Conditions: Esophageal Cancer GastroEsophageal Cancer
Keywords: esophagus gastroesophageal junction T1-3N0-1 GE junction
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 34
Healthy volunteers: no

Brief summary:
This pilot phase II trial studies the therapeutic effects and side effects of CD40 agonistic monoclonal antibody APX005M when combined with chemotherapy and radiation therapy, and to see how well they work to reduce or remove esophageal or gastroesophageal (GE) cancers when given before surgery in treating patients with esophageal cancer or GE cancer than can be removed by surgery. APX005M is intended to stimulate the body's own immune system so that the immune cells can more effectively invade and destroy the tumor, adding to the benefits of the chemotherapy and radiation therapy. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving APX005M, chemotherapy, and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Detailed description:
Primary Objective:

To assess the efficacy of this novel combination, as measured by the pathologic complete response (pCR) rate.

Secondary Objectives:

1. To further characterize the safety and feasibility of combining APX005M with SOC chemoradiation (external beam radiation in daily fractions, with concurrent weekly low-dose carboplatin/paclitaxel) in the neoadjuvant setting for patients with resectable esophageal and GE junction cancers.
2. To assess the efficacy of combining APX005M with SOC chemoradiation as measured by rates of R0 resection (microscopically negative margins, i.e., no tumor remains following surgery); and radiographic/metabolic response to neoadjuvant treatment on CT-PET.

Exploratory Objectives:

1. To identify possible predictive molecular or immune-based efficacy biomarkers for this novel combination.
2. To characterize and assess overall survival.

Arms:
arm 1: Participants will receive standard of care chemoradiation, consisting of:

* External beam radiation in daily fractions (28 fractions) from Weeks 1-6, administered once per day up to 5 days/week.
* Carboplatin (area under the carboplatin plasma concentration versus time curve = 2) and paclitaxel (50 mg/m\^2) chemotherapy intravenously (IV) over 1 hour, once weekly, from Weeks 1-5.

The participants also will receive concurrent 0.3 mg/kg APX005M IV over 1 hour, once weekly, on Weeks 1, 2, 4, and 6 (2-3 days after chemoradiation).

Surgical resection of the tumor will be planned from Week 10 up to approximately Week 17, as indicated in the protocol amendment under which each participant is enrolled.

Interventions: intervention 1: APX005M intervention 2: Radiation Therapy intervention 3: Paclitaxel intervention 4: Carboplatin intervention 5: Surgical resection of tumor
Intervention descriptions: intervention 1: APX005M IV infusion intervention 2: Radiation therapy, total dose 5040cGy in 180cGy fractions intervention 3: Paclitaxel IV infusion intervention 4: Carboplatin IV infusion intervention 5: Surgical removal of the tumor will occur between weeks 10-17

Protocol document:
Prot_000.pdf: 
Protocol Number: APX005M-006 
 
Official Title: A Phase 2 Study of APX005M in Combination with Concurrent Chemoradiation as 
Neoadjuvant Therapy for Resectable Esophageal and Gastroesophageal Junction Cancers 
 
NCT Number: NCT03165994 
 
Document Date: 17 August 2021 






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APX005M-006 Clinical Protocol 
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Date: 12 August 2021 
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DOCUMENT HISTORY 
Version 
Date 
Replaces 
Description of Changes 
Original 
Protocol 
(Version 1.2) 
to Version 8 
22 Nov 2016 to 
28 Oct 2019 
N/A 
•
This study was conducted under an Investigator-sponsored
IND (
, University of California, San
Francisco; and previous versions of the study protocol
through Version 8 have been submitted to FDA by 
Version 9 
16 Mar 2020 
Version 8 
•
Apexigen, Inc has replaced 
 as IND Sponsor; the
Sponsor has been changed to reflect Apexigen, Inc.
throughout the protocol
•
Clarified the visit schedule to detail the follow-up visits
after APX005M administration
•
Simplified the exploratory objectives to possible
predictive molecular or immune-based efficacy
biomarkers
•
Clarified correlative biomarker sample collection and
Central Lab shipment location in Appendix 2 (previously
Appendix 3)
•
Changed safety oversight by the DSMP (with deletion of
the plan in Appendix 2) to the Sponsor and the Sponsor’s
Medical Monitor or designee
•
Revised the number of subjects to be enrolled (
), the total number of clinical
sites enrolling (approx. 4-5), as well as the time period of
enrollment (changed from 18 months to ~3 years
[9 months from the start of enrollment under Version 9])
and expected overall study duration (changed from
24 months total to 19 months from the start of enrollment
under Version 9)
•
Clarified the duration of patient participation in the study
(changed from 11–17 weeks [first dose to completion of
surgery] to 9 months [first dose to completion of
post-surgery follow-up])
Version 10 
30 Dec 2020 
Version 9 
•
Updated IND number to reflect APX005M-006 added
under Apexigen IND 122725
•
Updated List of Abbreviations to reflect terminology
specific to proton beam radiation
•
Revised the number of subjects to be enrolled 
•
Increased number of sites from 4–5 to 8–12
•
Added rationale for protocol Version 10 to Section 2.4
•
Clarified timing of administration for oral and intravenous
pre-medications
•
Modified Schedule of Assessments, Study Procedures and
corresponding sections of the protocol to reflect revised
chemoradiation and APX005M dosing schedules.
Chemotherapy will occur from Weeks 1–5, radiation from
Weeks 1–6 and APX005M will be administered at Weeks
1, 2, 4, and 6.
•
Modified Schedule of Assessments, Study Procedures, and
Appendix 2 to allow archival tissue samples to be


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Version 
Date 
Replaces 
Description of Changes 
submitted at Screening if a subject is unable to complete 
the endoscopic biopsy 
•
Modified Schedule of Assessments, Study Procedures, and
Appendix 2 to reflect modifications to Blood and Plasma
sample collection for Immune Correlatives and Cytokines
•
Corrected Study Schema to reflect change to
Chemoradiation, APX005M, sample collection, and
Endoscopic biopsy schedule
•
Modified Inclusion Criterion 3 to state that T1-3 Nx
determination is preferred to be determined by endoscopic
ultrasound [EUS]
•
Modified Section 6.2.1 to reflect Endoscopic Ultrasound
historical results within 56 days of Screening to be used
•
Added exclusion criteria regarding history of organ
transplant and/or concurrent immunosuppressive
medication. These subjects must be discussed with
Medical Monitor or designee prior to consent
•
Added guidance under Prohibited Concomitant
Medications regarding Influenza and COVID-19 vaccines
•
Modified CT-PET at Screening to allow historical CT-
PET if completed within 28 days prior to first dose of
APX005M
•
Strongly recommended that chemotherapy is completed on
Mondays during treatment Weeks 1, 2, and 4 and
administration of APX005M is scheduled on Wednesday
or Thursday to allow for a 2-3 day-period between
administration of chemotherapy and infusion of
APX005M to ensure the least remaining effect of the
steroid component of the chemo premedication on
therapeutic activity of APX005M
•
Clarified that timing of pre-surgery CT-PET scan is
recommended to be scheduled no earlier than 4 weeks
after completion of chemoradiation
•
Added guidance regarding use of proton beam radiation
therapy
•
Updated title of Section 8.1 from Sample Size and Accrual
Rate to Sample Size and the following language was
added: A minimum number of 
 evaluable patients with
adenocarcinoma histology will allow to test the null
hypothesis that the true pCR is 23% against a 1-sided
alternative of 53% with a Type 1 error rate of 0.05 and
power of 77%. All language regarding Accrual rate was
removed.
•
Section 8.2 was updated to outline the safety analysis of
the first 6 patients enrolled under protocol Version 10 (or a
later protocol version)


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Version 
Date 
Replaces 
Description of Changes 
Version 11 
12 Aug 2021 
Version 10 
•
1.1 Abbreviated Synopsis was updated to note the correct
treatment period of 6 weeks
•
1.1 Abbreviated Synopsis, 1.2 Full Synopsis updated
Estimated Enrollment Period to reflect current duration of
enrollment
•
1.1 Abbreviated Synopsis, 1.2 Full Synopsis Duration of
Participation updated to include overall survival
•
1.1 Abbreviated Synopsis, 1.2 Full Synopsis updated to
add Overall Survival
•
1.2 Full Synopsis, 3.3 Exploratory Objective, 8.3.4
Exploratory Endpoints updated to add Overall Survival as
an exploratory objective
•
1.2 Full Synopsis, Trial Design, 5.1 Study Overview,
Figure 1 Study Schema updated reflect Overall Survival
period
•
2.2 Background on APX005M updated per the current
version of the Investigator Brochure
•
4.3.3 Inclusion Criteria was updated for creatinine
clearance to make this assessment required and updated
measured creatinine clearance requirement from ≥30 to
≥60 mL/min
•
4.3.4 Exclusion Criteria was updated to add criteria for
exclusion of subjects who concurrently participate in an
interventional trial
•
4.5 Duration of Follow-Up updated to reflect total follow
up period from post-surgical follow up through overall
survival
•
4.6 Study Timeline updated to reflect current enrollment
timeline
•
6.2.1 Screening Endoscopic Ultrasound updated to note
historical test results are to be obtained within 56 days of
first administration of APX005M instead of Screening
•
6.2.4 Follow-Up Visits updated to include overall survival
•
6.2.5 End of Study Visit, 6.6 Subject Withdrawal/Study
Discontinuation Criteria clarified to note that subjects
withdrawing or being discontinued prior to the 6- month
post-operative follow up visit should attend the EOS
Visit
•
5.2 Systemic Treatment, 6.2.2.3 Visit 2, and Table 7
Schedule of Assessments were updated to reduce the
frequency of the 4-hour post APX005M infusion
monitoring from Weeks 1, 2, 4, and 6 to after the first two
infusions of APX005M.
•
6.2.3Visit 3, and Table 7 Schedule of Assessments were
updated to allow for visit to be conducted remotely if
sample collection is not required. Vitals signs at Visit 3 are
required if the visit is conducted in clinic.


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SIGNATURE PAGE OF THE INVESTIGATOR 
Title: 
 
A Phase 2 Study of APX005M in Combination with Concurrent 
Chemoradiation as Neoadjuvant Therapy for Resectable 
Esophageal and Gastroesophageal Junction Cancers 
Protocol Number: APX005M-006 
Version: 11 
Date: 12 August 2021 
IND Number: 122725 
Sponsor: Apexigen, Inc. 
 
I have read and agreed to the protocol of the above-mentioned clinical study. I agree to conduct 
this study in compliance with procedures detailed in this document and according to the 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, the 
Declaration of Helsinki and applicable local regulations. This study will not be initiated without 
prior Institutional Review Board (IRB) or Ethics Committee approval.  
I agree to maintain adequate records in accordance with GCP and that source data will be 
attributable, legible, contemporaneous, original, accurate, and complete. I agree to ensure that all 
associates, colleagues, and employees assisting in the conduct of this study are informed about 
their obligations in meeting the above commitments and I agree to provide adequate oversight of 
study personnel involved in this study. 
 
 
 
Signature 
 
 
 
_______________________  
 
 
______________________ 
Name, title and affiliation of   
 
 
Date 
Investigator 
 
 


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TABLE OF CONTENTS 
SPONSOR APPROVAL PAGE ................................................................................................................... 2 
DOCUMENT HISTORY .............................................................................................................................. 3 
SIGNATURE PAGE OF THE INVESTIGATOR ....................................................................................... 6 
TABLE OF CONTENTS .............................................................................................................................. 7 
LIST OF TABLES ........................................................................................................................................ 9 
LIST OF FIGURES ...................................................................................................................................... 9 
LIST OF ABBREVIATIONS ..................................................................................................................... 10 
1. 
Synopsis ......................................................................................................................................... 12 
1.1 
Abbreviated Synopsis ................................................................................................................ 12 
1.2 
Full Synopsis ............................................................................................................................. 12 
2. 
Background and Rationale ............................................................................................................. 14 
2.1 
Background on Esophageal Cancer ........................................................................................... 14 
2.2 
Background on APX005M ........................................................................................................ 15 
2.3 
Rationale for the Proposed Study .............................................................................................. 17 
2.4 
Rationale for the Proposed Doses Used in This Study .............................................................. 17 
3. 
Objectives of the Study .................................................................................................................. 20 
3.1 
Primary Objective ...................................................................................................................... 20 
3.2 
Secondary Objectives ................................................................................................................ 20 
3.3 
Exploratory Objectives .............................................................................................................. 21 
4. 
Study Design .................................................................................................................................. 21 
4.1 
Characteristics ........................................................................................................................... 21 
4.2 
Number of Subjects ................................................................................................................... 21 
4.3 
Entry Criteria ............................................................................................................................. 21 
4.3.1 
Diagnosis/Condition for Entry into the Trial ........................................................................ 21 
4.3.2 
Administrative Procedures .................................................................................................... 21 
4.3.3 
Inclusion Criteria ................................................................................................................... 22 
4.3.4 
Exclusion Criteria .................................................................................................................. 23 
4.4 
Duration of Treatment ............................................................................................................... 24 
4.5 
Duration of Follow-Up .............................................................................................................. 24 
4.6 
Study Timeline .......................................................................................................................... 25 
5. 
Treatment Plan ............................................................................................................................... 25 
5.1 
Study Overview ......................................................................................................................... 25 
5.2 
Systemic Treatment ................................................................................................................... 25 
5.2.1 
Study Drug - Description, Supply and Storage of Investigational Product ........................... 26 
5.3 
Radiotherapy ............................................................................................................................. 28 
5.4 
Surgical Considerations ............................................................................................................. 33 
5.5 
Dose Modifications and Dosing Delays .................................................................................... 34 
5.5.1 
Hematologic Toxicity ............................................................................................................ 34 
5.5.2 
Non-Hematologic Toxicity ................................................................................................... 35 
6. 
Study Procedures and Observations ............................................................................................... 37 
6.1 
Participant Registration ............................................................................................................. 37 
6.2 
Schedule of Procedures and Observations ................................................................................. 37 
6.2.1 
Screening ............................................................................................................................... 37 
6.2.2 
Treatment Period (Week 1-6) ................................................................................................ 38 
6.2.3 
Post Treatment Period (Weeks 7-16) .................................................................................... 40 
6.2.4 
Follow-Up Visits ................................................................................................................... 40 
6.2.5 
End of Study Visit ................................................................................................................. 41 
6.3 
Schedule of Assessments ........................................................................................................... 42 
6.4 
Usage of Concurrent/Concomitant Medications ....................................................................... 44 


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6.4.1 
Prohibited Concomitant Medications .................................................................................... 45 
6.4.2 
Management of Infusion Related Reaction/Cytokine Release Syndrome ............................. 45 
6.5 
Diet/Activity/Other Considerations ........................................................................................... 46 
6.5.1 
Diet ........................................................................................................................................ 46 
6.5.2 
Contraception ........................................................................................................................ 46 
6.6 
Subject Withdrawal/Study Discontinuation Criteria ................................................................. 47 
6.7 
Replacement Policy ................................................................................................................... 48 
6.8 
Criteria for Early Trial Termination .......................................................................................... 48 
7. 
Reporting and Documentation of Results ...................................................................................... 48 
7.1 
Evaluation of Efficacy ............................................................................................................... 48 
7.2 
Assessing and Recording Adverse Events ................................................................................. 49 
7.2.1 
Definitions of Adverse Events .............................................................................................. 49 
7.3 
Adverse Event Classification .................................................................................................... 51 
7.3.1 
Relationship to Study Treatment ........................................................................................... 51 
7.3.2 
Severity ................................................................................................................................. 51 
7.4 
Collection and Reporting ........................................................................................................... 52 
7.4.1 
General AE Reporting ........................................................................................................... 52 
7.4.2 
Disease Progression ............................................................................................................... 53 
7.4.3 
Serious AEs or Serious SARs ............................................................................................... 53 
7.4.4 
Handling of Expedited Safety Reports .................................................................................. 54 
7.4.5 
Non-serious AEs ................................................................................................................... 54 
7.4.6 
Laboratory Test Abnormalities ............................................................................................. 54 
7.5 
Pregnancy Reporting ................................................................................................................. 54 
8. 
Statistical Considerations and Evaluation of Results ..................................................................... 55 
8.1 
Sample Size ............................................................................................................................... 55 
8.2 
Interim Analyses and Stopping Rules ....................................................................................... 55 
8.3 
Analyses Plans ........................................................................................................................... 56 
8.3.1 
Populations for Analyses ....................................................................................................... 56 
8.3.2 
Primary Endpoint .................................................................................................................. 56 
8.3.3 
Secondary Endpoints ............................................................................................................. 56 
8.3.4 
Exploratory Endpoints ........................................................................................................... 57 
9. 
Administrative and Regulatory Details .......................................................................................... 58 
9.1 
Compliance with the Protocol and Protocol Revisions ............................................................. 58 
9.2 
Institutional Review Board/Independent Ethics Committee ..................................................... 58 
9.3 
Informed Consent ...................................................................................................................... 58 
9.4 
Monitoring ................................................................................................................................. 60 
9.5 
Confidentiality ........................................................................................................................... 60 
9.6 
Investigational Site Training ..................................................................................................... 60 
9.7 
Data Collection and Handling ................................................................................................... 61 
9.7.1 
Case Report Forms ................................................................................................................ 61 
9.8 
Publications ............................................................................................................................... 62 
10. 
References ...................................................................................................................................... 63 
11. 
Appendices ..................................................................................................................................... 65 
Appendix 1:  Performance Status Criteria .............................................................................................. 65 
Appendix 2:  Immune Correlative Tissue and Blood Sample Collection ............................................... 66 
 


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LIST OF TABLES 
Table 1 
AEs Observed with APX005M at Dose Level 0.3 mg/kg ....................................................... 18 
Table 2 
Regimen Description: Systemically Administered Agents ..................................................... 26 
Table 3 
Regimen Description: Radiation ............................................................................................. 29 
Table 4 
Dose Levels ............................................................................................................................. 34 
Table 5 
Dose Modifications Due to Hematologic Toxicity.................................................................. 35 
Table 6 
Dose Modifications Due to Non-Hematologic Toxicities ....................................................... 35 
Table 7 
Schedule of Assessments ......................................................................................................... 42 
Table 8 
Management of IRR/CRS ....................................................................................................... 46 
Table 9 
General Toxicity Grading of AEs ............................................................................................ 52 
 
LIST OF FIGURES 
Figure 1 
Study Schema .......................................................................................................................... 25 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
4DCT 
4-dimensional computed tomography 
ABC 
Active breathing control 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APC 
Antigen presenting cell 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AveIP  
Average intensity pixel 
bsPTV 
Beam specific Planning Target Volume 
CBC 
Complete blood count 
CBC diff 
Complete blood count with differential 
CR 
Complete response 
CRF 
Case report form 
CRS 
Cytokine release syndrome 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA 
Cytotoxic T-lymphocyte-associated protein 
CTV 
Clinical Target Volume 
DC 
Dendritic cell 
DLT 
Dose limiting toxicity 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EKG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOS 
End of Study 
EUS 
Endoscopic ultrasound 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GE 
Gastroesophageal  
GEJ 
GE junction 
GTV 
Gross tumor volume 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 


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Abbreviation 
Definition 
IgG 
Immunoglobulin G 
IND 
Investigational New Drug application 
IMRT 
Intensity modulated radiation therapy 
IRB 
Institutional Review Board 
IRR 
Infusion related reaction 
ISR 
IND safety report 
IV 
Intravenous 
LAO 
Left anterior-posterior oblique 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFO 
Multiple field optimization 
OS 
Overall survival 
NCI 
National Cancer Institute 
PBS 
Pencil beam scanning 
PD-1 
Programmed death 1 (PD-1) 
PD-L1 
Programmed death-ligand 1 (PD-L1) 
PET 
Positron emission tomography 
pCR 
Pathologic complete response 
PSPT 
Passively scattered proton therapy 
PTV 
Planning Target Volume 
RAO 
Right anterior-posterior oblique 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RO 
Robust optimization 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SAR 
Suspected adverse reaction 
SFO 
Single field optimization 
SOC 
Standard-of-care; standard of care 
SSAR 
Serious suspected adverse reaction 
ULN 
Upper limit of normal 
V 
Visit 
W 
Week 
WOCBP 
Women of childbearing potential 
XRT 
External radiation therapy 
 
 
 


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1. SYNOPSIS 
1.1 
Abbreviated Synopsis 
Title 
A Phase 2 Study of APX005M in Combination with Concurrent Chemoradiation 
as Neoadjuvant Therapy for Resectable Esophageal and Gastroesophageal 
Junction Cancers 
Trial Phase 
2 
Clinical Indication 
Patients with resectable (T1-3Nx, excluding T1N0) cancers of the esophagus and 
gastroesophageal (GE) junction, including both squamous cell and 
adenocarcinomas 
Trial Type 
Open-label, single arm, Phase 2 study 
Type of Control 
Historical control 
Route of Administration 
Intravenous (IV) APX005M  
Trial Blinding 
None 
Treatment Groups  
Single arm study 
 
 
Estimated Enrollment 
Period 
Approximately 3 years (13 months from the start of enrollment under protocol 
Version 9) 
Treatment Period 
6 weeks  
Post–treatment Period  
(ending on the date of 
surgery) 
4–10 weeks (between Study Weeks 7 and 16) 
Post-operative Follow-up 
Period  
6 months 
Overall Survival Follow-up 
Period 
18 months 
Duration of Participation 
Planned study duration from first dose to completion of the overall survival 
follow-up period is approximately 28 months  
Estimated Duration of Trial 
Approximately 41 months from the start of enrollment under protocol Version 9  
 
1.2 
Full Synopsis 
 
Title 
A Phase 2 Study of APX005M in Combination with Concurrent Chemoradiation as 
Neoadjuvant Therapy for Resectable Esophageal and Gastroesophageal Junction Cancers. 
Patient 
Population 
Patients with resectable (T1-3Nx, excluding T1N0) cancers of the esophagus and GE junction, 
including both squamous cell and adenocarcinomas. 
Rationale for 
Study 
Immunotherapeutic approaches have demonstrated clear evidence of therapeutic activity in a 
subset of patients with advanced gastroesophageal cancers. CD40 agonistic antibodies 
represent an attractive and novel form of immunotherapy that stimulate an immune response 
by activating antigen processing and presentation, recruiting immune effectors such as natural 
killer cells and macrophages, and additionally have direct cytotoxic effects on tumor cells. 
However, the activity of this class of agents in esophageal/GE junction cancers is unknown 
and will be evaluated in the context of this study by combining it with standard 
chemoradiation in the neoadjuvant setting, with serial collection of tissue and blood along the 
way for correlative purposes to monitor on-target treatment and pharmacodynamics effects. 




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Duration of 
Participation 
Planned study duration, from first dose to completion of the overall survival follow-up period 
is approximately 28 months. 
Treatment 
Period 
6 weeks 
Post Treatment 
Period (up to 
the date of 
surgery) 
4-10 weeks (between Study Weeks 7 and 16) 
Duration of 
Post-operative 
Follow up 
6 months 
Overall 
Survival 
Follow-up 
Period 
18 months 
Estimated 
Duration of 
Trial 
The study will reach completion approximately 41 months from the start of enrollment under 
protocol Version 9  
Study Drug/ 
Investigational 
Product 
APX005M, a CD40 agonist antibody 
 
2. BACKGROUND AND RATIONALE 
2.1 
Background on Esophageal Cancer 
There are an estimated 17,000 incident cases of esophageal cancer in the United States annually, 
with a yearly mortality rate that almost approximates the incidence rate.1 This number may in 
fact underestimate the true number of cases, depending on how GE junction adenocarcinomas 
(which can be categorized as either esophageal or gastric) are classified. Trends for histologic 
subtypes have been shifting, with the incidence of adenocarcinomas steadily climbing over the 
past several decades in Western countries, with a concomitant decline in squamous cell 
carcinomas (which still comprise the majority of cases globally).1,2 
The most commonly accepted treatment approach for patients with localized or locoregional 
esophageal/GE junction cancers consists of trimodality therapy. The CROSS trial, a Dutch 
Phase 3 trial, established the combination of preoperative low-dose weekly carboplatin, 
paclitaxel, and daily radiation over a 5-week course as the current standard of care (SOC) in 
this disease setting.3 In this trial, 92% of patients undergoing trimodality therapy underwent 
successful R0 resection, pathologic complete response (pCR; ypT0N0) rate was 29%, and 
median overall and disease-free survival rates were 49.4 months and (not yet reached), 
respectively. 


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2.2 
Background on APX005M 
CD40 and its role in tumor immunity. CD40 is a member of the tumor necrosis factor receptor 
superfamily and plays an important role in induction of tumor apoptosis and regulation of 
immune activation, especially in crosstalk between T cells and antigen presenting cells (APCs).4 
CD40 is expressed by dendritic cells (DCs), B cells, monocytes, and other non-lymphoid cells.5 
CD40 ligand (CD40L), also known as CD154, is the chief ligand described for CD40 and is 
expressed primarily by activated T lymphocytes and platelets. CD40-agonistic antibodies can 
substitute for the function of CD40/CD154 on activated T cells to boost immunity. Signaling 
through CD40 on APCs, including DCs, B cells, and monocytes, results in improved antigen 
processing and presentation, and cytokine release from activated APCs, which in turn enhance 
T-cell response.6,7 Therefore, a CD40-agonistic antibody can activate and stimulate both innate 
and adaptive immunity. 
CD40 is also expressed on many tumor cells and can mediate a direct cytotoxic effect. In 
addition to B-cell lymphoma, CD40 expression has been reported in 30−70% of primary human 
solid tumor samples, including melanoma and carcinomas.8 Activation of CD40 on tumor cells 
results in tumor cell apoptosis and inhibition of tumor growth.9 CD40-agonistic antibodies have 
demonstrated potent anti-tumor immune response in both animal models and cancer patients. 
Due to its action on both immune and tumor cells, CD40 is being studied as a target for novel 
cancer immunotherapy; agonistic anti-CD40 antibodies have been demonstrated to be potent 
stimulators of tumor immune responses in both animal models and cancer subjects.10-13 
A human or humanized immunoglobulin G (IgG) 1 antibody that can utilize Fc receptors to 
cluster CD40 and enhance CD40-agonistic effects, like APX005M, might be preferable both in 
terms of potential decreased immunogenicity and increased anti-tumor activity for use in cancer 
immunotherapy. 
Development of APX005M and preclinical data. To develop a potent CD40 agonist with 
antibody effector functions, Apexigen initially generated a humanized IgG1 anti-CD40 agonistic 
antibody named “APX005” using Apexigen’s proprietary rabbit monoclonal antibody (mAb) 
technology and mutational linkage guided humanization technology. This antibody binds to 
CD40 with high affinity and induces activation of antigen-presenting cells (APCs). In 2011, 
Li and Ravitch demonstrated that CD40 agonistic activities and its adjuvant effect on tumor 
vaccination could be enhanced by increasing the binding affinity of a CD40 agonistic antibody to 
FcγIIb receptors through a point mutation at position 267 from serine to aspartic acid (S267E).14 
To further enhance the agonistic activities of APX005, the same S267E mutation was introduced 
onto APX005 to create APX005M where “M” stands for mutation. APX005M is the drug 
candidate to be evaluated in human clinical trials. 


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APX005M is a humanized IgG1 mAb. In vitro, APX005M binds to both human and cynomolgus 
monkey CD40 with high affinity, triggering activation of APCs, including B cells, monocytes, 
and DCs and stimulating cytokine release from both human and monkey lymphocytes and 
monocytes. APX005M does not bind to rodent CD40. Through activation of APCs, APX005M is 
capable of stimulating antigen-specific T-cell responses to alloantigens, viral antigens, and tumor 
antigens. 
In vivo, APX005M demonstrated potent anti-tumor activity in multiple human CD40-expressing 
lymphoma xenograft models. Treatment with APX005M resulted in dose-dependent inhibition of 
tumor growth, tumor regression, and significant prolongation of survival in lymphoma xenograft 
models. The in vivo APX005M anti-tumor activity is possibly mediated through the mechanisms 
of antibody-dependent cell-mediated phagocytosis and induction of apoptosis. Further details 
regarding the preclinical data of APX005M are provided in the Investigator’s Brochure. 
Clinical data to date with APX005M. Study APX005M-001 is a first in human Phase 1 dose 
escalation study of APX005M with 8 pre-planned dose levels. APX005M was administered to 
study subjects at doses up to 
. At the 
 dose level, 1 out of 6 dose limiting toxicity 
(DLT)-evaluable subjects experienced a DLT [(Grade 4 cytokine release syndrome (CRS)]. Two 
additional subjects at the 
 dose level experienced serious adverse events (SAEs) in later 
cycles (Grade 3 CRS and Grade 4 thrombocytopenia). On 02 May 2016 Apexigen decided to 
discontinue dose escalation and enroll up to 6 subjects in dose level 
 (originally 
designed as an intermediate de-escalation dose level) and an additional 3 subjects at the 
previously completed dose level 
 to better characterize the safety and 
pharmacodynamics of APX005M and to help establish the single agent recommended Phase 2 
dose (RP2D). 
As of 03 April 2020, 
 subjects had received at least one dose of APX005M across 4 company 
sponsored trials (APX005M-001, APX005M-002, APX005M-006 and APX005M-010) 
(130 males [61%], age range 28–86 years):  
• 
 (28.6%) received monotherapy   
• 
 (65.3%) received systemic combination therapy with nivolumab 
• 
 (83.1%) received APX005M at the RP2D 
 
• 
 (11.3%) at doses lower than the RP2D 
• 
 (5.6%) at doses higher than the RP2D  
Across the 4 CSTs, a total of 3643 TEAEs, including 140 SAEs, have been reported in the safety 
population of 
 subjects. Almost all subjects (95.3%) experienced at least one TEAE. About 
half of all TEAEs (47.1%) were considered by the investigator to be related to APX005M 
(regardless of the relationship to other study treatments where applicable, i.e., nivolumab in 
Study APX005M-002). 


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APX005M demonstrated a dose-dependent activation of APCs (as demonstrated by increases in 
expression of activation markers such as CD54, CD70, CD80, CD86, HLA-DR), T cell 
activation and increases in circulating levels of IL-12, IFN-γ, TNF-α and IL-6.  
For further details on the completed APX005M-001 study and the other ongoing company 
sponsored studies please refer to latest version of the APX005M Investigator’s Brochure. 
2.3 
Rationale for the Proposed Study 
Immunotherapeutic approaches have demonstrated clear evidence of therapeutic activity in a 
subset of patients with advanced gastroesophageal cancers. The KEYNOTE-012 and -028 trials 
evaluated the immune checkpoint inhibitor pembrolizumab (10 mg/kg every 2 weeks) in 
advanced gastric and esophageal (squamous cell and adenocarcinomas), respectively, selected 
for programmed death-ligand 1 (PD-L1) positivity (approx. 40% of screened patients). Objective 
response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria was similar in 
both of these studies, in the 22–23% range.15,16  
To date, the activity of CD40 agonistic antibodies in esophageal/GE junction cancers is unknown. 
Patients with esophageal/GE junction cancers who have their primary tumors intact are in some 
ways ideal candidates for correlative study purposes, as they can readily undergo repeated 
endoscopic biopsies for serial tumor tissue acquisition in order to monitor on-target treatment 
and pharmacodynamic effects. 
2.4 
Rationale for the Proposed Doses Used in This Study 
The decision on appropriate starting dose of APX005M follows discussions with Apexigen and 
is based on the available safety data in the ongoing Phase 1 trial, as well as the desire to maintain 
a biologically active dose. It is recognized that the administration of study drug concurrently 
with chemoradiation has not been formally evaluated to this point and may theoretically lead to 
potentiation of toxicities, such as pneumonitis that can develop related to both thoracic radiation 
and immunotherapy.  
One conservative approach that could be undertaken would be to conduct separate dose-finding 
studies to test each combination separately. However, CD40 agonist antibodies have already 
been shown to be safe when combined with full-dose chemotherapy17, and a suitable clinical 
context in which to examine APX005M in combination with radiation to a primary tumor site 
(sans chemotherapy) is elusive. Also of note, clinical experience with other immune checkpoint 
inhibitors (anti-programmed death 1 [PD]-1/PD-L1 and anti-cytotoxic T-lymphocyte-associated 
protein [CTLA]4 mAbs) in combination with radiation in a variety of disease settings have 
suggested no major safety concerns, with immune-related AEs occurring at an observed rate 


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similar to that expected at baseline, and none that appeared specifically associated with the 
particular site irradiated.18  
Therefore, we have instead elected to test this novel combination in the neoadjuvant setting, 
using full doses of chemotherapy (carboplatin/paclitaxel) plus radiation as informed by the 
CROSS trial. Given that this is being administered in a potentially curative disease setting, we 
are employing the following strategies to maximally address safety concerns: 
• The starting dose of APX005M will be 0.3 mg/kg, which is two dose levels below the 
maximum tolerated dose identified in the ongoing Phase 1 study (
), and 1 dose 
level below the RP2D (
). The AEs observed at the 
 dose level 
(7 patients enrolled; 5 evaluable) are shown in Table 1 below; with only 1 exception 
(Grade 3 hyperuricemia) these represent Grade 1/2 (mostly Grade 1) toxicities. 
Table 1 
AEs Observed with APX005M at Dose Level 
 
MedDRA System Organ Class  
Number (%) of Patients per Maximum Reported CTCAE Grade 
  - Preferred Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Total 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  - Thrombocytopenia 
1 (20.0) 
 -  
 -  
 -  
 -  
1 (20.0) 
  - Leukocytosis 
1 (20.0) 
 -  
 -  
 -  
 -  
1 (20.0) 
CODE PENDING 
  - Code Pending 
 -  
1 (20.0) 
 -  
 -  
 -  
1 (20.0) 
GASTROINTESTINAL DISORDERS 
  - Vomiting 
1 (20.0) 
 -  
 -  
 -  
 -  
1 (20.0) 
  - Constipation 
1 (20.0) 
 -  
 -  
 -  
 -  
1 (20.0) 
  - Ascites 
1 (20.0) 
 -  
 -  
 -  
 -  
1 (20.0) 
  - Abdominal Distension 
1 (20.0) 
 -  
 -  
 -  
 -  
1 (20.0) 
  - Dry Mouth 
1 (20.0) 
 -  
 -  
 -  
 -  
1 (20.0) 
  - Rectal Haemorrhage 
1 (20.0) 
 -  
 -  
 -  
 -  
1 (20.0) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  - Fatigue 
 -  
2 (40.0) 
 -  
 -  
 -  
2 (40.0) 
  - Chills 
 -  
1 (20.0) 
 -  
 -  
 -  
1 (20.0) 
  - Asthenia 
 -  
1 (20.0) 
 -  
 -  
 -  
1 (20.0) 
  - Oedema Peripheral 
1 (20.0) 
- 
- 
- 
- 
1 (20.0) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  - Infusion Related Reaction 
- 
1 (20.0) 
- 
- 
- 
1 (20.0) 
INVESTIGATIONS 
  - Alanine Aminotransferase Increased 
1 (20.0) 
- 
- 
- 
- 
1 (20.0) 
  - Aspartate Aminotransferase Increased 
1 (20.0) 
- 
- 
- 
- 
1 (20.0) 
  - Body Temperature Increased 
1 (20.0) 
- 
- 
- 
- 
1 (20.0) 


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MedDRA System Organ Class  
Number (%) of Patients per Maximum Reported CTCAE Grade 
  - Preferred Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Total 
  - Platelet Count Decreased 
1 (20.0) 
- 
- 
- 
- 
1 (20.0) 
  - Transaminases Increased 
- 
1 (20.0) 
- 
- 
- 
1 (20.0) 
METABOLISM AND NUTRITION DISORDERS 
  - Decreased Appetite 
1 (20.0) 
- 
- 
- 
- 
1 (20.0) 
  - Hyperuricaemia 
- 
- 
- 
1 (20.0) 
- 
1 (20.0) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  - Neck Pain 
1 (20.0) 
- 
- 
- 
- 
1 (20.0) 
NERVOUS SYSTEM DISORDERS 
  - Seizure 
- 
- 
1 (20.0) 
- 
- 
1 (20.0) 
PSYCHIATRIC DISORDERS 
  - Insomnia 
1 (20.0) 
- 
- 
- 
- 
1 (20.0) 
RENAL AND URINARY DISORDERS 
  - Acute Kidney Injury 
- 
- 
2 (40.0) 
- 
- 
2 (40.0) 
RESPIRATORY DISORDERS 
 
 
 
 
 
 
  - Dyspnoea 
1 (20.0) 
- 
- 
- 
- 
1 (20.0) 
  - Hiccups 
1 (20.0) 
- 
- 
- 
- 
1 (20.0) 
SKIN/SUBCUTANEOUS 
DISORDERS 
 
 
 
 
 
 
  - Pruritus 
1 (20.0) 
- 
- 
- 
- 
1 (20.0) 
  - Rash 
1 (20.0) 
- 
- 
- 
- 
1 (20.0) 
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events;  
MedDRA = Medical Dictionary for Regulatory Activities. 
• All patients will also start with a single dose of APX005M by itself, to ensure no 
significant toxicities from administration of study drug alone (i.e. CRS) prior to initiating 
concurrent chemoradiation. 
• Stringent early stopping rules/interim safety analyses will be performed after the first 
6 patients have been enrolled, to ensure that patient safety is being maintained and that 
subjects are able to proceed to their curative resection in timely fashion. 
• Version 6 (7/24/2018): Review of the first 3 patients treated on this protocol, all of whom 
proceed to surgical resection in timely fashion, was notable for intraoperative findings of 
a significant inflammatory response and “lymphatic weeping” per description of the 
operating surgeon. Of note, 1 of these patients developed a postoperative chylous leak 
and eventually died from progressive respiratory failure; however, as this represents a 
known complication associated with esophagectomy (occurring in 3–4% of individuals), 
this was deemed unlikely related to study treatment. However, based on these findings, in 
order to mitigate the potential greater operative challenges associated with such an 
inflammatory response, the protocol is being amended to eliminate the 4th and final dose 


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of APX005M that had originally been administered 2 weeks following completion of 
chemoradiation. 
• Version 10 (12/30/2020) integrates the first dose of APX005M in the chemoradiation 
treatment period so all doses of APX005M are given concurrently with chemoradiation. 
This significantly reduces the time between screening and start of chemoradiation, which 
is especially beneficial for patients who suffer from dysphagia and pain. One additional 
dose of APX005M has been added early during the treatment phase so that patients now 
receive APX005M 
 at Weeks 1, 2, 4, and 6, which should optimize the 
therapeutic effect of the combination regimen. The increase in the frequency of 
APX005M administration should not result in significantly increased toxicity. Two-week 
and 1-week administration schedules have been evaluated in the FIH Study APX005M-
001 and no significant increase in toxicity or cumulative toxicity have been observed, 
while the 1-week schedule provided a more sustained T cell activation comparative to 
every 3-week schedule. The recommended time period between the last dose of 
APX005M and the surgery is the same as in the last protocol version so any theoretical 
concern of a potential greater operative challenge associated with an APX005M-
dependent inflammatory response remains mitigated. A safety analysis of this APX005M 
administration schedule will be performed after the first 6 patients treated under protocol 
Version 10 complete the neoadjuvant treatment period. 
• For further details on the overall safety of APX005M please refer to latest version of the 
APX005M Investigator’s Brochure. 
3. OBJECTIVES OF THE STUDY 
3.1 
Primary Objective 
To assess the efficacy of this novel combination, as measured by the pathologic complete 
response (pCR) rate 
3.2 
Secondary Objectives 
(1) To further characterize the safety and feasibility of combining APX005M with SOC 
chemoradiation (external beam radiation in daily fractions, with concurrent weekly 
low-dose carboplatin/paclitaxel) in the neoadjuvant setting for patients with resectable 
esophageal and GE junction cancers. 
(2) To assess the efficacy of combining APX005M with SOC chemoradiation as measured 
by rates of R0 resection; pathologic stage at time of surgery; and 
radiographic/metabolic response to neoadjuvant treatment on CT-PET. 


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3.3 
Exploratory Objectives 
(1) To identify possible predictive molecular or immune-based efficacy biomarkers for this 
novel combination 
(2)  To characterize and assess overall survival 
4. STUDY DESIGN 
4.1 
Characteristics 
This is a non-randomized, single-arm, open-label study.  
4.2 
Number of Subjects 
evaluable patients will be enrolled across multiple (approx. 8–12) clinical sites within 
the US. A patient is considered evaluable for the purpose of the primary analysis if she/he meets 
study eligibility criteria and have undergone surgical resection. 
4.3 
Entry Criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria. In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required evaluations and all 
regulatory requirements for informed consent. The written informed consent must be obtained 
from the patient prior to enrollment. The following criteria apply to all patients enrolled onto the 
study unless otherwise specified. 
4.3.1 Diagnosis/Condition for Entry into the Trial 
Patients with resectable (T1-3Nx, excluding T1N0) cancers of the esophagus and GE junction, 
including both squamous cell and adenocarcinomas. 
4.3.2 Administrative Procedures 
4.3.2.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 


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General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form (ICF), any subsequent revised written ICF, and any written 
information provided to the subject must receive the IRB/ERC’s approval/favorable opinion in 
advance of use. The subject or his/her legally acceptable representative should be informed in a 
timely manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the trial. The communication of this information will be 
provided and documented via a revised consent form or addendum to the original consent form 
that captures the subject’s dated signature or by the subject’s legally acceptable representative’s 
dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements. 
4.3.3 Inclusion Criteria 
1. Age ≥18 years of age 
2. Histologically proven squamous cell carcinoma, adenocarcinoma or undifferentiated 
carcinoma of the esophagus or GE junction. No more than 50% patient with squamous 
cell carcinoma should be included in the study 
3. Surgically resectable (T1-3 Nx preferably by endoscopic ultrasound [EUS]). Excluded 
are: 
a. Very early stage tumors (T1N0) 
b. Cervical esophageal tumors  
c. Tumors invading the tracheobronchial tree or associated with tracheoesophageal 
fistula 
d. Any evidence of distant metastases (as determined by EUS or CT/PET) 
e. Cervical, supraclavicular, or other nodal disease that is either not included in the 
radiation field or is not able to be resected at the time of esophagectomy 
4. Eastern Cooperative Oncology Group (ECOG) performance status 0–1 
5. Adequate hematological, renal, and hepatic parameters defined as follows: 


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a. Absolute neutrophil count (ANC) ≥1.5×109/L in absence of growth factor support  
b. Platelet count ≥150×109/L  
c. Hemoglobin >9 g/dL  
d. Serum creatinine ≤1.5 mg/dL, and calculated (using the formula of Cockcroft and 
Gault) or measured creatinine clearance ≥60 mL/min  
e. Aspartate aminotransferase and alanine aminotransferase (ALT) ≤2.5× the upper 
limit of normal (ULN)  
f. Total bilirubin ≤1.5× ULN  
6. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test 
within the 7 days prior to investigational product administration and a negative urine 
pregnancy test within the 3 days prior to the first investigational product administration, 
or a negative serum pregnancy test within the 3 days prior to the first investigational 
product administration  
7. WOCBP and male subjects who are sexually active with WOCBP must agree to use 2 
highly effective methods of contraception (including a physical barrier) during the study 
and for 30 days following the last dose of investigational product 
8. Ability to understand a written informed consent document, and the willingness to sign it 
4.3.4 Exclusion Criteria 
1. Any history of or current hematologic malignancy  
2. History of a second primary cancer is allowed in the event the cancer is curatively 
resected and there is no evidence of recurrence/metastatic disease x 1 year. Subjects who 
have a history of cervical or breast carcinoma in situ, localized prostate cancer, 
adequately treated basal cell or squamous cell carcinoma of the skin, or superficial 
bladder tumors [Ta, Tis & T1] are also allowed  
3. Major surgery within 4 weeks of first dose of investigational product  
4. Prior or concurrent treatment with any anticancer agent for the same cancer diagnosis 
5. Prior exposure to any immuno-oncology agents, including CD40/PD-1/PD-L1/CTLA-4 
inhibitors (if any ambiguity, should be discussed with the Apexigen Medical Monitor or 
designee)  
6. History of bone marrow transplantation  
7. History of organ transplant and/or concurrent immunosuppressive medication. Subjects 
with a history of organ transplant and/or concurrent immunosuppressive medication must 
be discussed with the Medical Monitor or designee prior to consent 
8. Uncontrolled diabetes or hypertension  
9. History of autoimmune disorders with the exception of vitiligo or autoimmune thyroid 
disorders 


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10.  Chronic steroid dependency (prednisone equivalent >10 mg/day). Any steroid use should 
be discontinued at least 2 weeks prior to initiation of study treatment. 
11. History of sensitivity or allergy to mAbs or IgG  
12. History of severe hypersensitivity reaction to Cremaphor EL. 
13. Pre-existing > Grade 2 peripheral sensory neuropathy. 
14. Congestive heart failure (New York Heart Association Class III to IV), symptomatic 
ischemia, conduction abnormalities uncontrolled by conventional intervention, or 
myocardial infarction within 6 months before first dose  
15. History of any arterial thromboembolic event within 3 months prior to first dose of 
investigational product  
16. Active coagulopathy  
17. Active known clinically serious infections (> Grade 2 National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI-CTCAE] Version 4.03)  
18. Known HIV infection  
19. Subjects of reproductive potential who do not use effective methods of birth control  
20. Pregnant or actively breastfeeding women 
21. Any clinically significant psychiatric, social, or medical condition that, in the opinion of 
the Investigator, could increase subject’s risk, interfere with protocol adherence, or affect 
a subject’s ability to give informed consent. 
22. Concurrent participation in any interventional trial 
4.4 
Duration of Treatment 
Treatment will continue until: 
• The patient has completed all protocol-specified aspects of study therapy.  
• Disease progression. 
• Inter-current illness prevents further administration of treatment. 
• Unacceptable AE(s) 
• Patient decides to withdraw from the study. 
• Significant patient non-compliance with protocol. 
• General or specific changes in the patients’ condition render the patient unacceptable for 
further treatment in the judgment of the Investigator. 
4.5 
Duration of Follow-Up 
Patients will be followed up to 24 months after completion of all components of study treatment. 


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4.6 
Study Timeline 
This study is anticipated to accrue patients over a 3-year period (13 months from the start of 
enrollment under protocol Version 9. 
5. TREATMENT PLAN 
5.1 
Study Overview 
Figure 1 
Study Schema 
 
Abbreviations: CT-PET = computed tomography-positron emission tomography; GEJ = gastroesophageal junction; 
XRT = external radiation therapy. 
5.2 
Systemic Treatment 
Treatment will be administered on an outpatient basis. 
Weekly low-dose carboplatin/paclitaxel will be administered as per SOC (Table 2) on the first 
visit (V1) of Study Weeks 1–5 (see Section 5.3). 
Pre-medication for carboplatin and paclitaxel will be administered according to institutional 
standards, typically consisting of anti-emetics, dexamethasone, and an H2 blocker. 


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Table 2 
Regimen Description: Systemically Administered Agents 
Drug 
Dose 
Route 
Schedule 
Paclitaxel 
50 mg/m2 
IV over 1 hour 
On the first visit (V1) of Study Weeks 1–5  
Carboplatin 
AUC = 2 
IV over 1 hour 
On the first visit (V1) of Study Weeks 1–5 
APX005M 
0.3 mg/kg 
IV over 1 hour 
On the second visit (V2) of Weeks 1, 2, 4 and 6 (2–3 days after 
chemotherapy) 
Abbreviations: AUC = area under the curve; IV = intravenous.  
During concurrent treatment (Study Weeks 1, 2, 4 and 6), APX005M will be administered on 
second visit (V2) offset by 2–3 days, from carboplatin/paclitaxel (Table 2). For example, patients 
traditionally receive their chemotherapy on a Monday, in which case APX005M would be 
administered on a Wednesday or Thursday of that same week. 
APX005M is diluted in sterile 0.9% sodium chloride solution and will be administered via an 
intravenous (IV) infusion set-up over 60 minutes. A window between ‒5 minutes and 
+10 minutes is permitted (i.e., infusion time is 55 minutes to 70 minutes). The infusion can be 
interrupted in the case of infusion-related reaction (IRR)/CRS. Once patient symptoms resolve 
infusion should be restarted at half the initial infusion rate.  
An appropriate pre-medication regimen, to be administered approximately 30 ± 5 minutes before 
any administration of APX005M, 
  
 
  
 
 
 
 
 
 
Administration of any intravenous formulations of these medications should be completed 10 ± 5 
minutes before administration of APX005M. 
After completion of the first 2 infusions of APX005M, patients will be monitored for 4 hours in 
the infusion center and will be asked to return for an outpatient follow-up the next day. 
5.2.1 Study Drug - Description, Supply and Storage of Investigational Product  
5.2.1.1 APX005M 
APX005M is a humanized mAb of the immunoglobulin G1 (IgG1) CD40 agonist and activates 
APCs (e.g., DCs, monocytes, and B cells) that stimulates cancer-specific T-cell responses. 


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Packaging and Labeling 
APX005M investigational product is supplied in 20 mL Type 1 clear glass vials for IV injection. 
Each depyrogenated vial contains 
APX005M in a sterile, clear to slightly opalescent, 
colorless to slightly yellow, preservative-free solution (pH 5.5) 
 
 for injection with a target fill 
volume of 16.9 mL per vial. Glass vials are plugged with Teflon®-coated rubber stoppers and 
sealed with aluminum seals. The 20 mL vials (16.9 mL/vial) are intended for single use.  
Additional APX005M details including labeling, storage, and preparation information are 
provided in the Pharmacy Manual. It should be noted that the Pharmacy Manual may be 
updated/revised as additional information becomes available. 
APX005M will be labeled and packaged according to Good Manufacturing Practice and product 
manufacturing specifications, adhering to applicable local and federal laws. 
Storage and Dispensing 
The APX005M investigational product should be stored in a secure location with limited access 
under controlled temperature conditions of 2–8°C and in accordance with local regulations. Vials 
should be stored in their original folding carton to protect from light. If concerns regarding the 
quality or appearance of the investigational product arise, do not dispense the investigational 
product and contact the sponsor immediately. 
The investigational product must be dispensed only from official study sites by authorized 
personnel according to local regulations. It is the responsibility of the Investigator to ensure that 
the investigational product is only dispensed to study subjects. APX005M must be administered 
to study subjects by qualified personnel. 
Safety Precautions 
When handling investigational product, wear laboratory coats and disposable protective gloves. 
Avoid contact with eyes, skin, and clothing. Protect it from light and contamination. 
Drug Accountability 
It is the responsibility of the Investigator to ensure that a current record of APX005M disposition 
is maintained at each study site where APX005M is inventoried and disposed. Records or logs 
must comply with applicable regulations and guidelines and should include: 
• Quantity of APX005M received and placed in storage area  
• Quantity of APX005M currently in storage area  
• APX005M label information  


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• Dates and initials of person responsible for each APX005M inventory entry/movement  
• Quantity of APX005M dispensed to each subject, including unique subject identifiers  
• Non-study disposition of APX005M (e.g., lost, wasted, and/or broken)  
• Quantity of APX005M returned to Apexigen or designee for destruction  
• Quantity of APX005M destroyed at study site, if applicable  
Apexigen or designee will provide forms to facilitate inventory control if the staff at the 
investigational site does not have an established system that meets these requirements. 
Upon completion or termination of the study, all unused and/or partially used APX005M must be 
returned to Apexigen or designee if not authorized by Apexigen or designee to be destroyed at 
the site. All APX005M returned to Apexigen or designee must be accompanied by the 
appropriate documentation and clearly identified by protocol number and study site number on 
the outermost shipping container. Returned supplies should be in the original containers 
(e.g., kits that have clinical labels attached). Empty containers should not be returned. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures and appropriate records of disposal are kept. 
If APX005M vials are to be destroyed onsite, it is the Investigator’s responsibility to ensure that 
arrangements have been made for the disposal, written authorization has been granted by 
Apexigen or designee, procedures for proper disposal have been established according to 
applicable regulation and guidelines and institutional procedures, and appropriate records of the 
disposal have been documented. The unused APX005M can only be destroyed after being 
inspected and reconciled by the responsible Apexigen or designee Study Monitor. Complete and 
updated AE information is available in the Investigator’s Brochure. 
Each participating site/institution is responsible for site management of drug accountability 
records. 
Drug Ordering 
Each participating site will obtain APX005M directly from Apexigen as study supply. The 
details for initial and resupply will be described in the pharmacy manual. 
5.3 
Radiotherapy 
Summary: Total dose of radiation will be 5040 cGy in 180 cGy fractions (Table 3). 


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Table 3 
Regimen Description: Radiation 
Radiation 
Therapy 
Dose 
Schedule 
5040 cGy in 28 fractions of 180 cGy 
28 daily fractions administered Weeks 1−6 
 
Technical Factors: Linear accelerators with a minimum energy of 6-15 MV will be used. A 
multiple field 3-D conformal technique or intensity modulated radiation therapy (IMRT) will be 
used. All fields will be treated each day. The patient will be treated in the supine position. 
Radiation will be delivered up to 5 days/week, once per day. 
CT-based conformal planning is required on this study. In accordance with current guidelines for 
use of IMRT in clinical trials (see http://qarc.org/), IMRT may be used only if the degree of 
tumor motion is assessed and can be limited to 1.0 cm or techniques are used to compensate for 
respiratory motion. 
Protocol Treatment Volumes: A volumetric treatment planning CT study will be required for 
this study. Each patient will be positioned in an individualized immobilization device in the 
treatment position on a flat table. Contiguous CT slices, with 3-5 mm thickness, will be obtained 
starting from the level of the cricoid cartilage and extending inferiorly through the liver. A 
measurement scale for the CT image shall be included. 
Gross Tumor Volume (GTV): The GTV is based on the pre-chemotherapy extent of disease 
using the initial PET/CT scan, endoscopy report, and CT scan. The entire esophageal wall, 
including any disease that has extended through the wall should be contoured as the GTV as well 
as any PET/CT-avid or enlarged lymph nodes. 
Clinical Target Volume (CTV): The intent of pre-operative treatment is to include the tumor plus 
the nodal groups at risk (whether clinically positive or negative). The CTV should encompass the 
peri-esophageal lymph nodes, mediastinal lymph nodes for mid- and upper- thoracic esophageal 
tumors, and the submucosal spread longitudinally along the esophagus. This is generally a  
3–4 cm expansion on the GTV superiorly and inferiorly and 1.0 cm expansion radially. For distal 
esophageal tumors and GE junction tumors, the CTV should include the celiac lymph nodes. For 
tumors above the carina, the supraclavicular lymph nodes should be included in the CTV. 
Planning Target Volume (PTV): The PTV is established by expanding the CTV by 0.5 cm in all 
directions. This will result in a margin of up to 5 cm superior and inferior and approximately 
1.0–2 cm radially to the extent of tumor (GTV). For distal esophageal and GE junction tumors 
where motion management is not being used, the superior-inferior expansion can be 0.7–1.0 cm 
to account for the respiratory motion. 


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Target Dose Constraints: 
Dose Prescription: The prescribed dose to the PTV is 5040 cGy delivered in 180 cGy/day over 
28 fractions, to be administered during Weeks 1–6, ideally, 5 fractions from Monday to Friday 
during Weeks 1–5 and Monday to Wednesday during Week 6. 
Dose Uniformity: The dose to 99% of the PTV must be at least 93% of the prescribed dose, and a 
contiguous volume of no more than 2cc inside the PTV may exceed 20% of the prescribed dose. 
Tissue Heterogeneity: Calculation shall take into account the effects of tissue heterogeneities. 
Planning must be performed using an approved dose calculation algorithm. Approved algorithms 
include: convolution superposition, collapsed cone convolution, and Monte Carlo. 
Normal tissue Dose Constraints: The normal structures to be contoured will depend on the 
level of the esophagus involved, but can include left and right lungs, heart, esophagus, brachial 
plexus, left and right kidneys, liver, stomach, small intestine, and spinal canal. The dose to 
normal tissues must be kept within the parameters described below. 
1. Lungs 
a. V20Gy ≤20% 
b. and V30Gy ≤15% 
c. and V40Gy ≤10% 
d. V10Gy ≤40% 
e. V5Gy <60% 
2. Cord 
a. Max ≤4500 cGy 
3. Bowel 
a. Max bowel dose < Max PTV dose 
b. and D05 ≤45 Gy 
4. Heart 
a. V40Gy ≤50%  
b. Mean <3000 cGy 
5. L and R kidney: 
a. No more than 33% of the volume can receive 1800 cGy 
6. Liver 
a. V20Gy ≤30 % 
b. V30Gy ≤20 
c. mean <21 Gy 


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7. Stomach 
a. Mean <3000 cGy (if not within PTV) 
b. Max dose <54 Gy 
Treatment Planning: 
Simulation: Patients will be positioned supine with arms above the head. A CT simulation will 
be performed using 3–5 mm slice thickness. In patients for whom treatment will be delivered 
using respiratory gating or tracking, the planning CT scan should be performed with the patient 
in a breath-hold in end expiration. 
Motion Management: For distal esophageal and GE junction tumors, respiratory motion can be 
significant, requiring an assessment of the degree of tumor motion at the time of simulation. 
To determine the extent of respiratory motion, a respiratory correlated CT scan may be obtained 
at the time of simulation. This scan will be performed throughout the breathing cycle (i.e., 
4-dimensional CT) so that separate CT data sets associated with each phase of respiration can 
later be reconstructed. Treatment delivery can be done using the motion management technique 
available at the institution and can include treatment during free-breathing as long as an internal 
target volume has been designed based on the motion of the tumor on the 4D-CT.  
Beam Arrangements: 
1. 3D Conformal Beam Arrangements: Beam arrangement selection for 3D conformal treatment 
will vary based on the shape, size, and location of the CTV and the resulting PTV in relation 
to normal organs.  
2. IMRT - Beam Arrangement: A five-field beam arrangement is preferred to minimize the low 
dose distributed to the lungs. Suggested beam arrangements are: 
a. For distal esophagus the following beam arrangement is useful for minimizing dose to the 
heart and lungs: left posterior-anterior oblique (155), left anterior-posterior oblique 
(LAO; 70–80), anteroposterior (0), right anterior-posterior oblique (RAO; 280–290), 
right posterior-anterior oblique (205)  
Note that the range of gantry angles for the LAO and RAO fields is due to the fact that 
one needs to find the best compromise between the amount of heart and lung in the field. 
b. For GE-junction esophagus, the following beam arrangement may be substituted if it is 
better for minimizing dose to the kidney. All beams are 15 MVx: posteroanterior (180º), 
close to left lateral (90º±10º), LAO (30–35º), RAO (325–330º), close to right lateral 
(270º±10º). All beams are 15 MV X-ray beams.  
These recommended beam arrangements may be changed to one more fitting for the 
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Field Verification: As a minimum requirement, verification images are obtained at the start of 
treatment and at least each week thereafter. Patients treated with IMRT should have daily 
planning. Prior to the first treatment, images that verify the position of the isocenter placement 
must be obtained. Imaging can consist of portal or orthogonal images, or cone beam CT.  
Definitions of Deviations in Protocol Performance 
Prescription Dose 
• No Deviation: ≥99% of the PTV receives ≥93% of the prescribed dose, and a contiguous 
volume of no more than 2cc inside PTV exceeds 20% of the prescribed dose. 
• Minor Deviation: Deviations of this magnitude are not desirable, but are acceptable. 
Coverage that is equal to 93% of the prescribed dose and falls between 99% and 95% of 
the PTV, or a contiguous volume of no more than 2cc inside the PTV exceeds 20–25% of 
the prescribed dose. 
• Major Deviation: Doses in this region are not acceptable. More than 1 cm3 of tissue 
outside the PTV receives ≥120% of the prescribed dose, or 93% of the prescribed dose 
falls below 95% of the PTV, or a contiguous volume of no more than 2cc inside the PTV 
exceeds 25% of the prescribed dose. 
Volume 
• Minor Deviation: Margins less than specified, or field(s) 1–3 cm greater than specified. 
• Major Deviation: Fields transect tumor or specified target volume(s), or fields are more 
than 3 cm greater than specified. 
Critical Organ 
• Major Deviation: The maximum dose to the spinal cord exceeds 4500 cGy; the heart 
mean dose exceeds 3000 cGy; the lung V20 exceeds 30% or the V10 exceeds 50%  
• Minor Deviation: The lung V20 exceeds 20% or the V10 exceeds 40% 
Treatment Interruption 
• Minor Deviation: Treatment interruptions between five and nine normally scheduled 
treatment days. 
• Major Deviations: Treatment interruptions totaling more than nine normal scheduled 
treatment days. 
For centers that prefer to use proton beam therapy prescription dose, target and organ at risk 
volumes, field verification, and other radiation procedures for proton beam therapy will be 
similar to IMRT, unless defined otherwise.  


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Proton Simulation and Motion Management 
A motion management technique-specific treatment planning CT (e.g., 4DCT, breath-hold, 
gating, Active Breathing Control (ABC) etc.) will be required for every patient.  
Proton Planning Procedures  
Free-breathing CT that is generated from a 4DCT, such as an average intensity pixel CT 
(AveIP), mid-ventilation CT, the breath-hold/gated CT, or the free-breathing CT acquired with 
no other motion management will be the primary dataset for dose calculation. Passively scattered 
proton therapy (PSPT) or pencil beam scanning (PBS) proton beams will be used for patients 
enrolled in the proton arm, but PBS is recommended when available. 
For proton planning, each beam has an individual and unique beam specific PTV (bsPTV) 
expansion from the CTV. In the plane perpendicular to the beam axis, the bsPTV expansion from 
the CTV is according to the method used for photons. The CTV expansion along the distal and 
proximal margins of the beam axis will be based on established algorithms to account for range 
uncertainty of the beam. The PTV is only used for evaluation purposes. 
For PSPT planning, two or three beam approaches have been most commonly used, using 
posterior-anterior, left lateral oblique +/- left posterior-lateral oblique beams. For PBS planning, 
two or three beam approaches have also been most commonly utilized, using a pair of right and 
left posterior-oblique beams +/- posterior-anterior beam. 
For PSPT planning the compensator will be smeared based on accepted algorithms. 
For PBS, single field optimization (SFO) and multi field optimization (MFO) are permitted. 
Robust optimization (RO) is recommended. Robust evaluation for setup and range uncertainties 
should be performed and the dose on the worst case scenario should meet planning criteria for 
GTV and CTV. The plan should be recalculated and evaluated on both inhale and exhale phases 
if a 4DCT is used and dose to GTV and CTV on both phases should meet planning criteria. 
5.4 
Surgical Considerations 
All patients will be evaluated by a surgeon at the pre-registration visit and at the end of their 
neoadjuvant therapy. It is recommended that patients have surgery no earlier than 4 weeks and 
no greater than 10 weeks after last dose of APX005M (Study Weeks 10 to 16). Determination of 
resectability after completion of neoadjuvant therapy will be at the discretion of the treating 
team.  


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Any of the following surgical approaches are deemed acceptable, as long the approach includes 
the surgical removal of any lymph nodes felt to be suspicious: 
• Ivor Lewis esophagogastrectomy 
• Thoracoabdominal esophagectomy 
• 3-hole esophagectomy (McKeown procedure) 
• Transhiatal esophagectomy 
• Minimally invasive esophagectomy 
A gross surgical margin of at least 5 cm both proximally and distally are recommended. A frozen 
section of both the proximal and distal surgical margin should be obtained to confirm a negative 
microscopic surgical margin. Surgeons are encouraged to dissect the entirety of each lymph node 
station as opposed to sampling individual lymph nodes. Cumulative pathologic evaluation of at 
least 15 lymph nodes, with a preferred target of 18 lymph nodes, is recommended to allow for 
complete staging and accurate prediction of prognosis.  
5.5 
Dose Modifications and Dosing Delays 
Management of suspected AEs may require temporary interruption and/or dose reduction of 1 or 
more components of study treatment, as shown in Table 4. Toxicity will be described and graded 
according to the NCI-CTCAE Version 4.03. If a patient experiences several toxicities, the 
recommended dose adjustment should be based on the highest grade toxicity. Up to 2 dose 
reductions of each agent are permissible; beyond this, the subject will be discontinued from 
treatment. 
Table 4 
Dose Levels 
 
Starting Dose 
Dose Level ‒1 
Dose Level ‒2 
APX005M 
0.3 mg/kg 
Carboplatin 
AUC 2 
AUC 1.5 
AUC 1 
Paclitaxel 
50 mg/m2 
40 mg/m2 
30 mg/m2 
Abbreviations: AUC = area under the curve. 
5.5.1 Hematologic Toxicity 
During concurrent chemoradiation, given the known potential for cytopenia associated with 
carboplatin and paclitaxel, these chemotherapy agents will be first to be modified with any 
episode of clinically relevant hematologic toxicity (Table 5). 


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Table 5 
Dose Modifications Due to Hematologic Toxicity 
Hematologic Toxicity 
Chemotherapy 
(carboplatin/paclitaxel) 
APX005M 
≥ Grade 3 ANC 
Interrupt chemotherapy* until ANC 
improves to ≤ Grade 2, then resume 
treatment at 1 dose level lower of 
carboplatin and paclitaxel 
Maintain dose level 
For neutropenic fever (body temperature 
>38.3ºC (oral) and ANC <1000/mm3) consider 
reducing the APX005M dose following 
discussion with the Apexigen Medical Monitor 
or designee. 
≥ Grade 3 platelets 
Interrupt chemotherapy* until 
platelets improve to ≤ Grade 2, then 
resume treatment at 1 dose level 
lower of carboplatin and paclitaxel 
Maintain dose level. 
Reduce by 1 dose level for platelets Grade ≥3 
with bleeding or requiring blood transfusion  
Abbreviations: ANC = absolute neutrophil count. 
* 
Investigator will defer to the radiation oncologist as to whether an interruption of the radiation therapy is also 
indicated. 
Any scheduled dose of APX005M should also be held while chemoradiation is being held.  
5.5.2 Non-Hematologic Toxicity 
During concurrent chemoradiation, non-hematologic toxicities may prompt dose reductions of 
either or both chemotherapy agents (carboplatin and paclitaxel) and/or APX005M, depending on 
the treating physician’s adjudication of which agents are most likely to be contributing to the 
specific toxicity(ies). As a general rule, for known common side effects associated with 
carboplatin and paclitaxel such as nausea, fatigue, and/or peripheral sensory neuropathy, these 
agents may be reduced first while the dose of APX005M remains unchanged. However, in 
specific instances, it may be appropriate to simultaneously consider a dose reduction of 
APX005M, including Grade 3 nausea, vomiting, or diarrhea lasting >72 hours despite optimal 
medical management. 
Table 6 
Dose Modifications Due to Non-Hematologic Toxicities 
Toxicity 
Severity 
Carboplatin/paclitaxel 
APX005M 
Neurologic toxicity 
(peripheral 
neuropathy) 
Grade 2 
Reduce paclitaxel by 1 dose level 
for all subsequent doses. 
No change in carboplatin dosing. 
Maintain dose level. 
Grade 3 
Permanently discontinue 
paclitaxel. 
No change in carboplatin dosing. 
Maintain dose level. 
Grade 4 
Discontinue study treatment. 
Discontinue study 
treatment. 


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Toxicity 
Severity 
Carboplatin/paclitaxel 
APX005M 
Hepatic dysfunction 
Total bilirubin  
1.5−3 × ULN AND 
AST/ALT  
≤2.5 × ULN 
Decrease paclitaxel by 1 dose 
level for all subsequent doses. 
No change in carboplatin dosing. 
Maintain dose level. 
Total bilirubin  
≤1.5 × ULN AND 
AST/ALT  
2.5−10 × ULN 
Decrease paclitaxel by 1 dose 
level for all subsequent doses. 
No change in carboplatin dosing. 
Maintain dose level. 
Total bilirubin 
1.5−3 × ULN, AND 
AST/ALT 
2.5−10 × ULN 
Decrease paclitaxel by 2 dose 
levels for all subsequent doses. 
No change in carboplatin dosing. 
Maintain dose level. 
Total bilirubin 
>3 × ULN OR 
AST/ALT 
>10 × ULN 
Permanently discontinue 
paclitaxel. 
No change in carboplatin dosing. 
Decrease by 1 dose level 
for all subsequent doses 
IRR to paclitaxel 
Grade 1-2 
Stop infusion. Administer H1 
and/or H2 blockers, and/or 
steroids according to institutional 
policy. Restart the infusion when 
symptoms resolve and pretreat 
before all subsequent doses. 
Maintain dose level. 
Delay APX005M to the 
following week if 
steroids were used to 
treat the infusion 
reaction. 
Grade 3-4 
Stop infusion and permanently 
discontinue paclitaxel; may 
continue with carboplatin for 
remaining doses.  
Maintain dose level. 
Delay APX005M to the 
following week if 
steroids were used to 
treat the infusion 
reaction. 
IRR/CRS to 
APX005M 
Grade 1-2 
Maintain dose level. 
Stop infusion 
Symptomatic treatment. 
Maintain dose level. 
Grade 3 
Maintain dose level. 
Decrease by 1 dose level 
for all subsequent doses. 
Grade 4 
Maintain dose level. 
Permanently 
discontinue. 
Nausea/vomiting  
Grade 3 
(≥6 episodes of 
vomiting in 24 hours)  
for 3 days or more, 
despite optimal medical 
management 
Interrupt chemotherapy* until 
improves to ≤ Grade 2, then 
resume treatment. 
1st incidence: Maintain dose level 
2nd incidence +: Reduce by 1 
dose level 
Treat at same time as 
chemoradiation is 
resumed. 
1st and 2nd incidence: 
Maintain dose level 
≥3rd incidence: Reduce 
by 1 dose level  
Grade 4 
Discontinue study treatment. 
Discontinue study 
treatment. 


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Toxicity 
Severity 
Carboplatin/paclitaxel 
APX005M 
Diarrhea 
Grade 3  
(≥7 stools per 24 hours 
over baseline)  
for 3 days or more, 
despite optimal medical 
management 
Interrupt chemotherapy* until 
improves to ≤ Grade 2, then 
resume treatment. 
1st incidence: Maintain dose level 
2nd incidence +: Reduce by 1 
dose level 
Treat at same time as 
chemoradiation is 
resumed. 
1st and 2nd incidence: 
Maintain dose level 
≥3rd incidence: Reduce 
by 1 dose level 
Grade 4 
Discontinue study treatment. 
Discontinue study 
treatment. 
Other 
Grade 3 
Interrupt chemotherapy* until 
improves to ≤ grade 2, then 
resume treatment at 1 reduced 
dose level. 
Treat at same time as 
chemoradiation is 
resumed; consider 
reducing the APX005M 
dose following 
discussion with the 
Apexigen Medical 
Monitor or designee 
Grade 4 
Discontinue study treatment. 
Discontinue study 
treatment (unless 
discussed and approved 
by the Apexigen Medical 
Monitor or designee) 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal. 
* 
Investigator will defer to the radiation oncologist as to whether an interruption of the radiation therapy is also 
indicated. 
6. STUDY PROCEDURES AND OBSERVATIONS 
6.1 
Participant Registration 
A written, signed ICF and a Health Insurance Portability and Accountability Act authorization 
must be obtained before any study-specific assessments are initiated. A copy of the signed ICF 
will be given to the subject and a copy will be filed in the medical record. The original will be 
kept on file with the study records.   
6.2 
Schedule of Procedures and Observations 
The study-specific assessments are detailed in this section. Any safety laboratory results falling 
outside of the reference ranges may be repeated at the discretion of the Investigator. Please refer 
to the Table 7 for a summary of all study procedure and assessments. 
6.2.1 Screening 
The Screening procedures and assessments must be completed within 28 days of Day 1 of the 
treatment period unless otherwise stated: 


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• Physical examination 
• Vital signs 
• Complete medical history and demographics 
• ECOG performance status 
• Baseline medications/concomitant medication (conmeds) 
• Baseline AE assessment 
• CT-PET scan (historical test results for CT-PET may be acceptable if within 28 days 
prior to first administration of APX005M) 
• Endoscopic ultrasound confirming appropriate T and N staging for study eligibility is 
recommended (historical test results for endoscopic ultrasound obtained within 56 days 
prior to first administration of APX005M may be acceptable) 
• Laboratory evaluation per local laboratory assessment including: 
o Complete blood count (CBC) with differential (CBC diff) 
o Chemistry panel  
o Coagulation assessments (PT/INR, PTT) 
• Serum and urine pregnancy test for WOCBP 
• Urinalysis 
• Electrocardiogram 
• Upper endoscopy with biopsy for immune correlates completed within 14 days prior to 
Day 1 of study treatment (archival tissue samples from initial diagnosis may be 
acceptable if the patient is unable to complete an endoscopy) 
6.2.2 Treatment Period (Week 1-6) 
Every effort should be made to adhere to this schedule, acknowledging there may be delays or 
treatment interruptions due to AEs that produce some deviations in schedule.  
6.2.2.1 Radiotherapy 
Twenty-eight daily fractions of radiotherapy administered up to 5 times/week (recommended 
Monday-Friday during Weeks 1–5 and Monday–Wednesday during Week 6).  
6.2.2.2 Visit 1 (Chemotherapy Visit, Week 1–5) 
Visit strongly recommended to be scheduled on Monday. 


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• Vital signs 
• ECOG performance status 
• Conmeds 
• AE assessment 
• Laboratory evaluation including: 
o CBC diff 
o Chemistry panel 
o Weeks 1, 3 and 5 only, Coagulation panel (PT/INR, PTT) 
• Week 1 prior to chemotherapy dosing only, Blood/plasma samples for molecular or 
immune-based correlates (Appendix 2) 
• Administration of carboplatin + paclitaxel  
6.2.2.3 Visit 2 (Immunotherapy Visit, Week 1, 2, 4, 6) 
Visit during Weeks 1, 2, and 4 is strongly recommended to be scheduled on a Wednesday 
or Thursday (2–3 days after carboplatin + paclitaxel administration). 
Visit during Week 6 can be scheduled Monday or Tuesday. 
• Vital Signs 
• Conmeds 
• AE assessment 
• Week 6 only, ECOG performance status  
• Week 6 only, laboratory evaluation including: 
o CBC diff 
o Chemistry panel 
• Week 1 prior to APX005M dosing only, Plasma samples for cytokines (Appendix 2) 
• Week 6 prior to APX005M dosing only, Blood/plasma samples for molecular or 
immune-based correlates (Appendix 2) 
• Infusion of APX005M  
• Monitor the patient for 4 hours after APX005M infusion (first 2 infusions only) 
 
6.2.2.4 Visit 3 (Safety Follow-up, Week 1, 2, 4, 6) 
Visit should be scheduled 24 hours ± 6 hours after infusion of APX005M and may be 
conducted remotely if no sample collection is required.  


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• Vital signs (required if visit is conducted in clinic) 
• Conmeds 
• AE assessment 
• Week 1 24 hours ± 6 hours post APX005M dosing only, Plasma samples for cytokines 
(Appendix 2) 
6.2.3 Post Treatment Period (Weeks 7-16) 
Prior to Surgery  
• CT-PET scan (no earlier than 4 weeks after last dose of APX005M) 
• Vital signs 
• ECOG performance status 
• Conmeds 
• AE assessment 
• Laboratory evaluation including (after CT-PET/prior to surgery): 
o CBC diff 
o Chemistry panel 
o Coagulation panel (PT/INR, PTT) 
• Blood/plasma samples for molecular or immune-based correlates (Appendix 2) prior to 
CT-PET scan 
• Surgical Resection (recommended no earlier than 4 weeks and no later than 10 weeks 
after last dose of APX005M (Study Weeks 10 to 16). 
• Tissue collection (surgical specimen) for molecular or immune-based correlates (Appendix 2) 
6.2.4 Follow-Up Visits 
Post-Operative Follow-Up 
Three post-operative visits should be scheduled at Months 1, 3, and 6 post-operatively. The 
following procedures should be performed at those time points: 
• Vital signs 
• ECOG performance status 
• Conmeds 
• AE assessment 
• Laboratory evaluation including: 


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o CBC diff 
o Chemistry panel 
• Blood/plasma samples for molecular or immune-based correlates (Appendix 2) at the 
3-month follow up prior to CT/CT-PET scan 
• CT or CT-PET scan at 3 and 6 months post-operatively (or at End of Study visit) 
Overall Survival Follow-Up 
After the 6 months post-operative follow up visit, patients will be contacted approximately every 
3 months for approximately 18 months to determine survival status. When contacting the patient, 
the following will be determined: 
• Subject status 
• Disease progression (as determined by routine CT/CT-PET, if available) 
• Subsequent anti-cancer therapy 
6.2.5 End of Study Visit 
All patients who discontinue study or withdraw consent (see Section 6.6) prior to the 6 months 
post-operative follow up visit should attend an End of Study (EOS) visit: 
• Vital signs 
• ECOG performance status 
• Conmeds 
• AE assessment 
• Laboratory evaluation including: 
o CBC diff 
o Chemistry panel 
• Blood/plasma samples for molecular or immune-based correlates (Appendix 2) prior to 
CT/CT-PET scan 
• CT or CT-PET scan 






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6.4 
Usage of Concurrent/Concomitant Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for 1 of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The Investigator should discuss any questions regarding this with 
the Apexigen Medical Monitor or designee. The final decision on any supportive therapy or 
vaccination rests with the Investigator and/or the subject's primary physician.  
All treatments that the Investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter, herbal supplements, and IV medications and fluids. 
If changes occur during the trial period, documentation of drug dosage, frequency, route, and 
date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of APX005M and 
30 days after the last dose of APX005M should be recorded. Concomitant medications 
administered after 30 days after the last dose of APX005M should be recorded for SAEs. 
The following medications are optional and are allowed during the study:  
• Anti-nausea and anti-emetics: per institutional standards  
• Antidiarrheals: For subjects developing Grade 1–2 diarrhea, loperamide (2 mg every 
2 hours) is strongly recommended at the first onset of symptoms. For subjects with 
persistent diarrhea despite the use of loperamide, the use of octreotide is recommended. 
Other antidiarrheal agents may be used if necessary; a work-up for other etiologies is 
suggested for subjects who progress to Grade 3 or 4 diarrhea while taking loperamide  
• Myeloid growth factors (e.g., granulocyte-colony stimulating factor) may be used if 
neutropenia occurs, in accordance with American Society of Clinical Oncology 
Guidelines [34], but are not to be given prophylactically and should not be substituted for 
a required dose reduction  
• Red blood cell transfusions, erythropoietic-stimulating agents, or platelet transfusions, if 
clinically indicated in accordance with institutional guidelines  
• Treatment with non-conventional therapies (e.g., acupuncture), and vitamin/mineral 
supplements is acceptable provided that they do not interfere with treatment and the study 
endpoints  
• Subjects may receive SOC for any underlying illness or treatment emergent AEs  


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6.4.1 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-CR relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy for either palliative or 
therapeutic intent  
• Herbal medicine for anticancer treatment should be stopped 1 week prior to 1st dose of 
investigational product. 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol  
• Investigational agents other than APX005M 
• Radiation therapy not specified in this protocol 
• Live vaccines within 30 days prior to the first dose of APX005M and while participating 
in the trial. Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, intranasal influenza 
vaccines and typhoid vaccine. Seasonal influenza vaccines for injection and COVID-19 
vaccines are allowed as long as they can be administered 6–7 days prior and after a 
dose of APX005M (minimum 6–7 days prior to treatment period, Week 3 or 5 of 
treatment period, minimum 6–7 days after end of treatment period). 
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology (excluding standard pre-
medication for paclitaxel and management of acute AEs). The use of physiologic doses of 
corticosteroids may be approved after consultation with the Medical Monitor or designee.  
Subjects who, in the assessment by the Investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial. Subjects may receive other 
medications that the Investigator deems to be medically necessary. 
6.4.2 Management of Infusion Related Reaction/Cytokine Release Syndrome 
Subjects should be instructed that symptoms associated with IRR/CRS can occur at any time 
following the administration of the APX005M, and if such symptoms develop while they are at 
home, they should contact the study doctor/study team and/or seek emergency medical care if 
appropriate.  
Steroids should not be used routinely to prevent or treat IRR/CRS as steroidal therapy may 
significantly impair the therapeutic benefit, however, these suggestions do not contraindicate the 
use of any medicine clinically needed under emergency circumstances including epinephrine, 


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diphenhydramine, methylprednisolone or other steroids, nebulized albuterol, or any other 
medicine needed including additional narcotics to manage treatment-related symptoms as 
clinically indicated. 
In the event of toxicities consistent with IRR/CRS consider the recommendations in Table 8: 
Table 8 
Management of IRR/CRS 
Toxicity Suspected to be Related to Infusion/ 
Cytokine Release 
Recommended Treatment 
• 
Mild toxicity requiring symptomatic treatment only  
(e.g., fever with or without constitutional symptoms, 
nausea, fatigue, headache, myalgia, malaise) 
• 
Vigilant supportive care 
• 
Maintain adequate hydration 
• 
Antipyretics, nonsteroidal 
anti-inflammatory drugs, antihistamines, 
anti-emetics, analgesics as needed 
• 
In case of mild symptoms persisting for 
>48 hours assess for infection, empiric 
treatment of concurrent bacterial 
infections 
• 
Symptoms or clinical findings requiring 
and responding to moderate 
intervention, such as:  
o 
O2 requirement <40% 
o 
Hypotension responsive to fluids ± 
low dose of 1 vasopressor  
(e.g., <50 mg/min phenylephrine) 
o 
CTCAE Grade 2 organ toxicity 
No extensive 
comorbidities 
• 
All of the above 
• 
Monitor cardiac and other organ 
functions closely 
Extensive 
comorbidities 
Age ≥70 years 
• 
All of the above 
• 
Administer tocilizumab first 
• 
Administer corticosteroids if symptoms 
worsen or do not improve in <4 hours 
• 
Symptoms or clinical findings requiring aggressive 
intervention, such as: 
o 
O2 requirement ≥40% 
o 
Hypotension requiring high dose or multiple 
vasopressors 
o 
Ventilator support required 
Abbreviations: CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse Events; 
IRR = infusion related reaction. 
6.5 
Diet/Activity/Other Considerations 
6.5.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
6.5.2 Contraception 
The effect of APX005M on a fetus in utero is unknown. It is also not known if APX005M has 
transient adverse effects on the composition of sperm. 


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Carboplatin has been shown to be embryotoxic and teratogenic in rats. Paclitaxel caused embryo- 
and fetotoxicity in rabbits. There are no adequate and well-controlled studies of carboplatin or 
paclitaxel in pregnant women. Carboplatin or paclitaxel may cause fetal harm when administered 
to a pregnant woman. WOCBP participating in this study must avoid becoming pregnant. 
It is not known whether carboplatin or paclitaxel is excreted in human milk. Because there is a 
possibility of toxicity in nursing infants secondary to carboplatin or paclitaxel treatment of the 
mother, breast-feeding must be discontinued if the mother is treated with carboplatin/paclitaxel. 
The human embryo and fetus are sensitive to ionizing radiation. As such, radiation exposure to 
an embryo/fetus may increase the risk of cancer in the developing baby or even increase the 
probability of miscarriage depending on the radiation dose. 
Subjects must agree to use an adequate method of contraception starting prior to the first dose of 
study therapy through 90 days after the last dose of study therapy, and their partners should be 
encouraged to use adequate method of contraception as well. The following are considered 
adequate barrier methods of contraception: condom, spermicide (by the partner), diaphragm (by 
the partner), copper intrauterine device (by the partner), sponge (by the partner), or spermicide. 
Appropriate hormonal contraceptives (for the partner) will include any registered and marketed 
contraceptive agent that contains an estrogen and/or a progestational agent (including oral, 
subcutaneous, intrauterine, or intramuscular agents). Male subjects must agree to not donate 
sperm during the period of the study and for a period of 90 days after the last dose of study 
therapy. 
Subjects must be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study by the subject’s partner. If there 
is any question that a subject will not reliably comply with the requirements for contraception, 
that subject must not be enrolled into the study. 
6.6 
Subject Withdrawal/Study Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be taken off the trial at the 
discretion of the Investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the Investigator or the Sponsor if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons. Specific details regarding 
discontinuation or withdrawal procedures are provided in Section 6.2.5. A subject withdrawing 
or being discontinued prior to the 6-month post-operative follow up visit should attend the EOS 
Visit, if feasible. 


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A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws consent 
• Confirmed radiographic disease progression 
• Unacceptable adverse experiences 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed the study follow-up period. 
• Administrative reasons 
6.7 
Replacement Policy 
All patients who receive at least 1 dose of APX005M will be analyzed for safety. A patient is 
considered evaluable for the purpose of the primary analysis if she/he meets study eligibility 
criteria and have undergone surgical resection. Patients who are not evaluable for the purpose of 
the primary analysis or who discontinue from study participation prior to receiving any study 
therapy may be replaced after discussion with the Apexigen Medical Monitor or designee. 
6.8 
Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
• Quality or quantity of data recording is inaccurate or incomplete 
• Poor adherence to protocol and regulatory requirements 
• Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
• Plans to modify or discontinue the development of the study drug 
In the event of the Sponsor’s decision to terminate the study notification will be provided to sites 
so that appropriate adjustments to patient treatment can be made. 
7. REPORTING AND DOCUMENTATION OF RESULTS 
7.1 
Evaluation of Efficacy  
Subjects are not expected to have RECIST measurable disease; therefore, response and 
progression in this study will be evaluated as follows: 


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a) Post-treatment CT-PET: Results will be based on combination of change in wall 
thickening, size of regional lymph nodes, and metabolic activity of involved areas, and 
will be categorized as 1 of the following: 
i) Responding 
ii) Stable/unchanged 
iii) Progressing 
iv) Not evaluable. 
Responses will be assessed by the Investigator. Raw standardized uptake values will also 
be entered into electronic data capture (EDC). 
b) pCR at surgery: yes/no 
Responses will be assessed by the Investigator. The pathology report will also be 
submitted to the Sponsor. 
7.2 Assessing and Recording Adverse Events 
The AE definitions and reporting procedures provided in this protocol comply with the current 
Code of Federal Regulations for IND safety reporting (21CFR312.32). The Apexigen Medical 
Monitor (or designee) must promptly review all information relevant to the safety of the 
investigational product received from any source. The Investigator or appropriately qualified 
designee (e.g., a certified nurse practitioner or physician’s assistant properly listed on the Form 
FDA 1572) will carefully monitor each subject throughout the study for possible AEs. 
7.2.1 Definitions of Adverse Events 
Adverse Event 
AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. 
Suspected Adverse Reaction 
Suspected adverse reaction (SAR) means any AE for which there is a reasonable possibility that 
the drug caused the AE. For the purposes of IND safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the drug and the AE. SAR 
implies a lesser degree of certainty about causality than adverse reaction, which means any AE 
caused by a drug. 
Serious AE or Serious SAR 
An AE or SAR is considered “serious” (SAE or serious SAR [SSAR]) if, in the view of either 
the Investigator or sponsor, it results in any of the following outcomes:  


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• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
any of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Life-threatening 
An AE or SAR is considered “life-threatening” if, in the view of either the Investigator or 
Sponsor, its occurrence places the patient or subject at immediate risk of death. It does not 
include an AE or SAR that, had it occurred in a more severe form, might have caused death. 
Unexpected AE or Unexpected SAR 
An AE or SAR is considered "unexpected" if it is not listed in the Investigator’s Brochure or is 
not listed at the specificity or severity that has been observed; or, if an Investigator’s Brochure is 
not required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as amended. For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the 
Investigator’s Brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, 
cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the Investigator’s Brochure listed only cerebral vascular accidents. "Unexpected," 
as used in this definition, also refers to AEs or SARs that are mentioned in the Investigator’s 
Brochure as occurring with a class of drugs or as anticipated from the pharmacological properties 
of the drug, but are not specifically mentioned as occurring with the particular drug under 
investigation. 
Overdose of APX005M 
For this trial, an overdose will be defined as APX005M >1 mg/kg body weight.  
No specific information is available on the management of an overdose of APX005M. It is 
expected that an overdose of APX005M will be associated with severe CRS. In the event of 
overdose, the subject should be observed closely for signs of toxicity. Appropriate supportive 


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treatment should be provided if clinically indicated. Retreatment after an overdose must be 
discussed with Apexigen Medical Monitor or designee. 
7.3 
Adverse Event Classification 
7.3.1 Relationship to Study Treatment 
The Investigator will assess the possible attribution of the each of the different modalities of 
study treatment (APX005M and/or chemotherapy [carboplatin/paclitaxel] and/or radiation) to the 
event; this information will be entered into EDC system using the classification as related or 
unrelated as defined listed below:  
The event is suspected to be related if: 
• There is a clinically plausible time sequence between the AE onset and study treatment 
• There is a biologically plausible mechanism for the study treatment to cause or contribute 
to the AE 
• The event improves or diminishes upon temporary interruption of the study treatment 
without the initiation of any specific treatment for the event (dose delay) and/or recurs or 
worsens when resuming treatment after criteria for retreatment are met 
• The AE cannot be reasonably attributed to concurrent or underlying illness, other drugs, 
or procedures 
The Apexigen Medical Monitor (or designee) will review all Investigator-reported assessments 
of relationship and confirm. 
The event is not suspected to be related if: 
• The AE is more likely to be explained by the subject’s underlying disease, clinical state, 
concomitant medication, or study or non-study procedure 
• The time occurrence of the AE is not reasonably related to study treatment 
• The event is not related to study treatment 
7.3.2 Severity 
The NCI-CTCAE, v4.03, will be used to describe the event and to assess the severity of AEs. 
For AEs not adequately addressed in the NCI-CTCAE Version 4.03, Table 9 should be used. 


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Table 9 
General Toxicity Grading of AEs 
Severity 
Description 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of ADL* 
Grade 3 
Severe; medically significant but not immediately life threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self-care ADL** 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death related to AE 
Abbreviations: ADL = activities of daily living; AE = adverse event. 
Semi-colon indicates “or” within the description 
* 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden 
Abnormal laboratory findings should be reported as AEs only if they are clinically relevant.  
AE will be reported at the highest grade experienced. An AE that completely resolves and then 
recurs will be recorded as a new AE. 
7.4 
Collection and Reporting 
7.4.1 General AE Reporting 
All AEs will be collected from the time the subject receives any investigational product through 
30 days after receiving the last dose of investigational product, death, or initiation of new 
anticancer therapy, whichever occurs first. SAEs and AEs with potential immunologic etiology 
will be recorded up to 100 days and pregnancies up to 120 days after the last dose of 
investigational product, death, or initiation of new anticancer therapy, whichever occurs first. 
Events that occur after the subject signs the informed consent but prior to the first dose of 
investigational product will be recorded as past medical history; events that start after the first 
dose of investigational product will be recorded as AEs. In addition, the Investigator should 
report any AEs that may occur after this time period which are assessed to have a reasonable 
possibility of being associated with investigational products. 
All AEs must be promptly documented on the AE electronic CRF (eCRF). The minimum 
information required for each AE includes event, duration (start and end dates), start time 
(for events occurring within 48 hours after the start of APX005M infusion) severity, seriousness, 
causality to investigational product, action taken, and outcome. Whenever possible, reporting 
specific diagnosis is preferred when reporting AEs in the AE eCRF rather than reporting 
individual signs and symptoms except for infusion related reactions and CRS.  


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All AEs that are considered related to investigational products must be followed to resolution, 
stabilization, until improvement is not expected, 30 days after receiving the last dose of 
investigational product, death, or initiation of new anticancer therapy, whichever occurs first. 
SSARs will be followed until resolution, stabilization, or until resolution is not anticipated. 
If an office visit is not possible, a follow-up of ongoing AEs should be attempted by telephone 
and documented in the subject’s source file. AEs continuing at 30 days after the last dose of 
investigational product should have a comment in the source file by the Investigator that the 
event has stabilized or is not expected to improve. 
The Investigator is responsible for evaluating all AEs, obtaining supporting source documents, 
and determining that documentation of the event is adequate. The Investigator may delegate 
these duties to sub-investigators and must ensure that these sub-investigators are qualified to 
perform these duties under the supervision of the Investigator and that they are listed on the 
Form FDA 1572. 
7.4.2 Disease Progression 
Disease progression will be documented in an eCRF intended to capture such information. Signs 
and symptoms related to disease progression should be reported in the appropriate eCRF as an 
AE or as a SAE if applicable. Verbatim terms such as “disease progression,” “progressive 
disease,” etc. should not be reported as AEs or SAEs unless the Investigator considers the 
progression to be atypical, accelerated, or caused by the investigational products. Similarly, 
death occurring as a result of disease progression should be reported on the eCRF intended to 
capture death information and should not be reported as an SAE. 
7.4.3 Serious AEs or Serious SARs 
Apexigen (or designee) must be notified of the occurrence of any SAE/SSAR within 24 hours of 
Investigator’s knowledge of the event. The SAE/SSAR will be reported by completing and 
submitting the SAE/SSAR report form by: 
Email: 
 
If only limited information is initially available, follow-up reports are required and must be 
submitted in a timely fashion as additional information becomes available. The immediate and 
follow-up reports should identify subjects by unique code numbers assigned to the trial subjects 
rather than by the subjects' names, personal identification numbers, and/or addresses. 
The Investigator should also comply with the applicable regulatory requirements related to the 
reporting of SAEs/SSARs to the regulatory authorities and the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC). The sponsor may request additional source 
documentation pertaining to the SAE/SSAR from the investigational site. If a subject is 


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permanently withdrawn from the study due to an SAE/SSAR, this information must be included 
in the initial or follow up SAE/SSAR report in the eCRF. 
The sponsor is responsible for notifying the appropriate health authorities of unexpected SSARs 
through expedited IND safety reports (ISR) in accordance with applicable laws and regulations. 
7.4.4 Handling of Expedited Safety Reports 
Apexigen (or designee) will notify Investigators of all ISRs. Upon receiving an ISR from 
Apexigen (or designee), the Investigator must review and retain the ISR with the Investigator’s 
Brochure. Where required by local regulations or when there is a central IRB/IEC for the study, 
Apexigen (or designee) will submit the ISR to the appropriate IRB/IEC. The Investigator and 
IRB/IEC will determine if the informed consent requires revision. The Investigator should also 
comply with the IRB/IEC procedures for reporting any other safety information. 
7.4.5 Non-serious AEs 
The collection of AE information begins after subject’s written consent to participate in the 
study; AEs that occur after consent, but prior to the first dose should be recorded as medical 
history. If an ongoing AE changes in its intensity or in its perceived relationship to 
investigational product, a new AE entry for the event should be completed. AEs should be 
followed to resolution, stabilization, a minimum of 30 days after the discontinuation of the 
investigational product or reported as SAEs if they become serious. 
7.4.6 Laboratory Test Abnormalities 
Laboratory test values captured as part of the study should be recorded on the appropriate pages 
of the eCRF. Laboratory abnormalities that meet any of the following criteria will also be 
captured on the AE or SAE reporting eCRF page as appropriate: 
• Require the subject to have any of the investigational products discontinued, delayed, or 
interrupted 
• Require the subject to receive specific corrective therapy 
• Are clinically significant 
• Meet the definition of an SAE/SSAR. 
7.5 
Pregnancy Reporting 
Subjects will be instructed to notify the Investigator as soon as possible after becoming pregnant 
or learning of the pregnancy of a partner. If a subject or partner of a subject becomes pregnant 
during treatment or up to 120 days following the last study drug administration, the Investigator 
will notify Apexigen (or designee) within 24 hours of learning of the pregnancy.  


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If the subject becomes pregnant while receiving study treatment, the study treatment should be 
permanently discontinued. Exceptions to the discontinuation may be considered for life-
threatening conditions only after consultation with the sponsor. The Investigator will discuss the 
risks and concerns of study treatment to a developing fetus and counsel the subject and/or 
pregnant partner (or ensure that such counseling is provided).  
Pregnancies will be followed through the outcome of the pregnancy. Newborns should be 
followed for a minimum of 8 weeks.  
The Investigator will complete a Pregnancy Surveillance Form and report the information 
regarding the pregnancy, outcome, and status of the newborn, as appropriate. 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy. Other appropriate pregnancy follow-up procedures 
should be considered if indicated. 
8. STATISTICAL CONSIDERATIONS AND EVALUATION OF RESULTS 
8.1 
Sample Size 
The primary objective of this study is to assess the efficacy of combining APX005M with SOC 
chemoradiation (carboplatin/paclitaxel/radiation therapy), as measured by the pCR rate. 
evaluable patients will be enrolled to this Phase 2 study. The null hypothesis that 
the true pCR is 29% will be tested against a 1-sided alternative of 53% using an Exact Binomial 
Test with a Type 1 error rate of 0.05 and power of 81%. A minimum number of 
evaluable 
patients with adenocarcinoma histology will allow to test the null hypothesis that the true pCR is 
23% against a 1-sided alternative of 53% with a Type 1 error rate of 0.05 and power of 77%. 
8.2 
Interim Analyses and Stopping Rules 
Due to this study being conducted in the neoadjuvant setting, this trial will have to following 
safeguards in place to ensure that study treatment does not compromise patients’ ability to make 
it to their planned (potentially) curative operation in a timely fashion: 
The study will be halted to accrual for analyses of safety/tolerability after the first 6 patients have 
been enrolled. Enrollment may continue once this cohort of patients has completed their 
neoadjuvant therapy. 
The first 6 patients enrolled under protocol Version 10 or later will undergo a safety assessment. 
If >2 of the first 6 patients enrolled in the study and if >2 of the first 6 patients enrolled after the 
implementation of protocol Version 10 or later experience unacceptable toxicities attributable to 


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the addition of APX005M to standard chemoradiation, then enrollment will be halted and the 
trial design will be reconsidered, including but not limited to the possibility of amending the 
study to use a lower starting dose of APX005M (while maintaining an unchanged fixed dose of 
chemoradiation) or reverting to APX005M administration schedule in Version 9 of the protocol. 
Unacceptable toxicities include: 
• Grade 3 or higher non-hematologic toxicity, excluding the following: 
o Grade 3 nausea, vomiting or diarrhea lasting <48 hours after providing optimal 
supportive care 
o Grade 3 anorexia 
o Grade 3 fatigue 
o Grade 3–4 IRR to paclitaxel 
• Grade 3–4 IRR to APX005M or Grade 3-4 CRS 
• If any AE(s) (of any grade) attributable to study treatment leads to a delay in the patient 
being able to make it to surgery within 20 weeks of starting study treatment, the study 
will be suspended and the trial design reconsidered. Scheduling conflicts, patient 
preference, or other logistic reasons unrelated to toxicity do not count. 
8.3 
Analyses Plans 
8.3.1 Populations for Analyses 
All subjects receiving APX005M will be included in the safety population. 
Primary efficacy population include patients who meet all study eligibility criteria and have 
undergone surgical resection. Secondary efficacy population include patients who meet all study 
eligibility criteria and have a post-treatment CT-PET scan. 
8.3.2 Primary Endpoint 
The primary efficacy measure is the proportion of patients who achieve a pCR (pCR rate). These 
data will be reported both for the entire study cohort and for each histologic subgroup. An exact 
Clopper-Pearson lower 95% confidence limit will be used to test the null hypothesis that the pCR 
rate is ≤30%. If the lower 95% confidence limit is above 30%, the null hypothesis will be 
rejected and it will be concluded that the pCR rate is higher than 30%. 
8.3.3 Secondary Endpoints 
Other efficacy data (secondary endpoints) that will be captured include rates of R0 resection; 
pathologic stage at time of surgery; and radiographic/metabolic response to neoadjuvant 
treatment on CT-PET. As this patient population does not typically have measurable disease by 
RECIST, the radiographic/metabolic response will be described in qualitative terms 


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(i.e., improved/stable/worse). This data will be reported both for the entire study cohort and for 
each histologic subgroup. 
The assessment of safety (secondary endpoint) will be based mainly on the frequency of AEs and 
on the number of laboratory values that fall outside of pre-determined ranges. AEs will be 
summarized by presenting, at each dose level, the number and percentage of patients having any 
AE, having an AE in each body system and having each individual AE. Any other information 
collected (e.g. severity or relatedness to study medication) will be listed as appropriate. 
Toxicities will be tabulated by grade and organ system using the NCI-CTCAE v4.03. Number of 
patients with dose modifications and reason for dose modification will be tabulated. 
In the CROSS trial establishing this preoperative chemoradiation regimen as SOC, the overall 
incidence of non-hematologic Grade 3–4 toxicity was 13%. We hypothesize that the 
experimental treatment being evaluated in the current protocol will be safe and tolerable, which 
we define as not substantially increasing the incidence of non-hematologic Grade 3–4 toxicity 
(or operative delays) in this patient population. 
Feasibility: This study will be considered feasible if no patients require a delay in their planned 
surgery for reasons of toxicity attributable to investigational product.  
8.3.4 Exploratory Endpoints 
Descriptive statistics will be used for the exploratory studies, as this work should be considered 
preliminary in nature and the sample size inadequate to clearly demonstrate the predictive utility 
of any of the correlatives being evaluated or their changes in response to treatment. This will 
include: 
(1) Identification of possible predictive molecular or immune-based efficacy biomarkers for 
this novel combination 
(2)  Characterization and assessment of overall survival 
Exploratory readouts will be summarized by descriptive statistics for each time point. Wilcoxon 
singed-rank test will be used to compare the measurements between baseline and post-induction 
with APX005M alone/post-APX005M/chemoradiation, separately to assess if there is any 
change from baseline to post-treatment. In addition, the baseline measurements will be compared 
between the pCR patients vs. non-pCR patients by Wilcoxon rank-sum test. 


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9. ADMINISTRATIVE AND REGULATORY DETAILS 
9.1 
Compliance with the Protocol and Protocol Revisions 
This study will be conducted in accordance with this study protocol and with ICH GCP 
guidelines, the United States Code of Federal Regulations, Title 21, Part 50 (21CFR50), as well 
as all other applicable country and regional legal and regulatory requirements. The Investigator is 
responsible for ensuring that this protocol, the site’s ICF, and any other information that will be 
presented to potential subjects are reviewed and approved by the appropriate IRB/IEC prior to 
the enrollment of any study subjects. 
If a protocol revision substantially alters the study design or increases the potential risk to the 
subject:  
1. The consent form must be revised and submitted to the IRB/IEC for review and 
approval/favorable opinion 
2. The revised consent form must be used to obtain consent from subjects currently enrolled 
in the study if they are affected by the revision 
3. The new consent form must be used to obtain consent from new subjects prior to 
enrollment 
If the revision is an administrative letter, Investigators must inform their IRB/IEC. 
9.2 
Institutional Review Board/Independent Ethics Committee 
The Investigator must obtain written and dated approval/favorable opinion from the IRB/IEC for 
the protocol, consent form, subject recruitment materials/process (e.g., subject leaflets), and any 
other written information to be provided to subjects. The Investigator or sponsor should also 
provide the IRB/IEC with a copy of the Investigator’s Brochure or product labeling, information 
to be provided to subjects and any updates. Revisions to the protocol must also be approved by 
the IRB/IEC prior to the implementation of changes in this study.  
The Investigator or sponsor should provide the IRB/IEC with reports, updates, and other 
information (e.g., expedited safety reports, protocol revisions, and administrative letters) 
according to regulatory requirements or institution procedures. 
9.3 
Informed Consent 
Written informed consent is required from each subject prior to any testing under this protocol, 
including screening tests and evaluations. The ICF, as specified by the clinical site’s IRB/IEC, 
must follow the Protection of Human Subjects regulations listed in the CFR, Title 21, Part 50. 


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Investigators must ensure that subjects or, in those situations where consent cannot be given by 
subjects, their legally acceptable representative, are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding this clinical study in which they volunteer to 
participate. The information that is given to the subject or the representative shall be in a 
language understandable to the subject or representative. Freely given written informed consent 
prior to clinical study participation must be obtained from every subject or, in those situations 
where consent cannot be given by subjects, their legally acceptable representative, including 
informed consent for any screening procedures conducted to establish subject eligibility for the 
study. 
If a subject is unable to read or if a legally acceptable representative is unable to read, an 
impartial witness should be present during the entire informed consent discussion. After the 
written ICF and any other written information to be provided to subjects, is read and explained to 
the subject or the subject’s legally acceptable representative, and after the subject or the subject’s 
legally acceptable representative has orally consented to the subject’s participation in the trial 
and, if capable of doing so, has signed and personally dated the ICF, the witness should sign and 
personally date the consent form. By signing the consent form, the witness attests that the 
information in the consent form, and any other written information, was accurately explained to, 
and apparently understood by, the subject or the subject's legally acceptable representative, and 
that informed consent was freely given by the subject or the subject’s legally acceptable 
representative. 
Preparation of the consent form is the responsibility of the Investigator and must include all 
elements required by ICH, GCP and applicable regulatory requirements as well as adhere to GCP 
and ethical principles that have their origin in the Declaration of Helsinki. The consent form 
must also include a statement that sponsor and Regulatory Authorities have direct access to 
subject records. Apexigen (or designee) will provide the Investigator with a sample consent 
form.  
Prior to the beginning of the study, the Investigator must have the IRB/IEC’s written 
approval/favorable opinion of the written ICF and any other information to be provided to the 
subjects. The Investigator must provide the subject or legally acceptable representative with a 
copy of the consent form and allow time necessary for subject or subject’s legally acceptable 
representative to inquire about the details of the study, then informed consent must be signed and 
personally dated by the subject or the subject’s legally acceptable representative and by the 
person who conducted the informed consent discussion.  
The subject or legally acceptable representative should receive a copy of the signed informed 
consent and any other written information provided to study subjects prior to subject’s 
participation in the trial. 


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9.4 
Monitoring 
The Investigator/institution must agree to the inspection of study-related records by the 
regulatory authority/Apexigen (or designee) representative and must allow direct access to 
source documents to the regulatory authority/Apexigen (or designee) representative/IRB/IEC. 
Apexigen (or designee) representative will review onsite study records and directly compare 
them with source documents, discuss the conduct of the study with the Investigator, and verify 
that the facilities remain acceptable. 
The Investigator must notify Apexigen (or designee) promptly of any inspections by regulatory 
authorities and forward promptly copies of inspection reports to Apexigen (or designee).  
9.5 
Confidentiality 
All records identifying the subject will be kept confidential to the full extent of the law. 
Subject names will not be supplied to the sponsor. Only the subject number will be recorded on 
the eCRF. If the subject name appears on any other document (e.g., pathologist report) or study 
materials (e.g., biopsy tissue slides), then that information must be redacted before a copy of the 
document is supplied to Apexigen (or designee). Study data stored on a computer will be stored 
in accordance with local data protection laws and regulations. Subjects will be informed in 
writing that representatives of the sponsor, IRB/IEC, or regulatory authorities may inspect their 
medical records to verify the information collected, and all personal information made available 
for inspection will be handled in strictest confidence and in accordance with local data protection 
laws and regulations. 
If the results of the study are published, the subject’s identity will remain confidential. 
The Investigator will maintain a list to enable subjects’ records to be identified in accordance 
with applicable laws and regulations and according to the terms and agreed upon in such 
subjects’ signed consent forms. 
9.6 
Investigational Site Training 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective task(s). 
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (e.g., loss of medical licensure or 
debarment). 


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Systems with procedures that assure the quality of every aspect of the study will be implemented. 
If necessary, Apexigen (or designee) will provide investigational staff training prior to study 
initiation. Training topics will include, but are not limited to, GCP, AE reporting, study details 
and procedure, study documentation, informed consent, and enrollment of WOCBP. 
9.7 
Data Collection and Handling 
9.7.1 Case Report Forms 
As part of the responsibilities assumed by participating in the study, the Investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol. The Investigator agrees to maintain accurate eCRFs and source documentation as part 
of the case histories. These source documents may include subject diaries, laboratory reports, and 
other documents. Apexigen (or designee) will supply the eCRF, which will be completed in 
English. 
Data collection will involve the use of the EDC system, to which only authorized personnel will 
have access. 
The Investigator or designee must enter all results collected during the clinical study into eCRFs. 
Guidelines for completion of eCRFs will be reviewed with study site personnel at the site 
initiation visits. Investigators are responsible for approval of the entered/corrected data. Detailed 
instructions may be found in the other study-specific documents. 
All entries made on the eCRF must be verifiable against source documents. In addition to 
periodic monitoring occurring within the system by study monitors, programmatic edit checks 
and data listings will be used to review the data for completeness, logic, and adherence to study 
protocol. As a result of this monitoring and these checks and queries may be electronically issued 
to the clinical study sites and electronically resolved by those sites. 
All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records. Also, data will be stored and 
evaluated in such a way as to assure subject confidentiality in accordance with the legal and 
regulatory requirements applying to protected health information. Study records (e.g., copies of 
eCRFs and regulatory documents) will be retained at the study site, along with adequate source 
documentation. The study file and all source data should be retained for the time period required 
by applicable regulatory requirements and will not be destroyed until written notification is given 
by Apexigen (or designee) for destruction. 


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9.8 
Publications 
The data collected during this study are confidential and proprietary to Apexigen. Any 
publications or abstracts arising from this study require approval by Apexigen prior to 
publication or presentation and must adhere to Apexigen’s publication requirements (as set forth 
in the approved clinical trial agreement). All draft publications, including abstracts or detailed 
summaries of any proposed presentations, must be submitted to the sponsor at the earliest 
practicable time for review, but at any event not less than 30 days before submission. Apexigen 
shall have the right to delete any confidential or proprietary information contained in any 
proposed presentation or abstract and may delay publication for up to 60 days for purposes of 
filing a patent application. 
 
 


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10. REFERENCES 
1 
Hur, C. et al. Trends in esophageal adenocarcinoma incidence and mortality. Cancer 119, 
1149-1158, doi:10.1002/cncr.27834 (2013). 
2 
Rustgi, A. K. & El-Serag, H. B. Esophageal carcinoma. The New England journal of 
medicine 371, 2499-2509, doi:10.1056/NEJMra1314530 (2014). 
3 
van Hagen, P. et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. 
The New England journal of medicine 366, 2074-2084, doi:10.1056/NEJMoa1112088 
(2012). 
4 
Aggarwal, B. B. Signalling pathways of the TNF superfamily: a double-edged sword. 
Nature reviews. Immunology 3, 745-756, doi:10.1038/nri1184 (2003). 
5 
Banchereau, J. et al. The CD40 antigen and its ligand. Annual review of immunology 12, 
881-922, doi:10.1146/annurev.iy.12.040194.004313 (1994). 
6 
Clark, E. A. & Ledbetter, J. A. How B and T cells talk to each other. Nature 367, 425-
428, doi:10.1038/367425a0 (1994). 
7 
Grewal, I. S. & Flavell, R. A. CD40 and CD154 in cell-mediated immunity. Annual 
review of immunology 16, 111-135, doi:10.1146/annurev.immunol.16.1.111 (1998). 
8 
Eliopoulos, A. G. & Young, L. S. The role of the CD40 pathway in the pathogenesis and 
treatment of cancer. Current opinion in pharmacology 4, 360-367, 
doi:10.1016/j.coph.2004.02.008 (2004). 
9 
Hess, S. & Engelmann, H. A novel function of CD40: induction of cell death in 
transformed cells. The Journal of experimental medicine 183, 159-167 (1996). 
10 
Khong, A., Nelson, D. J., Nowak, A. K., Lake, R. A. & Robinson, B. W. The use of 
agonistic anti-CD40 therapy in treatments for cancer. International reviews of 
immunology 31, 246-266, doi:10.3109/08830185.2012.698338 (2012). 
11 
Law, C. L. & Grewal, I. S. Therapeutic interventions targeting CD40L (CD154) and 
CD40: the opportunities and challenges. Advances in experimental medicine and biology 
647, 8-36, doi:10.1007/978-0-387-89520-8_2 (2009). 
12 
Rakhmilevich, A. L., Alderson, K. L. & Sondel, P. M. T-cell-independent antitumor 
effects of CD40 ligation. International reviews of immunology 31, 267-278, 
doi:10.3109/08830185.2012.698337 (2012). 
13 
Tong, A. W. & Stone, M. J. Prospects for CD40-directed experimental therapy of human 
cancer. Cancer gene therapy 10, 1-13, doi:10.1038/sj.cgt.7700527 (2003). 
14 
Li, F. & Ravetch, J. V. Inhibitory Fcgamma receptor engagement drives adjuvant and 
anti-tumor activities of agonistic CD40 antibodies. Science (New York, N.Y.) 333, 1030-
1034, doi:10.1126/science.1206954 (2011). 
15 
Bang, Y.-J. et al. Relationship between PD-L1 expression and clinical outcomes in 
patients with advanced gastric cancer treated with the anti-PD-1 monoclonal antibody 
pembrolizumab (MK-3475) in KEYNOTE-012. Journal of Clinical Oncology 33, 4001-
4001, doi:10.1200/jco.2015.33.15_suppl.4001 (2015). 


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16 
Doi, T. et al. Pembrolizumab (MK-3475) for patients (pts) with advanced esophageal 
carcinoma: Preliminary results from KEYNOTE-028. Journal of Clinical Oncology 33, 
4010-4010, doi:10.1200/jco.2015.33.15_suppl.4010 (2015). 
17 
Beatty, G. L. et al. A phase I study of an agonist CD40 monoclonal antibody 
(CP-870,893) in combination with gemcitabine in patients with advanced pancreatic 
ductal adenocarcinoma. Clinical cancer research : an official journal of the American 
Association for Cancer Research 19, 6286-6295, doi:10.1158/1078-0432.ccr-13-1320 
(2013). 
18 
Pike, L. et al. Multi-institution evaluation of outcomes following radiation and PD-1 
inhibition (abstract). In 31st Annual Meeting of the Society of Immunotherapy of Cancer 
(SITC) (National Harbor, MD, 2016). 
 
 
 


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11. APPENDICES 
Appendix 1:  Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity 
Fully active, able to carry on all pre-
disease performance without restriction 
100 
Normal, no complaints, no evidence of 
disease 
90 
Able to carry on normal activity; minor signs 
or symptoms of disease 
1 
Symptoms, but ambulatory 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work) 
80 
Normal activity with effort; some signs or 
symptoms of disease 
70 
Cares for self, unable to carry on normal 
activity or to do active work 
2 
In bed < 50% of the time 
Ambulatory and capable of all self-care, 
but unable to carry out any work 
activities 
Up and about more than 50% of waking 
hours 
60 
Requires occasional assistance, but is able to 
care for most of his/her needs 
50 
Requires considerable assistance and 
frequent medical care 
3 
In bed > 50% of the time 
Capable of only limited self-care, 
confined to bed or chair more than 50% 
of waking hours 
40 
Disabled, requires special care and assistance 
30 
Severely disabled, hospitalization indicated 
Death not imminent 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
20 
Very sick, hospitalization indicated 
Death not imminent 
10 
Moribund, fatal processes progressing 
rapidly 
5 
Dead 
0 
Dead 
Abbreviations: ECOG = Eastern Cooperative Oncology Group. 
 
 
 


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Appendix 2:  Immune Correlative Tissue and Blood Sample Collection 
A. Tumor tissue collection 
Patients will undergo upper endoscopy with tissue biopsy at screening. When a patient is unable 
to complete an endoscopy a formalin fixed paraffin embedded historical tissue sample may be 
acceptable after consultation with the Medical Monitor or designee. Details about the number of 
core biopsies and procedure specific recommendation are provided in the laboratory manual. In 
general, the size and the number of cores collected is determined by patient safety, accessibility 
and size of lesion at the discretion of the physician performing the procedure. 
Patients will undergo surgical resection of their primary tumor and associated lymph nodes. 
Tissue samples should be collected from primary tumor or from dissected lymph nodes that 
could contain tumor tissue. If available, normal tissue form the proximal and distal surgical 
margins could be collected.  
Three to four core biopsies/tissue fragments will be collected and processed separately with the 
following priority: 
• Formalin fixed paraffin embedded (FFPE) 
• Fresh frozen tumor specimen for RNA analysis 
• Fresh frozen tumor specimen for DNA analysis 
B. Blood samples collection 
Whole blood and plasma samples for molecular or immune-based correlates will be collected at 
the following time points: 
• Treatment Period Week 1 Visit 1 (prior to chemotherapy dosing)   
• Treatment Period Week 6 Visit 2 (prior to APX005M dosing) 
• Post Treatment Period, prior to CT-PET scan 
• At the 3-month follow-up visit or EOS visit prior to CT/CT-PET 
Additional plasma samples for cytokines will be collected at the following time points: 
• Treatment Period Week 1 Visit 2 (prior toAPX005M dosing) 
• Treatment Period Week 1 Visit 3 (24 hours ± 6 hours post APX005M dosing)  
Details about collection procedure, volumes, and processing and shipping of tissue, whole blood 
and plasma samples are provided in the Laboratory Manual.  

SAP_001.pdf: 
Protocol Number: APX005M-006 
 
Official Title: A Phase 2 Study of APX005M in Combination with Concurrent Chemoradiation as 
Neoadjuvant Therapy for Resectable Esophageal and Gastroesophageal Junction Cancers 
 
NCT Number: NCT03165994 
 
Document Date: 08 March 2023 


 
 
QMS Document Name: Statistical Analysis Plan 
Page 1 of 23 
QMS No (include version ref): STF-015-GL.02 
Document date: 09JUL2019 
CONFIDENTIAL 
 
 
 
 
 
Protocol No: APX005M-006 
CP Project ID: APE19006 
 
 A Phase 2 Study of APX005M in Combination with Concurrent 
Chemoradiation as Neoadjuvant Therapy for Resectable Esophageal and 
Gastroesophageal Junction Cancers 
 
 
 
 
Statistical Analysis Plan 
Final Analysis 
Version: 3.0 
Date: 8 March 2023 
 
 
 
 
 
 




 
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Statistical Analysis Plan: Final  
 
 
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QMS No (include version ref): STF-015-GL.02 
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Table of Contents 
 
 
1 
Introduction .................................................................................................................................... 5 
1.1 
Preface ................................................................................................................................... 5 
1.2 
Background ............................................................................................................................ 5 
1.3 
Timing of statistical analyses ................................................................................................. 5 
2 
Modification History ....................................................................................................................... 6 
2.1 
Changes to the study protocol .............................................................................................. 6 
2.2 
Changes to previous SAP versions ......................................................................................... 6 
3 
Study Design.................................................................................................................................... 7 
3.1 
Protocol synopsis................................................................................................................... 8 
3.2 
Sample size estimation .......................................................................................................... 8 
3.3 
Randomisation, blinding and unblinding procedures ........................................................... 8 
4 
Analysis Populations ....................................................................................................................... 9 
4.1 
Screening Population ............................................................................................................ 9 
4.2 
Safety Population .................................................................................................................. 9 
4.3 
Per Protocol Population ........................................................................................................ 9 
4.4 
Efficacy Population ................................................................................................................ 9 
5 
General Statistical Methods and Definitions .................................................................................. 9 
5.1 
General statistical methods ................................................................................................ 10 
5.2 
Covariates and strata .......................................................................................................... 10 
5.3 
Subgroups ............................................................................................................................ 10 
5.4 
Missing data ........................................................................................................................ 11 
5.5 
Observation and analysis times........................................................................................... 11 
6 
Subject Accounting and Disposition ............................................................................................. 13 
6.1 
Subject accounting .............................................................................................................. 13 
6.2 
Disposition and withdrawals ............................................................................................... 13 
6.3 
Protocol deviations ............................................................................................................. 14 
7 
Demographics and Background Characteristics ........................................................................... 14 
7.1 
Demographics...................................................................................................................... 14 
7.2 
Baseline characteristics ....................................................................................................... 14 
7.3 
Medical history .................................................................................................................... 15 
8 
Previous and Concomitant Therapies ........................................................................................... 15 


 
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9 
Exposure ........................................................................................................................................ 16 
10 Efficacy .......................................................................................................................................... 17 
10.1 Primary efficacy analysis ..................................................................................................... 17 
10.2 Secondary efficacy analyses ................................................................................................ 17 
10.3 Exploratory Objective .......................................................................................................... 18 
11 Safety ............................................................................................................................................ 19 
11.1 Adverse events .................................................................................................................... 19 
11.2 Vital signs ............................................................................................................................. 20 
11.3 Clinical safety laboratory ..................................................................................................... 20 
11.4 ECG ...................................................................................................................................... 21 
11.5 Physical examination ........................................................................................................... 22 
11.6 Overall Survival .................................................................................................................... 22 
11.7 Disease Free Survival (DFS) ................................................................................................. 22 
11.8 ECOG performance status ................................................................................................... 22 
12 Interim Analyses............................................................................................................................ 22 
13 Software ........................................................................................................................................ 22 
14 Abbreviations ................................................................................................................................ 23 
15 References .................................................................................................................................... 23 
 
 
 


 
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1 
Introduction 
1.1 
Preface 
The objective of this document is to detail the statistical methodology to be used for the final 
statistical analysis of APX005M-006 study. APX005M-006 study underwent 10 amendments and 
details are described in the protocol amendments. 
The statistical analysis plan is based on the following study protocol APX005M-006: 
• 
Version 1 dated 05 July 2016 
• 
Version 2 dated 21 March 2017 
• 
Version 3 dated 25 May 2017 
• 
Version 4 dated 05 February 2018 
• 
Version 5 dated 05 March 2018 
• 
Version 6 dated 24 July 2018 
• 
Version 7 dated 15 April 2019 
• 
Version 8 dated 28 October 2019 
• 
Version 9 dated 16 March 2020 
• 
Version 10 dated 30 December 2020 
• 
Version 11 dated 12 August 2021. 
1.2 
Background 
There are an estimated 17,000 incident cases of esophageal cancer in the United States annually, 
with a yearly mortality rate that almost approximates the incidence rate. This number may in fact 
underestimate the true number of cases, depending on how GE junction adenocarcinomas (which 
can be categorized as either esophageal or gastric) are classified. Trends for histologic subtypes have 
been shifting, with the incidence of adenocarcinomas steadily climbing over the past several decades 
in Western countries, with a concomitant decline in squamous cell carcinomas (which still comprise 
the majority of cases globally).  
Immunotherapeutic approaches have demonstrated clear evidence of therapeutic activity in a 
subset of patients with advanced gastroesophageal cancers. CD40 agonistic antibodies represent an 
attractive and novel form of immunotherapy that stimulate an immune response by activating 
antigen processing and presentation, recruiting immune effectors such as natural killer cells and 
macrophages, and additionally have direct cytotoxic effects on tumor cells. However, the activity of 
this class of agents in esophageal/GE junction cancers is unknown and will be evaluated in the 
context of this study by combining it with standard chemoradiation in the neoadjuvant setting, with 
serial collection of tissue and blood along the way for correlative purposes to monitor on-target 
treatment and pharmacodynamics effects. This study represents the first of its kind to evaluate the 
safety and preliminary efficacy of combining a CD40 agonist antibody with standard chemoradiation 
in patients with resectable disease. 
1.3 
Timing of statistical analyses 
The following statistical analyses are planned for this study: 
▪ 
Safety analyses: yearly safety analyses for development safety update report (DSUR) 
▪ 
Final efficacy and safety analysis, split into two parts:  


 
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o The data base freeze analysis after the primary and secondary endpoints are 
available for all patients and the database is frozen. 
o The  final analysis after study termination and the database is locked. 
This statistical analysis plan (SAP) is related to the final analyses.  
2 
Modification History 
2.1 
Changes to the study protocol 
The statistical analyses specified in this SAP are consistent with the statistical analyses contained in 
the study protocols except for the following points: 
1. In this study, it was planned to observe patients for long-term follow-up and survival. 
However, during the course of the study the treatment landscape changed with the approval 
of new adjuvant therapies. Only approximately one third of patients chose to go into long-
term follow-up, and it was determined that the long-term data as originally planned would 
not be meaningful with the reduced number of patients. Therefore, overall survival analyses 
were removed accordingly. Since this study examines neoadjuvant therapy, disease-free 
survival will be analyzed in the efficacy population. 
 
2. All concomitant medications received within 28 days before the first dose of APX005M and 
to 90 days (30 days as specified in protocol) after the last dose of APX005M should be 
recorded. 
 
3. For the final analysis, the primary and secondary efficacy populations were removed and the 
efficacy population will be used for the primary and secondary endpoints. The definition of 
efficacy population will include those patients that had planned surgery or had it aborted 
due to progressive disease (same patients as primary efficacy population).   In the prior 
version of the SAP, the secondary efficacy population did not include patients who had 
aborted planned surgery due to progressive disease. It was decided to remove this 
population for the final analysis in order to include those patients. Therefore the primary 
and secondary endpoints will be based on the newly defined efficacy population.   
2.2 
Changes to previous SAP versions 
The following changes were made compared to the first version of the SAP: 
Version 
Date 
Change 
number 
Change description 
2 
14-Jul-2022 
1 
No additional analysis will be performed on the Per Protocol 
Population, the change is included under section Per Protocol 
Population 
2 
14-Jul-2022 
2 
Per client request, the Primary Efficacy Population definition 
is updated under section Efficacy Population 
2 
14-Jul-2022 
3 
Steroids Subgroup definition is updated under section 
Subgroups 
2 
14-Jul-2022 
4 
Surgery Subgroup definition is updated under section Primary 
efficacy analysis 


 
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2 
14-Jul-2022  
5 
Observation and analysis times is corrected due to the wrong 
update of track changes in the signed first version. 
3 
28-Feb-2023 
6 
Due to the CSR requirements for the final analysis, the 
following additional analysis: SAC, DSUR and ASCO were 
explained in the previous version of the SAP V2.0 and 
removed in this version. This part is updated under section 
Timing of statistical analysis and the sections: SAC Analysis, 
DSUR Analysis and ASCO Analysis will be removed from this 
version of the SAP. 
3 
28-Feb-2023 
7 
For the final analysis, the primary and secondary efficacy 
populations were removed and the efficacy population will be 
used for the primary and secondary endpoints. The definition 
of efficacy population will include those patients that had 
planned surgery or had it aborted due to progressive disease 
(same patients as primary efficacy population). In the prior 
version of the SAP, the secondary efficacy population did not 
include patients who had aborted planned surgery due to 
progressive disease. It was decided to remove this population 
for the final analysis in order to include those patients. 
Therefore the primary and secondary endpoints will be based 
on the newly define efficacy population.  This part is updated 
under section Analysis Population. 
3 
28-Feb-2023 
8 
Observation and analysis times are updated to match the 
protocols. This section is updated under observation and 
analysis times. 
3 
28-Feb-2023 
9 
Disease-Free Survival is added to the final analysis. This part is 
updated under section disease free survival. 
3 
28-Feb-2023 
10 
Overall Survival analysis is updated due to insufficient follow-
up time and a small number of deaths among efficacy 
patients. No analysis will be attempted and Overall Survival 
data will only be provided in listings. This part is updated 
under section overall survival. 
3 
28-Feb-2023 
11 
The Appendices were removed as none of them were needed 
for the statistical analysis. 
3 
28-Feb-2023 
12 
Progression-Free Survival analyses have been removed. 
 
3 
Study Design 
Indication 
Patients with resectable (T1-3Nx, excluding T1N0) cancers of the 
esophagus and gastroesophageal (GE) junction, including both squamous 
cell and adenocarcinomas. 
Design 
non-comparative open-label multi-site single-arm study  


 
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Phase 
Phase 2 
Primary Objective 
To assess the efficacy of this novel combination (APX005M with standard 
of-care (SOC) chemoradiation (external beam radiation in daily fractions, 
with concurrent weekly low-dose carboplatin/paclitaxel)), measured by 
the pathologic complete response (pCR) rate. 
Secondary 
Objective 
(1) To further characterize the safety and feasibility of combining 
APX005M with standard of-care (SOC) chemoradiation (external beam 
radiation in daily fractions, with concurrent weekly low-dose 
carboplatin/paclitaxel) in the neoadjuvant setting for patients with 
resectable esophageal and GE junction cancers  
(2) To assess the efficacy as measured by rates of R0 resection; pathologic 
stage at time of surgery; and radiographic/metabolic response to 
neoadjuvant treatment on computed tomography-positron emission 
tomography (CT-PET). 
Exploratory 
Objective 
(1) To identify possible predictive molecular or immune-based efficacy 
biomarkers for this novel combination 
(2) To characterize and assess overall survival and Disease Free Survival 
Study treatment 
APX005M, a CD40 agonist antibody 
 
 
Interim analysis 
Not planned 
3.1 
Protocol synopsis 
Please refer to the Protocol Version 11, 12 August 2021 (and its Appendices). 
3.2 
Sample size estimation 
The primary objective of this study is to assess the efficacy of combining APX005M with SOC 
chemoradiation (carboplatin/paclitaxel/radiation therapy), as measured by the pCR (pathological 
Complete Response) rate. 
 evaluable patients will be enrolled to this phase 2 study. The null hypothesis that the 
true pCR is 29% will be tested against a 1-side alternative of 53% using Exact Binomial Test with type 
I error rate of 0.05 and power of 81%. A minimum number of 
evaluable patients with 
adenocarcinoma history will allow to test the null hypothesis that the true pCR is 23% against a 1-
sided alternative of 53% with a type I error rate of 0.05 and power of 77%. 
3.3 
Randomisation, blinding and unblinding procedures 
This study is not randomized. 


 
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4 
Analysis Populations 
4.1 
Screening Population 
The screening analysis population includes all patients screened and who provide informed consent. 
Analysis of the disposition of the patients will be presented on the screening population.  
4.2 
Safety Population 
All patients who receive at least one dose of APX005M will be analysed for safety.  
Analysis of demographics, background characteristics, study drug exposure, adverse events, 
laboratory data, ECOG performance status, and vital signs will be presented on the Safety 
population. The appropriate listings will be presented on the screened or safety population.  
4.3 
Per Protocol Population 
All patients who receive at least one dose of APX005M without any major protocol violation that 
would impact the assessment of the primary and secondary endpoints. Several analyses  would be 
repeated by Per Protocol Population if the difference between Per Protocol and Safety population is 
greater than 10%. During the Data Review Meeting, the Final Per Protocol Population was defined 
and no additional analysis would be repeated by Per Protocol Population.  
4.4 
Efficacy Population 
All patients who are eligible,  received neoadjuvant APX005M chemoradiation therapy followed by 
surgery, or had their planned surgery aborted due to the discovery of progressive disease, are 
included in the efficacy population.  Data is specified in the investigator’s assessment of pathologic 
response (SRRESP).   
 
Analyses 
Screened 
Safety 
Efficacy  
Per Protocol  
Disposition 
X 
 
 
 
Demographics and background 
characteristics 
 
X 
 
X* 
Exposure 
 
X 
 
 
Previous and concomitant therapies 
 
X 
 
 
Primary Efficacy Endpoint  
 
 
X 
X* 
Secondary Efficacy Endpoints 
 
 
X 
X* 
Disease free survival 
 
 
X 
 
Safety 
 
X 
 
 
*As previously noted, during the Data Review Meeting, the Final Per Protocol Population was 
defined and no additional analyses would be repeated by Per Protocol Population. 
 
5 
General Statistical Methods and Definitions 


 
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5.1 
General statistical methods 
The statistical analyses will be presented for the different analysis sets as defined in section 4 
Analysis Populations. 
In general, continuous variables will be summarised using descriptive statistics, i.e. generally 
displaying number of patients in the respective analysis population, number of patients with missing 
values, number of patients with data, mean, standard deviation, minimum, lower quartile, median, 
upper quartile, and maximum.  
Categorical variables will be summarised by using frequency counts and percentages. In addition, the 
number of patients with missing values will be displayed. Percentages relate to the number of 
patients with data.  
Means and medians will be presented by 1 additional decimal place and standard deviation will be 
presented by 2 additional decimal places than the standard presentation level of the respective 
patient data. Minimum and maximum values will be presented using the same number of decimal 
places as the patient data. 
 
Percentages will be presented to 1 decimal place if not otherwise stated. In case of 100  % only the 
integer 100 wil be presented. If the number of patients in a category is 0, then percentage will not 
be displayed, and only a count of 0 will be shown.  
 
In cases where variables are derived and have floating point values (no fixed number of decimal 
places), an appropriate level of precision will be determined based on the context. 
P-values will be reported to 4 decimal places at least. Values less than 0.0001 will be displayed as 
<0.0001. Values above 0.9999 will be displayed as >0.9999. 
In listings, data will be sorted by site, and patient, and when appropriate by visit or other identifiers 
for sequence or type of observation.  
If not otherwise specified, all statistical tests will be two-sided with alpha level of 0.05.  
The analysis will be exploratory in nature and will primarily involve descriptive statistical methods.  
In addition, exploratory statistical testing will be used to highlight interesting aspects of the data and 
to investigate differences between baseline and post-baseline assessments. 
Study sites, countries and regions 
8-12 study sites in the US were planned to participate in the study. No efficacy or safety analyses by 
site will be performed.  10 sites were activated; 9 sites enrolled patients. 
5.2 
Covariates and strata 
There are no covariates or strata. 
 
5.3 
Subgroups 
Below, the subgroup analysis will be defined.  
• 
Histological subgroup  
o Squamous Cell Carcinoma 


 
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o Adenocarcinoma  
o Other 
• 
Tumor location subgroup: 
o GE Juction 
o Non-GE Juction (Upper Third of Esophagus, Middle Third of Esophagus, 
Lower Third of Esophagus) 
• 
Steroids use: 
o Sterioids use Yes: patients with any steroid (ATC2 class CORTICOSTEROIDS 
FOR SYSTEMIC USE) from within 30 days of the first dose of APX005M  to up to 
7 days after the first dose 
o Steroids use No: patients not fulfilling previous requirements   
• 
Tumor staging classification, the information from Tumor Staging assessment page 
from eCRF will be used to define the following: 
o cTNM(before treatment)/ yCTNM (after chemo-radiation; before surgery) 
o ypTNM (afterchemo-radiation; after surgery) 
5.4 
Missing data 
In general, missing data will not be imputed and the data will be analysed as they are recorded. 
Exceptions are partial and missing dates, see below. 
Partial or missing dates and times 
Where the start date of an event or medical condition or medication is missing or partially missing, 
the event will be assumed to be started after the start of study medication, unless there is clear 
evidence (through comparison of partial dates/times) to suggest otherwise. 
In case of a partial or missing end date the medical condition will be assumed to be ongoing after 
start of study medication except if the partial date indicates that the condition stopped prior to start 
of study medication.  
5.5 
Observation and analysis times 
The study consists of 3 periods after screening period.  
1. Neoadjuvant treatment period with APX005M plus carboplatin plus paclitaxel with tumor 
targeted curative intent radiation to Esophagus and/or GEJ region. 
2. Followed by curative intent surgical resection.  
3. Followed by period of observation for disease recurrence and last period of survival follow 
up.  
As the study protocol underwent multiple amendments, the study treatment schedules relative 
to curative intent surgery changed.  Versions 1-8 of the protocol were under an Investigator 
Sponsor Trial (IST); Versions 9-11 were under Company Sponsor Trial (CST). 
The figure below describes the different study treatment schedules for each of protocol versions 
and how many study participants enrolled under each different Study Treatment Schedules. 
In this neoadjuvant study, the primary and secondary endpoints include rates of pathologic 
response and R0 resection, which are determined by surgical resection and pathologic 
evaluation. Disease-free survival, defined as the time from curative intent surgery to disease 
recurrence or death, is clinically meaningful and will be analyzed as an exploratory endpoint. 


 
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Study Treatment Schedules: 
 
*APX005M is also known as sotigalimab (sotiga). 
Schedule:  A – Protocol versions 1 to 5; B – versions 6 to 9; C – versions 10 to 11 
All patients regardless of protocol version were to receive 5040 cGY over 28 fractions  (Note: In 
version 3, the treatment schedule figure was inconsistent with the protocol’s schedule of events, 
and one patient received 25 fractions instead of 28. This was documented as a deviation). For 
protocol versions 1-9, surgery was to be performed between weeks 11-17; in protocol versions 10 
and 11, the surgery window was 10-16 weeks. 
The assessment of OS was added in version 11.   
Since patients are treated according to different Protocol versions different treatment schedules will 
be taken into account for exposure analysis.   
For data analysis the 5 periods are defined as follows: 
• 
Screening period 
o For all patients the screening period is defined as screening measurements 
performed from 28 days up to treatment start  
• 
Treatment period 
o For all patients the treatment period is defined as the treatment start (the first 
treatment administered (Carboplatin/ Paclitaxel /APX005M/Radiotherapy) to 
treatment end (to the last treatment administered Carboplatin/ Paclitaxel 
/APX005M /Radiotherapy) 
• 
Post Treatment period 
o For all patients, the post treatment period is defined from the day after treatment 
end to the Surgery, Weeks 10-16 or 11-17, as indicated in the protocol version. 
• 
Follow up period 
o For all patients the follow-up period is defined from the day after surgery to the 6 
months post operative visit. 


 
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• 
Survival evaluation period 
o For the efficacy population, disease-free survival analysis will be performed. Due to 
insufficient follow-up time and a small number of deaths among efficacy patients, no 
overall survival analysis will be attempted, and Overall Survival data will only be 
provided in listings. 
Definition of baseline values 
For all patients treated, the baseline value is defined to be last value assessed before the first 
infusion of Carboplatin/Paclitaxel/ APX005M/Radiotherapy. 
Definition of analysis timepoints  
The variables will be evaluated for the time points as indicated for them in the schedule of 
assessments from the study protocol. 
For the data base freeze analysis after the primary and secondary endpoints are available for all 
patients and the database is frozen, all the study periods beside the Survival Follow-up were used. 
Also, all the analyses described in the SAP beside the 11.6 Overall Survival and 11.7 Disease Free 
Survival (DFS) were performed.  
For the final analysis after the study has ended and the database is locked, the disease-free  
analyses, Overall Survival listing and secondary analysis (CT-PET analysis and all data collected after 
database freeze) and some data base freeze analyses will be performed. 
6 
Subject Accounting and Disposition 
6.1 
Subject accounting 
An overview of screened patients will be presented in the table showing the number of patients and 
the percentages based on the screening population. Also the number of not eligible patients will be 
presented with the inclusion/ exclusion criteria that are not met.  
The number and relative frequencies of patients in each analysis populations as defined in section 
4. This study is not randomized. 
Analysis Populations will be presented overall and by site.  
A listing including disposition information will be also created. A separate listing will be created with 
patients excluded from efficacy analysis.  
6.2 
Disposition and withdrawals 
The number and relative frequency will be presented for patients who completed the study including 
follow–up and who prematurely discontinued the study with reason for discontinuation. The following 
reasons for premature study discontinuation will be presented: 
• 
Adverse event 
• 
Confirmed radiographic disease progression 
• 
Death 
• 
Lost to follow-up 
• 
Non-compliance with study treatment or procedure requirements  
• 
Physician decision, other than Adverse event (AE) 
• 
Pregnancy 


 
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• 
Site terminated by sponsor 
• 
Study terminated by sponsor 
• 
The subject or legal representative withdraws consent 
• 
Intercurrent Illness that Prevents Further Administration of Treatment 
• 
Administrative Reasons  
• 
Withdrawal due to COVID-19 
• 
Other 
6.3 
Protocol deviations 
Protocol deviations will be summarized by frequency tables and all patients with protocol deviations 
will be listed. The protocol deviations will be defined by Protocol Deviation Plan version 3.0 dated 23 
August 2022 and will be provided in an excel spreadsheet.  
7 
Demographics and Background Characteristics 
Demographic and baseline characteristics as specified in detail below will be presented descriptively 
based on safety population. 
7.1 
Demographics 
The following demographic characteristics will be presented 
• 
Age (years) 
• 
Sex (male/female) 
• 
Woman of childbearing potential (no/yes) 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• 
Race (White, Black or African American, American Indian or Alaska Native, Asian, Native 
Hawaiian or other Pacific Islander, Other) 
• 
Weight (kg) 
• 
Height (cm) 
7.2 
Baseline characteristics 
The results from the following investigations at baseline will be presented: 
Tumor staging assessment: 
o Histology (Squamous cell carcinoma, Adenocarcinoma, Other) 
o Tumor location (Upper Third of Esophagus, Middle Third of Esophagus, Lower Third of 
Esophagus, GE Junction) 
o Grade (Grade X, Grade 1, Grade 2, Grade 3) 
o T Stage (TX, T0, T1, T1a, T1b, T2, T3, T4, T4a, T4b) 
o N Stage (NX, N0, N1, N2, N3) 
o M Stage (M0, M1) 
o Stage group (Missing, 0, I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB) 


 
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• 
CT-PET scan performed 
o Is the primary tumor measurable? (no, yes) 
o Type of scan recorded (CT scan, CT-PET scan) 
o SUV Mean of Primary Tumor 
o SUV Max of Primary Tumor 
o SUR-Liver 
o SUR-Blood pool 
o Are enlarged lymph nodes present? (no, yes) 
7.3 
Medical history 
The diseases are coded according to Medical Dictionary for Regulatory Activities (MedDRA® version 
23.0 or later). Medical history includes history of any pre-existing conditions and/or any malignancy 
that is not cancer under investigation in this trial. They will be classified as follows 
▪ 
Previous medical conditions, i.e. medical conditions that stopped prior to first infusion of 
study treatment (Carboplatin/Paclitaxel/APX005M/Radiotherapy) 
▪ 
Ongoing (concomitant) medical conditions, i.e. medical conditions still present after first 
infusion of study treatment (Carboplatin/Paclitaxel/APX005M/Radiotherapy) 
All ongoing events at study entry have also to be classified by the CTCAE severity grade 1 to 5.  
 
The frequency of diseases recorded from medical history will be presented for safety population 
after classification into previous and concomitant conditions 
• 
by system organ class (SOC)  
• 
by preferred terms (PT) within each SOC 
• 
by CTCAE grade within each preferred term 
If patients have more than one disease within an SOC or PT or CTCAE Grade they will be counted 
only once for the respective SOC or PT or CTCAE Grade. 
For the summaries, Primary System Organ Classes (SOCs) will be ordered alphabetically and 
Preferred Terms (PTs) will be ordered by descending count or alphabetically for PTs with the same 
count. 
8 
Previous and Concomitant Therapies 
Previous and concomitant medications are coded according to the World Health Organization drug 
dictionary (WHO-Drug version 2021Q2, 21, March or later) and stored with ATC codes/decodes and 
generic names. 
All medications received within 28 days before the first dose of study treatment 
(Carboplatin/Paclitaxel/APX005M/Radiotherapy) and 90 days after the last dose of 
(Carboplatin/Paclitaxel/APX005M/Radiotherapy)  are to be recorded.  
 


 
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Therapies are classified as previous if the stop date is before the first dose study treatment 
(Carboplatin/Paclitaxel/APX005M/Radiotherapy). All other medications are defined as concomitant. 
Missing or partly missing stop dates will be imputed using the rules defined in Section 5.4. 
The number and frequency of previous and concomitant medications will be given per Anatomical 
Therapeutic Chemical (ATC) categories (Level 2: pharmacological or therapeutic subgroup and Level 
3: chemical or therapeutic or pharmacological subgroup).  
If a patient has received more than 1 drug within an ATC class, he/she will be counted only once for 
this ATC class. 
9 
Exposure  
Treatments will be labelled as follows: 
▪ 
APX005M 
▪ 
Carboplatin 
▪ 
Paclitaxel 
▪ 
Radiotherapy 
Descriptive statistics for the characteristics of the non-radiotherapies are presented by timepoint for 
the safety population. The following items are analysed: 
Item 
Outcome 
APX005M 
Carboplatin 
Paclitaxel 
Treatment received 
no 
yes 
X 
X 
X 
Reason APX005M 
not administered 
Adverse event 
Other 
X 
 
 
Preinfusion 
medication taken 
no 
yes 
X 
X 
X 
Infusion 
interrupted 
no 
yes 
X 
 
 
Reason Infusion 
interrupted 
Adverse event 
Other 
X 
 
 
Infusion completed    no 
yes 
X 
X 
X 
Prescribed Dose  
 
 
 
0.3 
other (mg/kg) 
1 
1.5 
2 
other (AUC) 
30 
40 
50 
other (mg/m2) 


 
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Total dose 
administered (mg) 
Amount in mg 
X 
X 
X 
Total volume 
administered (mL) 
Amount in mL 
X 
X 
X 
For radiotherapy, descriptive statistics of the daily dose (cGy) will be presented by day.   
Listings of all APX005M, Carboplatin, Paclitaxel, and radiotherapy exposures will be provided.  
10 Efficacy 
10.1 
Primary efficacy analysis 
The primary efficacy measure is the proportion of patients who achieve a pathological complete 
response (pCR rate) as assessed by the investigator. This efficacy analysis will be performed in the 
Efficacy Population.  The pathological complete response will be defined as ypTNM (after chemo-
radiation; after surgery) with T0, N0 stages.   
 
An exact Clopper-Pearson lower 95% confidence limit will be used to test the null hypothesis that 
the pCR rate is ≤30%. If the lower 95% confidence limit is above 30%, the null hypothesis will be 
rejected and it will be concluded that the pCR rate is higher than 30%. 
These data will be reported for each histologic, tumor location and steroids-use subgroups. The 
pathologic complete response will also be presented by the following subgroup: 
• 
Patients who have surgery before or at 16/17 weeks 
o Defined as start of study treatment to Surgery date from the surgical resection form,  
less than or equal to 17 weeks (119 days = 17 weeks * 7 days)   
o Patients who were scheduled to have surgery but had their procedure aborted due 
to progressive disease at the time of the procedure or immediately before and did 
not have surgery because of metastasis  
• 
Patients who have surgery after week 17 
o Defined as from start date of study treatment to Surgery date from Surgical 
Resection eCRF is after the week 17 (119 days = 17 weeks * 7 days). 
The pathologic complete response will also be presented in a table by post-treatment response.  
10.2 Secondary efficacy analyses 
The following tumor staging assessment endpoints are assessed after treatment/before surgery and 
after treatment/after surgery: 
o Histology (Squamous cell carcinoma, Adenocarcinoma, Other) 
o Tumor location (Upper Third of Esophagus, Middle Third of Esophagus, Lower Third of 
Esophagus, GE Junction) 
o Grade (Grade X, Grade 1, Grade 2, Grade 3) 
o T Stage (TX, T0, T1, T1a, T1b, T2, T3, T4, T4a, T4b) 
o N Stage (NX, N0, N1, N2, N3) 


 
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o M Stage (M0, M1) 
o Stage group (Missing, 0, I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB) 
These data will be summarized for the Efficacy population by time point and presented for each 
histologic and tumor location subgroup 
CT-PET scan performed will be presented by timepoints. The following endpoints are reported: 
o Is the primary tumor measurable? (no, yes) 
o Type of scan recorded (CT scan, PET-CT scan) 
o SUV Mean of Primary Tumor 
o SUV Max of Primary Tumor 
o SUR-Liver 
o SUR-Blood pool 
o Are enlarged lymph nodes present? (no, yes) 
o Is there evidence of response relative to baseline? (responding, stable/unchanged, 
progressing, not evaluable) 
These data will be summarized for the efficacy population and the last variable also by histological 
and tumor location subgroups. 
The surgical resection will be presented in the table showing the number of patients and the 
percentages based on the efficacy population. The number of patients with surgical resection 
performed, R0 resection achieved, investigators assessment of pathologic response, major 
pathologic response will be presented for each histologic, tumor location and tumor staging 
classification. The surgical resection will be also presented by histologic subgroup separately by 
each of the tumor time staging classification where the information will be presented by each 
stage group.  
The lesion/RECIST form was added in the updated eCRF. 
For target lesion overall, the number of patients with lesions in organs, measurements of longest 
diameter (mm) or measurements of short axis (mm), method will be presented with the percentages 
based on the efficacy population by visit. Also this table would be repeated by each of the 
lesion/organ. The change from baseline will be presented by each timepoint. For non-target lesion 
overall, the number of patients with lesions in organs, method and status of non-target lesion will be 
presented with the percentages based on the efficacy population by visit. Also this table would be 
repeated by each of the lesion/organ. 
The summary table of response assessment will be presented showing the number of patients and 
the percentages based on the efficacy population. The number of patients with RECIST 1.1 Target 
lesion response, RECIST 1.1 Non-target Lesion response, Overall RECIST 1.1 Response and new lesion 
will be presented by visit.  
All results from efficacy analyses will also be listed by patient. 
10.3 Exploratory Objective 
The exploratory analysis related to the identification of possible predictive molecular or immune-
based efficacy biomarkers for this novel combination is not going to be described in this SAP. 


 
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Considering this is a neoadjuvant study, disease-free survival will be a clinically relevant exploratory 
end point. Overall survival (OS) will be in listings, however no formal statistical analysis is planned as 
not all study patients consented for OS follow up.  
11 Safety 
11.1 Adverse events 
Adverse events will be coded using MedDRA version 23.0 or later, and analysed for the safety 
population. 
The analysis will focus on the treatment-emergent AEs (TEAE), i.e., AEs which started on or after the 
first infusion of study treatment (Carboplatin/Paclitaxel/APX005M/Radiotherapy) until 100 days 
after receiving the last dose of study treatment (Carboplatin/Paclitaxel/APX005M/Radiotherapy), 
death, or initiation of new anticancer therapy (from Overall Survival Form), whichever occurs first. 
Number and frequencies of patients with at least one adverse event of the following types of TEAEs 
will be summarized: 
• 
At least one TEAEs 
• 
Serious TEAEs 
• 
Serious TEAEs (includes number of events) 
• 
TEAEs with outcome of death  
• 
TEAEs leading to treatment discontinuation  
• 
TEAEs leading to discontinuation of APX005M 
• 
TEAEs leading to discontinuation of Carboplatin   
• 
TEAEs leading to discontinuation of Paclitaxel 
• 
TEAEs leading to discontinuation of Radiotherapy 
• 
TEAEs at least possibly related to APX005M 
• 
TEAEs at least possibly related to Carboplatin 
• 
TEAEs at least possibly related to Paclitaxel 
• 
TEAEs at least possibly related to radiotherapy 
• 
TEAEs at least  possibly related to surgery 
• 
>= Grade 3 TEAEs 
• 
>= Grade 3 TEAEs at least possibly related to APX005M 
• 
>= Grade 3 TEAEs at least possibly related to Carboplatin 
• 
>= Grade 3 TEAEs at least possibly related to Paclitaxel 
• 
>= Grade 3 TEAEs at least possibly related to radiotherapy 
• 
>= Grade 3 TEAEs at least  possibly related to surgery 
• 
Non-serious AEs 
• 
Non-serious AEs (includes number of events) 
• 
Related TEAEs by treatment (excluding surgery) and overall related 
The number of TEAEs will also be presented by decreasing frequency within each primary System 
Organ Class (SOC), Preferred Term (PT). SOCs will be ordered alphabetically. 
Additionally, the number of TEAEs will be presented by decreasing frequency within each primary 
System Organ Class (SOC), Preferred Term (PT) and maximum CTCAE toxicity grade. 
A patient listing will be provided including all adverse events with reported term, preferred term,  
adverse event start and end date, seriousness, relationship to treatments, action taken with 


 
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treatments, relationship to study surgery, NCI CTCAE toxicity grade and outcome as well as duration 
of adverse event and onset after first infusion of study treatment 
(Carboplatin/Paclitaxel/APX005M/Radiotherapy). 
An additional listing will be created for patients with serious adverse events showing the seriousness 
criteria and for patients with adverse events leading to treatment discontinuation. 
All information associated with deaths is collected on death eCRF page. Number and frequencies 
of all cause death will be presented in a table and also listed.  
11.2 Vital signs 
The following variable will be described descriptively by time point for the safety population: 
• 
Systolic blood pressure (mmHg) 
• 
Diastolic blood pressure (mmHg) 
• 
Heart rate (bpm) 
• 
Respiratory rate (bpm) 
• 
Body weight (kg) 
• 
Body height (cm) 
• 
Oxygen saturation (%) 
• 
Body temperature (°F) 
 
The actual values and change from baseline in vital signs will be summarized by time point with n, 
mean, standard deviation, and 25th percentile, median, 75th percentile, min, and max. All data will 
also be listed by patient. 
11.3 Clinical safety laboratory  
Hematology, clinical chemistry and coagulation 
The following variables will be analysed descriptively by time point for the safety population: 
• 
Hematology: 
 
o Hemoglobin 
o Hematocrit 
o Red Blood Cell Count (RBC) 
o White Blood Cell Count (WBC) 
o Platelet Count 
o Absolute Neutrophil Count (ANC) 
o Lymphocytes (absolute) 
o Monocytes (absolute) 
o Eosinophils (absolute) 
o Basophils (absolute) 
o Mean Corpuscular Hemoglobin Concentration (MCHC) 
o Mean Corpuscular Volume (MCV) 
• 
Clinical Chemistry: 
 
o ALT/ SGPT 
o Albumin 


 
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o AST/ SGOT 
o Alkaline Phosphatase 
o Total Bilirubin 
o Bicarbonate  
o Blood Urea Nitrogen 
o Calcium 
o Chloride 
o Creatinine 
o Creatinine Clearance 
o Glucose 
o Potassium 
o Total Protein 
o Sodium 
• 
Coagulation: 
 
o Prothrombin Time (PT) 
o Activated Partial Thromboplastin Time (aPTT) 
o International Normalized Ratio (INR) 
 
In addition, summary tables will be provided for elevated AST, ALT, Total Bilirubin and Alkaline 
Phosphate, and also for abnormal neutrophils, white blood cells, platelets and lymphocytes. 
 
The actual values and change from baseline in laboratory variables will be summarized by time point 
with n, mean, standard deviation, and 25th percentile, median, 75th percentile, min, and max. All 
data will also be listed by patient. 
Additionally, the number of laboratory values that fall outside of pre-determined ranges are 
displayed by timepoint for the safety population. 
Laboratory values that are outside the pre-determined range will also be flagged in the data listings, 
along with corresponding normal ranges. Any out-of-range values that are identified by the 
investigator as being clinically significant will also be shown in a data listing. 
Selected laboratory variables will be classified According to Common Terminology Criteria  for 
Adverse Events (CTCAE) Version 4.03 and frequencies of the respective variables will be tabulated by 
CTCAE Grade. 
Urinalysis 
Data from Urinalysis are only collected at screening and are not analysed.  
Immune-based correlates 
Data from Immine-based correlates can be collected and will not be analysed. 
Blood samples collection 
Data from Blood samples collection can be collected and will not be analysed.  
11.4 ECG 
Data from ECG are only to be collected at screening and are not analysed, only listed.  


 
Protocol No.:  APX005M-006     CP Project ID: APE19006   
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11.5 Physical examination 
Data from physical examination are only to be collected at screening and are not analysed.  
11.6 Overall Survival 
An exploratory assessment of overall survival was planned for 18 months after the 6 months follow-
up visit or End of Study visit. Due to insufficient follow-up time  and a small number of deaths among 
efficacy patients, no analysis will be attempted, and OS data will only be provided in listings. 
The  subject status, disease progression and subsequent anti-cancer therapy will be assessed every 3 
months.  
11.7  Disease Free Survival (DFS)  
Disease Free Survival is defined as the time from date of surgery until progession or death, and will 
be  analyzed for the Efficacy Population using Kaplan-Meier methodology when the study is 
terminated and the database is locked. For patients who aborted planned surgery due to progressive 
disease, the date of progression will be recorded as day 0 and duration of disease-free survival will 
be 0. 
11.8 ECOG performance status 
The ECOG performance status will be described descriptively with frequency and percentage by 
outcome (0, 1, 2, 3, 4, 5) for each time point for the safety population. 
12 Interim Analyses 
An interim analysis is not planned for this study. 
13 Software  
If not stated otherwise, the data will be analysed using SAS Version 9.4 or higher.  
 
 


 
Protocol No.:  APX005M-006     CP Project ID: APE19006   
Version: 3.0 Final 
Version Date: 8 March 2023 
Statistical Analysis Plan: Final  
 
 
QMS Document Name: Statistical Analysis Plan 
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QMS No (include version ref): STF-015-GL.02 
Document date: 09JUL2019 
CONFIDENTIAL 
 
14 Abbreviations 
 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
CRF 
Case Report Form 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CT 
Computer tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT-PET 
Computed Tomography-Positron Emission Tomography 
CTR 
Clinical Trial Registry 
DFS 
Disease Free Survival 
DSUR 
Development Safety Update Report 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
GE 
Gastroesophageal 
ICH 
International Conference on Harmonization 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for Adverse events 
OS 
Overall Survival 
pCR 
Pathological complete response 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SUV 
Standardized Uptake Value 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Tables, Listings, and Figures 
15 References 
1. ICH guideline E2F, Note for guidance on development safety update reports, 
EMA/CHMP/ICH/309348/2008, September 2010 
2.   Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, Guidance for Industry, 
U.S. Department of Health and Human Services,Food and Drug Administration,Oncology Center of 
Excellence, December 2018