexibility to be consistent with global variation in standard-of-
care management in front-line therapy for gastric cancer 
Protocol Section 5.4 
If the investigator needs to know the study drug 
assignment for any reason, he or she should contact the 
Sponsor’s Medical Monitor. The decision and ability 
to unblind the treatment code in emergency 
situations resides with the investigator.   
To specify that the investigator has the prerogative and ability to break the 
treatment code in the case of a medical emergency without a requirement to 
contact the sponsor prior to unblinding. 


FPA144-004 Clinical Protocol 
Amendment 2 
19 November 2018 
Five Prime Therapeutics 
7 of 11 
Confidential 
 
Protocol Section 
Change 
Rationale 
Protocol Section 6.3.2 
Step 1: Patients will sign a Pre-Screening ICF provide 
informed consent to allow testing for FGFR2b 
overexpression by archival or fresh tissue with IHC and 
a blood sample for FGFR2 amplification by ctDNA. The 
time between signing the Pre-Screening ICF (for 
enrollment/participation) informed consent and site 
notification of the result of the test is considered the pre-
screening period (refer to Section 3.3).  
Language has been clarified to avoid inconsistency as applies to informed 
consent process introduced by regional and/or site requirements. Informed 
consent framework for pre-screening and screening is unchanged. 
 
Protocol Section 6.6.2 
After Cycle 1, the FPA144 dose will be recalculated at 
each infusion visit only if the patient’s weight has 
changed > 10% from either C1D1 or from the time of 
the most recent dose of FPA144, whichever change in 
dose is greater. 
The dose of FPA144 and mFOLFOX6 is based on 
body weight at C1D1 and should be recalculated only 
if the weight changes > 10% from the C1D1 weight. 
If the dose is recalculated due to a > 10% weight 
change from C1D1, the weight used for the 
recalculated dose should function as the new baseline 
for subsequent evaluation of dose recalculations.   
Clarified when and how dose recalculations for FPA144 and mFOLFOX6 
should be performed to be consistent with general consensus in the weight-
based administration of cancer therapy.  
 
Protocol Section 6.6.3 
During Phase 3, comprehensive ophthalmologic 
examinations will be conducted at Screening, at 8 weeks 
from C1D1 (± 7 14 days), at the EOT visit (± 7 days), 
and at any time there are ophthalmologic symptoms up 
to 100 days after the last dose of FPA144. 
Revised the allowable window for comprehensive ophthalmologic exams at 
8 weeks from C1D1 to ± 7 days.  


FPA144-004 Clinical Protocol 
Amendment 2 
19 November 2018 
Five Prime Therapeutics 
8 of 11 
Confidential 
 
Protocol Section 
Change 
Rationale 
Protocol Section 6.8, 
Appendix 2, Appendix 3, and 
Appendix 4 
Urinalysis includes dipstick for protein, glucose, blood, 
pH, and ketones on Day 1 for both FPA144 and 
mFOLFOX6 of odd cycles (every other cycle). If 
dipstick findings are clinically significant, 2+ or 
greater, then a microscopic evaluation will be performed 
to assess the abnormal findings per institutional 
standard. 
Removed requirement of dipstick use as long as analyte testing is 
performed per institutional standard.  
Protocol Section 6.18 
Added language for reporting of corneal and all retinal 
events to this section of the protocol referring to end of 
treatment procedures.   
To align with language already included in Section 6.17.1.  
Protocol Section 7.1 
Intent-to-treat (ITT) Population: all randomized patients 
(Phase 3). The final analysis of efficacy outcomes will 
be conducted in the ITT population. 
Simplified language on the definition of ITT population. Second sentence 
is redundant to information already contained in statistical analysis section. 
Protocol Section 7.4.2 
The hypothesis of OS will be tested first. As described 
above in Section 7.4.1, there will be 1 planned interim 
analysis and a final analysis for OS; both analyses (the 
interim and the final) will be event-based analyses. The 
O’Brien-Fleming monitoring boundary will be used to 
preserve the 2.5% false-positive error rate (1-sided), 
with a Lan-DeMets implementation to allow flexibility 
in the number and timing of the interim analysis. The 
hypothesis of OS will be tested at α1=0.01 (1-sided) at 
the interim, and α2=0.022 (1-sided) at final. 
This information will be contained more appropriately in the Statistical 
Analysis Plan (SAP). 
 


FPA144-004 Clinical Protocol 
Amendment 2 
19 November 2018 
Five Prime Therapeutics 
9 of 11 
Confidential 
 
Protocol Section 
Change 
Rationale 
Protocol Section 7.4.3 
If the testing for OS is significant, PFS will be tested 
further. This analysis will be based on 350 PFS events. 
Statistical significance for PFS at 1-sided p=0.025 will 
occur with an estimated HR=0.81, corresponding 
approximately to an improvement of 23.4% in median 
PFS from 6 months to 7.41 months. The final analysis of 
PFS will be conducted using a stratified log-rank test. 
The stratification factors will be the same used to 
stratify the randomization schedule as documented in 
the IXRS. 
The PFS analysis will be event-driven analysis and 
conducted based on the ITT principle, in which the final 
analysis of PFS will include only radiographic 
progression events as determined by the investigator’s 
assessment per RECIST v1.1 and deaths. A clinical 
deterioration determined by an investigator will not be 
considered as a progression event in the final analysis.  
Clarified language with regards to secondary endpoint of PFS such that 
language is consistent with prior regulatory feedback. 
Protocol Section 7.4.3 
Included additional details for ORR analysis.  
In addition, the analysis of ORR will be performed 
based on Efficacy-evaluable Population as sensitivity 
analysis. 
Specified that a sensitivity analysis will be performed for the secondary 
endpoint of ORR by restricting subjects to those in the efficacy-evaluable 
population. 
Protocol Section 7.5 
Included language around capturing treatment emergent 
adverse events beyond an onset date of +28 days after 
the date of the last dose.  
This language was previously in the Protocol Synopsis and has been moved 
to this section for clarity and ease of reference.  
Protocol Section 8.2 
Added Section 8.2 on Data Protection. 
Added language to address privacy and data protection. 


FPA144-004 Clinical Protocol 
Amendment 2 
19 November 2018 
Five Prime Therapeutics 
10 of 11 
Confidential 
 
 
Protocol Section 
Change 
Rationale 
Appendix 1 
Addition of the CKD-EPI CrCl formula and clarification 
of the CG formula: 
 
Cockcroft Gault formula:  
 
𝑪𝑪𝑪𝑪𝑪𝑪𝑪𝑪=
(𝟏𝟏𝟏𝟏𝟏𝟏−𝒂𝒂𝒂𝒂𝒂𝒂)∗𝒘𝒘𝒘𝒘𝒘𝒘𝒘𝒘𝒘𝒘𝒘𝒘
𝟕𝟕𝟕𝟕∗𝑺𝑺𝑺𝑺𝑺𝑺
(∗𝟎𝟎. 𝟖𝟖𝟖𝟖 𝒊𝒊𝒊𝒊 𝒇𝒇𝒇𝒇𝒇𝒇𝒇𝒇𝒇𝒇𝒇𝒇) 
 
Abbreviations/Units: age in years; weight in kg; SCr 
= serum creatinine in mg/dL.  
  
CKD-EPI formula: 
eGFR = 141 x min(SCr/κ, 1)α x max(SCr /κ, 1)-1.209 
x 0.993Age x 1.018 [if female] x 1.159 [if Black] 
 
Abbreviations/Units: eGFR (estimated glomerular 
filtration rate) = mL/min/1.73 m2; SCr = 
standardized serum creatinine in mg/dL; κ = 0.7 
(females) or 0.9 (males); α = -0.329 (females) or -
0.411 (males); min = indicates the minimum of SCr. 
To clarify calculation of CrCl per the CG formula (added units that the 
variables should be in) and provide a reference for calculation of eGFR per 
the CKD-EPI formula.   


FPA144-004 Clinical Protocol 
Amendment 2 
19 November 2018 
Five Prime Therapeutics 
11 of 11 
Confidential 
 
Protocol Section 
Change 
Rationale 
Appendix 4 
Chemistry panel updated to allow for collection of either 
blood urea nitrogen or urea.  
This change was previously communicated in a Protocol Clarification 
Memo dated 30 April 2018. 
Appendix 5 
Clarified collection requirements for the comprehensive 
ophthalmologic examinations in both Phase 1 and 
Phase 3.  
This change was previously communicated in a Protocol Clarification 
Memo dated 09 February 2018.  
Global  
Simplified language specifying assessment of disease 
progression per RECIST v1.1.  
Clarified language to be consistent with the fact that radiographic 
progression is one component of assessment of progression per RECIST 
v1.1. 
Global  
Clarified language that time-dependent outcome variables are calculated starting from the time of randomization. No change in 
Protocol Section 3.3 which explains that a patient is considered enrolled at the time of randomization. 
Global 
Updated the Medical Dictionary for Regulatory Activities (MedDRA) version and Common Terminology Criteria for Adverse Events 
(CTCAE) version to be used. MedDRA version 20.1 will be used, and CTCAE version 4.03 will be used in Phase 1 and version 5.0 in 
Phase 3.  
Global 
Minor administrative changes and clarifications involving grammar, diction, punctuation, and other editorial changes that do not affect 
study design have been made throughout the document.  
 


Approval Signatures
Document Name:
Protocol-Published Amendment  bemarituzumab 20210113 4
Document Description:
Document Number:
CLIN-000287750
Approval Date:
26 Apr 2022
Type of Study Protocol:
Amendment
Protocol Amendment No.: 4
Document Approvals
Reason for Signing: Functional Area
Name: Carolyn Britten
Date of Signature: 26-Apr-2022 15:52:44 GMT+0000

SAP_001.pdf: 
FPA144-004 Statistical Analysis Plan 
Version 1.0, 20 October 2020 
STATISTICAL ANALYSIS PLAN 
Study Title: 
FIGHT: A Phase 2 Randomized, Double-Blind, Controlled Study 
Evaluating FPA144 and Modified FOLFOX6 in Patients with 
Previously Untreated Advanced Gastric and Gastroesophageal 
Cancer: Phase 2 Preceded by Dose-Finding in Phase 1 
Name of Test Drug: 
FPA144 
Protocol Number: 
FPA144-004 
Protocol Version (Date): Amendment 3 (5 June 2020) 
Analysis Type: 
Final Analysis 
Analysis Plan Version: 
1.0 
Analysis Plan Date: 
20 October 2020 
Analysis Plan Author: 
, PhD 
Page 1 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126
NCT Number: NCT03694522
This NCT number has been applied to the document
for the purposes of posting on clinicaltrials.gov


Fiveer(me-
Document No.: FP-DOC-00650 
Statistical Analysis Plan 
Version No.: 1 
Prolilln MtJk:11105 fr,r Life 
Approval Form 
Page 1 of 1 
Protocol#: FPA144-004 
Version#: 
1.0 
I Version Date: 
20 October 2020 
l'8l New Statistical Analysis Plan 
0 Revised Statistical Analysis Plan 
Summary of changes provided for revised version? 
□Yes 
□No 
This Statistical Analysis Plan has been approved by Five Prime Therapeutics, Inc. The following signature 
documents this approval. 
Lead Statistician 
Signature: 
Date: 
Name: 
 
 
 
Clinical Pharmacology Lead 
Signature: 
Date: 
Name: 
 
Head of Biometrics 
Signature: 
Date: 
Name:
 
Clinical Team Lead 
Signature: 
Date: 
Name: 
 
Head of Clinical Development 
Signature: 
Date: 
Name: 
 
Confidential 
Page 2 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FivePr1me 
__ ,.. ___ _ 
!'1 :."\It \ 1,•,t,, fl!, ' ( " 
( , :, 
Prolocol #. FPA 144-004 
Version #: 
1 .o 
----------
Statistical Analysis Plan 
Approval Form 
I 
ve:S1~11 ~ate· 
-
---·- ·-- --
I 
i Documonl No.: FP-DOC-00650 / 
' Version No · 
/ 
Payo 1 or 1 
! 
20 October 2020 
r2] New Statistical Analysis Plan 
O Revised Statistical Analysis Plan 
,___ ______ 
--· - ---· 
-
------ -
Summa,y or changes provided ror revised version? 0 Yes 
O No 
This Statistical Analysis Plan has been approved by Five Prime Therapeutics. Inc. The following signature 
documents this approval. 
Lead Statistician 
Name. 
 
Signature. 
,___ _______________ -----·--
--
---------- -
Clinical Pharmacology Lead 
Name: 
 
Head or Biometrics 
Name·
 
Signature: 
Clinical Team Lead 
Signature: 
Name:
Head of Clinical Development 
Name. 
 
Signature 
Confidential 
Date. 
Date: 
Date: 
Dale: 
Date. 
Page 3 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


Statistical Analysis Plan 
Approval Form 
Document No.: FP-DOC-00650 
Version No.: 1 
Page 1 of 1 
Confidential 
Protocol #: FPA144-004 
Version #: 
1.0 
Version Date: 
20 October 2020 
 New Statistical Analysis Plan 
 Revised Statistical Analysis Plan 
Summary of changes provided for revised version? 
 Yes 
 No 
This Statistical Analysis Plan has been approved by Five Prime Therapeutics, Inc. The following signature 
documents this approval. 
Lead Statistician 
Name: 
 
Signature: 
Date: 
Clinical Pharmacology Lead 
Name: 
 
Signature: 
Date: 
Head of Biometrics 
Name: 
 
Signature: 
Date: 
Clinical Team Lead 
Name: 
 
Signature: 
Date: 
Head of Clinical Development 
Name: 
 
Signature: 
Date: 
21 Oct 2020
Page 4 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
TABLE OF CONTENTS 
1 
Background and Rationale .................................................................................................................... 8 
1.1 
Study Design ................................................................................................................................. 8 
1.1.1 
Treatment Assignment .......................................................................................................... 9 
1.1.2 
Blinding and Unblinding ....................................................................................................... 9 
1.2 
Study Objectives ........................................................................................................................... 9 
1.2.1 
Phase 1 Objectives ................................................................................................................ 9 
1.2.2 
Phase 2 Objectives .............................................................................................................. 10 
1.3 
Study Endpoints .......................................................................................................................... 11 
1.3.1 
Phase 1 Endpoints ............................................................................................................... 11 
1.3.2 
Phase 2 Endpoints ............................................................................................................... 11 
1.4 
Sample Size and Power ............................................................................................................... 12 
2 
Type of Planned Analyses .................................................................................................................. 13 
2.1 
Interim Analyses ......................................................................................................................... 13 
2.2 
Final Analysis ............................................................................................................................. 13 
2.3 
Follow-up Analysis ..................................................................................................................... 13 
3 
General Considerations ....................................................................................................................... 14 
3.1 
Analysis Sets ............................................................................................................................... 14 
3.1.1 
Intent-to-treat (ITT) Analysis Set........................................................................................ 14 
3.1.2 
Efficacy-Evaluable Analysis Set ......................................................................................... 14 
3.1.3 
Safety Analysis Set ............................................................................................................. 15 
3.1.4 
DLT-Evaluable Analysis Set .............................................................................................. 15 
3.1.5 
PK-Evaluable Analysis Set ................................................................................................. 15 
3.1.6 
ADA-Evaluable Analysis Set .............................................................................................. 15 
3.2 
Subject Grouping ........................................................................................................................ 15 
3.3 
Stratification Factors ................................................................................................................... 16 
3.4 
Examination of Subject Subgroups ............................................................................................. 16 
3.5 
Multiple Comparisons ................................................................................................................. 17 
3.6 
Missing Data and Outliers .......................................................................................................... 17 
3.6.1 
Missing Data ....................................................................................................................... 17 
3.6.2 
Outliers ................................................................................................................................ 17 
3.7 
Data Handling Conventions and Transformations ...................................................................... 17 
3.8 
Analysis Visit Windows ............................................................................................................. 18 
3.8.1 
Definition of Study Day ...................................................................................................... 18 
Page 5 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
3.8.2 
Analysis Visit Windows ...................................................................................................... 18 
4 
Subject Disposition ............................................................................................................................. 20 
4.1 
Subject Enrollment and Disposition ........................................................................................... 20 
4.2 
Extent of Exposure and Adherence ............................................................................................. 20 
5 
Demographics and Baseline Characteristics ....................................................................................... 22 
5.1 
Demographics ............................................................................................................................. 22 
5.2 
Other Baseline Disease Characteristics....................................................................................... 22 
5.3 
Medical History .......................................................................................................................... 22 
5.4 
Prior and Concomitant Medications ........................................................................................... 23 
5.5 
Prior Anticancer Therapy ............................................................................................................ 23 
6 
Efficacy Analyses ............................................................................................................................... 24 
6.1 
Efficacy Endpoints in Phase 1 .................................................................................................... 24 
6.2 
Primary Efficacy Endpoint in Phase 2 ........................................................................................ 24 
6.2.1 
Definition of the Primary Efficacy Endpoint ...................................................................... 24 
6.2.2 
Statistical Hypothesis for the Primary Efficacy Endpoint .................................................. 25 
6.2.3 
Analysis of the Primary Efficacy Endpoint ........................................................................ 25 
6.2.4 
Sensitivity Analysis of the Primary Efficacy Endpoint ...................................................... 25 
6.2.5 
Exploratory Analysis of the Primary Efficacy Endpoint .................................................... 26 
6.3 
Secondary Efficacy Endpoints in Phase 2................................................................................... 27 
6.3.1 
Definition of the Secondary efficacy Endpoints ................................................................. 27 
6.3.2 
Analysis of the Secondary Efficacy Endpoints ................................................................... 27 
6.4 
Exploratory Efficacy Endpoints in Phase 2 ................................................................................ 29 
6.4.1 
Duration of Response .......................................................................................................... 29 
6.4.2 
Time to Response ................................................................................................................ 30 
6.4.3 
Change in Tumor Size ......................................................................................................... 30 
6.4.4 
Patient-Reported Outcome Assessments............................................................................. 30 
6.4.5 
ECOG PS ............................................................................................................................ 31 
6.5 
Changes from Protocol-Specified Efficacy Analysis .................................................................. 31 
7 
Safety analyses .................................................................................................................................... 32 
7.1 
Adverse Events and Deaths ........................................................................................................ 32 
7.1.1 
Adverse Event Dictionary ................................................................................................... 32 
7.1.2 
Adverse Event Severity ....................................................................................................... 32 
7.1.3 
Relationship of Adverse Event to Study Drug .................................................................... 32 
7.1.4 
Serious Adverse Events ...................................................................................................... 32 
7.1.5 
Treatment-Emergent Adverse Events ................................................................................. 32 
Page 6 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
7.1.6 
Summary of Adverse Events and Deaths ............................................................................ 33 
7.1.7 
Adverse Events of Special Interest ..................................................................................... 34 
7.1.8 
Dose-Limiting Toxicity ....................................................................................................... 35 
7.2 
Clinical Laboratory Evaluations ................................................................................................. 35 
7.3 
Body Weight and Vital Signs ..................................................................................................... 36 
7.4 
Electrocardiograms ..................................................................................................................... 36 
7.5 
Other Safety Measures ................................................................................................................ 36 
8 
Pharmacokinetic and immunogenicity Analyses ................................................................................ 38 
8.1 
Bioanalytical Methods ................................................................................................................ 38 
8.2 
PK Analysis ................................................................................................................................ 38 
8.2.1 
PK Sample Collection ......................................................................................................... 38 
8.2.2 
Estimation of Pharmacokinetic Parameters ........................................................................ 38 
8.2.3 
Assessment of Dose-Proportionality for Phase 1 ................................................................ 40 
8.2.4 
Assessment of Steady-State Attainment for both Phase 1 and Phase 2 .............................. 40 
8.2.5 
Assessment of Immunogenicity Impact on Serum FPA144 Concentration and 
Pharmacokinetic Parameters .............................................................................................. 41 
8.2.6 
Summary of Serum Concentration data and Pharmacokinetic Parameters ......................... 41 
8.2.7 
Quality Control Methods for PK data Analysis .................................................................. 42 
8.3 
Immunogenicity Analysis ........................................................................................................... 42 
8.3.1 
Immunogenicity Samples Collection .................................................................................. 42 
8.3.2 
Summary of Immunogenicity Results ................................................................................. 42 
9 
References ........................................................................................................................................... 43 
10 Software .............................................................................................................................................. 44 
 
 
LIST OF FIGURES 
Figure 1: 
Phase 1/2 Study Schema ........................................................................................................... 8 
Figure 2: 
Phase 2 Patient Timeline .......................................................................................................... 9 
 
 
Page 7 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
 LIST OF Abbreviations 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ATC 
Anatomical Therapeutic Chemical classification 
AUC 
area under the observed concentration-time curve 
BMI 
body mass index 
BOR 
best overall response 
Cmax 
maximum observed concentration determined from the observed concentration values post first 
dose 
Ctrough 
minimum observed concentration determined from the observed concentration values 
CI 
confidence interval 
CL 
total body clearance 
CMH method 
Cochran-Mantel-Haenszel method 
CR 
complete response 
CSR 
Clinical Study Report 
CVT 
computed tomography 
DLT 
dose-limited toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EORTC 
QLQ-C30 
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
Version 3.0 
EOT 
end of treatment 
EQ-5D-5L 
EuroQOL-5D-5L 
GC 
gastroesophageal cancer 
GI 
gastrointestinal tumors 
GLP 
Good Laboratory Practices 
HR 
hazard ratio 
ITT 
intent-to-treat 
IXRS 
interactive voice or web response system 
LTFU 
long-term follow-up 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCA 
non-compartmental analysis method 
NCI-CTCAE 
National Cancer Institute Common Toxicity Criteria for Adverse Events 
NE 
not evaluable 
OECD 
Organization for Economic Cooperation and Development  
ORR 
objective response rate 
OS 
overall survival 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
Page 8 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
PROs 
patient-reported outcomes 
PT 
preferred term 
Q1, Q3 
first quantile, third quantile 
Q2W 
every 2 weeks 
QOL 
quality of life 
RECIST v1.1 
New Response Evaluation Criteria in Solid Tumors (version 1.1) 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SE 
standard error 
SMQ 
standardised MedDRA queries 
SOC 
system organ class 
StD 
standard deviation 
t1/2 
terminal half-life 
TEAE 
treatment-emergent adverse event 
TFLs 
Tables, Figures, and Listings 
TTR 
time to response 
WHODD 
World Health Organization Drug Dictionary 
 
 
Page 9 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
1 
BACKGROUND AND RATIONALE 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures and listings (TFLs) of the final analysis in the clinical 
study report (CSR) for study FPA144-004. This SAP is based on the study protocol Amendment 
3 dated 05 June 2020. The SAP will be finalized prior to data finalization for the final analysis 
(Section 1.5.1). 
1.1 
Study Design 
This is a double-blind, randomized, controlled, multicenter Phase 1/2 study to evaluate the 
safety, tolerability, efficacy, pharmacokinetic (PK), of FPA144 + mFOLFOX6 versus placebo + 
mFOLFOX6. This study includes a Phase 1 safety run-in portion and a Phase 2 portion. Patients 
may enroll in either Phase 1 or Phase 2 but may not enroll in both phases of the study. 
The Phase 1 safety run-in is an open-label dose-escalation of FPA144 + mFOLFOX6 in patients 
with gastrointestinal (GI) tumors (not FGFR2 selected). The Phase 2 portion of the study (to 
follow the Phase 1 safety run-in) is a global, randomized, double-blind, controlled, study to 
evaluate the efficacy of FPA144 + mFOLFOX6 versus placebo + mFOLFOX6 in patients with 
FGFR2-selected gastroesophageal cancer (GC), as determined by prospective IHC demonstrating 
FGFR2b overexpression and/or a ctDNA blood assay demonstrating FGFR2 gene amplification. 
The study schema (Phase 1/2) is shown in Figure 1. Patient timelines are shown in Figure 2 
(Phase 2). 
Figure 1: 
Phase 1/2 Study Schema 
 
Abbreviations: Q2W = every 2 weeks. 
Page 10 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
Figure 2: 
Phase 2 Patient Timeline 
  
Abbreviations: CVT = computed tomography; EOT = end of treatment; LTFU = long term follow up; Q2W = every 
2 weeks. 
1.1.1 
Treatment Assignment 
Based on an assessment of Phase 1 overall safety, tolerability, and PK data of FPA144 in 
combination with mFOLFOX6 by the CRC, the dose of 15 mg/kg Q2W with an additional dose 
of 7.5 mg/kg on Cycle 1 Day 8 will be used for the Phase 2 portion of the trial. 
In Phase 2, approximately 155 FGFR2-selected GC patients will be randomized 1:1 to be treated 
with either FPA144 + mFOLFOX6 or placebo + mFOLFOX6 in 2-week cycles. 
1.1.2 
Blinding and Unblinding 
The Phase 2 portion of this study is double-blind. Placebo will be matched to FPA144. 
Treatment codes should not be broken except in emergency situations. With the exception of 
unblinding for the analysis, all individuals involved in the conduct of the study (eg, all site staff 
and participants, monitoring personnel, Sponsor personnel) will remain blinded to randomized 
treatment assignment. 
The investigator should document and provide an explanation for any premature unblinding 
(eg, accidental unblinding or unblinding because of a serious adverse event). 
1.2 
Study Objectives 
1.2.1 
Phase 1 Objectives 
The primary objective of the Phase 1 portion is to determine the RD of FPA144 combined with a 
fixed dose of mFOLFOX6 (hereinafter referred to as FPA144 + mFOLFOX6) in patients with 
advanced GI tumors. 
The secondary objectives are: 
Page 11 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
• To evaluate the safety and tolerability of FPA144 + mFOLFOX6 in patients with GI 
tumors 
• To characterize the PK profile of FPA144 in the presence of mFOLFOX6 in patients with 
GI tumors 
• To characterize the immunogenicity of FPA144 
The exploratory objective is to characterize the 
 
 
1.2.2 
Phase 2 Objectives 
The primary objective of the Phase 2 portion is to compare investigator-assessed progression-
free survival (PFS) in patients with FGFR2-selected GC treated with FPA144 + mFOLFOX6 to 
those treated with placebo combined with mFOLFOX6 (hereafter referred to as placebo + 
mFOLFOX6). 
The secondary objective is to compare the following in patients with FGFR2-selected GC treated 
with FPA144 + mFOLFOX6 to those treated with placebo + mFOLFOX6: 
• Overall survival (OS) 
• Investigator-assessed objective response rate (ORR) 
• Safety and tolerability 
The exploratory objective is to compare the following in patients with FGFR2-selected GC 
treated with FPA144 + mFOLFOX6 to those treated with placebo + mFOLFOX6: 
• Duration of response (DOR) 
• Patient-reported outcomes (PROs) and quality of life (QOL) outcomes until investigator-
assessed disease progression 
• To explore the association between FGFR2 status (in tumor tissue and/or blood) with 
clinical outcome 
• To explore the concordance between FGFR2b overexpression in tumor tissue and FGFR2 
gene amplification in blood 
To characterize the following: 
• PK profile of FPA144 in the presence of mFOLFOX6 in patients with FGFR2-selected 
GC 
• Immunogenicty of FPA144 
Page 12 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
1.3 
Study Endpoints 
1.3.1 
Phase 1 Endpoints 
The primary endpoint of Phase 1 portion is the incidence of Grade 2 or higher adverse events 
(AEs) assessed as related to FPA144 by the investigator and the incidence of clinical laboratory 
abnormalities defined as Dose-Limited Toxicity (DLT). 
The secondary endpoints are: 
• The incidence of AEs, clinical laboratory abnormalities, corneal and retinal findings, and 
electrocardiogram (ECG) abnormalities  
• PK parameters of FPA144, such as AUC, Cmax, Ctrough, CL, t1/2, volume of distribution, 
the time to achieve steady state, dose-linearity, and accumulation ratio 
• Incidence of treatment-emergent anti-FPA144 antibody response 
The exploratory endpoint is the
 
1.3.2 
Phase 2 Endpoints 
The primary endpoint of the Phase 2 portion is PFS, defined as time from randomization until the 
date of disease progression based on investigator assessment per RECIST v1.1 or death from any 
cause, whichever comes first. 
The secondary endpoints are: 
• OS, defined as time from randomization until death from any cause 
• ORR, defined as the proportion of patients with partial or complete response in all 
enrolled patients based on investigator assessment of tumor lesions per RECIST v1.1 
• Incidence of AEs, clinical laboratory abnormalities, corneal and retinal findings, and 
ECG abnormalities  
The exploratory endpoints are: 
• DOR limited to patients who are responders to treatment, as determined by the 
investigator per RECIST v1.1, and defined as the time of first response to progression or 
death from any cause, whichever comes first 
• Change from baseline in functional outcomes as measured by EuroQOL-5D-5L (EQ-5D-
5L) and the European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Version 3.0 (EORTC QLQ-C30) 
Page 13 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
• The correlation between identified FGFR2 status in tumor tissue and/or ctDNA blood 
assay, as determined by IHC and blood-based molecular diagnostic assay, with OS, PFS, 
and objective response per RECIST v1.1 
• The correlation between identified FGFR2b overexpression in tumor tissue by IHC and 
FGFR2 gene amplification as determined by ctDNA blood assay  
• PK parameters, such as Cmax and Ctrough of FPA144 in combination with mFOLFOX6  
• Incidence of treatment-emergent anti-FPA144 antibody response 
1.4 
Sample Size and Power 
The Phase 1 portion planned to enroll approximately 9 to 21 patients depending on incidence of 
DLTs; this allows for evaluation of safety, PK, and pharmacodynamics at 1 or more dose levels. 
The Phase 2 portion is designed to assess the hazard ratio (HR) for PFS for the FPA144 + 
mFOLFOX6 compared with placebo + mFOLFOX6. It is planned to observe at least 84 PFS 
events in order to achieve 71% power to detect an HR of 0.67 for PFS at a 1-sided significance 
level of 0.1. Assuming an exponential distribution, this corresponds approximately to an 50% 
increase in median PFS (e.g. from 5 months to 7.5 months).  Statistical significance (at 1-sided 
alpha of 0.1) for PFS will occur with an observed HR=0.756, corresponding approximately to a 
32.3% increase in observed median PFS (e.g. from 5 months to 6.6 months). 
 
 
Page 14 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
2 
TYPE OF PLANNED ANALYSES 
2.1 
Interim Analyses 
No formal interim efficacy analysis, which may lead to early termination for efficacy or futility, 
is planned in the study. 
2.2 
Final Analysis 
The final efficacy analysis will be conducted after at least 84 PFS events are observed. It is 
expected that this number of PFS events will occur approximately 11 months after the last 
patient is enrolled. Once outstanding data queries have been resolved, the database will be 
cleaned and finalized, and the final analysis of the data will be performed. 
2.3 
Follow-up Analysis 
After the final analysis, additional supplemental analyses of efficacy and safety may be 
performed for long-term efficacy (eg, overall survival) and follow-up safety assessments. 
 
 
Page 15 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
3 
GENERAL CONSIDERATIONS 
All statistical tabulations and analyses will be done using SAS®, Version 9.3 or higher. 
Unless otherwise noted, continuous variables will be summarized using the number of subjects 
(n), mean, standard error (SE) or standard deviation (StD), median, minimum, and maximum; 
categorical variables will be summarized using the number and percentage of subjects in each 
category. 
By-subject listings will be presented for all subjects in the Safety Analysis Set (for Phase 1) or 
Intent-to-Treat (ITT) Analysis Set (for Phase 2) and sorted by subject ID number, visit date, and 
time (if applicable). Data collected on log forms, such as AEs, will be presented in chronological 
order within the subject. The treatment group to which subjects were enrolled/randomized will 
be used in the listings. Age, sex at birth, race, and ethnicity will be included in the listings, as 
space permits. 
The summaries of the efficacy data will be presented by treatment group. Unless otherwise 
specified, non-efficacy analyses will be descriptive and will be presented by treatment group and 
overall. 
Unless stated otherwise, Phase 1 and Phase 2 portions of the study will be summarized and listed 
separately. 
3.1 
Analysis Sets 
3.1.1 
Intent-to-treat (ITT) Analysis Set 
The ITT Analysis Set is defined for Phase 2 portion of the study. It includes all subjects who 
were randomized in the study. 
The ITT Analysis Set will be used in the summary of subject disposition, demographics and 
baseline characteristics and the primary analyses for efficacy endpoints. 
3.1.2 
Efficacy-Evaluable Analysis Set 
The Efficacy-Evaluable Analysis Set is defined for Phase 2 portion of the study. It includes all 
randomized subjects who met key eligibility criteria and received at least 1 dose of study drug 
(FPA144 + mFOLFOX6 or placebo + mFOLFOX6), had at least 1 postbaseline evaluable tumor 
assessment, had ≥75% exposure intensity of FPA144/placebo, with no major protocol deviations 
that could introduce bias in efficacy analysis. Major protocol deviations that could bias efficacy 
analysis will be assessed and determined on a case-by-case basis prior to unblinding. 
The Efficacy-Evaluable Analysis Set is the secondary analysis set for efficacy analyses.  
Page 16 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
3.1.3 
Safety Analysis Set 
Phase 1 
The Safety Analysis Set includes all enrolled subjects who have received any portion of at least 1 
dose of study treatment (FPA144 + mFOLFOX6). 
Phase 2 
The Safety Analysis Set included all subjects in the ITT Analysis Set who have received any 
portion of at least 1 dose of study treatment (FPA144 + mFOLFOX6 or placebo + mFOLFOX6). 
The Safety Analysis Set will be used in the summary for safety data as well as study treatment 
administration. 
3.1.4 
DLT-Evaluable Analysis Set 
The DLT-Evaluable Analysis Set is defined for Phase 1 portion of the study. It includes all 
enrolled subjects who received at least 2 doses of FPA144 and mFOLFOX6 and completed 
Cycles 1 and 2 of treatment, or who experienced a DLT in Cycle 1 or Cycle 2. 
3.1.5 
PK-Evaluable Analysis Set 
The PK-Full Analysis Set and the PK-Evaluable Analysis Set are defined for Phase 1 and Phase 
2 portion separately. The PK-Full Analysis Set includes all enrolled subjects (for Phase 1) or all 
randomized subjects (for Phase 2) who received at least 1 dose of FPA144 and have at least 1 
serum FPA144 concentration datapoint. 
Pharmacokinetic-Evaluable Analysis Set includes all subjects in the PK Full Analysis Set who 
had sufficient PK data for the reliable calculation of at least one PK parameter. 
The PK-Evaluable Analysis Set is the primary analysis set for all PK analyses. 
3.1.6 
ADA-Evaluable Analysis Set 
The Anti-Drug Antibody (ADA)-Evaluable Analysis Set is defined for Phase 1 and Phase 2 
portion separately. It includes all enrolled subjects (for Phase 1) or all randomized subjects (for 
Phase 2) who received at least 1 dose of FPA144 and have at least 1 ADA sample drawn at any 
timepoint with available ADA data. 
The ADA-Evaluable Analysis Set is the primary analysis set for ADA analyses. 
3.2 
Subject Grouping 
For analyses based on the ITT Analysis Set or Efficacy-Evaluable Analysis Set, subjects will be 
grouped according to the treatment to which they were randomized. 
Page 17 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
For analyses based on the Safety Analysis Set, DLT-Evaluable Analysis Set, PK-Evaluable 
Analysis Set, or ADA-Evaluable Analysis Set, subjects will be grouped according to the actual 
treatment received. In the Phase 2 portion, the actual treatment received will differ from the 
randomized treatment only when their actual treatment differs from randomized treatment for the 
entire treatment duration. 
3.3 
Stratification Factors 
In the Phase 2 portion of the study, subjects will be randomized 1:1 to receive FPA144 + 
mFOLFOX6 or placebo + mFOLFOX6, stratified based on the following factors: 
• Geographic region: Region 1 (including US, Europe and Australia) vs. Region 2 (China) 
vs. Region 3 (Rest of Asia including Japan, South Korea, Taiwan and Thailand) vs. 
Region 4 (Rest of World) 
• Prior treatment status: de novo vs. adjuvant/neo-adjuvant 
• Administration of a single dose of mFOLFOX6 prior to enrollment: Yes vs. No 
If there are discrepancies in stratification factor values between the interactive voice or web 
response system (IXRS) and the clinical database, the values recorded in the clinical database 
will be used for analyses. 
Given the small number of subjects in the adjuvant/neo-adjuvant stratums, the stratification 
factor of prior treatment status will not be considered for the stratified efficacy analysis in the 
final analysis. 
Analyses for efficacy endpoints will be adjusted for the stratification factors. In the situation 
where there is insufficient information in a stratum (ie, if there are < 20 subjects or there are no 
informative events in a stratum), pooling of the stratum with the smallest adjacent stratum for 
stratified analyses will be considered; the smallest stratum is defined as the stratum having the 
fewest number of subjects or the fewest number of events in case the former is a tie and the 
adjacent stratum is defined as a stratum having 1 factor of the 2 at the same level and the other 
factor at an adjacent level. 
3.4 
Examination of Subject Subgroups 
In the analysis of the primary and secondary efficacy endpoints, subgrouping of subjects based 
on randomization stratification factors will be explored for subgroup analyses. In addition, 
subgroups defined by presumed prognostic baseline characteristics may also be explored. The 
presumed prognostic baseline characteristics include but not limited to the following: 
• Age (<65 years and ≥65 years) 
• Sex (male and female) 
Page 18 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
• FGFR2b expression 
o Overexpression by IHC irrespective of ctDNA 
o Amplification by ctDNA irrespective of IHC 
o Both overexpressed by IHC and amplified by ctDNA 
o Tumor IHC staining score of 2+ or 3+ in greater than 10% of cells  
o Tumor IHC staining score of 2+ or 3+ in greater than 5% of cells 
To graphically display treatment effect changes across subsets, forest plots of PFS and OS 
hazard ratios, and difference in ORR will be provided. 
3.5 
Multiple Comparisons 
In the Phase 2 portion of the study, the primary endpoint, PFS, will be tested first at a one-sided 
level of 0.1. If the null hypothesis is rejected, then the secondary endpoints OS and ORR will be 
tested hierarchically at the same one-sided level of 0.1. OS will be tested first and if it is 
significant, the ORR will be tested. The family-wise Type I error rate of testing the primary and 
the secondary endpoints will be controlled by employing this gate-keeping testing procedure at 
one-sided level of 0.1. 
3.6 
Missing Data and Outliers 
3.6.1 
Missing Data 
In general, missing data will not be imputed unless methods for handling missing data are 
specified. 
The handling of missing or incomplete dates for disease diagnosis and prior anticancer therapy is 
described in Section 5.3; for prior and concomitant medications in described in Section 5.4; for 
the single dose of mFOLFOX6 allowed prior to enrollment is described in Section 5.5; for new 
anticancer therapy is described in Section 6.1.1, for death date is described in Section 6.3.1, for 
AE onset is described in Section 7.1.5. 
3.6.2 
Outliers 
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis. 
3.7 
Data Handling Conventions and Transformations 
In PK analysis, individual serum FPA144 concentrations, if deemed to be anomalous, may be 
excluded from the analysis at the discretion of the pharmacokineticist following a review of 
Page 19 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
available documentation (eg, bioanalytical report). Any such exclusion will be communicated 
and clearly listed in the study report along with a justification for the exclusion. 
Individual serum concentrations will be excluded from descriptive statistics for serum 
concentration data, including mean concentration versus time plots, if the sample was planned to 
be collected predose but was actually collected postdose.  
Entire serum concentration-time profiles for a patient may be excluded following review of 
available documentation (eg, bioanalytical report) and communication. Any such exclusion will 
be communicated and clearly listed in the study report along with justification for exclusion. 
Results of the analysis with and without the excluded profiles will be presented in the study 
report when it is necessary. 
All serum concentrations reported as No Result (NR or Not Collected/Not Done, ND) values will 
be treated as missing and will appear in the data set as “.”. For the purpose of calculating or 
plotting mean concentration-time data, or calculating PK parameters, concentration values 
determined to be below the limit of quantitation (BLQ) will be treated as zero if they occur prior 
to the first measurable concentration; all other BLQ values will be treated as missing and set to 
“.”.  Quantifiable concentrations after two consecutive BLQ values following the same dose will 
also be set to “.” for the purposes of calculating PK parameters. 
3.8 
Analysis Visit Windows 
3.8.1 
Definition of Study Day 
For subjects in the Phase 1 portion, study day will be calculated from the first dosing date of any 
portion of the study drug: 
• Postdose Study Days = Assessment Date – First Dosing Date + 1 
• Study Day prior to First Dose = Assessment Date – First Dosing Date 
For subjects in the Phase 2 portion, study day will be calculated from the randomization date: 
• Postdose Study Days = Assessment Date – Randomization Date + 1 
• Study Day prior to Randomization = Assessment Date – Randomization Date 
3.8.2 
Analysis Visit Windows 
No analysis visit window will be assigned in the analysis. No summary by visit is planned except 
for PK analysis. In the by-visit summary provided for PK data, nominal visit will be used. 
In general, the baseline value will be the last nonmissing value on or prior to the first dosing date 
of study drug (for Phase 1 subjects) or randomization date (for Phase 2 subjects) unless specified 
differently. 
Page 20 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
For continuous measurements, if multiple measurements occur on the same day, the last 
nonmissing value will be considered as the baseline value. If these multiple measurements occur 
at the same time or the time is not available, the average of these measurements will be 
considered the baseline value. For categorical measurements, if multiple measurements occur on 
the same day, the last nonmissing value will be considered as the baseline value. If these multiple 
measurements occur at the same time or the time is not available, the value with the lowest 
severity will be considered the baseline value. 
Values collected after the first dosing date of study drug (for Phase 1 subjects) or randomization 
date (for Phase 2 subjects) will be considered as postbaseline values. For PK data, the 
measurement collected at protocol specified nominal timepoint will be selected for analysis. 
 
 
Page 21 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
4 
SUBJECT DISPOSITION 
4.1 
Subject Enrollment and Disposition 
A summary of subject disposition will be provided by treatment group. Percentages will be based 
on the Safety Analysis Set for Phase 1 portion, and ITT Analysis Set for Phase 2 portion. The 
number of subjects in the following categories will be provided: 
• Pre-screened (Phase 2 only) 
• Signed the inform consent 
• Randomized (Phase 2 only) 
• Randomized but not treated (Phase 2 only) 
• Received any study treatment 
• Continuing study treatment 
• Discontinued from study treatment with reasons for treatment discontinuation 
• Continuing study 
• Discontinued from study with reasons for study discontinuation 
4.2 
Extent of Exposure and Adherence 
Descriptive statistics of extent of exposure will be presented by treatment group for each 
component of treatment (FPA144/placebo, Oxaliplatin, Leucovorin, 5FU) separately: 
• Duration of exposure (weeks) 
• Cumulative exposure by week 
• Number of infusions 
• Dose intensity (Phase 2 only) 
Total duration of exposure to study drug (in weeks) will be defined as (last available dosing date 
– first dosing date + 14)/7, regardless of any temporary interruptions in study drug 
administration. 
Dose intensity is defined as 100* (Total study drug administered in mg/ Total study drug 
expected to be administered in mg during exposure to study drug). Percentage of subjects in the 
intensity categories (<75% and ≥75%) will be provided. 
Page 22 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
The number and percentage of subjects who have dose reduction, dose delay or interruption, and 
infusion interruption will be summarized with reasons. 
Summaries of exposure will be performed with the Safety Analysis Set. A by-subject listing of 
study drug administration will be provided. 
 
 
Page 23 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
5 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
5.1 
Demographics 
Demographic data will be summarized using descriptive summary statistics for the Safety 
Analysis Set (Phase 1 portion) or the ITT Analysis Set (Phase 2 portion). The demographic 
characteristics include age, sex, race, ethnicity, body height (in cm), body weight (in kg) and 
body mass index (BMI; in kg/m2). 
A by-subject listing will be provided for demographic data. 
5.2 
Other Baseline Disease Characteristics 
Baseline characteristics including baseline Eastern Cooperative Oncology Group Performance 
Status (ECOG PS), geographic region (US and EU vs China versus Rest of Asia [including 
Japan, South Korea, Taiwan and Thailand]), prior treatment status (de novo vs adjuvant/neo-
adjuvant), and administration of a single dose of mFOLFOX6 prior to enrollment (yes vs no) will 
be summarized by treatment group for the Safety Analysis Set (Phase 1 portion) or the ITT 
Analysis Set (Phase 2 portion) as part of the disease-specific baseline characteristics. 
5.3 
Medical History 
Medical history will be collected at screening for disease-specific and general conditions (ie, 
conditions not specific to the disease being studied). 
A summary of disease-specific medical history will be provided for the Safety Analysis Set 
(Phase 1 portion) or the ITT Analysis Set (Phase 2 portion) as part of the disease-specific 
baseline characteristics. Time since initial diagnosis of cancer (months) and time since diagnosis 
of unresectable disease (months) will be calculated by (date of randomization – date of 
diagnosis) / 30.4375. They will be summarized using summary statistics for a continuous 
variable. Disease stage at diagnosis and at screening will be summarized using summary 
statistics for a categorical variable. 
In deriving the time since diagnosis, all partial dates of diagnosis and last regimen will be 
identified, and the partial dates will be imputed as follows: 
• If day and month are missing but year is available, then the imputed day and month will 
be 01 Jan. 
• If day is missing but the month and year are available, then the imputed day will be the 
first day of the month. 
• Partial date will not be imputed if the year is missing. 
General medical history data will be coded according to Medical Dictionary for Regulatory 
Page 24 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
Activities (MedDRA) Version 20.1. It will be listed only. A by-subject listing will be provided 
for disease-specific medical history. 
5.4 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODD) and classified according to Anatomical Therapeutic Chemical 
classification (ATC) codes levels 2 (therapeutic sublevel) and 4 (chemical sublevel). 
All medications with an end date prior to the first dose of any study drug will be considered as 
prior medication regardless of the stop date. If a partial start date is entered the medication will 
be considered prior unless the month and year (if day is missing) or year (if day and month are 
missing) of the start date are after the first dosing date. Medications with a completely missing 
start date will be considered as prior medication, unless otherwise specified 
Concomitant medications are defined as medications taken while a subject took study drug. If a 
partial stop date is entered, any medication with the month and year (if day is missing) or year (if 
day and month are missing) prior to the date of first study drug administration will not be 
considered as concomitant medication. If a partial start date is entered, any medication with the 
month and year (if day is missing) or year (if day and month are missing) after the study drug 
stop date will not be considered as concomitant medication. Medications with completely 
missing start and stop dates will be considered as concomitant medication, unless otherwise 
specified. 
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing. 
5.5 
Prior Anticancer Therapy 
Number of prior regimens, time since the completion of last regimen will be summarized by 
treatment group using descriptive statistics. The best response to the last regimen will be 
summarized using summary statistics for a categorical variable. The summaries will be based on 
the Safety Analysis Set (Phase 1 portion) or the ITT Analysis Set (Phase 2 portion) as part of the 
disease-specific baseline characteristics. A partial completion date will be imputed using the 
algorithm defined in Section 4.3. The prior anticancer therapy will be listed by subject. 
For the single dose of mFOLFOX6 allowed prior to enrollment, a partial dose date will be 
imputed as follows: 
• If the day is missing but the month and year are available, then impute the day as first day 
of the month, or the informed consent date for pre-screening if they have the same month 
and year, whichever is later. 
• If the day and month are missing but year is available, then impute the day and the month 
as 01Jan, or the informed consent date for prescreening if they have the same year, 
whichever is later. 
• Partial date will not be imputed if the year is missing. 
 
Page 25 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
6 
EFFICACY ANALYSES 
The efficacy analysis for Phase 1 and Phase 2 portions will be performed and reported 
separately. Efficacy summaries will be presented by treatment group based on the Safety 
Analysis Set (Phase 1 portion) or the ITT Analysis Set (Phase 2 portion). 
6.1 
Efficacy Endpoints in Phase 1 
Best overall response (BOR) is reported directly by the investigators in the Phase 1 portion of the 
study. A summary of the number of subjects in response categories and the overall response rate, 
defined as the proportion of subjects who achieve BOR of either complete response (CR) or 
partial response (PR), will be provided. A by-subject listing of BOR will also be provided. 
6.2 
Primary Efficacy Endpoint in Phase 2 
6.2.1 
Definition of the Primary Efficacy Endpoint 
The primary efficacy endpoint in the Phase 2 portion of the study is PFS, defined as time from 
randomization until the date of radiographic disease progression based on investigator 
assessment (using RECIST v1.1) or death from any cause, whichever comes first. 
The PFS analysis will include only radiographic progression events as determined by the 
investigator’s assessment per RECIST v1.1 and deaths. A clinical deterioration determined by an 
investigator will not be considered as a progression event. Data will be censored on the date of 
last adequate tumor assessment for subjects: 
• who do not have documented progression or die, or 
• who start new anticancer therapy before documented progression or death without 
documented progression, or 
• who have ≥2 consecutive missing tumor assessments before documented progression or 
death without documented progression 
If a subject does not have a baseline tumor assessment, then PFS will be censored at the date of 
randomization, regardless of whether or not radiographic progression or death has been 
observed. 
When the date of initiation of new anticancer therapy other than the study treatment is 
incomplete or missing, the following algorithm will be followed: 
• If the day is missing but the month and year are available, then the imputed day will be 
the last day of the month. 
• If day and month are missing but year is available, then the imputed day and month will 
be the last day of the month for the last adequate disease assessment if they have the 
Page 26 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
same year. 
6.2.2 
Statistical Hypothesis for the Primary Efficacy Endpoint 
The primary efficacy hypothesis to be tested is that there is no difference in PFS between 
FPA144 + mFOLFOX6 and placebo + mFOLFOX6. Using ST(t) and SC(t) to denote the PFS 
distribution functions of FPA144 + mFOLFOX6 and placebo + mFOLFOX6, respectively, the 
statistical hypotheses to be tested in this study will be: 
𝐻𝐻0: ST(t) = SC(t) 
𝐻𝐻1: ST(t) > SC(t) (FPA144 + mFOLFOX6 is superior to placebo + mFOLFOX6 in terms of PFS) 
6.2.3 
Analysis of the Primary Efficacy Endpoint 
The primary analysis of PFS will be performed using the Kaplan-Meier method for the ITT 
Analysis Set. The PFS distribution of 2 treatment groups will be compared using the stratified 
log-rank test, stratified by the stratification factors at randomization. Medians, Q1, Q3, the 
proportion of subjects who progression-free at 6, 9, and 12 months from randomization will be 
provided along with corresponding 95% confidence intervals (CI). The unstratified log-rank test 
will also be performed. Kaplan-Meier curves will be provided by treatment group. 
In addition, the HR between the 2 treatment groups and its 95% CI will be estimated using the 
Cox proportional hazards regression model with treatment group as the only main effect and 
stratified by the stratification factors at randomization. 
A listing will be provided for the information of subject PFS, including randomization date, date 
of PFS event or censor date. 
6.2.4 
Sensitivity Analysis of the Primary Efficacy Endpoint 
To assess the robustness of the primary PFS results, the following sensitivity analyses will be 
performed: 
• PFS will be analyzed by considering initiation of new anticancer therapy as a PFS event. 
Furthermore, PFS will not be censored by having ≥2 consecutive missing tumor 
assessments before documented progression or death or initiation of new anticancer 
therapy. 
• PFS will be analyzed by considering clinical progression as a PFS event. The date of 
documented radiographic progression, clinical progression, or death, whichever is earlier, 
will be considered as PFS event date. 
• PFS will be analyzed based on the Efficacy-Evaluable Analysis Set with the same 
analysis methods specified for the primary analysis. 
Page 27 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
Other methods, e.g., restricted mean survival time, may be considered for PFS as exploratory 
analysis if the proportional hazard assumption is not hold. 
6.2.5 
Exploratory Analysis of the Primary Efficacy Endpoint 
Exploratory analysis will be performed to investigate the potential prognostic factors influencing 
PFS using the Cox regression model. The variables with prognostic potential will be included in 
the model to identify plausible significant factors on PFS. The potential variables include but not 
limit to the following: 
• Age (<60 years and ≥60 years) 
• Sex (male and female) 
• 3 stratification factors at randomization: geographic region, prior treatment status, and 
administration of a single dose of mFOLFOX6 prior to enrollment 
• Extent of disease (locally advanced and metastatic) 
• Primary tumor site (gastric adenocarcinoma and gastroesophageal junction 
adenocarcinoma) 
• Measurability of disease (measurable disease and non-measurable disease at baseline) 
• Number of lesions at baseline (1-4 lesions and >4 lesions) 
• Visceral metastasis (yes and no) 
• Prior gastrectomy (yes and no) 
• H score of IHC test (as continuous variable) 
Each candidate variable will be preliminarily evaluated in the Cox regression model with 
treatment. Only the variables significant at the 0.4 level will be considered to build the 
multivariate model. A stepwise selection process with significance level of 0.3 for entering 
variables will then be applied to those candidate variables to identify the final subset of relevant 
covariates in the Cox regression model with treatment. The hazard ratio of the variables in the 
final set will be provided. Same analysis may be done on geographic subgroups. 
PFS will also be analyzed based on the subgroups defined in Section 3.4. Same analysis as 
specified for the primary analysis will be performed, except that only the unstratified log-rank 
test will be provided and the hazard ratio estimated by the Cox proportional hazard model will 
not be adjusted by randomization stratification factors. 
Page 28 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
6.3 
Secondary Efficacy Endpoints in Phase 2 
6.3.1 
Definition of the Secondary efficacy Endpoints 
The secondary efficacy endpoints of this study are OS and ORR. 
OS is defined as time from randomization until death from any cause. Subjects who are lost to 
follow-up or do not have a date of death will be censored at the last date that they were known to 
be alive. Subjects with confirmed death or alive status after the data cutoff date will be censored 
at the data cutoff date. 
Every attempt will be made to ensure that complete death dates are recorded. In those rare 
instances where complete death dates are not recorded, the following algorithm will be used: 
• If day is missing but the month and year are available, then the imputed day will be the 
midpoint of the month or the last assessment date + 1, whichever is later. 
• If day and month are missing but year is available, then the imputed day and month will 
be 01Jan or the last day of the latest month that the subject was known to be alive if they 
have the same year, whichever is later. 
ORR is defined as the proportion of subjects who achieve BOR of either CR or PR based on 
investigator assessment tumor lesions per RECIST v1.1. The BOR is the best response 
documented from randomization until the end of study or data cut-off date, first disease 
progression, death, start of new anti-cancer therapy, or last documented assessment before ≥2 
consecutive missing tumor assessments, whichever is earlier. Subjects, who do not have 
sufficient baseline or on-study tumor status information to be adequately assessed for response 
status (ie, those with BOR of not evaluable [NE]), received anticancer therapy other than the 
study treatment, or missing ≥2 consecutive missing tumor assessments prior to achieving CR or 
PR, will be considered as non-responders and will be included in the denominators in 
calculations of response rates. 
To preserve the overall type I error rate across the primary and secondary endpoints of the study 
at a 1-sided significance level of 0.1, the primary efficacy hypothesis must be rejected at the 1-
sided 0.1 significance level before the efficacy hypotheses for the secondary efficacy endpoints 
can be tested. The 2 secondary endpoints will be tested sequentially at the 1-sided 0.1 
significance level in the order of OS then ORR. If a null hypothesis is not rejected, formal 
sequential testing will be stopped and only the nominal significance level will be presented for 
the remaining endpoints. 
6.3.2 
Analysis of the Secondary Efficacy Endpoints 
OS 
The primary analysis of OS will be performed using the Kaplan-Meier method for the ITT 
Page 29 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
Analysis Set. The OS distribution of 2 treatment groups will be compared using the stratified 
log-rank test, stratified by the stratification factors at randomization. Medians, Q1, Q3, the 
proportion of subjects who are alive at 6, 12, and 15 months from randomization will be 
provided along with corresponding 95% CIs. The unstratified log-rank test will also be 
performed. Kaplan-Meier curves will be provided by treatment group. 
In addition, the HR between the 2 treatment groups and its 95% CI will be estimated using the 
Cox proportional hazards regression model with treatment group as the only main effect and 
stratified by the stratification factors at randomization. 
A listing will be provided for the information of subject OS, including randomization date, date 
of OS event or censor date. 
To assess the robustness of the primary OS results, the analysis will be performed based on the 
Efficacy-Evaluable Analysis Set with the same analysis methods specified for the primary 
analysis as the sensitivity analysis. 
Exploratory analysis for OS will be performed with the same methods for PFS as descried in 
Section 6.2.5. Multivariate model with potential prognostic factors influencing OS will be built 
using Cox regression model. Subgroup analysis will also be performed. 
ORR 
The analysis of ORR will be performed based on the ITT Analysis Set. ORR with corresponding 
2-sided 95% CI based on Clopper-Pearson method along with each category of BOR will be 
summarized by treatment group. Patients who don’t have any postbaseline adequate tumor 
assessments will be counted as non-responders. A conventional 2-sided 95% CI of the difference 
in ORR of the two treatment groups and the corresponding p-value will be calculated based on 
stratum-adjusted Cochran-Mantel-Haenszel (CMH) proportions (Koch, Carr, Amara, Stokes, & 
Uryniak, 1989): 
𝑝𝑝̂𝑡𝑡−𝑝𝑝̂𝑐𝑐± 𝑍𝑍1−𝛼𝛼/2 ⋅𝑆𝑆𝑆𝑆(𝑝𝑝̂𝑡𝑡−𝑝𝑝̂𝑐𝑐), 
where 
• 𝑝𝑝𝑡𝑡 and 𝑝𝑝𝑐𝑐 denote the response rate in FPA144 + mFOLFOX6 and placebo + mFOLFOX6 
treatment group, respectively. 
• 𝑝𝑝̂𝑡𝑡−𝑝𝑝̂𝑐𝑐=
∑𝑊𝑊ℎ𝑑𝑑ℎ
∑𝑊𝑊ℎ, where 𝑑𝑑ℎ= 𝑝𝑝̂𝑡𝑡ℎ−𝑝𝑝̂𝑐𝑐ℎ  is the stratum-adjusted CMH proportion difference 
in stratum ℎ (ℎ= 1, 2, … , 𝐾𝐾).  
• 𝑊𝑊ℎ=
𝑛𝑛𝑡𝑡ℎ𝑛𝑛𝑐𝑐ℎ
𝑛𝑛𝑡𝑡ℎ+𝑛𝑛𝑐𝑐ℎ, is the weight based on the harmonic mean of sample size per treatment group 
for each stratum where 𝑛𝑛𝑡𝑡ℎ and 𝑛𝑛𝑐𝑐ℎ are the sample sizes of each treatment group in stratum ℎ. 
Page 30 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
• 𝑆𝑆𝑆𝑆(𝑝𝑝̂𝑡𝑡−𝑝𝑝̂𝑐𝑐) =
ඨ∑𝑊𝑊ℎ
2൬
𝑝𝑝ෝ𝑡𝑡ℎ
∗(1−𝑝𝑝ෝ𝑡𝑡ℎ
∗)
𝑛𝑛𝑡𝑡ℎ−1
+
𝑝𝑝ෝ𝑐𝑐ℎ
∗(1−𝑝𝑝ෝ𝑐𝑐ℎ
∗)
𝑛𝑛𝑐𝑐ℎ−1
൰
∑𝑊𝑊ℎ
, where 𝑝𝑝̂𝑡𝑡ℎ
∗=
𝑚𝑚𝑡𝑡ℎ+0.5
𝑛𝑛𝑡𝑡ℎ+1 , 𝑝𝑝̂𝑐𝑐ℎ
∗=
𝑚𝑚𝑐𝑐ℎ+0.5
𝑛𝑛𝑐𝑐ℎ+1 , 𝑚𝑚𝑡𝑡ℎ and 𝑚𝑚𝑐𝑐ℎ 
are the number of responders in stratum ℎ of each treatment group.  
• 𝑍𝑍(1−𝛼𝛼/2) is the 100(1-𝛼𝛼/2)th percentile of normal distribution, where α = 0.05. 
To assess the robustness of the primary ORR results, the analysis will be performed based on the 
Efficacy-Evaluable Analysis Set with the same analysis methods specified for the primary 
analysis as the sensitivity analysis. 
Exploratory analysis will be performed to investigate the potential prognostic factors influencing 
ORR using the logistic regression model. The potential variables include but not limit to the ones 
that have been identified in Section 6.2.5. 
Each candidate variable will be preliminarily evaluated in the logistic regression model with 
treatment. Only the variables significant at the 0.4 level will be considered to build the 
multivariate model. A stepwise selection process with significance level of 0.3 for entering 
variables will be applied to those candidate variables to identify the final subset of relevant 
covariates in the logistic regression model with treatment. The odds ratio of the variables in the 
final set will be provided. 
ORR will also be analyzed based on the subgroups defined in Section 3.4. Same analysis as 
specified for the primary analysis will be performed, except for p-value of the difference in ORR 
will not be provided and the 95% CI of the difference in ORR will be calculated without 
adjusting by the randomization stratification factors. 
6.4 
Exploratory Efficacy Endpoints in Phase 2 
6.4.1 
Duration of Response 
Duration of response is defined as the time from the first documented CR or PR to the earlier of 
the first documented PD or death from any cause. DOR will be evaluated using the investigator 
assessments based on subset of subjects in ITT Analysis Set who achieve a response. DOR will 
be summarized using Kaplan-Meier methods (median, Q1, Q3, and corresponding 95% CI). 
In the analysis of DOR, data will be censored on the date of the last tumor assessment for 
subjects 
• who do not have documented progression or die, or 
• who start new anticancer therapy before documented progression or death without 
documented progression, or 
• who have ≥2 consecutive missing tumor assessments before documented progression or 
Page 31 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
death without documented progression 
6.4.2 
Time to Response 
Time to response (TTR) is defined as the interval from randomization to the first documented 
CR or PR. TTR will be evaluated in the subset of subjects in ITT Analysis Set who achieve a 
response. Descriptive statistics of TTR will be provided. 
6.4.3 
Change in Tumor Size 
Tumor size based on the sum of the diameters of target lesions is collected in the eCRF through 
an MRI/CT scan at each tumor assessment visit. Change from baseline and the percent change 
from baseline will be determined for each post baseline assessment. The best change from 
baseline and the best percent change from baseline are defined as change or the percentage 
change from baseline to postbaseline minimum in tumor size while the assessment was taken 
prior to the time of initiation of anticancer treatment other than the study treatment or have ≥2 
consecutive missing tumor assessments before documented progression or death without 
documented progression. 
Change in tumor size will be analyzed for subjects in the ITT Analysis Set who have assessments 
at baseline and at least 1 post-baseline time point. Baseline, postbaseline maximum, postbaseline 
minimum, and their percent (%) change from baseline will be calculated and summarized. 
Waterfall plot will be provided for the best percent (%) change from baseline. A listing of target 
lesion will be provided. 
6.4.4 
Patient-Reported Outcome Assessments 
Patient-Reported Outcome includes EORTC QLQ-C30 and EQ-5D-5L. The EORTC QLQ-C30 
is a self-reported cancer health-related questionnaire. It includes five function domains (physical, 
role, emotional, cognitive, social), eight symptoms (fatigue, pain, nausea/vomiting, constipation, 
diarrhea, insomnia, dyspnea, and appetite loss), as well as global health/quality-of-life and 
financial difficulties. The EQ-5D-5L is a self-report questionnaire used to assess a subject’s 
general health quality of life consisting of five dimensions (mobility, self-care, usual activities, 
pain or discomfort, and anxiety or depression) as well as a VAS for overall health. 
Data from EORTC QLQ-C30 and EQ-5D-5L will be scored, processed, and standardized 
according to their user manuals. Data will be analyzed using appropriate methods specified in the 
user manuals to account for incomplete questionnaires. The maximum improvement postbaseline 
and change from baseline in subscales and global scores of EORTC QLQ-C30 and EQ-5D VAS, 
and the minimum and maximum postbaseline in dimensions of EQ-5D-5L will be summarized 
descriptively by treatment groups for subjects in the ITT Analysis Set. By subject listings will be 
provided for EORTC QLQ-C30 and EQ-5D-5L. 
Page 32 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
6.4.5 
ECOG PS 
The ECOG PS score has a range from 0 (Fully active; able to carry on all pre-disease 
performance without restriction) to 5 (Dead). The best postbaseline performance status will be 
the lowest score and the worst postbaseline performance status will be the highest score after 
randomization. A listing of ECOG PS will be provided. 
6.5 
Changes from Protocol-Specified Efficacy Analysis 
Analysis and summary are provided for time to response and change in tumor size. 
 
 
Page 33 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
7 
SAFETY ANALYSES 
Unless otherwise specified, all analyses will be performed using the Safety Analysis Set. The 
safety analysis for Phase 1 and Phase 2 portions will be performed and reported separately. 
No formal comparisons of safety endpoints are planned. 
7.1 
Adverse Events and Deaths 
7.1.1 
Adverse Event Dictionary 
All AEs will be coded to system organ class (SOC) and preferred term (PT) using MedDRA 
Version 20.1. 
7.1.2 
Adverse Event Severity 
Adverse events are graded for severity by the investigators using the National Cancer Institute 
Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 5. The severity grade of 
events for which the investigator did not record severity will be categorized as “missing” for 
tabular summaries and data listings. 
7.1.3 
Relationship of Adverse Event to Study Drug 
A treatment related AE is an AE noted as related to FPA144/placebo, Oxaliplatin, Leucovorin, or 
5FU by the investigator. Events for which the investigator did not record relationship to study 
drug will be considered related to study drug for summary purposes. However, by-subject data 
listings will show the relationship as missing. 
7.1.4 
Serious Adverse Events 
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definitions of SAEs that were specified in the study protocol. 
7.1.5 
Treatment-Emergent Adverse Events 
A treatment-emergent AE (TEAE) is defined as an AE that was not present prior to the start date 
of study drug or was worsened during treatment and 28 days after permanent discontinuation of 
study drug. An AE that was present at treatment initiation but resolved and then reappeared and 
the event severity increase while the subject was on treatment is also a TEAE. 
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met: 
• The AE onset is the same as or after the month and year (or year) of the first dosing date 
Page 34 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
of study drug, and 
• The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 28 days after the date of the last dose of study drug  
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent. 
7.1.6 
Summary of Adverse Events and Deaths 
The number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by SOC, PT, and treatment group. For other AEs described below, summaries will 
be provided by SOC, PT, maximum severity, and treatment group 
• TEAE (both Phase 1 and Phase 2) 
• TE SAE (both Phase 1 and Phase 2) 
• Summary of TEAE of Grade 3-5 (both Phase 1 and Phase 2) 
• TEAE related to FPA144/Placebo 
• TEAE related to mFOLFOX6 
• TE SAE related to FPA144/Placebo 
• TE SAE related to mFOLFOX6 
• TEAE leading to FPA144/Placebo treatment discontinuation 
• TEAE leading to mFOLFOX6 treatment discontinuation 
• TEAE leading to death (both Phase 1 and Phase 2) 
• TEAE leading to dose reduction in FPA144/Placebo 
• TEAE leading to dose reduction in mFOLFOX6 
• TEAE leading to dose delayed in FPA144/Placebo 
• TEAE leading to dose delayed in mFOLFOX6 
• TEAE leading to infusion interruption in FPA144/placebo 
Page 35 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
• TEAE leading to infusion interruption in mFOLFOX6 
• TEAE of dose limiting toxicity (Phase 1 only) 
These summaries will be provided for the Phase 2 portion if not otherwise specified. 
A brief, high-level summary of AEs described above will be provided for Phase 1 and Phase 2 
portions by treatment group and by the number and percentage of subjects who experienced the 
above AEs. 
Multiple events will be counted only once per subject in each summary. AEs will be summarized 
in alphabetic order of SOC and then by PT in descending order of total frequency within each 
SOC. For summaries by severity, the most severe severity will be used for those AEs that 
occurred more than once in a subject. 
In addition to the above summary tables, TEAEs, TEAEs of Grade 3 or higher, TE treatment-
related AEs, and TE SAEs will be summarized by PT only in descending order of total 
frequency. 
All AE and recorded deaths for the safety population will be listed. 
7.1.7 
Adverse Events of Special Interest  
An AE of special interest (AESI) (serious or non-serious) is an event of medical concern 
considered potentially associated to the investigational product or disease under study, for which 
ongoing monitoring and rapid communication by the investigator to the Sponsor is necessary. 
The following events are considered events of special interest in this study: 
• Ocular events associated with symptomatic corneal involvement and symptomatic and 
asymptomatic retinal involvement: these events are defined as those AEs in the 
Standardised MedDRA Queries (SMQs) (Broad) of Corneal Disorders and Retina 
Disorders 
• Events of hypersensitivity: these events are defined as those AE in the SMQ (Broad) of 
Hypersensitivity 
Treatment-emergent AESIs of ocular events are defined as those AEs present not prior to the 
start date of study drug or was worsened during treatment and 100 days after permanent 
discontinuation of study drug, as collected from CRF. The treatment-emergent definition for 
general AEs is still applied for AESIs of hypersensitivity events. 
Treatment-emergent AESIs will be summarized by PT and maximum CTCAE Grade for the 
Phase 2 portion. 
In addition, time to first onset of ocular events of any grade, Grade 2 and above, and Grade 3 and 
Page 36 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
above will be summarized, respectively. Kaplan Meier estimates of the median, Q1, Q3, and the 
number of subjects with event and censored subjects will be provided. Time to first onset of 
ocular events is defined as the time from start of study treatment to the date of first incident of 
ocular events. In the absence of an ocular event, the censoring date will be the earliest from the 
following dates: 
• Last dose date of FPA144/placebo + 100 days 
• Death date 
• Analysis cut-off date 
In case when the AE onset date is incomplete and needs to be imputed, the following algorithm 
will be followed: 
• If the day is missing but the month and year are available, then the imputed day will be 
the first day of the month or the first dosing date if they have the same month and year, 
whichever is later. 
• If the day and month are missing but year is available, then the imputed day and month 
will be 01Jan or the first dosing date if they have the same year, whichever is later. 
By subject listings of AESI will be provided. 
7.1.8 
Dose-Limiting Toxicity 
The summary and listing of DLTs will be performed on the DLT-Evaluable Analysis Set for the 
Phase 1 portion. A summary of DLT will be provided by SOC, PT, and severity. All DLTs will 
be listed. 
7.2 
Clinical Laboratory Evaluations 
Summaries of laboratory data will be provided in the Safety Analysis Set and will include data 
collected up to the last dose of study drug plus 28 days for subjects who have discontinued study 
drug, or all available data at the time of the final analysis data-cut for subjects who are ongoing 
at the time of the final analysis. 
Treatment-emergent laboratory abnormalities are defined as values that increase at least 1 
toxicity grade from baseline at any postbaseline time point. If the relevant baseline laboratory 
value is missing, any abnormality of at least Grade 1 observed within the time frame specified 
above will be considered treatment emergent. 
The following summaries will be provided by lab test and treatment group. Subjects will be 
categorized according to the most severe postbaseline abnormality grade for a given laboratory 
test: 
Page 37 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
• Laboratory abnormalities (both Phase 1 and Phase 2) 
• Grade 3 or 4 laboratory abnormalities (Phase 2 only) 
Shift tables displaying subject counts and percentages classified by baseline grade and maximum 
grade on treatment will be provided for chemistry, hematology, and coagulation tests with 
CTCAE v5 grading for Phase 2 portion of the study. 
By-subject listings of laboratory test results collected throughout the study will be provided for 
chemistry, hematology, and coagulation tests for both Phase 1 and Phase 2 portions of the study. 
7.3 
Body Weight and Vital Signs 
Descriptive statistics will be provided for both Phase 1 and Phase 2 portions of the study by 
treatment group for body weight and vital signs as follows: 
• Baseline 
• Postbaseline maximum 
• Postbaseline minimum 
• Change and percentage change from baseline to postbaseline maximum 
• Change and percentage change from baseline to postbaseline minimum 
A baseline value is defined as the last available value collected on or prior to the first dose of 
study drug. 
A by-subject listing of body weight and vital signs will be provided by subject ID and time point 
in chronological order. 
7.4 
Electrocardiograms 
Subjects with abnormal ECG findings will be listed for both Phase 1 and Phase 2 portions of the 
study. 
7.5 
Other Safety Measures 
Ocular examinations including fluorescein staining score, ocular symptoms, fundoscopy, ocular 
coherence tomography, visual acuity, intraocular pressure, slit lamp biomicroscopy, and 
confrontation visual field exams were performed at baseline and postbaseline in the study. The 
number of subjects shifted from Not Clinically Significant at baseline to Clinically Significant at 
any postbaseline assessment will be summarized by examination and treatment group. The 
summary will be provided for the Phase 2 portion of the study. 
Page 38 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
In addition, shift in fluorescein staining score from baseline to most extreme postbaseline grade 
will be presented for the Phase 2 portion of the study. 
A by-subject listing of the ocular examinations will be provided for both Phase 1 and Phase 2 
portions of the study. 
By-subject listings for pregnancy report and substance use of tobacco and alcohol will be 
provided for both Phase 1 and Phase 2 portions of the study. 
Page 39 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan 
Version 1.0, 20 October 2020 
8 
PHARMACOKINETIC AND IMMUNOGENICITY ANALYSES 
8.1 
Bioanalytical Methods 
The PK and ADA samples will be analyzed by validated ligand binding assays. The bioanalysis 
will be performed at ICON Bioanalytical Laboratories and will be conducted in a manner 
consistent with the FDA and Organization for Economic Cooperation and Development (OECD) 
Good Laboratory Practices (GLP) principles as they apply to bioanalytical chemistry. 
8.2 
PK Analysis 
8.2.1 
PK Sample Collection 
In the Phase 1 portion of the study, blood samples to determine serum FPA144 concentration 
will be acquired from each subject on C1D1 (predose, 15 minutes, 4 hours, 48 hours, and 168 
hours postdose), C1D8 (Cohort 2 subjects only, predose, 15 minutes, and 4 hours postdose), 
C2D1 (predose, 15 minutes, and 48 hours postdose), C3D1 (predose and 15 minutes postdose), 
C4D1 (same as C3D1), C5D1 (same as C3D1), C7D1 (same as C3D1), C9D1 (same as C3D1), 
C10D1 (same as C2D1) C11D1 (same as C3D1), every 8 Cycles starting from Cycle 15 (same 
as C3D1), and EOT. 
In the Phase 2 portion of the study, blood samples to determine serum FPA144 concentration 
will be acquired from each subject on C1D1 (predose and 15 minutes postdose), C3D1 (predose 
and 15 minutes postdose), C5D1 (predose), C9D1 (predose), C17D1 (predose), and EOT. 
8.2.2 
Estimation of Pharmacokinetic Parameters 
FPA144 pharmacokinetic parameters will be derived from the serum concentration versus time 
profiles for C1D1 from Phase 1. Individual PK parameter values will be derived using a 
non-compartmental analysis (NCA) method for IV Infusion in Phoenix WinNonlin (Plasma 200 
– 202).  Actual elapsed sampling times relative to start of FPA144 infusion will be used for all
parameter estimations.  Individual Cmax and Ctrough as well as their accumulation ratios (RA1 and
RA2, respectively) for Phase 1 and Phase 2 will be reported for the cycles with data. The PK
parameters are defined below:
Variable 
Units 
Definition 
AUCinf 
d*μg/mL (d=day) 
Area under the observed concentration-time curve 
from the time of dose administration extrapolated to 
infinity post first dose, based on the last observed 
quantifiable concentration: AUCinf = AUClast + Clast/λz 
where Clast is the last observed quantifiable serum 
concentration.  
AUCinf/Dose 
[d*μg/mL]/[mg/kg] 
AUCinf normalized by dose administered. 
AUC0-7 
d*μg/mL 
Area under the observed concentration-time curve 
from the time of dosing to Day 7 (0-168h) post first 
Page 40 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
dose calculated by log-linear trapezoidal 
approximation.  
DN-AUC0-7 
[d*μg/mL]/[mg/kg] 
AUC0-7 normalized by dose administered. 
AUC0-14 
d*μg/mL 
Area under the observed concentration-time curve 
from the time of dosing to Day 14 (0-336h) calculated 
by log-linear trapezoidal approximation. 
DN-AUC0-14 
[d*μg/mL]/(mg/kg] 
AUC0-14 normalized by dose administered.  
Clast 
μg/mL  
Last observed temporal quantifiable serum concentration 
for both Cohorts of Phase 1 post first dose (Day 14 for 
Cohort 2 of Phase 1 post second dose). 
CL  
mL/d/kg  
Total body clearance calculated post first dose. CL = 
Dose/AUCinf. 
Cmax 
μg/mL  
Maximum observed concentration determined from 
the observed concentration values post first dose.  
Cmax /Dose  
[μg/mL]/[mg/kg]  
Cmax normalized by dose administered.  
Cmax n (dose 2 
to last dose)  
μg/mL  
Observed concentration associated with the sample at 
the end of the infusion for each dose excluding the one 
on Study Day 8 for Cohort 2 of Phase 1. n = the dose 
number.  
Cmax n/Dose  
[μg/mL]/[mg/kg]  
Cmax n normalized by dose administered. n = the dose 
number. 
Ctrough n (dose 
1 to last 
dose)  
μg/mL  
Concentration associated with the sample at the end of 
each dose interval excluding the one on Study Day 8 
for Cohort 2 of Phase 1. n = the dose number. 
Ctrough n/Dose 
(dose 1 to 
last dose)  
[μg/mL]/[mg/kg] 
Ctrough n normalized by dose administered.  n = the dose 
number. 
Cterm 
μg/mL  
Observed concentration associated with the sample 
obtained at the end of the study.  
λz 
d-1 
Terminal phase rate constant of concentration-time 
profile.  
λz lower  
d  
Time associated with the last observed concentration 
used to calculate λz. 
λz upper  
d  
Time associated with the first observed concentration 
used to calculate λz. 
MRT 
d  
Mean residence time. MRT = (AUMC/AUCinf) – T/2 
where AUMC=Area Under Moments Curve and T= 
infusion duration.  
# Points 
Lambdaz  
 
Number of points used in computing λz. 
RA1 
 
Accumulation ratio based on measurement at the end 
of infusion of Cmax 1 compared to Cmax n calculated as 
Cmax n/Cmax 1. 
RA2 
 
Accumulation ratio based on measurement of Ctrough 1 
compared to Ctrough n calculated as Ctrough n/Ctrough 1.  
Adjusted r2  
 
Goodness of fit statistic for calculating λz.  
Page 41 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
t1/2 
d  
Terminal half-life calculated post first dose. t1/2= 
ln(2)/λz. 
tlast 
d  
Time of the last quantifiable concentration for both 
Cohorts of Phase 1 post first dose (for Cohort 2 of 
Phase 1 post second dose).  
tmax 
d  
Time to reach observed concentration corresponding 
to Tlast for both Cohorts of Phase 1 post first dose (for 
Cohort 2 of Phase 1 post second dose).  
Vss 
mL/kg  
Steady-state distribution volume projected post first 
dose. Vss= CL*MRT.  
Vz 
mL/kg  
Volume of distribution based on the terminal phase 
post first dose. Vz = Dose/(AUCinf*λz) 
In Phase 1, blood samples to determine serum FPA144 concentration before the second dose of 
7.5 mg/kg on C1D8 were collected twice at the same time for some patients in Cohort 2 of Phase 
1. One of the samples was named as Cycle 1 Day 8 pre-dose. Another one was named as 
unscheduled 1008.00002. Both samples were included in individual serum FPA144 
concentration listing, but only the samples named as Cycle 1 Day 8 pre-dose were used to 
estimate any PK parameters as it is the protocol specified nominal timepoint. 
Only data points that described the terminal elimination log-linear decline of the serum FPA144 
concentrations are to be used in the regression equation for calculation of terminal elimination 
phase rate constant; Cmax and any data point(s) in the distribution phase are not to be included in 
the calculation. A minimum of 3 points are to be used for determination of the terminal 
elimination phase rate constant. A general rule of adjusted r2 > 0.80 will be considered as 
acceptable for calculation of the terminal elimination phase rate constant. If adjusted r2 falls 
below 0.80, then the terminal elimination phase rate constant will be reported as not determined 
(ND) and that subject’s AUCinf and CL will be listed but excluded from descriptive summaries 
and statistical analysis. If the extrapolated AUCinf is more than 20%, then both AUCinf and CL 
will be listed but excluded from descriptive summaries and statistical analysis. 
8.2.3 
Assessment of Dose-Proportionality for Phase 1  
Dose-proportionality will be assessed for Cmax, AUC0-7, and Ctrough of C1D1 from Phase 1 at 6 
mg/kg and 15 mg/kg using either a power model or a direct comparison of dose-normalized 
values. In power model, log(parameter) = a + b * log(dose), where a is the intercept, b is the 
slope and dose is actual dose in mg. Each log-transformed PK parameter will be fit with a power 
model with a fixed effect term for log-transformed dose. For each PK parameter, the slope and 
associated 90% CI will be presented. A minimum of 3 values per dose cohort must be available 
for a given parameter to estimate dose-proportionality with the power model.  Dose-
proportionality will be inferred if the 90% CI for the estimate of the slope contains 1. 
8.2.4 
Assessment of Steady-State Attainment for both Phase 1 and Phase 2  
To assess steady-state attainment, graphical comparison will be performed using Cmax and Ctrough 
Page 42 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
of FPA144 for each Q2W cycle.  
8.2.5 
Assessment of Immunogenicity Impact on Serum FPA144 Concentration and 
Pharmacokinetic Parameters 
No FPA144 treatment induced ADA positive patients were identified in Phase 1. The impact of 
ADA on FPA144 exposure from Phase 2 will be assessed if there are any confirmed treatment 
induced ADA positive patient using descriptive statistics to compare Cmax and Ctrough values 
between ADA positive and ADA negative patients at each dose level by cycle and by dose.  
8.2.6 
Summary of Serum Concentration data and Pharmacokinetic Parameters 
Pharmacokinetic parameters will be generated for all subjects in the PK-Evaluable Analysis Set. 
Individual subject concentration data and individual subject PK parameters for FPA144 will be 
listed and summarized using descriptive statistics by Cohort and by Phase. Summary statistics (n, 
mean, StD, geometric mean, coefficient of variation of geometric mean [GeoCV], median, min, 
max, 95% CI) will be presented for both individual subject concentration data by time point and 
individual subject PK parameters by Cohort and by Phase. Non-continuous variables such as tmax 
will be summarized using n, median, minimum, and maximum. For summary statistics, BLQ 
values will be treated as specified in Section 3.6.1. Subjects in Phase 1 and Phase 2 portion of the 
study will be analyzed and summarized separately. 
The following tables will be provided: 
• Summary of FPA144 serum concentration (Phase 1 and Phase 2) 
• Summary of FPA144 serum concentration with response and ADA status (Phase 2) 
• Summary of pharmacokinetic parameters (Phase 1 and Phase 2) 
• Summary of pharmacokinetic parameters with response and ADA status (Phase 2) 
The following figures will be provided: 
• Group mean (+/-StD) FPA144 serum concentration vs time profiles post first and second 
doses (Phase 1) 
• Summary plot of Cmax and Ctrough versus time (Phase 1 and Phase 2) 
• Individual scatter plot of FPA144 Cmax and Ctrough versus time (Phase 1 and Phase 2) 
• Boxplot of FPA144 Cmax and Ctrough versus time with total patients, and with response and 
ADA status (Phase 2) 
The following listings will be provided: 
Page 43 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
• Individual serum FPA144 concentration (Phase 1 and Phase 2) 
• Individual Pharmacokinetic parameters (Phase 1) 
• Individual Pharmacokinetic parameters with response and ADA status (Phase 2) 
8.2.7 
Quality Control Methods for PK data Analysis 
The PK analysis will be subject to Quality Control (QC) review and reviewed by an independent 
pharmacokinetist at ICON. 
8.3 
Immunogenicity Analysis 
8.3.1 
Immunogenicity Samples Collection 
In the phase 1 portion of the study, blood samples were collected before the infusion on Cycles 
1, 2, 3, 7 and 10, and EOT to measure ADA for FPA144. In the phase 2 portion of the study, 
blood samples were collected before the infusion on Cycles 1, 2, 3, 5, 9, and 17, and EOT to 
measure ADA for FPA144. 
8.3.2 
Summary of Immunogenicity Results 
The number (%) of subjects with the following anti-drug responses will be reported for 
immunogenicity subjects. The on-treatment period starts at first dose and beyond. 
• Baseline FPA144 ADA-positive 
• Baseline FPA144 ADA-negative 
• FPA144 ADA-positive 
• FPA144 ADA-negative 
Postbaseline treatment induced ADA positive is derived as subjects with 
• ADA negative at baseline and ADA positive at any postbaseline timepoint, or 
• ADA positive at baseline and ADA positive with titer of at least 4-fold of the baseline 
titer at one or more postbaseline timepoint 
The following table will be provided: 
• Summary Statistics of Immunogenicity (Phase 2) 
The following listings will be provided: 
• Individual Immunogenicity Data (Phase 1 and Phase 2) 
Page 44 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
9 
REFERENCES 
Koch, G., Carr, G., Amara, I., Stokes, M., & Uryniak, T. (1989). Categorical Data Analysis. 
Chapter 13 in Berry, D.A. (ed.). Statistical Methodology in the Pharmaceutical Sciences. 
New York: Karcel Dekker, Inc.  
 
Page 45 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126


FPA144-004 Statistical Analysis Plan  
Version 1.0, 20 October 2020 
 
10 SOFTWARE 
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA 
Page 46 of 46
FPA144
FPA144-004 Statistical Analysis Plan Version 1.0
IND 117701/SN 0126