Clinical trial NCT04337931
Conditions: Unresectable Melanoma Metastatic Melanoma Cancer Cancer of Skin Melanoma Melanoma (Skin)
Keywords: CD40 Immunotherapy APX005M sotigalimab
Sponsor: Apexigen America, Inc.
Start date: 2019-06-12; Completion date: 2022-08-02
Enrollment: 45 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, open label, Phase 2 study, with 3 parallel cohorts. The aim of the study is to evaluate the efficacy of sotigalimab (APX005M) administered at 2 different schedules to adult participants with unresectable or metastatic melanoma. Participants who have not received prior immunotherapy will be alternately assigned to 1 of 2 cohorts with different sotigalimab administration schedules as long as both are open for enrollment. Participants who have failed any number of prior lines of therapy will be assigned to a 3rd cohort of sotigalimab in combination with radiation therapy.

Detailed description:
This is a multicenter, open label, Phase 2 study, with 3 parallel cohorts. The aim of the study is to evaluate the efficacy of Sotigalimab administered at 2 different schedules to adult participants with unresectable or metastatic melanoma who have not received prior immunotherapy. Enrolled participants will be alternately assigned to one of the following 2 cohorts (groups) as long as both cohorts are open.

Cohort 1: APX005M administered IV at 0.3 mg/kg every 3 weeks (21-day cycle) Cohort 2: APX005M administered IV at 0.3 mg/kg every 2 weeks (14-day cycle) Sotigalimab in combination with stereotactic body radiation therapy (SBRT) in adults with unresectable or metastatic melanoma who have failed any number of prior lines of therapy will be assigned to Cohort 3: Sotigalimab administered IV at 0.3 mg/kg in combination with radiation therapy every 2 weeks (14 day cycle) up to 16 weeks followed by sotigalimab administered IV at 0.3 mg/kg every 2 weeks (14-day cycle).

Primary Objective

• Evaluate the overall response rate (ORR) by RECIST 1.1 measurements in each of the cohorts.

Secondary Objectives

* Evaluate the safety of sotigalimab alone or in combination with radiation therapy in each cohort
* Evaluate ORR by modified RECIST 1.1 for immune-based therapeutics (iRECIST) in each cohort
* Evaluate median duration of response (DOR) in each cohort

Arms: arm 1: Sotigalimab administered IV at 0.3 mg/kg every 3 weeks (21 day) treatment cycles arm 2: Sotigalimab administered IV at 0.3 mg/kg every 2 weeks (14 day) treatment cycles arm 3: Metastatic melanoma participants who have failed any number of prior lines of therapy with minimum 3 measurable lesions.

Sotigalimab administered IV at 0.3mg/kg in combination with Stereotactic Body Radiation Therapy (SBRT) every 2 weeks (14-day) treatment cycles up to 16 weeks followed by sotigalimab administered IV at 0.3 mg/kg every 2 weeks (14-day) treatment cycles.
Interventions: intervention 1: sotigalimab
Intervention descriptions: intervention 1: Sotigalimab is a CD40 agonistic monoclonal antibody

Protocol documents:
Prot_000.pdf: 
Apexigen, Inc. 
 
APX005M-010 Clinical Protocol 
APX005M 
 
Amendment 2 
 
Date: December 28, 2020 
CONFIDENTIAL 
Page 1 of 68 
 
 
 
Protocol Number: 
 
APX005M-010 
IND Number: 
EudraCT Number: 
122725 
2018-003864-30 
Date of Original Protocol: November 2, 2018 
  
 
 
 
 
 
CLINICAL PROTOCOL APX005M-010 
A Phase II Multicenter, Open label Study to Evaluate the Safety and Efficacy of the CD40 
Agonistic Antibody APX005M With or Without Stereotactic Body Radiation Therapy in 
Adults with Unresectable or Metastatic Melanoma 
 
 
 
 
Sponsor: 
Apexigen, Inc. 
75 Shoreway Rd, Suite C 
San Carlos, CA 94070 
 
 
Central Medical Monitor: 
Thomas Jahn, M.D., Ph.D. 
75 Shoreway Rd, Suite C 
San Carlos, CA 94070 
Telephone: +1 (650) 822-4401 
Fax: +1 (650) 259-7655 
Email: TJahn@apexigen.com 
 
Date of Amendment 2: December 28, 2020 
  
  
  
The information contained in this document is the confidential and proprietary 
information of Apexigen, Inc. 
 
This study will be conducted in accordance with the protocol, the International Conference on 
Harmonisation (ICH) Guidelines for Good Clinical Practice (GCP) and the applicable country 
and regional (local) regulatory requirements. 
 


Apexigen, Inc. 
APX005M 
SPONSOR APPROVAL PAGE 
I 
Tho 
s Jahn, M.D., Ph.D. 
Vice President Clinical Development, 
Apexigen, Inc. 
Date: December 28, 2020 
CONFIDENTIAL 
APX005M-010 Clinical Protocol 
Amendment 2 
1/ P(c{ 
Date 
Page 2 of68 


Apexigen, Inc. 
 
APX005M-010 Clinical Protocol 
APX005M 
 
Amendment 2 
Date: December 28, 2020 
CONFIDENTIAL 
Page 3 of 68 
SIGNATURE PAGE OF THE INVESTIGATOR 
Title: 
 
A Phase II Multicenter, Open label Study to Evaluate the Safety 
and Efficacy of the CD40 Agonistic Antibody APX005M With or 
Without Stereotactic Body Radiation Therapy in Adults with 
Unresectable or Metastatic Melanoma 
Protocol Number: APX005M-010 
Amendment: 2 
Date: December 28, 2020 
EudraCT Number: 2018-003864-30 
Sponsor: Apexigen, Inc. 
 
 
I have read and agreed to the protocol of the above-mentioned clinical study. I am aware of my 
responsibilities as an Investigator and will conduct this study in compliance with ICH guidelines for GCP, 
local regulations (as applicable) and the study protocol. I agree to conduct the study according to these 
guidelines and to appropriately direct and assist the staff under my control, who are involved in the study. 
 
 
 
 
 
Signature 
 
 
 
_______________________ 
 
 
 
______________________ 
Name, title and affiliation of  
 
 
 
Date 
Investigator 
 
 


Apexigen, Inc. 
 
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APX005M 
 
Amendment 2 
Date: December 28, 2020 
CONFIDENTIAL 
Page 4 of 68 
DOCUMENT HISTORY 
Version 
Date 
Replaces 
Description of Changes 
Original Protocol  
November 2, 2018  
N/A 
New Document  
Version 1.1 
January 16, 2019 
Original Protocol 
The protocol was amended to add 
methods of contraception (Appendix C) 
Amendment 1.0 
March 8, 2019 
Version 1.1 
The protocol title was amended to 
reflect study design. 
 
The protocol was amended to edit 
Inclusion Criteria #2. 
 
The protocol was amended to add 
Exclusion Criteria of previous 
participation in another clinical trial of 
an investigational drug (or a medical 
device) within 30 days of study 
enrollment. 
 
The protocol was amended to update 
and resolve inconsistencies in sample 
collection schedule for correlative 
studies described in Section 4.4. 
Amendment 2.0 
December 28, 2020 
Amendment 1.0 
The protocol was amended to introduce 
Cohort 3 combining APX005M with 
stereotactic body radiation therapy in 
subjects with unresectable or metastatic 
melanoma that failed available therapies 
and to adjust the sample size in Cohorts 
1 and 2. 


Apexigen, Inc. 
 
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Amendment 2 
Date: December 28, 2020 
CONFIDENTIAL 
Page 5 of 68 
SYNOPSIS 
Protocol Number:  APX005M-010 
Protocol Title: A Phase II Multicenter, Open label Study to Evaluate the Safety and 
Efficacy of the CD40 Agonistic Antibody APX005M With or Without 
Stereotactic Body Radiation in Adults with Unresectable or Metastatic 
Melanoma  
Phase of Development: Phase 2 
Investigational  
Therapy(ies): 
APX005M  
Stereotactic Body Radiation (SBRT) 
Study Design: This is a multicenter, open label, Phase 2 study, with 3 parallel cohorts. 
The aim of the study is to evaluate the efficacy of:  
a) APX005M administered at 2 different schedules to adult subjects 
with unresectable or metastatic melanoma who have not received 
prior immunotherapy. Enrolled subjects will be alternately assigned 
to one of the following 2 cohorts as long as both cohorts are open: 
Cohort 1: APX005M administered IV at 0.3 mg/kg every 3 weeks 
(21-day cycle)  
Cohort 2: APX005M administered IV at 0.3 mg/kg every 2 weeks 
(14-day cycle)   
The intent of the alternating cohort assignment is to maintain 
approximately the same number of treated subjects in each of these 
2 cohorts at any given time. Therefore, enrolled subjects assigned to 
Cohorts 1 or 2 that do not receive APX005M or are not evaluable for 
tumor response will be replaced in that cohort before assigning new 
subjects to the other cohort. 
b) APX005M in combination with stereotactic body radiation therapy 
(SBRT) in adults with unresectable or metastatic melanoma who 
have failed approved immunotherapy regimens: 
Cohort 3: APX005M administered IV at 0.3 mg/kg in combination 
with radiation therapy every 2 weeks (14-day cycle) up to 16 weeks 
followed by APX005M administered IV at 0.3 mg/kg every 2 weeks 
(14-day cycle). 
Study Objectives: Primary Objective 
• 
Evaluate the overall response rate (ORR) by RECIST 1.1 in 
each cohort 
Secondary Objectives 
• 
Evaluate the safety of APX005M alone or in combination with 
radiation therapy in each cohort 
• 
Evaluate ORR by modified RECIST 1.1 for immune-based 
therapeutics (iRECIST) in each cohort 
• 
Evaluate median duration of response (DOR) in each cohort 


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Date: December 28, 2020 
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Exploratory Objectives 
• 
Evaluate PFS (by RECIST 1.1 and iRECIST) in each cohort 
• 
Evaluate the association between potential tumor and blood 
biomarkers and antitumor activity and/or resistance 
• 
Determine the presence and titer of anti-APX005M antibodies 
(ADA) 
Study Population  Inclusion Criteria  
1. Histologically or cytologically confirmed unresectable or 
metastatic melanoma 
2. Subjects with BRAF activating mutation must have received a 
BRAF inhibitor and/or MEK inhibitor regimen prior to study 
entry 
3. Signed written informed consent approved by the relevant local 
ethics committee(s) 
4. Male or female ≥18 years old at time of consent  
5. Measurable disease by RECIST 1.1 
a. 
For Cohort 3 only, subjects must have at least 3 
measurable target lesions 
6. ECOG performance status of 0 or 1 
7. Resolution of all disease or prior treatment-related toxicities to 
Grade ≤1, with the exception of alopecia, Grade 2 neuropathy 
and laboratory abnormalities (parameters below apply). If 
subject received major surgery or radiation therapy of >30 Gy, 
they must have recovered from the toxicity and/or 
complications from the intervention 
8. Adequate organ function within 14 days prior to first dose of 
investigational therapy(ies): 
a. WBC ≥2 x 109/L in absence of growth factor support 
b. ANC ≥1.0 x 109/L in absence of growth factor support 
c. Platelet count ≥100 x 109/L 
d. Hemoglobin ≥9 g/dL 
e. Serum creatinine ≤1.5 mg/dL 
f. Calculated (using the formula of local laboratory) or 
measured creatinine clearance ≥60 mL/min 
g. AST and ALT ≤2.5 x ULN 
h. Total bilirubin ≤1.5 x ULN, or direct bilirubin ≤ULN 
for subjects with total bilirubin levels >1.5 x ULN 
i. 
INR or PT ≤1.5 x ULN unless subject is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants 


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Amendment 2 
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j.
aPTT ≤1.5 x ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within
therapeutic range of intended use of anticoagulants
9.
Women of childbearing potential (WOCBP) must have a
negative serum pregnancy test within the 7 days prior to first
dose of investigational therapy(ies) and a negative urine
pregnancy test within the 3 days prior to first dose of
investigational therapy(ies), or a negative serum pregnancy test
within the 3 days prior to first dose of investigational
therapy(ies)
10. Women of childbearing potential must agree to follow
instructions for method(s) of contraception for the duration of
study treatment and 5 months after the last dose of
investigational therapy(ies). Males who are sexually active with
WOCBP must agree to follow instructions for method(s) of
contraception for the duration of study treatment and 7 months
after the last dose of investigational therapy(ies).
11. Available archived or fresh tumor tissue sample for biomarker
analysis.  Note: For Cohort 3, only available archived tissue is
required.
12. For subjects that consent to collection of tumor biopsies at
study entry and before the first scheduled tumor assessment,
primary or metastatic tumor that can be safely biopsied. Up to
18 subjects (6 subjects within each cohort) should consent to
fresh core biopsies.
Exclusion Criteria 
1.
Prior Therapy:
a.
Cohorts 1 and 2 only: Previous exposure to any 
immunomodulatory agent (such as CTLA-4, PD-1/
PD-L1, IDO inhibitors, interferon, CD40 agonists etc.).
b.
Cohort 3 only: Prior therapy with a CD40 agonist.
Any number of prior lines of therapy are eligible.
A minimum washout period of 21 days from last line of
therapy until investigational therapy(ies) administration
should be observed
2.
Second malignancy (solid or hematologic) within the past 3
years except locally curable cancers that have been apparently
cured, such as basal or squamous cell skin cancer, superficial
bladder cancer, or carcinoma in situ of the prostate, cervix, or
breast
3.
Active, known, clinically serious infections (≥ Grade 2
according to NCI-CTCAE v4.03) within the 14 days prior to
first dose of investigational therapy(ies)
4.
Use of systemic corticosteroids or other systemic
immunosuppressive drugs within 28 days prior to first dose of


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Date: December 28, 2020 
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investigational therapy(ies) (except inhaled corticosteroids) 
a. The use of physiologic doses of corticosteroids may be 
approved after consultation with the Apexigen Medical 
Monitor (or designee) 
5. Major surgery within 4 weeks prior to first dose of 
investigational therapy(ies) 
6. Concurrent treatment with any anticancer agent (except for 
hormonal therapy) and palliative radiation, unless approved by 
the Apexigen Medical Monitor (or designee) 
7. History of allogeneic bone marrow transplantation  
8. Active, known or suspected autoimmune disease  
9. Active autoimmune disease that has required systemic 
treatment in past 2 years (i.e. with use of disease modifying 
agents, corticosteroids or immunosuppressive drugs). Subjects 
with Type 1 diabetes mellitus, hypothyroidism only requiring 
hormone replacement, skin disorders (such as vitiligo, psoriasis, 
or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are 
permitted to enroll 
10. History of (non-infectious) pneumonitis that required 
corticosteroids or current pneumonitis 
11. History of interstitial lung disease 
12. History of sensitivity or allergy to mAbs or IgG  
13. 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 prior to the first dose of 
investigational therapy(ies) 
14. History of any thromboembolic event within 3 months prior to 
first dose of investigational therapy(ies) or active coagulopathy  
15. Known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis. Subjects with untreated brain 
metastases ≤3mm that are asymptomatic, do not have 
significant edema, cause shift, and do not require steroids or 
anti-seizure medications are eligible after discussion with the 
Medical Monitor. Lesions of any size in posterior fossa are 
excluded. Subjects with previously treated brain metastases 
may participate provided they are stable after treatment 
(without evidence of progression by imaging for at least 
4 weeks prior to the first dose of trial treatment and any 
neurologic symptoms have returned to baseline), have no 
evidence of new or enlarging brain metastases, and are not 
using corticosteroids for at least 7 days prior to trial treatment. 
This exception does not include carcinomatous meningitis 
which is excluded regardless of clinical stability 


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Date: December 28, 2020 
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16. Known human immunodeficiency virus (HIV), hepatitis B or 
hepatitis C infection 
17. Has received a live (attenuated) vaccine within 30 days prior to 
the first dose of investigational therapy(ies). Seasonal flu 
vaccines that do not contain live virus and COVID-19 vaccines 
are permitted (See Section 3.2.3.4) 
18. Has participated in another clinical trial of an investigational 
drug (or a medical device) within 30 days of study enrollment 
19. Pregnant, breastfeeding, or unwilling to practice birth control 
during participation in the study 
20. 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. 
Statistical Methods and 
Analyses: 
Safety Analyses  
Safety will be assessed by cohort through summaries of AEs, laboratory 
test results, ECG, vital signs, and APX005M exposure. All AE data 
collected will be listed by study site, cohort, subject number, and cycle 
day. 
Efficacy Analyses  
Tumor assessments by Investigator will follow RECIST 1.1 and 
iRECIST. ORR (and 90% confidence interval by exact distribution), 
DOR and PFS (Kaplan-Meier estimate) will be estimated for each 
cohort and for each tumor assessment method. Additional details will 
be provided in the Statistical Analysis Plan.  
Exploratory Analyses  
Potential tumor and blood biomarkers identified in the exploratory 
biomarker research may be correlated with safety and efficacy 
outcomes.  
 
 


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TABLE OF CONTENTS 
Sponsor Approval Page ................................................................................................................ 2 
Signature Page Of The Investigator ............................................................................................ 3 
Document History ......................................................................................................................... 4 
Synopsis .......................................................................................................................................... 5 
Table of Contents ........................................................................................................................ 10 
List of Tables ............................................................................................................................... 13 
List of Figures .............................................................................................................................. 13 
1. 
Introduction and Rationale ................................................................................................ 14 
1.1 
Background .................................................................................................................... 14 
1.2 
APX005M ...................................................................................................................... 15 
1.2.1 
Pharmacology ......................................................................................................... 15 
1.2.2 
Pharmacokinetics .................................................................................................... 16 
1.2.3 
Clinical Experience ................................................................................................. 16 
1.2.4 
Summary of the Known and Potential Risks and Benefits ..................................... 17 
2. 
Investigational Plan ............................................................................................................ 17 
2.1 
Study Objectives ............................................................................................................ 17 
2.1.1 
Primary Objective ................................................................................................... 17 
2.1.2 
Secondary Objectives .............................................................................................. 17 
2.1.3 
Exploratory Objectives ........................................................................................... 18 
2.2 
Study Design and Duration ............................................................................................ 18 
2.2.1 
Study Population ..................................................................................................... 20 
2.2.2 
Rationale for APX005M Dose ................................................................................ 23 
3. 
Study Periods ....................................................................................................................... 23 
3.1 
Screening Period ............................................................................................................ 23 
3.1.1 
Informed Consent.................................................................................................... 23 
3.1.2 
Subject Enrollment.................................................................................................. 23 
3.2 
Treatment Period ............................................................................................................ 23 
3.2.1 
APX005M Administration ...................................................................................... 24 
3.2.2 
Radiation Therapy ................................................................................................... 24 
3.2.3 
Concomitant Treatments ......................................................................................... 28 
3.2.4 
Retreatment Criteria ................................................................................................ 33 


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3.2.5 
Dose Modifications ................................................................................................. 33 
3.2.6 
Duration of Treatment............................................................................................. 34 
3.3 
Follow-up Period ............................................................................................................ 36 
3.3.1 
Discontinuation of Subjects from Study ................................................................. 36 
3.3.2 
Subject Premature Withdrawal ............................................................................... 37 
3.4 
Study Termination .......................................................................................................... 37 
4. 
Study Assessments and Procedures ................................................................................... 37 
4.1 
Procedures by Visits ....................................................................................................... 37 
4.1.1 
Screening Period ..................................................................................................... 37 
4.1.2 
Treatment Period ..................................................................................................... 38 
4.1.3 
Follow-up Period .................................................................................................... 41 
4.2 
Safety Assessments ........................................................................................................ 41 
4.2.1 
Medical History ...................................................................................................... 41 
4.2.2 
Physical Examinations ............................................................................................ 42 
4.2.3 
Electrocardiogram ................................................................................................... 42 
4.2.4 
Vital Signs ............................................................................................................... 42 
4.2.5 
ECOG Performance Status ..................................................................................... 42 
4.2.6 
Laboratory Tests ..................................................................................................... 43 
4.3 
Efficacy Assessments ..................................................................................................... 44 
4.3.1 
Collection of Tumor Assessment Images ............................................................... 45 
4.3.2 
Modified RECIST 1.1 for Immune-based Therapeutics ......................................... 45 
4.4 
Correlative Studies ......................................................................................................... 45 
4.4.1 
APX005M Pharmacokinetic Assessments .............................................................. 45 
4.4.2 
APX005M Anti-drug Antibodies ............................................................................ 45 
4.4.3 
Blood and Tumor Biomarkers ................................................................................ 45 
4.4.4 
Cytokines ................................................................................................................ 46 
5. 
Adverse Events .................................................................................................................... 46 
5.1 
Definitions ...................................................................................................................... 46 
5.1.1 
Adverse Event ......................................................................................................... 46 
5.1.2 
Suspected Adverse Reaction ................................................................................... 46 
5.1.3 
Life-threatening AE or Life-threatening SAR ........................................................ 47 
5.1.4 
Serious AE or Serious SAR .................................................................................... 47 


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5.1.5 
Unexpected AE or Unexpected SAR ...................................................................... 47 
5.1.6 
Overdose ................................................................................................................. 48 
5.2 
Adverse Event Classification ......................................................................................... 48 
5.2.1 
Relationship to Investigational Therapy(ies) .......................................................... 48 
5.2.2 
Severity ................................................................................................................... 49 
5.3 
AE Collection and Reporting ......................................................................................... 49 
5.3.1 
General AE Reporting ............................................................................................. 49 
5.3.2 
Intermittent Adverse Events ................................................................................... 50 
5.3.3 
Reporting Symptoms Versus Syndromes ............................................................... 50 
5.3.4 
Disease Progression ................................................................................................ 50 
5.3.5 
Reporting Serious AEs ............................................................................................ 51 
5.3.6 
Handling of Expedited Safety Reports ................................................................... 51 
5.3.7 
Non-Serious AEs .................................................................................................... 52 
5.3.8 
Laboratory Test Abnormalities ............................................................................... 52 
5.4 
Pregnancy ....................................................................................................................... 52 
6. 
Statistics ............................................................................................................................... 53 
6.1 
Sample Size Determination ............................................................................................ 53 
6.2 
Populations for Analyses ................................................................................................ 53 
6.3 
Endpoint Definitions ...................................................................................................... 53 
6.4 
Analyses ......................................................................................................................... 54 
6.4.1 
Demographics and Baseline Characteristics ........................................................... 54 
6.4.2 
Safety Analyses ....................................................................................................... 54 
6.4.3 
Efficacy Analyses ................................................................................................... 54 
6.4.4 
Exploratory Analyses .............................................................................................. 54 
7. 
Administrative Section ....................................................................................................... 54 
7.1 
Ethics .............................................................................................................................. 54 
7.1.1 
Compliance with the Protocol and Protocol Revisions ........................................... 54 
7.1.2 
Institutional Review Board / Independent Ethics Committee ................................. 55 
7.1.3 
Informed Consent.................................................................................................... 55 
7.2 
Study Materials .............................................................................................................. 56 
7.3 
Monitoring ...................................................................................................................... 56 
7.3.1 
APX005M ............................................................................................................... 56 


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7.4 
Confidentiality ................................................................................................................ 58 
7.5 
Investigational Site Training .......................................................................................... 58 
7.6 
Data Collection and Handling ........................................................................................ 58 
7.7 
Publications .................................................................................................................... 59 
8. 
List of Abbreviations .......................................................................................................... 60 
9. 
References ............................................................................................................................ 63 
Appendix A: Study APX005M-010 Schedule of Events ....................................................... 65 
Appendix B: Vital Signs and Correlative Lab Schedule ...................................................... 67 
Appendix C: Methods of Contraception ................................................................................ 68 
 
LIST OF TABLES 
Table 1A: 
Radiation Dose Constraints - Serial Tissue ..........................................................26 
Table 1B: 
Radiation Dose Constraints - Parallel Tissue .......................................................27 
Table 1C: 
Radiation Dose Criteria ........................................................................................27 
Table 2: 
Guidance for Management of Cytokine Release/Infusion Reaction  
Symptoms .............................................................................................................31 
Table 3: 
Dose Modifications for Toxicity ..........................................................................33 
Table 4: 
ECOG Performance Criteria ................................................................................42 
Table 5: 
Toxicity Grading for AEs Not Covered in NCI-CTCAE (Version 4.03) ............49 
 
LIST OF FIGURES 
Figure 1: 
Cohort 3 Study Design ...........................................................................................19 
 
 


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1. INTRODUCTION AND RATIONALE  
1.1 
Background  
Among the promising approaches to activating therapeutic antitumor immunity is the modulation 
of host immune system. Immune modulation includes inhibitory or stimulatory pathways in the 
immune system that are crucial for activating the immune response, maintaining self-tolerance, 
and modulating the duration and amplitude of physiological immune responses. Modulation of 
immune checkpoints by antibodies against immune inhibitory molecules has shown clinical 
benefits for patients with various solid tumors such as melanoma, lung cancer, bladder cancer, 
renal cell carcinoma [1–3]. Currently, both antagonistic monoclonal antibodies (mAb) against 
immune inhibitory molecules such as cytotoxic T-lymphocyte associated protein 4 (CTLA-4) 
and programmed death receptor-1 (PD-1)/ programmed death-ligand 1 (PD-L1) and agonistic 
antibodies against immune costimulatory molecules such as CD40 and OX40 are under active 
development for different cancer indications [4]. 
Apexigen has developed the mAb APX005M, which binds and activates CD40, a costimulatory 
molecule expressed by antigen presenting cells (APC). As such, APX005M is a CD40 agonistic 
antibody. The cell surface molecule CD40, a member of the tumor necrosis factor receptor 
(TNFR) superfamily, plays an important role in induction of tumor apoptosis and regulation of 
immune activation, especially in crosstalk between T cells and APCs [5]. CD40 is expressed by 
dendritic cells (DC), B cells, monocytes, and some non-lymphoid cells [6]. The natural ligand 
(CD40L) for CD40 is CD154, which is expressed on activated T cells and provides a major 
component of T cell “help” for immune response. Agonistic CD40 antibodies can substitute for 
the function of CD154 on T cells to boost immunity. Signaling through CD40 on APCs, 
including dendritic cells (DCs), monocytes, and B cells, can, in turn, enhance the T cell response 
via improvement in antigen processing and presentation, upregulation of costimulatory 
molecules and through the release of cytokines from activated APCs [7, 8]. Therefore, an 
agonistic CD40 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 [9]. Activation of CD40 on tumor cells 
results in tumor cell apoptosis and inhibition of tumor growth [10]. Due to its action on both 
immune and tumor cells, CD40 has been 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 [11–14]. 
The potential mechanisms of action for an agonistic anti-CD40 antibody, depending on its 
isotype, include stimulation of immune response by activating antigen processing and 
presentation, recruitment of immune effectors such as natural killer (NK) cells and macrophages, 
and direct cytotoxic effects on tumor cells, all of which could lead to therapeutic effects in 
tumors with high mutational burden such as melanoma. Thus, the desired therapeutic CD40 
agonist antibody should have these functionalities. 


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A few CD40 agonistic antibodies have been evaluated in human clinical trials. Many of the 
clinical studies in cancer subjects with solid tumors have been conducted with the fully human 
IgG2 CD40 antibody CP-870,893. In a Phase 1 clinical trial, CP-870,893 was well tolerated; the 
MTD was found to be 0.2 mg/kg. The main toxicity of CP-870,893 was cytokine release 
syndrome (CRS) of mild to moderate severity. Single agent antitumor activity was observed in 
several melanoma subjects treated with CP-870,893 [15, 16]. 
In several preclinical models the combination of RT with drugs that activate APCs results in 
synergistic anti-tumor effects [17, 18]. Activating tumor APCs via CD40 will enhance tumor 
antigen presentation and help prime or boost antitumor T cells in lymph nodes or in tumor-
embedded tertiary lymphoid structures. In addition, properly activated APCs provide potent 
costimulatory signals to CD8+ tumor-infiltrating lymphocytes in the tumor microenvironment 
and release appropriate chemokines, which guide effector T cells to home in the tumor 
microenvironment. In a triple-negative breast cancer model the combination of a CD40 agonist 
antibody and RT resulted in improved innate and adaptive immune response. Importantly, CD40 
treatment increased tumor response to radiotherapy and protected against metastatic spread in a 
metastatic model [19]. 
1.2 
APX005M 
1.2.1 
Pharmacology  
APX005M is an IgG1 humanized mAb with the S267E mutation at the Fc region. APX005M 
binds with high affinity to human CD40 (Kd = 1.2 × 10−10 M) and monkey CD40 (Kd = 3.5 × 
10−10 M), but does not cross-react with mouse or rat CD40. APX005M blocks the binding of 
CD40 to CD40L. The APX005M binding epitope has been mapped to 2 specific regions on 
CD40. These are 92TSEACESCVLHRSCSP107 and 125PCPVGFFSNVSSAFEKCHPW144. 
The region 92TSEACESCVLHRSCSP107 is known as a CD40L binding domain. It has been 
shown that CD40L-blocking antibodies tend to have more potent CD40 agonistic activities than 
CD40L-non-blocking antibodies [20]. 
Preclinical experiments with APX005M showed that it activates the CD40 signaling pathway, 
leading to APC activation, as demonstrated by an increased expression of CD80, CD83, and 
CD86 and by expression and release of cytokines from human DCs and lymphocytes. As a result 
of APC activation, APX005M enhances T-cell proliferation to alloantigen, triggers production of 
IFN-γ in response to viral antigens, and enhances T-cell response to tumor antigens. APX005M 
combined with a TLR 4 agonist or an antibody against programmed death ligand 1 (PD-L1) 
synergistically enhances T-cell responses. In comparison with other CD40-agonistic antibodies, 
such as CP-870,893, SGN-40, and ADC-1013 analogs, APX005M is the most potent CD40 
agonist. APX005M did not appear to have a substantive effect on normal human DC and T-cell 
counts, but could partially reduce B cell counts in vitro. The potential for APX005M to induce 
expression of cytokines was evaluated with peripheral blood mononuclear cells (PBMC) 
obtained from normal humans and treatment naïve cynomolgus monkeys, including anti CD3 
antibody as a positive control. Cytokine secretion differed significantly between species with 
much less secretion from monkey PBMCs compared with human PBMCs. These data suggest 


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that APX005M is a strong CD40-agonistic antibody that can activate APCs (DCs, B cells, and 
monocytes) and in turn stimulate T-cell response. 
The direct cytotoxicity effect and the antibody effector functions such as antibody-dependent 
cellular phagocytosis (ADCP) of APX005M were determined in CD40 positive human 
lymphoma xenograft models in mice. In human lymphoma Ramos models, APX005M was 
capable of inhibiting tumor growth in a dose-dependent manner, and eradicated established 
tumors at 3 mg/kg and 10 mg/kg. A significant anti-tumor effect was also observed in the 
rituximab-resistant Namalwa model [21]. These data suggest that APX005M, as a single agent, 
can induce potent growth inhibition of CD40-expressing human tumors. 
Preliminary human data shows that APX005M induces 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 IL12, INF-γ, TNF-α 
and IL6. 
1.2.2 
Pharmacokinetics 
Nonclinical pharmacokinetics (PK) of APX005M was determined in a Good Laboratory Practice 
(GLP) repeat-dose toxicology study using cynomolgus monkeys. Weekly intravenous (IV) 
administration of 5 doses of APX005M was well tolerated at 0.3, 3, and 30 mg/kg. The PK 
properties of APX005M are typical of other mAbs and comprise low clearance (average range of 
0.401–7.27 mL/h/kg), small volume of distribution (average range of 57–80.1 mL/kg), and long 
terminal half-life (average >66 hours at 3 mg/kg and 30 mg/kg). Positive anti-drug antibodies 
(ADA) titers were observed in all animals in the low-dose group (0.3 mg/kg) but not in the high-
dose group (30 mg/kg) [18]. Based on these results, the no observed adverse effect level 
(NOAEL) was considered 30 mg/kg. 
There are limited human PK data with APX005M at this time. Exposures to every 3-week IV 
administration of APX005M at dose levels of 0.03 mg/kg or less were for the most part below 
the limit of quantitation (BLOQ). Administration of APX005M at dose levels between 0.1 and 
1 mg/kg lead to rapid increase in serum concentrations, reaching a maximum just after the end of 
the infusion. Concentrations declined rapidly thereafter and were for the most part BLOQ 
between 24 and 168 hours after the start of dosing. Increases in the dose of APX005M 
(0.1 mg/kg to 1 mg/kg) led to approximately dose-proportional increases in maximum serum 
concentration (Cmax) and area under the curve at the last measurable time point (AUC0–t). 
No accumulation of APX005M was observed with every 21 days dosing.  
1.2.3 
Clinical Experience  
APX005M has been administered to cancer patients with heavily pretreated solid tumors at doses 
ranging from 0.0001 mg/kg to 1 mg/kg body weight every 3 weeks, 0.1 mg/kg and 0.3 mg/kg 
every 2 weeks and 0.1 mg/kg and 0.3 mg/kg every 1 week. In all 3 administration schedules, the 
dose of 0.3 mg/kg body weight was well tolerated, with toxicities ≤ Grade 2, and is the 
recommended Phase 2 dose. In the every 3-week administration schedule, APX005M 


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demonstrated a dose-dependent activation of APCs, T-cell activation, and increases in circulating 
levels of cytokines.  
1.2.4 
Summary of the Known and Potential Risks and Benefits  
Symptoms associated with cytokine release syndrome (including but not limited to flushing, 
itchiness, chills, fever, rash, tachycardia, hypotension, hypertension, rigor, and myalgia) after 
administration of APX005M are possible and have been observed in some of the subjects 
receiving APX005M. Guidance for monitoring and management of cytokine release syndrome 
are included in this protocol and in the APX005M Investigator’s Brochure.  
Asymptomatic transient transaminase elevations, with or without transient bilirubin increase, 
have been observed in subjects receiving APX005M and these elevations seem to correlated with 
the presence of liver metastases. Liver function test abnormalities tend to resolve to baseline 
within 7 days from APX005M administration. 
Transient decreases in peripheral blood lymphocyte count in general and B-cell count in 
particular have been observed for APX005M as well as for other CD40-agonistic mAbs, and are 
believed to be a pharmacodynamic (PDn) effect. Transient decreases in platelet counts were 
observed for some of the subjects receiving higher doses of APX005M but were not associated 
with bleeding or other clinical manifestations.  
Other symptoms might also occur, including allergic reactions, which could be severe, 
pulmonary edema, and rarely, thromboembolic events, myocardial infarction and/or death. 
In the Phase 1 study APX005M-001, APX005M demonstrated a dose-dependent activation of 
APCs, T-cell activation and increases in circulating levels of cytokines. 
The biological effects and the overall tolerability of APX005M up to 1 mg/kg body weight 
suggest a best-in-class profile for APX005M and the possibility of a safe and efficacious 
treatment for patients with melanoma. 
2. INVESTIGATIONAL PLAN  
2.1 
Study Objectives  
2.1.1 
Primary Objective 
• Evaluate the overall response rate (ORR) by RECIST 1.1 in each cohort 
2.1.2 
Secondary Objectives 
• Evaluate the safety of APX005M alone or in combination with radiation therapy in 
each cohort 
• Evaluate ORR by modified RECIST 1.1 for immune-based therapeutics (iRECIST) in 
each cohort 
• Evaluate median duration of response (DOR) in each cohort 


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2.1.3 
Exploratory Objectives 
•
Evaluate PFS (by RECIST 1.1 and iRECIST) in each cohort
•
Evaluate the association between potential tumor and blood biomarkers and antitumor
activity and/or resistance
•
Determine the presence and titer of anti-APX005M antibodies (ADA)
2.2 
Study Design and Duration  
This is a multicenter, open label, Phase 2 study, with 3 parallel cohorts. The aim of the study is 
to evaluate the efficacy of: 
a) APX005M administered at 2 different schedules to adult subjects with unresectable or
metastatic melanoma who have not received prior immunotherapy. Enrolled subjects will
be alternately assigned to one of the following 2 cohorts as long as both cohorts are open:
Cohort 1: APX005M administered IV at 0.3 mg/kg every 3 weeks (21-day cycle)
Cohort 2: APX005M administered IV at 0.3 mg/kg every 2 weeks (14-day cycle)
The intent of the alternating cohort assignment is to maintain approximately the same
number of treated subjects in each of these 2 cohorts at any given time. Therefore,
enrolled subjects assigned to Cohorts 1 or 2 who do not receive APX005M or are not
evaluable for tumor response (see below) will be replaced in that cohort before assigning
new subjects to the other cohort.
b) APX005M in combination with stereotactic body radiation therapy (SBRT) in adults with
unresectable or metastatic melanoma who have failed approved immunotherapy
regimens:
Cohort 3: APX005M administered IV at 0.3 mg/kg in combination with radiation
therapy every 2 weeks (14-day cycle) up to 16 weeks followed by APX005M
administered IV at 0.3 mg/kg every 2 weeks (14-day cycle).
Subjects enrolled in Cohort 3 are required to have a minimum of 3 non-central nervous
system (CNS) measurable target lesions as defined in RECIST 1.1 (see Section 3.2.2).
Subjects will receive APX005M combined with SBRT followed by single agent
APX005M:
•
Four cycles consisting of radiation (one fraction of 800 cGy per cycle delivered to
the same target lesion) followed by systemic administration of APX005M every
2 weeks for a total period of 8 weeks.
•
Tumor assessment
•
Four additional cycles consisting of radiation (one fraction of 800 cGy per cycle
delivered to one target lesion different from the one previously irradiated)
followed by systemic administration of APX005M every 2 weeks for a total
period of 8 weeks.
•
Tumor assessment


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•
Single agent APX005M until any of the criteria in Section 3.2.6.1 are met.
If the first or second radiation therapy targets disappear during radiation treatment, 
radiation induced toxicity occurs, or radiation dose constrains are met, the remaining 
radiation fraction scheduled for that particular radiation therapy target can be omitted 
(Sections 3.2.2 and 3.2.5).  
Figure 1: 
Cohort 3 Study Design 
Subjects in all 3 cohorts with unconfirmed PD (iUPD, iRECIST) (Section 4.3.2) will be 
permitted to continue treatment as long as  
•
they meet the criteria in Section 3.2.6.2and
•
they do not have confirmed PD as defined by iRECIST on a repeated tumor assessment
4-8 weeks later.
Subjects that are deemed clinically unstable are not required to have repeat imaging for 
confirmation of PD. 
For every subject the participation in the study consists of 3 periods: Screening Period, 
Treatment Period and Follow-up Period. 
All subjects signing the informed consent form will enter the Screening Period. Procedures and 
timing of all study related procedures are outlined in Section 4. Treatment period will start with 
the administration of 1st dose of APX005M ± SBRT and will continue for up to 12 months or 
until criteria in Section 3.2.6.1 are met.  
For the first 2 treatment cycles, subjects will be observed for at least 4 hours following the 
infusion of APX005M and will return for safety evaluations on Day 2 (24 hours post infusion) 
and Day 8 (168 hours post infusion). In subsequent cycles, the 4-hour post-infusion observation 
period and any intracycle safety visits should be scheduled as clinically indicated.  


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Tumor responses will be evaluated approximately every 8 weeks following the first dose of 
APX005M. Subjects that discontinue treatment before the first scheduled on-study tumor 
assessment (8 weeks following the first dose of APX005M) should have the tumor response 
evaluated at the end of treatment visit. Subjects that are non-evaluable for tumor response will be 
replaced. 
Subjects consenting to collection of tumor biopsies for tumor biomarkers must have a primary or 
metastatic lesion that can be biopsied without interfering with subsequent tumor assessments. 
Subjects who discontinue APX005M will enter the Follow-up Period unless treatment 
discontinuation is due to withdrawal of consent for all study procedures, initiation of any 
anticancer therapy, subject lost to follow-up, death, or study termination by Apexigen. 
2.2.1 
Study Population 
2.2.1.1 
Inclusion Criteria 
1) Histologically or cytologically confirmed unresectable or metastatic melanoma
2) Subjects with BRAF activating mutation must have received a BRAF inhibitor and/or
MEK inhibitor regimen prior to study entry
3) Signed written informed consent approved by the relevant local ethics committee(s)
4) Male or female ≥18 years old at time of consent
5) Measurable disease by RECIST 1.1
a.
For Cohort 3 only, subjects must have at least 3 measurable non-CNS target
lesions
6) ECOG performance status of 0 or 1
7) Resolution of all disease or prior treatment-related toxicities to Grade ≤1, with the
exception of alopecia, Grade 2 neuropathy and laboratory abnormalities (parameters
below apply). If subject received major surgery or radiation therapy of >30 Gy, they must
have recovered from the toxicity and/or complications from the intervention
8) Adequate organ function within 14 days prior to first dose of investigational therapy(ies):
a.
WBC ≥2 x 109/L in absence of growth factor support
b. ANC ≥1.0 x 109/L in absence of growth factor support
c.
Platelet count ≥100 x 109/L
d. Hemoglobin ≥9 g/dL
e.
Serum creatinine ≤1.5 mg/dL
f.
Calculated (using the formula of local laboratory) or measured creatinine
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g. AST and ALT ≤2.5 x ULN
h. Total bilirubin ≤1.5 x ULN, or direct bilirubin ≤ULN for subjects with total
bilirubin levels >1.5 x ULN
i.
INR or PT ≤1.5 x ULN unless subject is receiving anticoagulant therapy as long
as PT or PTT is within therapeutic range of intended use of anticoagulants
j.
aPTT ≤1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT
or PTT is within therapeutic range of intended use of anticoagulants
9) Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
within the 7 days prior to first dose of investigational therapy(ies) and a negative urine
pregnancy test within the 3 days prior to first dose of investigational therapy(ies), or a
negative serum pregnancy test within the 3 days prior to first dose of investigational
therapy(ies)
10) Women of childbearing potential must agree to follow instructions for method(s) of
contraception for the duration of study treatment and 5 months after the last dose of
investigational therapy(ies). Males who are sexually active with WOCBP must agree to
follow instructions for method(s) of contraception for the duration of study treatment and
7 months after the last dose of investigational therapy(ies)
11) Available archived or fresh tumor tissue sample for biomarker analysis. Note: For Cohort
3, only available archived tissue is required.
12) For subjects that consent to collection of tumor biopsies at study entry and before the first
scheduled tumor assessment, primary or metastatic tumor that can be safely biopsied. Up
to 18 subjects (6 subjects within each cohort) should consent to fresh core biopsies.
2.2.1.2 
Exclusion Criteria 
1) Prior Therapy:
a.
Cohorts 1 and 2 only: Previous exposure to any immunomodulatory agent (such as 
CTLA-4, PD-1/PD-L1, IDO inhibitors, interferon, CD40 agonist etc.).
b. Cohort 3 only: Prior therapy with a CD40 agonist. Any number of prior lines of
therapy are eligible. A minimum washout period of 21 days from last line of
therapy until investigational therapy(ies) administration should be observed
2) Second malignancy (solid or hematologic) within the past 3 years except locally curable
cancers that have been apparently cured, such as basal or squamous cell skin cancer,
superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast
3) Active, known, clinically serious infections (≥ Grade 2 according to NCI-CTCAE v4.03)
within the 14 days prior to first dose of investigational therapy(ies)
4) Use of systemic corticosteroids or other systemic immunosuppressive drugs within
28 days prior to first dose of investigational therapy(ies) (except inhaled corticosteroids)
a.
The use of physiologic doses of corticosteroids may be approved after
consultation with the Apexigen Medical Monitor (or designee)
5) Major surgery within 4 weeks prior to first dose of investigational therapy(ies)


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6) Concurrent treatment with any anticancer agent (except for hormonal therapy) and 
palliative radiation, unless approved by the Apexigen Medical Monitor (or designee) 
7) History of allogeneic bone marrow transplantation  
8) Active, known or suspected autoimmune disease  
9) Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with 
use of disease modifying agents, corticosteroids or immunosuppressive drugs). Subjects 
with Type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, skin 
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to 
enroll 
10) History of (non-infectious) pneumonitis that required corticosteroids or current 
pneumonitis 
11) History of interstitial lung disease 
12) History of sensitivity or allergy to mAbs or IgG  
13) 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 prior to the first dose of investigational 
therapy(ies) 
14) History of any thromboembolic event within 3 months prior to first dose of 
investigational therapy(ies) or active coagulopathy  
15) Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. 
Subjects with untreated brain metastases ≤3mm that are asymptomatic, do not have 
significant edema, cause shift, and do not require steroids or anti-seizure medications are 
eligible after discussion with the Medical Monitor. Lesions of any size in posterior fossa 
are excluded. Subjects with previously treated brain metastases may participate provided 
they are stable after treatment (without evidence of progression by imaging for at least 4 
weeks prior to the first dose of trial treatment and any neurologic symptoms have returned 
to baseline), have no evidence of new or enlarging brain metastases, and are not using 
corticosteroids for at least 7 days prior to trial treatment. This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability 
16) Known human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection 
17) Has received a live (attenuated) vaccine within 30 days prior to the first dose of 
investigational therapy(ies). Seasonal flu vaccines that do not contain live virus and 
COVID-19 vaccines are permitted (see Section 3.2.3.4) 
18) Has participated in another clinical trial of an investigational drug (or a medical device) 
within 30 days of study enrollment 
19) Pregnant, breastfeeding, or unwilling to practice birth control during participation in the 
study 
20) 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 


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a subject’s ability to give informed consent. 
2.2.2 
Rationale for APX005M Dose   
The APX005M regimens (dose and frequency) for all cohorts have been evaluated in prior 
studies and determined to be well-tolerated and pharmacodynamically-active. In an ongoing 
study, the combination of APX005M with local radiation treatment and chemotherapy did not 
result in excess or synergistic toxicity.  
3. STUDY PERIODS 
3.1 
Screening Period 
3.1.1 
Informed Consent  
All subjects will provide written informed consent prior to any study-related activities. All 
subjects who sign a consent form will enter the Screening Period and be assigned a unique 
Subject Identification Number. This number will be used to identify the subject throughout the 
study and must be used on all study documentation.  
Subjects will be reconsented, as appropriate, during the course of the study if the informed 
consent document is revised. Reconsent should be obtained as soon as practicable (e.g., prior to 
subsequent study drug exposure) or as directed by the local ethics committee(s).  
3.1.2 
Subject Enrollment  
Investigative sites will submit Subject Eligibility Packets (SEPs) for Apexigen Medical Monitor 
(or designee) review and approval. SEPs will include study-specific eligibility checklist and 
redacted/anonymized source documents such as the most recent history and physical, imaging 
reports, and laboratory reports. The Apexigen Medical Monitor (or designee) will review the 
subject’s medical information to confirm eligibility and approve subject’s enrollment in the 
study. During normal business days, a minimum of 2 business days will be required for the 
Apexigen Medical Monitor (or designee) to review a subject for enrollment. Additional time may 
be required when approval is sought during a weekend or holiday.  
Consented subjects who do not meet eligibility criteria will be considered screen failures. 
Enrolled subjects will be alternately assigned to one of the 2 cohorts as long as both cohorts are 
open. Enrolled subjects assigned to a certain cohort that do not receive APX005M or are not 
evaluable for tumor response will be replaced in that cohort before assigning new subjects to the 
other cohort. 
3.2 
Treatment Period 
Enrolled subjects who do not receive APX005M will be considered to have been withdrawn. The 
Treatment Period will start with the first administration of investigational therapy(ies) and will 
continue for up to 12 months or until criteria in Section 3.2.6.1 are met.  


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3.2.1 
APX005M Administration  
For Cohorts 1 and 2, APX005M is administered on Day 1 of each 3-week or 2-week treatment 
cycle. In Cohort 3 APX005M will be administered after each fraction of SBRT during the time 
of combination treatment.  
The APX005M infusion time will be 60 minutes. Sites should make every effort to target 
infusion timing to be as close to 60 minutes as possible. A window between -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 55 minutes to 70 minutes).  
The Pharmacy Manual contains specific instructions for the preparation of the APX005M 
infusion and administration of infusion solution. 
The APX005M infusion can be interrupted in the case of infusion reaction (see Section 3.2.3.2). 
Once symptoms resolve, infusion should be restarted at 50% of the initial infusion rate (e.g., 
from 100 mL/hr to 50 mL/hr). 
All subjects will be discharged from clinic after a clinical evaluation. Subjects should have stable 
vital signs including: lack of orthostatic hypotension (systolic blood pressure >100 mmHg, or no 
lower than 10 mm from baseline) without IV hydration (no hydration for at least 2 hours prior to 
discharge), lack of hypoxia (oxygen saturation >90% without oxygen), temperature <38◦C, and 
heart rate <110 beats/min. After discharge, all subjects should be monitored by a caregiver or by 
a healthcare professional for 24 hours after the first 2 infusions of APX005M and as clinically 
indicated thereafter.  
APX005M and SBRT may be administered up to 3 days after the scheduled Day 1 of Cycle 2 
and beyond in case of medical/surgical events, or logistical reasons not related to study therapy 
(e.g., elective surgery, unrelated medical events, patient vacation, and/or holidays). Treatment 
delays related to study therapy are discussed in Section 3.2.4. 
Administration of APX005M will continue for up to 12 months or until criteria in Section 3.2.6.1 
are met. 
3.2.2 
Radiation Therapy 
All subjects should be evaluated and treated by a local radiation oncologist. All radiation 
treatment will follow the standard guidelines for a SBRT treatment course. Each radiation 
therapy target lesion will receive up to a total of 3200 cGy in 4 fractions of 800 cGy, 
administered on the same day and prior to infusion of APX005M. Fractions will be delivered 
every 2 weeks with the requirement of a minimum of 4 field 3D conformal planning to meet 
dose constraints to limit normal tissue toxicity of organs at risk (OAR). The first target lesion 
and the subsequent target lesion will be identified by the treating investigator based upon 
considerations of clinical benefit and toxicity risk. The RT target lesions shall not be CNS 
metastases. 
First Radiation Therapy Target: One of 3 or more measurable disease lesions (as defined by 
RECIST 1.1) will be selected as the first radiation therapy target and will be treated every 


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2 weeks during the first 8 weeks. The radiation field of the first target shall not overlap with any 
other target lesions.  
Second Radiation Therapy Target: The second target shall be one of the remaining 
non-irradiated lesions where the radiation field does not overlap with the first radiation target. 
The radiation field shall not overlap with at least one non-irradiated target lesion. 
3.2.2.1 
Treatment Technology  
Based upon the location and size of tumors, treatment planning will be determined by clinical 
appropriateness. This protocol requires treatment with photons with minimum nominal energy 
specification of 6 MV. Intensity modulated radiotherapy (IMRT) is encouraged when dosimetric 
benefit would reduce risk to OARs and may be implemented with static gantry or volumetric 
modulated arc therapy (VMAT). Tomotherapy delivery is allowed. Though each individual dose 
may not require high level of precision requiring high level of technology, immobilization and 
verification the total dose over the 8 weeks will require close monitoring.  
3.2.2.2 
Immobilization and Simulation  
Immobilization: Proper immobilization is important for this protocol. Subject setup 
reproducibility must be achieved using appropriate clinical devices. A custom immobilization 
device (such as Alpha Cradle or Vac-Loc) is suggested to minimize set-up variability. SBRT 
frame and abdominal compression may be appropriate for thoracic and abdominal treatments to 
minimize motion.  
Simulation Imaging: CT Simulation is required, and the images must be acquired using a 
CT-simulator with a slice thickness ≤3 mm. Care should be taken to use the smallest possible 
FOV that contains the entire surface of the patient with a 512x512 image matrix. Oral and IV CT 
contrast is optional depending upon the location of the target lesions. The CT simulation must be 
performed with the patient in the treatment position.  
Typical CT scan limits will vary depending on the site. However, it is recommended that the 
patient will be imaged at least 10 cm cranial and caudal to the target especially if noncoplanar 
beams will be used.  
3.2.2.3 
Definition of Target Volumes and Margins  
The volumes are to be defined by planning CT/MRI techniques. The extent of palpable tumors 
should be determined by physical examination to complement imaging and external markers may 
be helpful for target delineation on CT scans. 
3.2.2.4 
Detailed Specification 
Gross tumor volume (GTV): This includes the target lesion and any adjacent extent or lymph 
nodes that are considered part of the target lesion. Assessment of the target lesion CT, PET-CT, 
MRI, or physical exam.  


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Clinical target volume (CTV): This includes the GTV and suspected microscopic extension and 
at-risk excluding bone and muscle. Appropriate expansion shall be determined by the treating 
radiation oncologist and made appropriate for the target site and risk.  
Internal target volume (ITV): For target lesions in regions of motion an ITV may be indicated 
that will take into consideration motion of the target during certain phases of respiration. An 
appropriate ITV shall be created using 4DCT scans or breath hold scans as indicated for the 
motion management strategy.  
Planning target volume 3200 (PTV): This will provide a margin around the CTV or ITV if 
appropriate to compensate for the inter- and intra-fraction uncertainty consequent to daily setup 
uncertainty. By definition, the PTV will consist of a symmetrical 3-7 mm expansion around the 
CTV or ITV as defined for by radiation oncologist that is specific to institutional standard for the 
site. In the event that a PTV extends outside of the skin surface, the clinician should manually 
trim the PTV contours to be 3 mm inside the outer skin (unless there is direct skin involvement).  
3.2.2.4.1 
Definition of Critical Structures  
Because treatment sites may vary throughout the body, the treating radiation oncologist shall 
define the critical structures for the case. This should be defined by the dose constraints (see 
Tables 1A and 1B) and the proximity of the treated lesion.  
Table 1A: 
Radiation Dose Constraints - Serial Tissue 
Serial Tissue 
Vol. 
(cc) 
Vol. Max 
(Gy) 
Max Point 
Dose (Gy)** 
Endpoint 
(≥ Grade 3) 
Optic Pathway 
<0.2 
19.2 
21.2 
neuritis 
Cochlea 
- 
- 
18 
hearing loss 
Brainstem (not medulla) 
<0.5 
20.8 
27.2 
cranial neuropathy 
Spinal Cord and Medulla 
<5 
30 
25.6 
myelitis 
Cauda Equina 
<5 
26 
28.8 
neuritis 
Sacral Plexus 
<5 
26 
28.8 
neuropathy 
Esophagus* 
<5 
30.4 
34 
esophagitis 
Brachial Plexus 
<3 
24.8 
29.6 
neuropathy 
Heart/Pericardium 
<15 
28 
33 
pericarditis 
Great Vessels 
<10 
32 
36 
aneurysm 
Trachea and Large Bronchus* 
<5 
32 
35 
impairment of pulmonary 
toilet 
Bronchus- Smaller Airways 
<0.5 
28.8 
35 
stenosis with atelectasis 
Rib 
<5 
32 
35 
pain or fracture 
Skin 
<10 
32 
35 
ulceration 
Stomach 
<5 
25 
33 
ulceration/fistula 
Bile Duct 
- 
- 
35 
stenosis 
Duodenum* 
<5 
25 
33 
ulceration 
Jejunum/Ileum* 
<30 
22.4 
31.6 
enteritis/obstruction 


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Serial Tissue 
Vol. 
(cc) 
Vol. Max 
(Gy) 
Max Point 
Dose (Gy)** 
Endpoint 
(≥ Grade 3) 
Colon* 
<20 
30.8 
35 
colitis/fistula 
Rectum* 
<20 
32 
35 
proctitis/fistula 
Ureter 
- 
- 
35 
stenosis 
Bladder Wall 
<15 
18.5 
35 
cystitis/fistula 
Penile Bulb 
<3 
27 
- 
impotence 
Femoral Heads 
<10 
27 
- 
necrosis 
Renal Hilum/Vascular Trunk 
15 
21.5 
- 
malignant hypertension 
* 
avoid circumferential irradiation 
** 
“point” defined as 0.035cc or less 
*** or one third of the “native” total organ volume (prior to any resection or volume reducing disease), whichever 
is greater 
Table 1B: 
Radiation Dose Constraints - Parallel Tissue 
Parallel Tissue 
Critical 
Volume (cc) 
Critical 
Volume Dose 
Max (Gy) 
Volumetric 
Constraint 
Endpoint 
(≥ Grade 3) 
Lung (right & left) 
1500 cc for 
males and 
950 cc for 
females*** 
12 
- 
basic lung function 
Lung (right & left) 
- 
- 
V12.8Gy <37% 
pneumonitis 
Liver 
700*** 
19.6 
- 
basic liver function 
Renal Cortex (right & left) 
200*** 
1 
- 
basic renal function 
*** or one third of the “native” total organ volume (prior to any resection or volume reducing disease), whichever 
is greater 
3.2.2.4.2 
Planning Technique  
A 3D conformal or IMRT planning technique must be used. If not using IMRT, field edges and 
MLC blocking must be conformal to the PTV. The dose distributions must include corrections 
for tissue density heterogeneities. Regardless of planning technique, the dose prescription criteria 
specified shall be prioritized.  
Table 1C: 
Radiation Dose Criteria 
Name of Structure 
Dosimetric Parameter 
Per Protocol 
Variation Acceptable 
PTV 
Dmin (%) 
D100% (%) 
Dmax (%) 
≥90 
≥95 
≤130 
≥85 
≥85 
≤150 
 
Replanning: Because melanoma can respond robustly to radiation and treatments will be every 
2 weeks it is possible that the tumor volume will be considerably smaller for subsequent 
fractions. It is recommended that response be assessed after two fractions for bigger tumors or 


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tumors where decrease in size can considerably impact OARs and toxicity risk. If there has been 
a decrease of tumor volume by more than 2-fold then a new plan should be considered.  
3.2.2.4.3 
Patient specific Quality Assurance (QA)  
For photon IMRT plans, patient specific QA is highly recommended. QA is performed by 
delivering the plan onto a phantom and measuring the dose using an ion chamber array or other 
2D/3D device. Typically, measured dose distributions will be compared to planned dose 
distribution using a Gamma criterion of 4% dose difference and 3 mm distance to agreement. 
The pass rate should be at least 90% measured for the entire plan.  
3.2.2.4.4 
Daily Treatment Localization/IGRT  
Daily image-guided radiation therapy (IGRT) localization is required for all patients. Either a 
daily orthogonal kV pair, or cone-beam computed tomography CBCT is acceptable. Institutional 
guidelines should be followed for daily treatment localization and IGRT. IGRT credentialing is 
not required for this protocol. 
3.2.2.4.5 
Duration of Radiation Therapy 
Duration of therapy will be per treatment schedule as above. Duration will be shortened, and 
treatment can be ended early if the patient develops: 
• Inter-current illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Participant decides to withdraw from the study, OR 
• General or specific changes in the patient’s condition render the participant unacceptable 
for further treatment in the judgment of the principal investigator or medical oncologist.  
3.2.3 
Concomitant Treatments 
3.2.3.1 
Premedication prior to APX005M  
All subjects should be premedicated 30 ± 5 minutes before the administration of APX005M with 
a regimen containing: 
• Oral H1 antagonist (e.g., loratadine 10 mg) 
• Optional oral H2 antagonist (e.g., ranitidine 150−300 mg, cimetidine 300−800 mg, 
nizatidine 150−300 mg, and famotidine 20−40 mg) 
• Oral nonsteroidal anti-inflammatory drug (may comprise ibuprofen 400 mg or equivalent) 
• Acetaminophen 650 mg. 
Equivalent quantities of IV formulations of these drugs should be completed 10 ± 5 minutes 
before the administration of APX005M. 


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3.2.3.2 
Rescue Medications & Supportive Care Guidelines  
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse events 
(AEs) with potential immunologic etiology are outlined below. These treatment guidelines are 
intended to be applied when the investigator determines the events to be related to the APX005M 
and should not substitute for dose delays and/or modifications. Additional guidance for 
management of AEs suspected to be related to APX005M is provided in the APX005M 
Investigator’s Brochure. 
If after evaluation the event is determined by the investigator not to be related, the investigator 
does not need to follow the treatment guidance outlined in this section. For each disorder, 
attempts should be made to rule out other causes (such as metastatic disease or bacterial/viral 
infection) which might require additional supportive care. 
• Diarrhea/Colitis 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus). All subjects who experience diarrhea/colitis 
should be advised to drink liberal quantities of clear fluids. If sufficient oral fluid intake is 
not feasible, fluid and electrolytes should be substituted via IV infusion. For Grade 2 or 
higher diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o Grade 1-2: 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, or Grade 2 colitis, the use 
of oral corticosteroids is recommended. Other antidiarrheal agents (e.g. octreotide) 
may be used if necessary. 
o Grade 3-4: treat with IV corticosteroids followed by oral corticosteroids until 
symptoms improve to Grade 1 or less. Add prophylactic antibiotics for 
opportunistic infections and consider lower endoscopy. 
• Creatinine Elevation Due to Inflammatory Causes 
o Grade 2-3: treat with IV or oral corticosteroids until symptoms improve to 
Grade 1 or less. Consider renal biopsy with nephrology consult.  
o Grade 4: treat with IV corticosteroids followed by oral corticosteroids until 
symptoms improve to Grade 1 or less. Consider renal biopsy and consult 
nephrologist. 
• Pneumonitis  
o Grade 2: request pulmonary and infectious disease consults. Treat with IV or oral 
corticosteroids until symptoms improve to Grade 1 or less. Consider 
bronchoscopy, lung biopsy and hospitalization.  
o Grade 3-4: request pulmonary and infectious disease consults. Hospitalize and 
treat immediately with IV corticosteroids. Administer additional anti-


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inflammatory measures, as needed. Consider adding prophylactic antibiotics for 
opportunistic infections. Consider bronchoscopy and lung biopsy.  
• Liver Function Tests 
o Grade 2, and Grade 3 transaminase elevation ≤72 hours: monitor liver 
function tests (incl. total bilirubin levels) more frequently until returned to 
Grade ≤1. 
o All other Grade 3, and any Grade 4 transaminase elevation: treat with 
IV corticosteroids for 24-48 hours followed by oral corticosteroids until 
symptoms improve to Grade ≤1. If no improvement in 3–5 days administer 
additional immunosuppressive measures (e.g. mycophenolate mofetil), as needed. 
Consider adding prophylactic antibiotics for opportunistic infections. Consult 
gastroenterologist.  
• Skin Adverse Events 
o Grade 1-2: symptomatic treatment (e.g. antihistamines, topical steroids). For 
persistent (>1–2 weeks) or recurrent symptoms consider skin biopsy and 
treatment delay. 
o Grade 3–4: consider skin biopsy and consult dermatologist. Treat with 
IV corticosteroids followed by oral corticosteroids until symptoms improve to 
Grade 1 or less.  
• Infusion Reaction/Cytokine Release Syndrome 
Precautions should be observed during the administration of APX005M. Emergency 
treatment including oxygen, oral and endotracheal airways, intubation equipment 
epinephrine, antihistamines, and corticosteroids should be available and used as 
medically required and at the Investigator’s discretion. 
o Grade 2: stop infusion and treat symptoms following guidance in Table 2. If 
symptoms resolve within two hours, the infusion may be restarted at 50% of the 
original infusion rate (e.g., from 100 mL/hr to 50 mL/hr).  
o Grade 3–4: stop infusion and treat symptoms following guidance in Table 2. 
Subjects should be instructed that symptoms associated with cytokine release 
syndrome/infusion reaction may occur within 48 hours following the administration of 
APX005M and if such symptoms develop while they are at home, they should contact the 
Investigator and/or seek emergency medical care if necessary. 


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Table 2: 
Guidance for Management of Cytokine Release/Infusion Reaction Symptoms  
Suspected Cytokine Release/Infusion-related Toxicity 
Recommended Treatment 
• Mild toxicity requiring symptomatic treatment 
only (e.g., fever, nausea, fatigue, headache, 
myalgia, malaise) 
• Vigilant supportive care 
• Maintain adequate hydration 
• Antipyretics, non-steroidal anti-
inflammatory drugs, 
antihistaminics, anti-emetics, 
analgesics as needed 
• In case of mild symptoms 
persisting for >24 hours assess for 
infections; 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 one 
vasopressor (e.g., <50 
mg/min phenylephrine) 
o CTCAE Grade 2 organ 
toxicity 
• No extensive 
co-morbidities 
• All of the above 
• Monitor cardiac and other organ 
functions closely 
• Extensive 
co-morbidities 
• 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 
o CTCAE Grade ≥3 organ toxicity 
• Any Other Possibly Immune Mediated Toxicity 
o Grade 2: symptomatic treatment per local guidelines  
o Grade 3–4: Consult Apexigen Medical Monitor (or designee). Administer IV 
corticosteroids followed by oral corticosteroids until symptoms improve to 
Grade 2 or less. Consider adding prophylactic antibiotics for opportunistic 
infections. If symptoms worsen or for atypical presentation consider and 
additional immunosuppressive measures per local guidelines.  


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3.2.3.3 
Permitted Concomitant Medications  
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 received from the time of first dose of APX005M and 
up to 30 days after the last dose will be recorded on the electronic case report form (eCRF) 
including all prescription, over-the-counter, herbal supplements and IV medications and fluids.  
3.2.3.4 
Prohibited and/or Restricted Therapies  
Subjects are prohibited from receiving the following therapies during the Screening Period and 
Treatment Period of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Investigational agents other than APX005M 
• Radiation therapy not specified in this protocol (radiation therapy to a 
symptomatic solitary lesion or to the brain may be considered on a case-by-case 
basis after consultation with Apexigen Medical Monitor [or designee]). The 
subject must have clear measurable disease outside the radiated field.  
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, 
intranasal influenza vaccines and typhoid (oral) vaccine. Seasonal influenza 
vaccines for injection and COVID-19 vaccines are allowed as long as they can be 
administered 6–7 days after last dose of APX005M. 
• Systemic corticosteroids for any purpose other than to modulate symptoms from 
an event of clinical interest of suspected immunologic etiology. The use of 
physiologic doses of corticosteroids may be approved after consultation with the 
Apexigen Medical Monitor (or designee). Inhaled corticosteroids are allowed for 
management of asthma. 
• Medications described in the Exclusion Criteria. 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management will be discontinued from study treatment.  
Herbal medicine for anticancer treatment (such as botanical formulation ‘Xiao Chai Hu Tang’) 
should be stopped 1 week prior to first dose of APX005M. Subjects taking narrow therapeutic 
index medications (such as warfarin, phenytoin, quinidine, carbamazepine, phenobarbital, 
cyclosporine, and digoxin) should be monitored proactively.  
There are no prohibited therapies during the Follow-up Period. 


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3.2.4 
Retreatment Criteria  
Subjects that do not meet any of the criteria for treatment discontinuation may start a new cycle 
of APX005M ± SBRT as scheduled if WBC ≥2,000/mm3, ANC≥1,000/mm3, platelets 
≥100,000/mm3, and suspected adverse reactions have resolved to baseline or Grade ≤1 
(excluding Grade 2 alopecia and Grade 2 fatigue). Subjects who have experienced a Grade ≤2 
skin suspected adverse reaction may resume treatment in the presence of Grade 2 skin toxicity. 
If a subject fails to meet criteria for retreatment then the treatment cycle should be delayed and 
the subject should be re-evaluated weekly. 
3.2.5 
Dose Modifications  
Management of suspected adverse drug reactions may require reduction of the APX005M dose 
or interruptions of the radiotherapy. If a subject experiences several toxicities, the recommended 
dose adjustment should be based on the highest grade toxicity. All dose reductions for 
APX005M, if required, will follow the instructions described in Table 3.  
Table 3: 
Dose Modifications for Toxicity 
 
Action Taken with APX005M 
Action Taken 
with SBRT 
1st Occurrence 
2nd Occurrence 
3rd Occurrence 
Hematologic Toxicity 
Neutrophils (ANC) 
<500/mm3 Lasting ≥5 days 
Reduce to 
0.2 mg/kg 
Reduce to 
0.1 mg/kg 
Discontinue 
Defer to radiation 
oncologist* 
Neutropenic Fever 
(Body Temperature 
≥38.5ºC (oral) and ANC 
<1000/mm3) 
Reduce to 
0.2 mg/kg 
Reduce to 
0.1 mg/kg 
Discontinue 
Defer to radiation 
oncologist* 
Platelets <25,000/mm3  
Reduce to 
0.2 mg/kg 
Reduce to 
0.1 mg/kg 
Discontinue 
Defer to radiation 
oncologist* 
Platelets <50,000/mm3 
with Significant Bleeding 
or Requiring Blood 
Transfusion 
Reduce to 
0.2 mg/kg 
Reduce to 
0.1 mg/kg 
Discontinue 
Defer to radiation 
oncologist* 
Non-hematologic Toxicities 
Nausea/Vomiting 
≥ Grade 3 Despite Optimal 
Medical Treatment 
Reduce to 
0.2 mg/kg 
Reduce to 
0.1 mg/kg 
Discontinue 
Hold treatment 
until symptoms 
improve to 
Grade ≤1 
Diarrhea ≥ Grade 3 Despite 
Optimal Medical 
Treatment 
Reduce to 
0.2 mg/kg 
Reduce to 
0.1 mg/kg 
Discontinue 
Hold treatment 
until symptoms 
improve to 
Grade ≤1 
CRS Grade 3 ≤7 days 
Reduce to 
0.2 mg/kg 
Reduce to 
0.1 mg/kg 
Discontinue 
Defer to radiation 
oncologist* 
CRS Grade 3 >7 days 
Discontinue 
- 
- 
Discontinue 
CRS Grade 4 
Discontinue 
- 
- 
Discontinue 
Increased Bilirubin 
Grade ≥ 3 
Discontinue 
- 
- 
Discontinue 


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Action Taken with APX005M 
Action Taken 
with SBRT 
1st Occurrence 
2nd Occurrence 
3rd Occurrence 
Increased AST, ALT 
Grade 3 
Reduce to 
0.2 mg/kg# 
Reduce to 
0.1 mg/kg# 
Discontinue 
Hold treatment 
until Grade ≤1 
Increased AST, ALT 
Grade 4 
Discontinue 
- 
- 
Discontinue 
Pneumonitis Grade 2 
Reduce to 
0.2 mg/kg 
Reduce to 
0.1 mg/kg 
Discontinue 
Hold treatment 
until Grade ≤1. 
Discontinue on 2nd 
occurrence 
Pneumonitis Grade ≥3 
Discontinue 
- 
- 
Discontinue 
Esophagitis Grade 2 
Reduce to 
0.2 mg/kg 
Reduce to 
0.1 mg/kg 
Discontinue 
Hold treatment 
until Grade ≤1 
Esophagitis Grade ≥3 
Discontinue 
- 
- 
Discontinue 
Gastric or Small Bowel 
Ulcer Grade ≥2  
Reduce to 
0.2 mg/kg 
Reduce to 
0.1 mg/kg 
Discontinue 
Discontinue 
Colitis or Proctitis 
Grade ≥3 
Discontinue 
- 
- 
Discontinue 
Other ≥3 Grade Toxicities 
(except Alopecia)§ 
Adjusted as medically indicated after discussion with 
Sponsor 
Defer to radiation 
oncologist* 
Abbreviations: CRS = cytokine release syndrome 
For all toxicity ≤Grade 2, the current dose should be maintained 
* Investigator will defer to the radiation oncologist as to whether an interruption of the radiation therapy is also 
indicated. 
# For subjects with liver metastasis reduce dose only if Grade 3 >72 hours 
§ In the event of the “other” Grade 3 or 4 non-hematologic toxicities that, in the opinion of the Investigator, are 
unrelated to the investigational therapy, subject may continue on therapy with or without dose reduction only after 
documented discussion with the Apexigen Medical Monitor (or designee). 
3.2.6 
Duration of Treatment 
Subjects may continue to receive SBRT and APX005M up to 16 weeks and APX005M for up to 
12 months or until any of the criteria in Section 3.2.6.1 are met.  
Tumor assessment will be performed within 21 days prior to start of investigational therapy and 
during the Treatment Period (every 8 ± 1 weeks). Tumor assessments will follow RECIST 1.1 
guidelines. 
Subjects with confirmed CR may continue APX005M up to 24 weeks, on a case-by-case basis, 
after careful evaluation and Investigator discussion with the Apexigen Medical Monitor (or 
designee) to determine whether the risk-benefit ratio supports administration of further study 
drug. 


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3.2.6.1 
Discontinuation of Subjects from Treatment  
Subjects MUST discontinue receiving APX005M for any of the following reasons: 
• Disease progression by RECIST 1.1, or disease progression following treatment beyond 
progression (Section 3.2.6.2) 
• Death 
• Toxicity requiring discontinuation of investigational therapy(ies) as outlined in the dose 
modification guidelines 
• Failure to recover from a disease or treatment-related AE to baseline or ≤ Grade 1 within 
12 weeks of last dose of APX005M (except Grade 2 alopecia, Grade 2 fatigue or Grade 2 
skin toxicity), unless the subject is benefiting from therapy and after discussion with and 
approval by Apexigen Medical Monitor (or designee) 
• Failure to recover from an AE related to infusion reaction/cytokine release within 
4 weeks of last dose of APX005M  
• Inability to reduce corticosteroid to ≤10 mg of prednisone or equivalent per day within 
12 weeks of last dose of APX005M 
• Subject’s decision to withdraw for any reason from study treatment (if subject withdraws 
from study treatment the subject should enter the Follow-up Period) 
• Pregnancy 
• Any clinical AE, laboratory abnormality or coincident illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of 
the subject 
• Requirement for alternative therapy 
• Noncompliance with study procedures, including use of prohibited medications 
• Subject is lost to follow-up 
• Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness 
• Study termination by Apexigen 
Apexigen (or designee) must be notified within 24 hours if a subject is withdrawn from 
treatment. The primary reason for treatment discontinuation will be documented in the eCRF.  
3.2.6.2 
Treatment beyond Progression  
Accumulating evidence indicates that patients with solid tumors treated with immunotherapy or 
the combination of immunotherapy with RT may derive clinical benefit despite initial evidence 
of progressive disease. Subjects will be permitted to continue on treatment beyond initial 
RECIST 1.1-defined progressive disease (iUPD, [iRECIST]) as long as they meet the following 
criteria:  


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• Investigator-assessed clinical benefit, without rapid disease progression, or with disease 
progression based primarily on changes in lymph nodes appearance 
• Subject continues to meet retreatment criteria (Section 3.2.4) 
• Subject tolerates study treatment 
• Subject has stable ECOG performance status  
• Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., CNS metastases).  
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. All decisions to 
continue treatment beyond initial progression should be discussed with the Apexigen Medical 
Monitor (or designee), and an assessment of the risk/benefit of continuing with study therapy 
must be documented in the study records.  
For subjects who stay on treatment beyond RECIST 1.1-defined progressive disease, all study 
procedures should be performed continuously, including tumor assessments (Section 4). 
Subjects will be discontinued from the treatment upon further evidence of disease progression, as 
described in the iRECIST guidelines by Seymour et al [22]. 
3.3 
Follow-up Period 
Subjects who discontinue APX005M will enter the Follow-up Period until criteria in 
Section 3.3.1 are met. Regular follow-up visits (or phone contact or chart reviews) should be 
scheduled every 3 months or more frequently if clinically indicated. 
All AEs that are considered related to APX005M must be followed to resolution, stabilization, 
until improvement is not expected, 30 days after receiving the last dose of APX005M, death, or 
initiation of new anticancer therapy, whichever occurs first. Serious AEs (SAEs), pregnancies 
and AEs with potential immunologic etiology will be recorded and followed up to 90 days after 
the last dose of APX005M, death, or initiation of new anticancer therapy, whichever occurs first. 
3.3.1 
Discontinuation of Subjects from Study  
Subjects who are withdrawn from APX005M will enter the Follow-up Period unless study 
treatment discontinuation is due to any of the following: 
• Subject death 
• Withdrawal of consent for all study procedures 
• Initiation of any anticancer therapy (except for subjects continuing immediately following 
this study on a PD-1/PD-L1 containing regimen for whom the regimen and the response 
to that regimen should be documented) 
• Subject is lost to follow-up 
• Study termination by Apexigen. 


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Subsequent anticancer regimen should be documented. For subjects, who switch to a 
PD-1/PD-L1 containing regimen immediately after study treatment the response to that regimen 
should be documented. Once this information is collected, a subject is considered off-study. 
3.3.2 
Subject Premature Withdrawal 
Any subject has the right to withdraw consent or to discontinue study treatment or study 
participation at any time for any reason. 
In the case that a subject decides to prematurely discontinue study treatment (“refuses 
treatment”), he/she should be asked if he/she agrees to continue to be followed-up until criteria 
for discontinuation from study are met (enter Follow-up Period). 
3.4 
Study Termination  
Apexigen has the right to terminate this study or a study site from participating in the study at 
any time. Reasons for terminating the study at a specific study site may include, but are not 
limited to, the following: 
• Subject enrollment is unsatisfactory 
• Data recording is inaccurate or incomplete 
• Investigator does not adhere to the protocol or applicable regulatory requirements in 
conducting the study 
Reasons for terminating the study overall may include, but are not limited to, the following: 
• The incidence or severity of AEs in this or other APX005M studies indicates a potential 
health hazard to subjects 
• All subjects enrolled in the study have completed the Treatment Period 
• All subjects enrolled in the study have completed the Follow-up Period. 
4. STUDY ASSESSMENTS AND PROCEDURES  
Time and events schedule is presented in Appendix A.  
4.1 
Procedures by Visits  
4.1.1 
Screening Period  
All patients must provide written informed consent before any study specific assessments or 
procedures are performed.  
The screening assessments should be performed within 21 days before beginning of the 
Treatment Period. The following study evaluations will be performed during the screening 
period:  


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• Collect demographics 
• Collect medical history (including concomitant medications) 
• Perform physical examination including (including weight, height, and vital signs) and a 
12-lead electrocardiogram 
• ECOG performance status 
• Laboratory evaluations: 
1) urinalysis 
2) serum chemistry 
3) hematology 
4) coagulation 
• Assess eligibility (inclusion/exclusion criteria) 
• Tumor assessment following RECIST 1.1 Guidelines 
• Collect archived tumor tissue 
• Collect and submit a tumor core biopsy from consenting subjects. Selection of tumor 
lesions should not interfere with subsequent tumor assessments when feasible 
• For Cohort 3: SBRT treatment planning 
• Pregnancy test (if applicable) 
4.1.2 
Treatment Period  
The following procedures and investigations should be performed during the Treatment Period: 
4.1.2.1 
Cycles 1 & 2: Day 1 
• Confirm eligibility (only in Cycle 1) 
• Perform physical examination (including weight and vital signs at preinfusion, end of 
infusion, 4 hours after the end of infusion) 
• ECOG performance status 
• Laboratory evaluations: 
1) Serum chemistry 
2) Hematology 
3) Coagulation 
• PK serum sample (preinfusion, end of infusion, 4 hours ± 30 minutes after the end of 
infusion) 
• ADA serum sample (preinfusion) 
• Whole blood and plasma (preinfusion) 


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• Cytokines plasma samples (preinfusion, end of infusion, 4 hours ± 30 minutes after the 
end of infusion) 
• Record AEs and concomitant medications (ConMeds) 
• For Cohort 3: administer SBRT 
• Administer premedication before APX005M 
• Administer APX005M 
4.1.2.2 
Cycles 1 & 2: Day 2 
• Collect vital signs 
• Laboratory evaluations: 
 Serum chemistry 
 Hematology 
 Coagulation 
• PK serum sample (24 ± 2 hours after the end of infusion) 
• Whole blood and plasma (24 ± 2 hours after the end of infusion) 
• Cytokines plasma sample (24 ± 2 hours after the end of infusion) 
• Record AEs and ConMeds 
4.1.2.3 
Cycles 1 & 2: Day 8 
• Collect vital signs 
• Laboratory evaluations: 
1) Serum chemistry 
2) Hematology 
3) Coagulation 
• Whole blood and plasma (168 ± 2 hours after the end of infusion) 
• Cytokines plasma sample (168 ± 2 hours after the end of infusion) 
• Record AEs and ConMeds 
4.1.2.4 
Cycles 3+ Day 1 
• Perform physical examination (including weight and vital signs at preinfusion, end of 
infusion) 
• ECOG performance status 
• Laboratory evaluations: 


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1) Serum chemistry 
2) Hematology 
3) Coagulation 
4) Pregnancy test every other cycle (if applicable) 
• PK serum sample in Cycles 3 and 5 (preinfusion, end of infusion) 
• ADA serum sample in Cycles 3 and 5 (preinfusion) 
• Whole blood and plasma -- Cohort 1: Cycles 3 and 6 (preinfusion); Cohorts 2 and 3: 
Cycles 4 and 8 (preinfusion) 
• Record AEs and ConMeds 
• For Cohort 3: administer SBRT for up to 8 cycles 
• Administer premedication before APX005M 
• Administer APX005M 
4.1.2.5 
Cycles 3+ Optional Safety Visit 
• Collect vital signs 
• Laboratory evaluations: 
1) Serum chemistry 
2) Hematology 
• Record AEs and ConMeds 
4.1.2.6 
Tumor Assessment Visit  
• Tumor Assessment  
4.1.2.7 
Second Tumor Biopsy Visit 
• Laboratory evaluations: 
1) Serum chemistry 
2) Hematology 
• Record AEs and ConMeds 
• Whole blood and plasma 
• Cytokines plasma sample 
• Collect fresh tumor tissue sample 


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4.1.2.8 
End of Treatment Visit  
• Perform physical examination (including weight and vital signs) 
• ECOG performance status 
• Laboratory evaluations: 
1) Serum chemistry 
2) Hematology 
3) Coagulation 
4) Pregnancy test (if applicable) 
• ADA serum sample 
• Whole blood and plasma 
• Cytokines plasma sample  
• Record AEs and ConMeds 
• Tumor assessment (for subjects that discontinue treatment before the first scheduled on 
study tumor assessment)  
4.1.3 
Follow-up Period  
• Follow-up AEs related to APX005M until resolution, stabilization, until improvement is 
not expected, 30 days, death, or initiation of new anticancer therapy, whichever occurs 
first 
• Record SAEs, pregnancies and AEs with potential immunologic etiology up to 90 days, 
death, or initiation of new anticancer therapy, whichever occurs first. Follow-up SAEs, 
pregnancies and AEs with potential immunologic etiology until resolution, stabilization, 
until improvement is not expected, 90 days from APX005M, death, or initiation of new 
anticancer therapy, whichever occurs first 
• Record ConMeds  
• Report date of death or progressive disease 
• Record subsequent treatment and date 
• For subjects continuing immediately following this study on a PD-1/PD-L1 containing 
regimen, the regimen and the response to that regimen should be documented. 
4.2 
Safety Assessments  
4.2.1 
Medical History 
At screening, a medical history will be obtained to capture relevant underlying conditions. 


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4.2.2 
Physical Examinations 
A physical examination will include examination of the skin, head and neck, chest (heart and 
lungs), abdomen, limbs, and a brief neurological examination. Rectal and pelvic examinations 
are optional.  
4.2.3 
Electrocardiogram  
A 12-lead electrocardiogram (ECG) including calculation of corrected QT interval will be 
conducted locally and is required at screening only. Additional ECGs can be performed as 
clinically indicated. 
4.2.4 
Vital Signs  
Vital sign measurements include blood pressure, pulse rate, respiration rate, and temperature. 
Subjects should be monitored during and after APX005M infusions for potential infusion 
reactions. Vital signs will be measured: 
• within 30 minutes prior to APX005M dose (pre-infusion) 
• within 30 minutes after the end of the APX005M infusion 
• 4 hours (±30 minutes) after the end of APX005M infusion (Cycles 1 and 2 only) 
• 24 hours and 168h after the end of APX005M infusion (Cycles 1 and 2 only) 
• On Day 1 of subsequent cycles (preinfusion, end of infusion) 
• As medically indicated 
• End of treatment visit 
4.2.5 
ECOG Performance Status 
ECOG performance status should be assessed a time points indicated in Appendix A. 
Table 4: 
ECOG Performance Criteria 
Grade 
Description 
0 
Normal activity, fully active, able to carry on all pre-disease performance without restriction 
1 
Symptoms, but fully ambulatory, restricted in physically strenuous but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light housework, office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Death 
It is recommended, where possible, that a patient’s performance status will be assessed by the 
same person throughout the study.  


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4.2.6 
Laboratory Tests  
All clinical laboratory tests (e.g., urinalysis, serum chemistry, hematology, coagulation) will be 
performed at local laboratories. Assessments performed within 3 days (with results available) 
prior to the administration of study treatment could be used for Day 1 of any cycle. 
4.2.6.1 
Urinalysis  
Routine urinalysis will be performed at screening and whenever clinically indicated. 
4.2.6.2 
Serum Chemistry  
The laboratory tests included in the full chemistry panel are: 
• Albumin 
• Alkaline phosphatase 
• Bicarbonate 
• Blood urea nitrogen 
• Calcium 
• Chloride 
• Creatinine 
• Creatinine clearance (calculated or measured) 
• Glucose 
• Lactate dehydrogenase 
• Magnesium 
• Phosphorous 
• Potassium 
• SGOT/AST 
• SGPTALT 
• Sodium 
• Total bilirubin 
• Total protein 
• Uric acid 
• Hematology  
• The laboratory tests included in the hematology panel are: 
• Hemoglobin 
• Hematocrit 


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• White blood cell count with complete manual or automated differential (reported as 
absolute counts): 
o Total neutrophils 
o Lymphocytes 
o Monocytes 
o Eosinophils 
o Basophils 
• Red blood cell count 
• Platelet count 
4.2.6.3 
Coagulation  
The laboratory tests included in the coagulation panel are: 
• Prothrombin time 
• Activated partial thromboplastin time 
• INR; required only at screening and as clinically indicated thereafter 
• D-dimer test; D-dimer test should be performed if available at local lab at baseline and on 
Day 8 in Cycles 1 and 2 and as clinically indicated thereafter. 
4.2.6.4 
Pregnancy Test  
For WOCBP, a pregnancy test is required for eligibility determination and should be performed 
at the local laboratory. A WOCBP as a sexually mature woman who: 
• has not undergone a hysterectomy or bilateral oophorectomy, or 
• has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had 
menses at any time in the preceding 12 consecutive months) 
At a minimum, serum pregnancy test will be done within 7 days followed by a urine pregnancy 
test within 3 days prior to first dose of investigational therapy(ies), or a serum pregnancy test 
will be done within 3 days prior to first dose of investigational therapy(ies). Pregnancy testing 
should be conducted every other cycle and at the End of Treatment Visit. More frequent 
pregnancy tests may be conducted if required per local regulations. 
4.3 
Efficacy Assessments  
Tumor assessment will be performed within 21 days prior to start of investigational therapy and 
during the Treatment Period (every 8 ± 1 week). Subject that discontinue treatment before the 
first scheduled on study tumor assessment (8 weeks following the first dose of APX005M) 
should have the tumor response evaluated at the end of treatment visit. Tumor assessments will 
follow RECIST 1.1 guidelines. Complete or partial responses should be confirmed at a 
subsequent time point 4 weeks later. 


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Subjects enrolled in Cohort 3 are required to have a minimum of 3 measurable target lesions. 
The lesions which are the first and second radiation therapy targets should be recorded.  
4.3.1 
Collection of Tumor Assessment Images 
Copies of all diagnostic and post-treatment tumor assessment images may be collected and may 
be used to confirm disease responses.  
4.3.2 
Modified RECIST 1.1 for Immune-based Therapeutics  
Accumulating evidence indicates that patients with solid tumors treated with immunotherapy 
may derive clinical benefit despite initial evidence of PD. For the purpose of establishing the 
Phase 2 secondary endpoint the iRECIST (modified RECIST 1.1 for immune-based therapeutics 
[22]) will be used to assess tumor response for all treated subjects. 
Subjects with RECIST 1.1-defined PD (iUPD [iRECIST]) should have a repeated tumor 
assessment 4-8 weeks later in order to confirm PD and will be permitted to continue treatment as 
long as they meet the criteria in Section 3.2.6.2 and they do not have confirmed PD as defined by 
iRECIST. Subjects that are deemed clinically unstable are not required to have repeat imaging 
for confirmation of PD.  
4.4 
Correlative Studies 
Correlative laboratory samples will be obtained in relation to the APX005M infusion. End of 
infusion sample should be collected within the 10 minutes after the completion of the infusion 
(before flush). Other post infusion time points in the within the first 24 hours are ± 30 minutes. 
A ± 2 hours window is allowed for the 24 hours and 168-hour time point. If samples cannot be 
collected within the protocol-specified window they should be collected as soon as practicable.  
4.4.1 
APX005M Pharmacokinetic Assessments  
Serum samples for pharmacokinetics (PK) will be obtained from all subjects in Cycles 1 and 2 
Day 1 (preinfusion, end of infusion, 4 hours ± 30 min after end of infusion), Day 2 (24 ± 2 hours 
after the end of infusion), and in Cycles 3 and 5 Day 1 (preinfusion, end of infusion).   
4.4.2 
APX005M Anti-drug Antibodies  
Serum samples will be collected for anti-drug antibody (ADA) analysis in Cycles 1, 2, 3 and 5 
Day 1 (preinfusion) and at the EOT Visit.  
4.4.3 
Blood and Tumor Biomarkers  
Whole blood and plasma will be collected from all participating subjects in Cycles 1 and 2 
(Day 1 [preinfusion], Day 2 [24 ± 2 hours]) and Day 8 [168 ± 2 hours]), Cycles 3 and 6 Day 1 
(preinfusion) for subjects in Cohort 1, Cycles 4 and 8 Day 1 (preinfusion) for subjects in Cohorts 
2 and 3, time of 2nd tumor core biopsy (if applicable; see below) and at the EOT visit. 
Submission of archived formalin-fixed paraffin embedded tumor tissue or 15 unstained slides is 
mandatory. Tissues may be from the primary tumor, or a metastatic site (or site of local 


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recurrence or advancement) if the primary tumor is unavailable, or if possible, from both primary 
tumor and a metastatic site.  
Subjects who enter Screening Period will be asked to consent to collection of paired fresh tumor 
tissue whenever possible. Up to 18 subjects (6 subjects within each cohort) should consent to 
fresh core biopsies.  
Fresh tumor core biopsies will be collected from consenting subjects prior to the first dose of 
APX005M and prior to first scheduled tumor assessment (at approximately 8 weeks from first 
dose of APX005M). 
For sampling procedures, storage conditions and shipment instructions, see the study Laboratory 
Manual.  
Markers of inflammation, angiogenesis, tumor biology, tumor necrosis, vascularity, cell 
turnover, and expression of molecules in gene families and their signaling pathway molecules 
may be assessed in tissue and blood samples. 
These data will also be used to derive new hypotheses about mechanisms of drug response, 
resistance, and safety. 
4.4.4 
Cytokines  
Plasma samples for cytokine analysis will be obtained from all subjects in Cycles 1 and 2 Day 1 
(preinfusion, end of infusion, 4 hour ± 30 min after end of infusion), Day 2 (24 ± 2 hours) and 
Day 8 (168 ± 2 hours) time of 2nd tumor core biopsy (if applicable; see below), and at EOT visit. 
5. ADVERSE EVENTS  
5.1 
Definitions  
The AE definitions and reporting procedures provided in this protocol comply with current 
21 Code of Federal Regulations Part 312.32. The Apexigen Medical Monitor (or designee) must 
promptly review all information relevant to the safety of APX005M received from any source. 
The investigator or appropriately qualified designee (e.g., a certified nurse practitioner or 
physician’s assistant) will carefully monitor each subject throughout the study for possible AEs, 
the designee must be properly listed on the Form FDA 1572.  
5.1.1 
Adverse Event  
Adverse event (AE) means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. Abnormal laboratory findings should be 
reported as AEs only if they are clinically relevant.  
5.1.2 
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 


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lesser degree of certainty about causality than adverse reaction, which means any AE caused by a 
drug. 
5.1.3 
Life-threatening AE or Life-threatening SAR  
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. 
5.1.4 
Serious AE or Serious SAR  
An AE or SAR is considered "serious" (SAE or SSAR) if, in the view of either the Investigator 
or sponsor, it results in any of the following outcomes: 
• 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 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
5.1.5 
Unexpected AE or Unexpected SAR 
An AE or SAR is considered "unexpected" if it is not listed in the Investigator Brochure or is not 
listed at the specificity or severity that has been observed; or, if an Investigator 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 
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 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. 


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5.1.6 
Overdose  
For this trial, an overdose will be defined as a dose of APX005M that is >1 mg/kg body weight. 
It is expected that an overdose of APX005M will be associated with severe cytokine release 
syndrome. In the event of overdose, the subject should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated. Retreatment after an 
overdose must be discussed with Apexigen Medical Monitor (or designee). 
5.2 
Adverse Event Classification  
5.2.1 
Relationship to Investigational Therapy(ies) 
The Investigator will assign attribution of the possible association of the event with use of the 
investigational therapy(ies) (APX005M and/or radiation), and this information will be entered 
into electronic data capture (EDC) system using the classification system listed below:  
Related to Investigational Therapy(ies) 
The event is suspected to be related if: 
• There is a clinically plausible time sequence between the AE onset and administration of 
investigational therapy(ies) 
• There is a biologically plausible mechanism for the investigational therapy(ies) to cause 
or contribute to the AE 
• The event improves or diminishes upon temporary interruption of the investigational 
therapy(ies) 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 
Apexigen Medical Monitor (or designee) will review all Investigator-reported assessments of 
relationship and confirm.  
Unrelated to Investigational Therapy(ies) 
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 medical, or study or non-study procedure 
• The time occurrence of the AE is not reasonably related to administration of 
investigational therapy(ies) 
• The event is not related to the investigational therapy(ies) 


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5.2.2 
Severity 
AE will be reported at the highest grade experienced. The NCI-CTCAE v 4.03 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 5 should be used. 
Table 5: 
Toxicity Grading for AEs Not Covered in NCI-CTCAE (Version 4.03) 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Mild; asymptomatic 
or mild symptoms; 
clinical or 
diagnostic 
observations only; 
intervention not 
indicated 
Moderate; minimal, 
local or noninvasive 
intervention 
indicated; limiting 
age-appropriate 
instrumental 
activities of ADL* 
Severe; medically 
significant but not 
immediately life 
threatening; 
hospitalization or 
prolongation of 
hospitalization 
indicated; disabling; 
limiting self-care 
ADL** 
Life-threatening 
consequences; urgent 
intervention 
indicated 
Death 
Semi-colon indicates “or” within the description 
Abbreviations: ADL = activities of daily living.  
* 
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. 
5.3 
AE Collection and Reporting  
5.3.1 
General AE Reporting  
All AEs will be collected from the time the subject receives any investigational therapy(ies) 
through 30 days after receiving the last dose of investigational therapy(ies), death, or initiation of 
new anticancer therapy, whichever occurs first. SAEs, pregnancies and AEs with potential 
immunologic etiology will be recorded up to 90 days after the last dose of investigational 
therapy(ies), death, or initiation of new anticancer therapy, whichever occurs first. 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 therapy(ies). 
Events that occur after the subject signs the informed consent but prior to the first dose of 
APX005M will be recorded as past medical history; events that start after the first dose of 
APX005M will be recorded as AEs.  
All AEs must be promptly documented on the AE eCRF. The minimum information required for 
each AE includes event, duration (start and end dates), severity, seriousness, relationship to 
iAPX005M, 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 (See Section 5.3.3) and Cytokine Release 
Syndrome (See Section 5.3.3).  
All AEs that are considered related to APX005M must be followed to resolution, stabilization, 
until improvement is not expected, 30 days after receiving the last dose of APX005M, death, or 


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initiation of new anticancer therapy, whichever occurs first. SSAR will be followed until 
resolution, stabilization, 90 days or until resolution is not anticipated. 
AE will be reported at the highest grade experienced. AEs which completely resolve and then recur 
will be recorded as a new AE. All AEs that are considered related to investigational therapy(ies) must 
be followed to resolution, stabilization, until improvement is not expected, 30 days after receiving the 
last dose of investigational therapy(ies), death, or initiation of new anticancer therapy, whichever 
occurs first. SSAR 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 therapy(ies) 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 FDA 
Form 1572. 
5.3.2 
Intermittent Adverse Events  
AEs which completely resolve and then recur will be recorded as a new AE. 
5.3.3 
Reporting Symptoms Versus Syndromes  
The constellation of symptoms that comprise an APX005M infusion related reaction or cytokine 
release syndrome has not been completely defined, so it is important that all symptoms be 
reported and not just the all-inclusive event of infusion-related reaction or cytokine release 
syndrome. All AEs and the overall syndrome will be graded in accordance with NCI-CTCAE 
criteria. 
5.3.4 
Disease Progression  
Progression of underlying malignancy is not reported as an AE if it is clearly consistent with the 
suspected progression of the underlying cancer as defined by RECIST, or other criteria as 
determined by protocol. Hospitalization due solely to the progression of underlying malignancy 
should NOT be reported as an SAE. Clinical symptoms of progression may be reported as AEs if 
the symptom cannot be determined as exclusively due to the progression of the underlying 
malignancy or does not fit the expected pattern of progression for the disease under study. 
If there is any uncertainty about an AE being due only to the disease under study, it should be 
reported as an AE or SAE. 
Symptomatic deterioration may occur in some patients. In this situation, progression is evident in 
the patient’s clinical symptoms, but is not supported by the tumor measurements. Or, the disease 
progression is so evident that the Investigator may elect not to perform further disease 


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assessments. In such cases, the determination of clinical progression is based on symptomatic 
deterioration. These determinations should be a rare exception as every effort should be made to 
document the objective progression of underlying malignancy. 
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 APX005M. 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. 
5.3.5 
Reporting Serious AEs 
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:  DrugSafety010@apexigen.com 
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). Apexigen (or designee) may request additional 
source documentation pertaining to the SAE/SSAR from the investigational site. If a subject is 
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. 
Apexigen (or designee) is responsible for notifying the appropriate health authorities of serious 
and unexpected SAR (SUSAR) through expedited IND safety reports (ISR) in accordance with 
applicable laws and regulations. 
5.3.6 
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. 


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5.3.7 
Non-Serious AEs  
The collection of AE information begins after subject’s written consent to participate in the 
study. AEs should be followed to resolution, stabilization, a minimum of 30 days after the last 
dose of APX005M or reported as SAEs if they become serious. 
5.3.8 
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 APX005M discontinued, delayed, or interrupted 
• Require the subject to receive specific corrective therapy 
• Are clinically significant 
• Meet the definition of an SAE/SSAR. 
5.4 
Pregnancy  
Subjects will be instructed to notify the investigator as soon as possible after becoming pregnant 
(or suspecting pregnancy) or learning of the pregnancy or suspected pregnancy of a partner. If a 
subject or partner of a subject becomes pregnant during treatment or up to 90 days following the 
last study drug administration, the investigator will notify Apexigen (or designee) within 
24 hours of learning of the pregnancy.  
If the subject becomes pregnant while receiving investigational therapy(ies), the investigational 
therapy(ies) will be permanently discontinued. Exceptions to the investigational therapy(ies) 
discontinuation may be considered for life-threatening conditions only after consultation with the 
Apexigen Medical Monitor (or designee). The Investigator will discuss the risks and concerns of 
investigational drug exposure 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. 


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6. STATISTICS  
6.1 
Sample Size Determination  
This is an exploratory Phase 2 study. Cohorts 1 and 2 will enroll 11 subjects each. Assuming a 
true response rate of about 18.2% (2 subjects with tumor response out of 11 subjects) in each of 
these cohorts, the estimated standard error of the response rate in each of these cohorts will be 
11.6%. Cohort 3 will enroll 18 subjects. Assuming a true response rate in this cohort of about 
16.7% (3 responders out of 18 patients) the estimated standard error will be 8.8%. 
6.2 
Populations for Analyses  
Analysis Population 
Description 
Safety 
All subjects receiving any APX005M 
Efficacy Evaluable  
All who have at least one on treatment (post baseline) tumor assessment 
6.3 
Endpoint Definitions  
Endpoint 
Description 
Primary 
• ORR (rate of CR and PR) by RECIST 1.1 in each cohort  
Secondary 
• Incidence and severity of AEs and specific laboratory abnormalities 
graded according to NCI-CTCAE, v4.03 
• Changes from baseline of vital signs and clinical laboratory results during 
and following investigational therapy(ies) administration 
• ORR (rate of CR and PR) by iRECIST in each cohort 
• DOR (by RECIST 1.1) by cohort, defined as the time from the first 
evidence of confirmed PR or better to disease progression or death due to 
any cause  
• DOR (by iRECIST) by cohort, defined as the time from the first evidence 
of confirmed PR or better to disease progression or death due to any cause  
Exploratory 
• PFS (by RECIST 1.1) by cohort, defined as time from first dose of 
investigational therapy(ies) to the earlier of PD or death due to any cause  
• PFS (by iRECIST) by cohort, defined as time from first dose of 
investigational therapy(ies) to the earlier of PD or death due to any cause 
• Association between potential tumor and/or blood biomarkers and 
antitumor activity and/or resistance to treatment 
• Presence and titer of anti-APX005M antibodies 


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6.4 
Analyses  
6.4.1 
Demographics and Baseline Characteristics  
Demographics and baseline characteristics by cohort will be summarized using descriptive 
statistics 
6.4.2 
Safety Analyses  
Safety will be assessed by cohort through summaries of AEs, laboratory test results, ECG, vital 
signs, and APX005M exposure. All AE data collected will be listed by study site, cohort, subject 
number, and cycle day. 
6.4.3 
Efficacy Analyses  
Tumor assessments by Investigator will follow RECIST 1.1 and iRECIST. ORR (and 90% 
confidence interval by exact distribution), DOR and PFS (Kaplan-Meier estimate) will be 
estimated for each cohort and for each tumor assessment method. Additional details will be 
provided in the Statistical Analysis Plan.  
6.4.4 
Exploratory Analyses  
Potential tumor and blood biomarkers identified in the exploratory biomarker research may be 
correlated with safety and efficacy outcomes.  
7. ADMINISTRATIVE SECTION  
7.1 
Ethics  
7.1.1 
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 an amendment substantially alters the study design or increases the potential risk to the 
subject:  
• The consent form must be revised and submitted to the IRB/IEC for review and 
approval/favorable opinion 
• The revised consent form must be used to obtain consent from subjects currently enrolled 
in the study if they are affected by the amendment 
• The new consent form must be used to obtain consent from new subjects prior to 
enrollment. 
If the revision is in the form of an administrative letter, Investigators must inform their IRB/IEC. 


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7.1.2 
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 Brochure or product labeling, information to 
be provided to subjects and any updates. Amendments 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, amendments, and administrative letters) according to 
regulatory requirements or institution procedures. 
7.1.3 
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. 
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 


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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. 
7.2 
Study Materials  
The following study materials will be provided at study start: 
• NCI-CTCAE version 4.03 
• APX005M Investigator’s Brochure 
• Laboratory Manual for collection and handling of archived or fresh tumor tissue, fresh 
tumor core biopsies, PK, PDn, and cytokines samples 
• Pharmacy Manual. 
7.3 
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).  
7.3.1 
APX005M  
APX005M study drug packaging will bear a label with the identification required by local law, 
including the protocol number, drug identification, dosage, and expiry date. The study drug must 
be stored according to the details on the product label. Local packaging in some countries may 
be different.  
Upon arrival of investigational therapy at the site, site personnel should check the shipment for 
damage and verify proper identity, quantity, integrity of seals and temperature conditions, and 
report any deviations or product complaints to the Apexigen (or designee) upon discovery. 


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7.3.1.1 
Assessment of Compliance 
Compliance will be assessed by maintaining adequate study drug dispensing records. The 
Investigator is responsible for ensuring that dosing is administered in compliance with the 
protocol. Delegation of this task must be clearly documented and approved by the investigator. 
The Investigator is responsible for the control of APX005M under investigation. Adequate 
records for the receipts (e.g. Drug Receipt Record) and disposition (e.g. Drug Dispensing Log) of 
the study drug must be maintained. Accountability and patient compliance will be assessed by 
maintaining adequate “drug dispensing” and return records. All records and drug supplies must 
be available for inspection by the Monitor at every monitoring visit. These records must contain 
the following information: 
• Documentation of drug shipments received from the Sponsor (date received, quantity, and 
batch numbers). 
• Disposition of unused study drug not dispensed for patient. 
A Drug Dispensing Log must be kept current and should contain the following information:  
• The identification of the patient for whom the study treatment was dispensed. 
• The date(s), quantity, and batch numbers of the study treatment dispensed. 
This inventory must be available for inspection by the Monitor. All supplies, including partially 
used or empty containers and copies of the dispensing and inventory logs, must be returned to 
Apexigen (or designee) at the end of the study, unless alternate destruction has been authorized 
by Apexigen (or designee), or required by local or institutional regulations (See Pharmacy 
Manual). 
The Pharmacy Manual contains further detailed information about packaging, labeling, storage, 
dispensing, preparation and administration of APX005M. 
7.3.1.2 
Destruction of the APX005M Investigational Therapy  
Local or institutional regulations may require immediate destruction of used APX005M for 
safety reasons e.g., cytotoxicity. In these cases, it may be acceptable for investigational site staff 
to destroy dispensed APX005M before a monitoring inspection provided that source document 
verification is performed on the remaining inventory and reconciled against the documentation of 
quantity shipped, dispensed, returned and destroyed. Written authorization must be obtained 
from the Apexigen at study start up before destruction. 
Written documentation of destruction must contain the following: 
• Identity (batch numbers and patient numbers) of investigational therapy destroyed 
• Quantity of investigational therapy destroyed 
• Date of destruction (date discarded in designated hazardous container for destruction) 
• Method of destruction (the site must provide the Sponsor with documentation of their 
institutional policy and procedures for handling and disposing of hazardous drugs) 


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• Name and signature of responsible person who discarded the investigational therapy in a 
hazardous container for destruction. 
7.4 
Confidentiality  
All records identifying the subject will be kept confidential to the full extent of the law. 
Subject names will not be supplied to Apexigen. 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 Apexigen, 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. 
7.5 
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). Systems with procedures that assure the 
quality of every aspect of the study will be implemented. If necessary, Apexigen (or designee) 
will provide investigative site 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. 
7.6 
Data Collection and Handling  
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 


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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. 
7.7 
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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8. LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ADA 
Anti-drug Antibodies 
ADCP 
Antibody-dependent Cellular Phagocytosis 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
APC 
Antigen-presenting Cell 
aPTT 
Activated Partial Thromboplastin Time  
AST 
Aspartate Aminotransferase 
AUC0‒∞ 
Area Under the Curve Extrapolated to Infinity 
BRAF 
Human Proto-oncogene Encoding B-Raf Protein 
CBCT 
Cone-beam Computed Tomography 
CD40 
Cluster of Differentiation 40 
CD40L 
CD40 Ligand 
Cmax 
Maximum Serum Concentration 
CNS 
Central Nervous System 
CR 
Complete Response 
CT 
Computed Tomography 
CTLA-4 
Cytotoxic T-lymphocyte Associated Protein 4 
CTV 
Clinical Target Volume 
DCs 
Dendritic Cells 
DOR 
Duration of Response 
DL 
Dose Level 
DLT 
Dose-Limiting Toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FOV 
Field of Vision 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GTV 
Gross Tumor Volume 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 


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Abbreviation 
Definition 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IGRT 
Image-guided Radiation Therapy 
IMRT 
Intensity Modulated Radiotherapy 
IND 
Investigational New Drug Application 
INR 
International Normalized Ratio  
IRB 
Institutional Review Board 
iRECIST 
Immune-related RECIST 
iUPD 
iRECIST Unconfirmed Progressive Disease 
ISR 
IND Safety Report 
ITV 
Internal Target Volume 
IV 
Intravenous 
Kd 
Dissociation Constant 
mAb 
Monoclonal Antibody 
mL 
Milliliter 
MLC 
Multi-leaf Collimator 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
MV 
Megavolt 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NOAEL 
No Observed Adverse Effect Level 
OAR 
Organ at Risk 
ORR 
Overall Response Rate 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease/Disease Progression 
PD-1 
Programmed Death Receptor-1 
PD-L1 
Programmed Death-ligand 1 
PDn 
Pharmacodynamics 
PET 
Positron Emission Tomography 
PK 
Pharmacokinetics 
PFS 
Progression-free Survival 
PR 
Partial Response 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
PTV 
Planning Target Volume 
QA 
Quality Assurance 
RECIST 
Response Evaluation Criteria in Solid Tumors 


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Abbreviation 
Definition 
RT 
Radiation Therapy (or radiotherapy) 
SAE 
Serious Adverse Event 
SAR 
Suspected Adverse Reaction 
SBRT 
Stereotactic Body Radiation Therapy 
SEP 
Subject Eligibility Packet 
SSAR 
Serious Suspected Adverse Reaction 
TNFR 
Tumor Necrosis Factor Receptor 
ULN 
Upper Limit of Normal 
VMAT 
Volumetric Modulated Arc Therapy 
WOCBP 
Women of Childbearing Potential 


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9. REFERENCES 
1. 
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev 
Cancer 2012;12:252–64. 
2. 
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, 
Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba 
BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton 
JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 
2013;369:122–33. 
3. 
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, 
Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, 
Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin 
J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. 
Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 
2015;373:1803-13. 
4. 
Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new 
immunomodulatory targets. Nat Rev Drug Discov 2015;14:561-84. 
5. 
Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat 
Rev Immunol 2003;3:745–56. 
6. 
Banchereau J, Bazan F, Blanchard D, Briere F, Galizzi JP, van Kooten C, Liu YJ, Rousset 
F, Saeland S. The CD40 antigen and its ligand. Annu Rev Immunol 1994;12:881–922. 
7. 
Clark EA, Ledbetter JA. How B and T cells talk to each other. Nature 1994;367:425–8. 
8. 
Grewal IS, Flavell RA. CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol 
1998;16:111–35. 
9. 
Eliopoulos AG, Young LS. The role of the CD40 pathway in the pathogenesis and 
treatment of cancer. Curr Opin Pharmacol 2004;4:360–7. 
10. Hess S, Engelmann H. A novel function of CD40: induction of cell death in transformed 
cells. J Exp Med 1996;183:159–67. 
11. Khong A, Nelson DJ, Nowak AK, Lake RA, Robinson BW. The use of agonistic anti-
CD40 therapy in treatments for cancer. Int Rev Immunol 2012;31:246–66. 
12. Law CL, Grewal IS. Therapeutic interventions targeting CD40L (CD154) and CD40: the 
opportunities and challenges. Adv Exp Med Biol 2009;647:8–36. 
13. Rakhmilevich AL, Alderson KL, Sondel PM. T-cell-independent anti-tumor effects of 
CD40 ligation. Int Rev Immunol 2012;31:267–78. 
14. Tong AW, Stone MJ. Prospects for CD40-directed experimental therapy of human cancer. 
Cancer Gene Ther 2003;10:1–13. 
15. Ruter J, Antonia SJ, Burris HA, Huhn RD, Vonderheide RH. Immune modulation with 
weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced 
solid tumors. Cancer Biol Ther 2010;10:983–93. 


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16. Vonderheide RH, Flaherty KT, Khalil M, Stumacher MS, Bajor DL, Hutnick NA, Sullivan 
P, Mahany JJ, Gallagher M, Kramer A, Green SJ, O'Dwyer PJ, Running KL, Huhn RD, 
Antonia SJ. Clinical activity and immune modulation in cancer patients treated with 
CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol 2007;25:876-83. 
17. Herrera FG, Bourhis J, Coukos G. Radiotherapy combination opportunities leveraging 
immunity for the next oncology practice. CA Cancer J Clin, 2017;67:65-85. 
18. Rech AJ, Dada H, Kotzin JJ, Henao-Mejia J, Minn AJ, Twyman-Saint Victor C, 
Vonderheide RH. Radiotherapy and CD40 Activation Separately Augment Immunity to 
Checkpoint Blockade in Cancer. Cancer Res, 2018;78:4282-4291. 
19. Aguilera TA, Elghonaimy EA, Shehade H, Rafat M, Castellini L, Jiang D, Kariolis M, 
Koong AC, Le QT, Ellies LG, Rankin EB, Graves EE, Giaccia AJ. Induced Tumor 
Heterogeneity Reveals Factors Informing Radiation and Immunotherapy Combinations. 
Clin Cancer Res, 2020;26:2972-2985. 
20. Barr TA, Heath AW. Functional activity of CD40 antibodies correlates to the position of 
binding relative to CD154. Immunology 2001;102:39–43.  
21. APX005M Investigator's Brochure. 
22. Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use 
in trials testing immunotherapeutics. The Lancet Oncology. 2017;18(3):e143-e152. 
 


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APPENDIX A: 
STUDY APX005M-010 SCHEDULE OF EVENTS 
 
Screening 
Period 
Treatment Period 
Follow-up 
 
Cycles 1 & 2 
Cycle 3+ 
EOT 
 
Day 1 
Day 2(24h) 
Day 8(168h) 
Day 1 
Optional Visit 
Tumor 
Assmnt 
2ndBiopsy 
Eligibility 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
& Med History 
X 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
X 
 
 
 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
 
 
X 
 
Vital Signs1 
X 
X 
X 
X 
X 
X 
 
 
X 
 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
Serum Chemistry 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Hematology 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Coagulation 
X 
X 
X 
X 
X 
 
 
 
X 
 
Pregnancy Test (if applicable)2 
X 
 
 
 
X 
 
 
 
X 
 
Tumor Assessment3 
X 
 
 
 
 
 
X 
 
X 
 
AEs and ConMeds 
 
X 
X 
X 
X 
X 
 
X 
X 
 
SBRT4 
 
X 
 
 
X 
 
 
 
 
 
Premedication 
 
X 
 
 
X 
 
 
 
 
 
APX005M Administration5 
 
X 
 
 
X 
 
 
 
 
 
PK6 
 
X 
X 
 
X 
 
 
 
 
 
ADA7 
 
X 
 
 
X 
 
 
 
X 
 
Whole Blood and Plasma for 
Biomarkers8 
 
X 
X 
X 
X 
 
 
X 
X 
 
Cytokines9 
 
X 
X 
X 
 
 
 
X 
X 
 
Archived Tumor Tissue 
Sample10 
X 
 
 
 
 
 
 
 
 
 
Fresh Tumor Tissue Sample11 
X 
 
 
 
 
 
 
X 
 
 
Date of PD and 
Subsequent Treatment 
 
 
 
 
 
 
 
 
 
X 


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1. Vital signs in Day 1 in Cycles 1 & 2 should be collected preinfusion, at the end of infusion, 4, 24, 168 hours after end of infusion, and as medically indicated. 
On Day 1 of subsequent cycles, vital signs should be collected preinfusion and at the end of infusion and as medically indicated. 
2. Serum pregnancy test will be done within 7 days followed by a urine pregnancy test within 3 days prior to first dose of investigational therapy(ies), or a serum 
pregnancy test will be done within 3 days prior to first dose of investigational therapy(ies). Pregnancy testing should be conducted every other cycle and at 
EOT. More frequent pregnancy tests may be conducted if required per local regulations. 
3. Tumor assessment will be performed within 21 days prior to start of investigational therapy(ies) and during Treatment Phase every 8 ± 1 weeks. Subjects that 
discontinue treatment before the first scheduled on study tumor assessment (8 weeks following the first dose of investigational therapy(ies)) should have the 
tumor response evaluated at the EOT visit. 
4. Cohort 3: SBRT will be administered the same day, prior to APX005M administration. 
5. APX005M may be administered up to 3 days after the scheduled Day 1 of Cycles 2 and beyond in case of medical/surgical events, or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or holidays). 
6. PK serum samples will be obtained in Cycles 1 and 2 Day 1 (preinfusion, end of infusion, 4 hours ± 30 min after end of infusion) and Day 2 (24 ± 2 hours after 
the end of infusion), Cycles 3 and 5 Day 1 (preinfusion, end of infusion) 
7. ADA serum samples will be collected in Cycles 1, 2, 3, and 5 Day 1 (preinfusion) and at the EOT visit. 
8. Whole blood and plasma will be collected from all participating subjects in Cycles 1 and 2 (Day 1 [preinfusion], Day 2 [24 ± 2 hours] and Day 8 [168 ± 
2 hours]), Cycles 3 and 6 Day 1 (preinfusion) for subjects in Cohort 1, Cycles 4 and 8 Day 1 (preinfusion) for subjects in Cohorts 2 and 3, time of 2nd tumor 
core biopsy (if applicable) and at the EOT. 
9. Cytokine plasma samples will be obtained in Cycles 1 and 2 Day 1 (preinfusion, end of infusion, 4 hour ± 30 min after end of infusion), Day 2 (24 ± 2 hours) 
and Day 8 (168 ± 2 hours), time of 2nd tumor biopsy (if applicable) and at EOT.  
10. Submission of archived formalin-fixed paraffin embedded tumor tissue or 15 unstained slides is mandatory. 
11. Fresh tumor core biopsies will be collected from consenting subjects prior to first dose of investigational therapy(ies) and prior to first scheduled tumor 
assessment (at approximately 7–8 weeks from first dose of investigational therapy(ies)). 


Apexigen, Inc. 
 
APX005M-010 Clinical Protocol 
APX005M 
 
Amendment 2 
Date: December 28, 2020 
CONFIDENTIAL 
Page 67 of 68 
APPENDIX B: 
VITAL SIGNS AND CORRELATIVE LAB SCHEDULE  
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6+ 
2nd Bx 
EOT 
Day 1 
Day 2 
Day 8 
Day 1 
Day 2 
Day 8 
Day 1 
Day 1 
Day 1 
Day 1 
Vital Signs  
  
  
  
  
  
  
  
  
  
  
  
X 
Preinfusion  
X 
  
  
X 
  
  
X 
X 
X 
X 
  
  
End of Infusion  
X 
  
  
X 
  
  
X 
X 
X 
X 
  
  
4 Hours After the End of Infusion  
X 
  
  
X 
  
  
  
  
  
  
  
  
24 Hours After the End of Infusion  
  
X 
  
  
X 
  
  
  
  
  
  
  
168 Hours After the End of Infusion  
  
  
X 
  
  
X 
  
  
  
  
  
  
Pharmacokinetics (PK) 
  
  
  
  
  
  
  
  
  
  
  
  
Preinfusion  
X 
  
  
X 
  
  
X 
 
X 
  
  
  
End of Infusion 
4 Hours After the End of Infusion 
X 
X 
  
  
X 
X 
  
  
X 
 
 
X 
 
  
  
  
24 Hours After the End of Infusion 
 
X 
 
 
X 
 
 
 
 
 
 
 
Anti-drug Antibodies (ADA) 
  
  
  
  
  
  
  
  
  
  
  
X 
Preinfusion  
X 
  
  
X 
  
  
X 
X 
  
Whole Blood and Plasma for Biomarkers 
X 
X 
X 
X 
X 
X 
Xa 
Xa 
 
Xa 
X 
X 
Cytokines  
  
  
  
  
  
  
  
  
  
  
  
X 
Preinfusion  
X 
  
  
X 
  
  
  
  
  
  
  
  
End of Infusion  
X 
  
  
X 
  
  
  
  
  
  
  
  
4 Hours After the End of Infusion  
X 
  
  
X 
  
  
  
  
  
  
  
  
24 Hours After the End of Infusion  
  
X 
  
  
X 
  
  
  
  
  
  
  
168 Hours After the End of Infusion  
  
  
X 
  
  
X 
  
  
  
  
  
  
a Cycles 3 and 6 Day 1 (preinfusion) for subjects in Cohort 1, Cycles 4 and 8 Day 1 (preinfusion) for subjects in Cohorts 2 and 3. 


Apexigen, Inc. 
 
APX005M-010 Clinical Protocol 
APX005M 
 
Amendment 2 
Date: December 28, 2020 
CONFIDENTIAL 
Page 68 of 68 
APPENDIX C: 
METHODS OF CONTRACEPTION  
Highly Effective Methods of 
Contraception 
Progestogen only hormonal contraception associated with inhibition of ovulation 
Hormonal methods of contraception including oral contraceptive pills (combination of estrogen and progesterone), 
vaginal ring, injectables, implants, transdermal, and intrauterine hormone-releasing system (IUS) 
Bilateral tubal ligation 
Vasectomized Partner 
Intrauterine Devices (IUD) 
Complete abstinence 
Additional Methods for Male 
Subjects 
Condom 
NOTE: Partners of male subjects are to use one highly effective method of contraception 
 

SAP_001.pdf: 
 
 
 
APX005M-010 
SAP version 1.0 
27-Oct-2022
 
Confidential and Property of Pivotal S.L.
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Study Code: 
 
 
APX005M-010 
Protocol Version: 
Amendment 2 
Protocol Date: 
28 - December - 2020 
A Phase II Multicenter, Open label Study to Evaluate the Safety and 
Efficacy of the CD40 Agonistic Antibody APX005M With or Without 
Stereotactic Body Radiation Therapy in Adults with Unresectable or 
Metastatic Melanoma 
Investigational Product 
Sotigalimab (also known as APX005M) 
Indication Studied 
Unresectable or metastatic melanoma 
EudraCT No 
2018-003864-30 
Phase of Study 
Phase 2 
Sponsor 
(company and address) 
Apexigen America, Inc., 75 Shoreway Road, Suite C, San Carlos, CA 94070, 
U.S.A. 
 
Pages Nº 
60  
SAP Version 
1.0 
SAP Date: 
27-Oct-2022 
 
 


 
 
 
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Confidential and Property of Pivotal S.L.
 
Approvals 
By signing this document, I acknowledge that I have read the Statistical Analysis Plan and approve of 
the planned statistical analysis described herein.  
I agree that the planned statistical analyses are appropriate for the objective of the study and are 
consistent with the methodology described in the protocol, clinical development plan. 
I also understand that any subsequent changes to the statistical analyses, as described herein, may have 
a regulatory impact and/or result in timeline adjustments. All changes to the planned analyses will be 
described in the clinical study report. 
PIVOTAL 
 
 
 
Developed by: 
 
 
 
Elena Santiago, Lead biostatistician, BS 
 
Signature / Date 
 
 
 
 
 
 
 
 
Review by: 
 
 
 
Ioulietta Mulligan, Executive Director 
Biometrics 
 
Signature / Date 
 
 
 
 
 
Sponsor 
 
 
 
Approved by: 
 
 
 
Bhardwaj Desai, Senior Medical Director  
 
Signature / Date  
 
 
 
 
 
 
 
 
Approved by: 
 
 
 
Jamie M. Downs, Senior CDM 
 
Signature / Date  
 
 
 
 
 
 


 
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This document is the property of PIVOTAL, S.L.U. and its affiliates and is strictly confidential. It 
contains information intended only for the COMPANY to whom it is transmitted. With receipt of this 
information, the recipient acknowledges and agrees that:  
This document is not intended to be distributed outside the recipient s COMPANY  
The recipient will not copy, fax, reproduce, divulge, or distribute this confidential information, in whole 
or in part, without the prior express written consent of PIVOTAL, except for distribution within the 
recipient s COMPANY; and, 
All the information herein will be treated as confidential material with no less care than that afforded to 
the 
 own confidential material. 
The opinions expressed are in good faith and while every care has been taken in preparing this document, 
PIVOTAL makes no representations and gives no warranties of whatever nature in respect of this 
document, including but not limited to the accuracy or completeness of any information, facts and 
opinions contained therein.  
 
 


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Table of contents 
 
List of Tables ............................................................................................................................ 7 
Statistical anaysis plan version ................................................................................................ 8 
1. 
List of Abbreviations ...................................................................................................... 9 
2. 
Introduction.................................................................................................................. 11 
2.1 
Background & Rationale ......................................................................................................... 11 
2.2 
Study Objectives ...................................................................................................................... 13 
2.2.1 
Primary Objective 
13 
2.2.2 
Secondary Objectives 
13 
2.2.3 
Exploratory Objectives 
13 
2.2.3.1 Exploratory Objectives included in the protocol 
13 
2.2.3.2 Exploratory Objectives not included in the protocol 
13 
2.2.4 
Subgroup Analysis not included in the protocol 
13 
2.2.4.1 Steroids during treatment- Subgroup 
13 
2.2.4.2 LDH pre-treatment values- Subgroup 
13 
2.2.4.3 LDH pre-treatment values and prior anti-CTLA4 - Subgroup 
13 
2.3 
Study Design ............................................................................................................................ 15 
2.3.1 
Eligibility and Randomization 
16 
2.3.2 
Eligibility Criteria 
17 
2.3.2.1 Inclusion Criteria 
17 
2.3.2.2 Exclusion Criteria 
18 
2.3.3 
Discontinuation of Subjects from treatment 
20 
2.3.4 
Study treatment 
21 
2.3.4.1 APX005M Administration 
21 
2.3.4.2 Radiation Therapy 
21 
2.3.4.3 Treatment beyond Progression 
21 
2.3.5 
Replacement of Subjects 
22 
2.3.6 
Follow up 
22 
2.4 
Modifications made in the Statistical Analysis Plan .............................................................. 23 
3. 
Analysis populations .................................................................................................... 25 
3.1 
Efficacy population .................................................................................................................. 25 
3.2 
Safety Population (SAF) .......................................................................................................... 25 
3.3 
Other analysis sets ................................................................................................................... 25 
3.3.1 
Screening population 
25 
3.3.2 
Screening Failure population 
25 
3.3.3 
Enrolled (Intent-to-treat) population 
25 
3.3.4 
Per Protocol population (PP) 
25 
4. 
Study Endpoints and Derived Variables definition .................................................... 28 
4.1 
General considerations ............................................................................................................ 28 


 
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4.2 
Baseline and Demographics Characteristics ........................................................................... 28 
4.3 
Prior and Concomitant medications ....................................................................................... 29 
4.4 
Efficacy Endpoints ................................................................................................................... 30 
4.4.1 
Best Overall Response 
30 
4.4.1.1 RECIST confirmed Best Overall Response (BOR) 
30 
4.4.1.2 iRECIST Best Overall Response (iBOR) 
30 
4.4.2 
Overall Response Rate 
31 
4.4.2.1 RECIST Overall Response Rate (ORR) - Primary Objective 
31 
4.4.2.2 iRECIST Overall Response Rate (iORR) - Secondary Objective 
31 
4.4.3 
Disease Control Rate 
31 
4.4.3.1 RECIST Disease Control Rate (DCR) 
31 
4.4.3.2 iRECIST Disease Control Rate (iDCR) 
31 
4.4.4 
Duration of Response 
32 
4.4.4.1 RECIST Duration of Response (DoR) - Secondary Objective 
32 
4.4.5 
Progression-Free survival 
34 
4.4.5.1 RECIST progression-free survival (PFS)-Exploratory Objective 
34 
4.4.5.2 iRECIST progression-free survival (iPFS)-Exploratory Objective 
35 
4.5 
Safety Endpoints ...................................................................................................................... 37 
4.5.1 
Treatment 
37 
4.5.1.1 Duration of treatment 
37 
4.5.1.2 Duration of treatment at starting dose 
37 
4.5.1.3 Dose intensity (DI) 
37 
4.5.1.4 Relative dose intensity (RDI) 
37 
4.5.1.5 Number of cycles 
37 
4.5.1.6 Dose delay, interruptions, and reduction 
37 
4.5.2 
Safety 
38 
4.5.2.1 Medical history, TEAEs and SAEs 
38 
4.5.2.2 Cytokine release syndrome / infusion reaction 
38 
4.6 
Other Derived Variables .......................................................................................................... 38 
5. 
General Statistical Methods ......................................................................................... 39 
5.1 
Sample Size .............................................................................................................................. 39 
5.2 
Subject´s Disposition ............................................................................................................... 39 
5.2.1 
Protocol Deviations 
39 
5.3 
Summary of Statistical Methods ............................................................................................. 40 
5.3.1 
Demographics, Other Baseline Characteristics and Medication 
41 
5.3.1.1 Demographic Characteristics 
41 
5.3.1.2 Disease characteristics 
41 
5.3.1.3 Medical History 
42 
5.3.1.4 Prior Systemic Therapy 
42 
5.3.1.5 Prior Radiation 
42 
5.3.1.6 Prior Surgery 
42 
5.3.1.7 Prior and Concomitant Medications 
42 
5.3.1.8 Concomitant Procedures 
42 
5.3.2 
Efficacy Analyses 
43 
5.3.2.1 Primary efficacy endpoint (ORR by RECIST 1.1) 
43 
5.3.2.2 Secondary efficacy endpoints: 
43 
5.3.2.3 Exploratory efficacy endpoints: 
43 
5.3.3 
Safety Analyses 
44 


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5.3.3.1 Treatment Exposure and pre-medication 
44 
5.3.3.1.1 
APX005M ................................................................................................................................................ 44 
5.3.3.1.2 
Radiotherapy .......................................................................................................................................... 44 
5.3.3.2 Treatment Emergent Adverse Events 
45 
5.3.3.2.1 
TEAEs  Overview .................................................................................................................................... 46 
5.3.3.2.2 
TEAEs. ..................................................................................................................................................... 49 
5.3.3.3 Deaths 
51 
5.3.3.4 Clinical Laboratory Evaluation 
51 
5.3.3.4.1 
Selected laboratory parameters .............................................................................................................. 51 
5.3.3.5 Vital Signs 
55 
5.3.3.6 12-Lead Electrocardiogram (ECG) 
55 
5.3.3.7 Physical Examination 
55 
5.3.3.8 ECOG Performance Status 
55 
5.3.4 
Subgroup analysis 
55 
5.3.4.1 Steroids during treatment- Subgroup 
55 
5.3.4.2 LDH pre-treatment values- Subgroup 
55 
5.3.4.3 LDH pre-treatment values and prior anti-CTLA4 - Subgroup 
56 
5.3.5 
Interim Analyses 
57 
5.3.6 
Handling of Missing Data 
58 
5.3.7 
Reporting Conventions 
58 
5.3.8 
Study Timelines 
58 
5.3.9 
Technical Details 
59 
5.3.10 
Software 
59 
6. 
References .................................................................................................................... 60 
7. 
Tables, Listings and Figures ......................................................................................... 60 
 
 


 
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LIST OF TABLES
Table 1 Analysis population .............................................................................................................. 27 
Table 2 Time unit conversion factors ................................................................................................ 28 
Table 3 Criteria for Best overall confirmation with RECIST 1.1........................................................ 30 
Table 4 BOR of NE reasons ................................................................................................................ 30 
Table 5 Event and censoring dates for DoR analyses ....................................................................... 32 
Table 6 Event and censoring dates for PFS analyses ........................................................................ 34 
Table 7 Event and censoring dates for iPFS analyses ....................................................................... 35 
Table 8 Grading of selected laboratory parameters - Hematology ................................................. 53 
Table 9 Grading of selected laboratory parameters  Serum chemistry ......................................... 54 
 
 
 


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STATISTICAL ANAYSIS PLAN VERSION 
This section details the changes compared to previous version of the statistical analysis plan (SAP). 
 
SAP Version  
Date of SAP 
version 
Author  
Changes from the previous version 
1.0 
XX-XXX-XXXX 
Elena Santiago 
NA 
 
 
 
 
 
 


 
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1. 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
APC 
Antigen-presenting Cell 
AST 
Aspartate Aminotransferase 
BOR 
Best Overall Response 
CD40 
Cluster of Differentiation 40 
CD40L 
CD40 Ligand 
CR 
Complete Response 
CRS 
Cytokine release syndrome  
DCs 
Dendritic Cells 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOT 
End of Treatment 
iBOR 
iRECIST Best Overall Response 
ICF 
Informed Consent Form 
iCR 
iRECIST Complete Response 
iCPD 
iRECIST Confirmed Progressive Disease 
iPR 
iRECIST Partial Response 
iRECIST 
Immune-related RECIST 
iORR 
iRECIST Overall Response Rate 
iSD 
iRECIST Stable disease 
iUPD 
iRECIST Unconfirmed Progressive Disease 
LDH 
Lactate Dehydrogenase  
LLN 
Lower Limit of Normal 
MedDRA  
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NK 
Natural Killer  
ORR 
RECIST Overall Response Rate 
PD 
Progressive Disease/Disease Progression 
PD-1 
Programmed Death Receptor-1 
PD-L1 
Programmed Death-ligand 1 
PET 
Positron Emission Tomography 
PK 
Pharmacokinetics 
PFS 
Progression-free Survival 
PP 
Per protocol 
PR 
Partial Response 
PT 
Preferred Term 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RT 
Radiation Therapy (or radiotherapy) 
SAE 
Serious Adverse Event 


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Abbreviation 
Definition 
SAF 
Safety population 
SAP  
Statistical Analysis Plan 
SBRT 
Stereotactic Body Radiation Therapy 
SD 
Stable disease 
SD 
Standard deviation (only applicable in statistical results) 
SOC 
System Organ Class 
TEAE 
Treatment -emergent adverse event 
TNFR 
Tumor Necrosis Factor Receptor 
ULN 
Upper Limit of Normal 
 
 


 
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2. 
INTRODUCTION 
The Statistical Analysis Plan (SAP) has been written based on the Clinical Protocol Amendment 2 (28 
December 2020).  
The purpose of this document is to describe the procedures and the statistical methods to be applied in 
the data analysis and to ensure that the statistical methodologies that will be used are complete and 
appropriate to the study objectives. 
The focus of this SAP is for the planned primary, secondary, and exploratory analysis at the final analysis 
in the study.  
Pivotal will perform the statistical analyses described in the protocol, except for the TFLs associated with 
the below exploratory objectives: 
 
Evaluate the association between potential tumor and blood biomarkers and antitumor activity 
and/or resistance 
 
Determine the presence and titer of anti-APX005M antibodies (ADA) 
 
Result of the analyses described in this SAP will be include in the Clinical Study Report (CSR). 
2.1 
Background & Rationale 
Among the promising approaches to activating therapeutic antitumor immunity is the modulation of host 
immune system. Immune modulation includes inhibitory or stimulatory pathways in the immune system 
that are crucial for activating the immune response, maintaining self-tolerance, and modulating the 
duration and amplitude of physiological immune responses. Modulation of immune checkpoints by 
antibodies against immune inhibitory molecules has shown clinical benefits for patients with various solid 
tumors such as melanoma, lung cancer, bladder cancer, renal cell carcinoma. Currently, both 
antagonistic monoclonal antibodies (mAb) against immune inhibitory molecules such as cytotoxic T-
lymphocyte associated protein 4 (CTLA-4) and programmed death receptor-1 (PD-1)/ programmed 
death-ligand 1 (PD-L1) and agonistic antibodies against immune costimulatory molecules such as CD40 
and OX40 are under active development for different cancer indications. 
Apexigen America, Inc. (Apexigen) has developed the mAb APX005M, which binds and activates CD40, 
a costimulatory molecule expressed by antigen presenting cells (APC). As such, APX005M is a CD40 
agonistic antibody. The cell surface molecule CD40, a member of the tumor necrosis factor receptor 
(TNFR) superfamily, plays an important role in induction of tumor apoptosis and regulation of immune 
activation, especially in crosstalk between T cells and APCs. CD40 is expressed by dendritic cells (DC), 
B cells, monocytes, and some non-lymphoid cells. The natural ligand (CD40L) for CD40 is CD154, which 
is expressed on activated T cells and p
Agonistic CD40 antibodies can substitute for the function of CD154 on T cells to boost immunity. Signaling 
through CD40 on APCs, including dendritic cells (DCs), monocytes, and B cells, can, in turn, enhance 
the T cell response via improvement in antigen processing and presentation, upregulation of 


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costimulatory molecules and through the release of cytokines from activated APCs. Therefore, an 
agonistic CD40 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 
including melanoma and carcinomas. Activation of CD40 on tumor cells results in tumor cell apoptosis 
and inhibition of tumor growth. Due to its action on both immune and tumor cells, CD40 has been 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. 
The potential mechanisms of action for an agonistic anti-CD40 antibody, depending on its isotype, include 
stimulation of immune response by activating antigen processing and presentation, recruitment of 
immune effectors such as natural killer (NK) cells and macrophages, and direct cytotoxic effects on tumor 
cells, all of which could lead to therapeutic effects in tumors with high mutational burden such as 
melanoma. Thus, the desired therapeutic CD40 agonist antibody should have these functionalities. 
A few CD40 agonistic antibodies have been evaluated in human clinical trials. Many of the clinical studies 
in cancer subjects with solid tumors have been conducted with the fully human IgG2 CD40 antibody CP-
870,893. In a Phase 1 clinical trial, CP-870,893 was well tolerated; the MTD was found to be 0.2 mg/kg. 
The main toxicity of CP-870,893 was cytokine release syndrome (CRS) of mild to moderate severity. 
Single agent antitumor activity was observed in several melanoma subjects treated with CP-870,893. 
In several preclinical models the combination of RT with drugs that activate APCs results in synergistic 
anti-tumor effects. Activating tumor APCs via CD40 will enhance tumor antigen presentation and help 
prime or boost antitumor T cells in lymph nodes or in tumor-embedded tertiary lymphoid structures. In 
addition, properly activated APCs provide potent costimulatory signals to CD8+ tumor-infiltrating 
lymphocytes in the tumor microenvironment and release appropriate chemokines, which guide effector 
T cells to home in the tumor microenvironment. In a triple-negative breast cancer model the combination 
of a CD40 agonist antibody and RT resulted in improved innate and adaptive immune response. 
Importantly, CD40 treatment increased tumor response to radiotherapy and protected against metastatic 
spread in a metastatic model. 
 
 


 
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2.2 
Study Objectives  
2.2.1 
Primary Objective 
 
Evaluate the Overall Response Rate (ORR) by RECIST 1.1 in each cohort. 
2.2.2 
Secondary Objectives 
 
Evaluate the safety of APX005M alone or in combination with radiation therapy in each cohort 
 
Evaluate ORR by modified RECIST 1.1 for immune-based therapeutics (iRECIST) in each cohort 
 
Evaluate median duration of response (DOR) in each cohort 
2.2.3 
Exploratory Objectives  
2.2.3.1 
Exploratory Objectives included in the protocol 
 
Evaluate PFS (by RECIST 1.1 and iRECIST) in each cohort 
 
Evaluate the association between potential tumor and blood biomarkers and antitumor activity 
and/or resistance 
 
Determine the presence and titer of anti-APX005M antibodies (ADA) 
Pivotal will not be responsible for TLFs using data from the correlative laboratory samples. The current 
SAP will not include the analyses about the following endpoints: PK, ADA, the association between PDn 
markers and PK, and the association between biomarkers and anti-tumor activity. These analyses will be 
carried out by Apexigen, Inc. or a different provider. 
2.2.3.2 
Exploratory Objectives not included in the protocol 
 
Duration of stable disease (SD) in each cohort. 
2.2.4 
Subgroup Analysis not included in the protocol 
2.2.4.1 
Steroids during treatment- Subgroup  
For subjects receiving steroids, the Best Overall Response (BOR) will be provided. We will consider two 
scenarios: 
- Subjects receiving steroids during treatment. For the first dose, the window should be from screening 
to 5 days after the first dose - all other cycles should be +/-5 days from the APX005M 
- Subjects receiving steroids for the first dose. The window should be from screening to 5 days after 
the first dose. 
2.2.4.2 
LDH pre-treatment values- Subgroup 
Subjects will be classified according to their presenting Lactate Dehydrogenase (LDH) pre-treatment 
(screening or/and C1D1) values above the upper normal range vs. below the upper normal range. 
 
Best Overall Response, ORR and DCR will be presented in a table. (Overall and by cohort) 
 
PFS will be provided in a table. (Overall and by cohort) 
2.2.4.3 
LDH pre-treatment values and prior anti-CTLA4 - Subgroup 
 
Summary of Subjects prior anti-CTLA4 and elevated pre-treatment LDH and BOR.  


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A table of BOR will be included. For each level of response, the number of subjects who received 
prior-anti CTLA4, and the number of subjects with elevated pre-treatment LDH. 
 
The following variables will be provided for each subject in a listing. 
Subject ID, Time on Prior PD1(months), Prior anti-CTLA4 (yes/no), Elevated pre-treatment LDH 
(>ULN) (yes/no)), Pre-study anti-PD1 to study start (months) and Best Overall Response on 
Study. 
 
 


 
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2.3 
Study Design  
This is a multicenter, open label, Phase 2 study, with 3 parallel cohorts. The aim of the study is to evaluate 
the efficacy of: 
a) APX005M administered at 2 different schedules to adult subjects with unresectable or metastatic 
melanoma who have not received prior immunotherapy. Enrolled subjects will be alternately 
assigned to one of the following 2 cohorts as long as both cohorts are open:  
Cohort 1: APX005M administered IV at 0.3 mg/kg every 3 weeks (21-day cycle) 
Cohort 2: APX005M administered IV at 0.3 mg/kg every 2 weeks (14-day cycle) 
The intent of the alternating cohort assignment is to maintain approximately the same number of treated 
subjects in each of these 2 cohorts at any given time. Therefore, enrolled subjects assigned to Cohorts 1 
or 2 who do not receive APX005M or are not evaluable for tumor response will be replaced in that cohort 
before assigning new subjects to the other cohort. 
b) APX005M in combination with stereotactic body radiation therapy (SBRT) in adults with 
unresectable or metastatic melanoma who have failed approved immunotherapy regimens: 
Cohort 3: APX005M administered IV at 0.3 mg/kg in combination with radiation therapy every 2 weeks 
(14-day cycle) up to 16 weeks followed by APX005M administered IV at 0.3 mg/kg every 2 weeks (14-
day cycle).  
Subjects in all 3 cohorts with unconfirmed PD (iUPD, iRECIST) will be permitted to continue treatment 
as long as they meet the criteria in Section (3.2.6.2 Treatment beyond Progression) 
a. 
Investigator-assessed clinical benefit, without rapid disease progression, or with disease 
progression based primarily on changes in lymph nodes appearance 
b. 
Subject continues to meet retreatment criteria 
c. 
Subject tolerates study treatment 
d. 
Subject has stable ECOG performance status  
e. 
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., CNS metastases). 
They do not have confirmed PD as defined by iRECIST on a repeated tumor assessment 4-8 weeks 
later.  
Study periods: 
For every subject the participation in the study consists of 3 periods: Screening Period, Treatment Period, 
and Follow-up Period. 
Screening period: 
All subjects signing the informed consent form will enter the Screening Period 
Treatment period: 
Treatment period will start with the administration of 1st dose of APX005M ± SBRT and will continue for 
up to 12 months or until criteria Section 3.2.6.1 (Discontinuation of subjects from treatment) are met.  
Follow-up period: 


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Subjects who discontinue APX005M will enter the Follow-up Period unless treatment discontinuation is 
due to withdrawal of consent for all study procedures, initiation of any anticancer therapy (except for 
subjects continuing immediately following this study on a PD-1/PD-L1 containing regimen for whom the 
regimen and the response to that regimen should be documented), subject lost to follow-up, death, or 
study termination by Apexigen. 
 
Tumor responses will be evaluated approximately every 8 weeks following the first dose of APX005M. 
Subjects that discontinue treatment before the first scheduled on-study tumor assessment (8 weeks 
following the first dose of APX005M) should have the tumor response evaluated at the end of treatment 
visit. Subjects that are non-evaluable for tumor response will be replaced. 
 
2.3.1 
Eligibility and Randomization 
This is an open-label study in three Parallel cohorts and there is no randomization or blinding needed. 


 
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2.3.2 
Eligibility Criteria 
2.3.2.1 
Inclusion Criteria 
1. 
Histologically or cytologically confirmed unresectable or metastatic melanoma 
2. 
Subjects with BRAF activating mutation must have received a BRAF inhibitor and/or MEK inhibitor 
regimen prior to study entry 
3. 
Signed written informed consent approved by the relevant local ethics committee(s) 
4. 
 
5. 
Measurable disease by RECIST 1.1 
a. For Cohort 3 only, subjects must have at least 3 measurable non-CNS target lesions 
6. 
ECOG performance status of 0 or 1 
7. 
Resolution of all disease or prior treatment-
alopecia, Grade 2 neuropathy and laboratory abnormalities (parameters below apply). If subject 
received major surgery or radiation therapy of >30 Gy, they must have recovered from the toxicity 
and/or complications from the intervention 
8. 
Adequate organ function within 14 days prior to first dose of investigational therapy(ies): 
a. 
 absence of growth factor support 
b. 
 
c. 
 
d. 
 
e. 
 
f. 
mL/min 
g. 
 
h. 
x ULN 
i. 
is within therapeutic range of intended use of anticoagulants 
j. 
within therapeutic range of intended use of anticoagulants 
9. 
Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within the 7 
days prior to first dose of investigational therapy(ies) and a negative urine pregnancy test within the 
3 days prior to first dose of investigational therapy(ies), or a negative serum pregnancy test within 
the 3 days prior to first dose of investigational therapy(ies) 
10. Women of childbearing potential must agree to follow instructions for method(s) of contraception for 
the duration of study treatment and 5 months after the last dose of investigational therapy(ies). Males 
who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception 
for the duration of study treatment and 7 months after the last dose of investigational therapy(ies) 


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11. Available archived or fresh tumor tissue sample for biomarker analysis. Note: For Cohort 3, only 
available archived tissue is required. 
12. For subjects that consent to collection of tumor biopsies at study entry and before the first scheduled 
tumor assessment, primary or metastatic tumor that can be safely biopsied. Up to 18 subjects (6 
subjects within each cohort) should consent to fresh core biopsies. 
2.3.2.2 
Exclusion Criteria 
1. 
Prior Therapy: 
a. Cohorts 1 and 2 only: Previous exposure to any immunomodulatory agent (such as CTLA-4, PD-
1/PD-L1, IDO inhibitors, interferon, CD40 agonist etc.).  
b. Cohort 3 only: Prior therapy with a CD40 agonist. Any number of prior lines of therapy are eligible. 
A minimum washout period of 21 days from last line of therapy until investigational therapy(ies) 
administration should be observed 
2. 
Second malignancy (solid or hematologic) within the past 3 years except locally curable cancers 
that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder 
cancer, or carcinoma in situ of the prostate, cervix, or breast 
3. 
-CTCAE v4.03) within the 
14 days prior to first dose of investigational therapy(ies) 
4. 
Use of systemic corticosteroids or other systemic immunosuppressive drugs within 28 days prior to 
first dose of investigational therapy(ies) (except inhaled corticosteroids) 
a. The use of physiologic doses of corticosteroids may be approved after consultation with the 
Apexigen Medical Monitor (or designee) 
5. 
Major surgery within 4 weeks prior to first dose of investigational therapy(ies) 
6. 
Concurrent treatment with any anticancer agent (except for hormonal therapy) and palliative 
radiation, unless approved by the Apexigen Medical Monitor (or designee) 
7. 
History of allogeneic bone marrow transplantation  
8. 
Active, known or suspected autoimmune disease  
9. 
Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of 
disease modifying agents, corticosteroids or immunosuppressive drugs). Subjects with Type 1 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as 
vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur 
in the absence of an external trigger are permitted to enroll 
10. 
History of (non-infectious) pneumonitis that required corticosteroids or current pneumonitis 
11. 
History of interstitial lung disease 
12. 
History of sensitivity or allergy to mAbs or IgG  
13. 
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 prior to the first dose of investigational therapy(ies) 


 
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14. 
History of any thromboembolic event within 3 months prior to first dose of investigational 
therapy(ies) or active coagulopathy  
15. 
Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. 
Subject
edema, cause shift, and do not require steroids or anti-seizure medications are eligible after 
discussion with the Medical Monitor. Lesions of any size in posterior fossa are excluded. Subjects 
with previously treated brain metastases may participate provided they are stable after treatment 
(without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial 
treatment and any neurologic symptoms have returned to baseline), have no evidence of new or 
enlarging brain metastases, and are not using corticosteroids for at least 7 days prior to trial 
treatment. This exception does not include carcinomatous meningitis which is excluded regardless 
of clinical stability 
16. 
Known human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection 
17. 
Has received a live (attenuated) vaccine within 30 days prior to the first dose of investigational 
therapy(ies). Seasonal flu vaccines that do not contain live virus and COVID-19 vaccines are 
permitted  
18. 
Has participated in another clinical trial of an investigational drug (or a medical device) within 30 
days of study enrollment 
19. 
Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study 
20. 
Any clinically significant psychiatric, social, or medical condition that, in the opinion of the 
ability to give informed consent. 
 
 


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2.3.3 
Discontinuation of Subjects from treatment  
Subjects MUST discontinue receiving APX005M for any of the following reasons: 
 
Disease progression by RECIST 1.1, or disease progression following treatment beyond 
progression 
 
Death 
 
Toxicity requiring discontinuation of investigational therapy(ies) as outlined in the dose 
modification guidelines 
 
Failure to recover from a disease or treatment-
weeks of last dose of APX005M (except Grade 2 alopecia, Grade 2 fatigue or Grade 2 skin 
toxicity), unless the subject is benefiting from therapy and after discussion with and approval by 
Apexigen Medical Monitor (or designee) 
 
Failure to recover from an AE related to infusion reaction/cytokine release within 4 weeks of last 
dose of APX005M  
 
 weeks 
of last dose of APX005M 
 
study treatment the subject should enter the Follow-up Period) 
 
Pregnancy 
 
Any clinical AE, laboratory abnormality or coincident illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
subject 
 
Requirement for alternative therapy 
 
Noncompliance with study procedures, including use of prohibited medications 
 
Subject is lost to follow-up 
 
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration for 
treatment of either a psychiatric or physical (e.g., infectious disease) illness 
 
Study termination by Apexigen 
The primary reason for treatment discontinuation will be documented in the eCRF. 
 
 


 
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2.3.4 
Study treatment 
2.3.4.1 
APX005M Administration 
For Cohorts 1 and 2, APX005M is administered on Day 1 of each 3-week or 2-week treatment cycle. In 
Cohort 3 APX005M will be administered after each fraction of SBRT during the time of combination 
treatment.  
The APX005M infusion time will be 60 minutes. Sites should make every effort to target infusion timing 
to be as close to 60 minutes as possible. A window between -5 minutes and +10 minutes is permitted.
The APX005M infusion can be interrupted in the case of infusion reaction. Once symptoms resolve, 
infusion should be restarted at 50% of the initial infusion rate (e.g., from 100 mL/hr to 50 mL/hr). 
All subjects will be discharged from clinic after a clinical evaluation. Subjects should have stable vital 
signs including lack of orthostatic hypotension (systolic blood pressure >100 mmHg, or no lower than 10 
mm from baseline) without IV hydration (no hydration for at least 2 hours prior to discharge), lack of 
hypoxia (oxygen saturation >90% without oxygen), temperature <38 C, and heart rate <110 beats/min. 
After discharge, all subjects should be monitored by a caregiver or by a healthcare professional for 24 
hours after the first 2 infusions of APX005M and as clinically indicated thereafter.  
APX005M and SBRT may be administered up to 3 days after the scheduled Day 1 of Cycle 2 and beyond 
in case of medical/surgical events, or logistical reasons not related to study therapy  
Administration of APX005M will continue for up to 12 months or until criteria in Protocol Section 3.2.6.1 
(Discontinuation of Subjects from Treatment) are met. 
2.3.4.2 
Radiation Therapy 
All subjects assigned to cohort 3 should be evaluated and treated by a local radiation oncologist. All 
radiation treatment will follow the standard guidelines for a SBRT treatment course. Each radiation 
therapy target lesion will receive up to a total of 3200 cGy in 4 fractions of 800 cGy, administered on the 
same day and prior to infusion of APX005M. Fractions will be delivered every 2 weeks with the 
requirement of a minimum of 4 field 3D conformal planning to meet dose constraints to limit normal tissue 
toxicity of organs at risk (OAR). The first target lesion and the subsequent target lesion will be identified 
by the treating investigator based upon considerations of clinical benefit and toxicity risk. The RT target 
lesions shall not be CNS metastases. 
2.3.4.3 
Treatment beyond Progression 
Accumulating evidence indicates that subjects with solid tumors treated with immunotherapy or the 
combination of immunotherapy with RT may derive clinical benefit despite initial evidence of progressive 
disease. Subjects will be permitted to continue treatment beyond initial RECIST 1.1-defined progressive 
disease (iUPD, [iRECIST]) as long as they meet the following criteria:  
 
Investigator-assessed clinical benefit, without rapid disease progression, or with disease 
progression based primarily on changes in lymph nodes appearance 
 
Subject continues to meet retreatment criteria  
 
Subject tolerates study treatment 


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Subject has stable ECOG performance status  
 
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., CNS metastases).  
The assessment of clinical benefit should take into account whether the subject is clinically deteriorating 
and unlikely to receive further benefit from continued treatment. All decisions to continue treatment 
beyond initial progression should be discussed with the Apexigen Medical Monitor (or designee), and an 
assessment of the risk/benefit of continuing with study therapy must be documented in the study records.  
For subjects who stay on treatment beyond RECIST 1.1-defined progressive disease, all study 
procedures should be performed continuously, including tumor assessments. 
Subjects will be discontinued from the treatment upon further evidence of disease progression, as 
described in the iRECIST guidelines by Seymour et al. 
2.3.5 
Replacement of Subjects 
Enrolled subjects assigned to a specific cohort who do not receive APX005M or are not evaluable for 
tumor response will be replaced in that cohort. 
The decision to replace subjects will be made by the Sponsor. 
Details of the replaced subjects will be listed in the FSR. 
Note: Apexigen decided on 02-Nov-2021 that no more subjects would be replaced. 
2.3.6 
Follow up  
Subjects who discontinue APX005M will enter the Follow-up Period unless study treatment 
discontinuation is due to any of the following: 
 
Subject death 
 
Withdrawal of consent for all study procedures 
 
Initiation of any anticancer therapy (except for subjects continuing immediately following this 
study on a PD-1/PD-L1 containing regimen for whom the regimen and the response to that 
regimen should be documented) 
 
Subject is lost to follow-up 
 
Study termination by Apexigen. 
Regular follow-up visits (or phone contact or chart reviews) should be scheduled every 3 months or more 
frequently if clinically indicated. 
All AEs that are considered related to APX005M must be followed to resolution, stabilization, until 
improvement is not expected, 30 days after receiving the last dose of APX005M, death, or initiation of 
new anticancer therapy, whichever occurs first. Serious AEs (SAEs), pregnancies and AEs with potential 
immunologic etiology will be recorded and followed up to 90 days after the last dose of APX005M, death, 
or initiation of new anticancer therapy, whichever occurs first. 
Subsequent anticancer regimen should be documented. For subjects, who switch to a PD-1/PD-L1 
containing regimen immediately after study treatment the response to that regimen should be 
documented. Once this information is collected, a subject is considered off-study. 


 
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2.4 
Modifications made in the Statistical Analysis Plan 
The following modifications have been made to the analyses specified in Protocol Amendment 2 (28 
December 2020): 
Replacement of subjects: 
Apexigen decided that no more subjects would be replaced after 02-Nov-2021.  
Efficacy population definition: 
The definition of the efficacy population has been updated. 
Original definition: 
Subjects evaluable for efficacy (tumor response) are defined as those who have at least one on-treatment 
(post baseline) tumor assessment. 
Modified definition: 
Subjects evaluable for efficacy (tumor response) are defined as those who have measurable disease and 
at least one evaluable (post-baseline) tumor assessment performed during the treatment period or within 
30 days after the administration of the last dose of treatment. 
Note: 
reason before the first scheduled tumor assessment (first tumor assessment will be evaluated 
approximately 8 ± 1 week following the first dose of APX005M.), the subject will be included in 
this population.   
Response for these subjects will be considered Not Evaluable. 
Per Protocol Population definition: 
The definition of the Per Protocol population has been added for sensitivity analysis. 
Enrolled Population definition: 
The definition of the Enrolled population has been added. 
 
Disease control rate: 
This variable is not included in the analysis within the protocol, it has been defined in the SAP and will 
be shown in the tables 
 
Duration of Response and PFS 
In addition to RECIST progressions and deaths, the clinical progressions have been considered an event 
in these analyses. 
 
Exploratory analysis 
The duration of Stable disease will be provided as exploratory analysis. 
 
 


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Subgroup analysis 
Some subgroups analyses have been added. 
 
Steroids received during treatment. 
 
LDH pre-treatment values above the upper normal range vs. below upper normal range  
 
Elevated pre-treatment LDH and prior CTLA4 
 
 


 
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3. 
ANALYSIS POPULATIONS 
The following analysis populations are described in the study protocol. 
3.1 
Efficacy population  
Subjects evaluable for efficacy (tumor response) are defined as those who have measurable disease and 
at least one evaluable (post-baseline) tumor assessment performed during the treatment period or within 
30 days after the administration of the last dose of treatment. 
Note: 
If 
eath  or 
linical Progression  without confirmation has been reported as the end of treatment reason 
before the first scheduled tumor assessment (first tumor assessment will be evaluated approximately 8 
± 1 week following the first dose of APX005M.), the subject will be included in this population.   
These subjects will be considered not evaluable for the response. 
3.2 
Safety Population (SAF) 
All subjects receiving any APX005M will be included in the safety population. The subjects will be 
analyzed in the received treatment group. 
3.3 
Other analysis sets 
3.3.1 
Screening population 
The Screened population is defined as all screened subjects, including screening failures, who are in the 
database. A list will be included. 
3.3.2 
Screening Failure population 
The Screening Failure population is defined as all Screened Failure subjects. A list will be included, with 
the number of subject and why it is considered a screening failure. 
3.3.3 
Enrolled (Intent-to-treat) population 
The enrolled population is defined as all screened subjects that are assigned to a cohort. 
3.3.4 
Per Protocol population (PP) 
The Per Protocol population (PP) is defined as all the subjects of the efficacy population who do not meet 
one or more of the following criteria that will potentially impact the primary efficacy objective: 
 
Deviations for the inclusion or exclusion criterion. 
 
Use of prohibited and/or restricted therapies. 
 
Patients who have clinical progression without any evidence of pathological or imaging data. 
To assess the deviations that may result in the exclusion of subjects from the Per Protocol population, 
these will be reviewed and approved by the sponsor before database lock for analysis. 


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The Per Protocol population will be used for sensitivity analysis of the efficacy endpoints and will be 
considered supportive. 
 


 
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Table 1 Analysis population  
 
Efficacy
SAF
PP 
DEMOGRAPHIC CHARACTERISTICS 
 
 
 
-Baseline characteristics  
x 
x 
x 
-Previous treatment 
x 
 
 
EFFICACY (Primary & secondary endpoints) 
Primary endpoint:  
-ORR by RECIST in each cohort 
x 
 
x 
Secondary endpoints: 
-Evaluate ORR by modified RECIST 1.1 for immune-based therapeutics 
(iRECIST) in each cohort 
-Evaluate median duration of response (DOR) by RECIST in each cohort 
 
 
x 
 
 
 
 
SAFETY  
Secondary objective:   
-Evaluate the safety of APX005M alone or in combination with radiation 
therapy in each cohort 
-Treatment exposure 
 
x 
 
 
 
Efficacy
SAF
PP 
Exploratory endpoints
- PFS (by RECIST 1.1 and iRECIST) by cohort 
- Duration of stable disease by cohort. 
x 
 
 
Subgroup analysis 
- Subjects receiving steroids during treatment period by cohort. 
- LDH pre-treatment values above the upper normal range vs. below upper 
normal range overall and by cohort 
- Elevated pre-treatment LDH and prior CTLA4 overall and by cohort 
x 
 
 
 
 
 


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4. 
STUDY ENDPOINTS AND DERIVED VARIABLES DEFINITION 
4.1 
General considerations 
The following time unit conversion factors will be applied to convert days into weeks, months, or years 
Table 2 Time unit conversion factors  
1 week 
7 days 
1 month 
30.4375 days 
1 year  
365.25 days 
Study day: The date on which the first dose of APX005M is administered is considered as Day 1 of the 
study. 
For the events occurring on or after this day, the study day is calculated as the event date minus the date 
of the first administration of APX005M plus 1 day. 
For the events occurring before the start of treatment, study day is calculated as the event date minus 
the date of the first administration of APX005M. 
Baseline: is define as the last non-missing value before treatment. 
On treatment period is defined as the time elapsed (in months) from the first dose of APX005M and the 
date of End of Treatment reported at the End of Treatment form. 
Follow up period is defined as the time elapsed (in months) from the date of the End of Treatment 
reported at the End of Treatment form and the date of the End of the Study reported at the End of the 
Study form. 
4.2 
Baseline and Demographics Characteristics  
Demographics and baseline characteristics by cohort will be summarized using descriptive statistics. 
Age:  
Is defined as the time elapsed (in years) between the birth date and the informed consent date. This 
variable is a derived variable that appears in the demographics form. 
Previous diagnosis before the diagnosis of metastatic or advanced disease (Yes/No): 
If the date of the first positive biopsy for the disease is before the diagnosis date of advanced or metastatic 
disease the subjects will be classified as subjects with previous diagnosis before the diagnosis of 
metastatic or advanced disease. 
Note: 
If the difference between these dates is less than or equal to one month, the subject will be classified as 
first diagnosed metastatic or advanced disease. 
Time from the first diagnosis to the diagnosis of advanced or metastatic disease:  
Is defined as the time elapsed (in months) from the date of the first positive biopsy for this disease to the 
diagnosis date of advanced or metastatic disease.  
Time from the diagnosis of advanced or metastatic disease to informed consent:  
Is defined as the time elapsed (in months) from the date of the diagnosis of advanced or metastatic 
disease to the informed consent date. 
Any metastatic sites at study entry (Yes/No) 


 
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If the subject has any reported metastases at study entry this variable will take the value 'Yes'. 
4.3 
Prior and Concomitant medications  
Prior medications: are defined as medications that started and stopped before the first dose of any 
investigational product.  
Concomitant medications: are defined as medication (including all prescription, over the counter, herbal 
supplements, and IV medications and fluids) that continued or started on or after the first dose of any 
investigational product, up to 30 days after the last dose of investigational product. 
 
 


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4.4 
Efficacy Endpoints 
For subjects included in Cohort 3, information on the lesions that are radiated will be recorded for follow-
up purposes.  
These radiated lesions will not be considered in the tumor evaluation of the subjects. 
4.4.1 
Best Overall Response 
4.4.1.1 
RECIST confirmed Best Overall Response (BOR) 
The confirmed Best Overall Response (BOR) is defined as the best response presented according to 
RECIST v1.1 from the inclusion in the study to documented disease progression. (Only tumor 
assessments performed before the end of treatment visit date or within 30 days after the administration 
of the last dose of treatment will be considered in the assessment of BOR). 
Partial and complete responses should be confirmed.  
Table 3 Criteria for Best overall confirmation with RECIST 1.1 
Overall response 
 at previous time point 
Overall response  
at current time-point
 Best Overall Response 
CR 
 CR  
CR  
CR/PR 
 PD 
SD  
PR  
 CR 
PR 
PR  
 PR  
PR  
SD  
Any 
SD  
 
Non-evaluable subjects for BOR will be summarized by reason.  
Table 4 BOR of NE reasons 
BOR of non-evaluable reasons 
BOR 
No baseline tumor assessment 
NE 
No post baseline assessment 
NE 
All post baseline tumor Assessments have overall response NE. 
NE 
First tumor assessment with overall response as PD reported after 2 or more missing or NE on treatment tumor assessment  
(16 weeks or more from the first dose of treatment administered.) 
NE 
 
Note: 
 
Best response could be confirmed during the follow up period. 
 
Clinical progression /deterioration will not be considered as documented disease progression. 
4.4.1.2 
iRECIST Best Overall Response (iBOR) 
The Best Overall Response according to iRECIST (iBOR) is the best response recorded from the start of 
the study treatment until the end of treatment, taking into account any requirement for confirmation. 
iUPD will not override a subsequent Best Overall Response of iSD, iPR, or iCR, meaning that iPR or iSD 
can be assigned, providing that the criteria for iCPD are not met. 
 
 


 
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4.4.2 
Overall Response Rate  
4.4.2.1 
RECIST Overall Response Rate (ORR) - Primary Objective 
The confirmed Overall Response Rate (ORR) is defined as the proportion of subjects having reached a 
confirmed Complete Response (CR) or Partial Response (PR) by RECIST 1.1, relative to the number of 
subjects belonging to the analysis population set. 
4.4.2.2 
iRECIST Overall Response Rate (iORR) - Secondary Objective 
The immune Overall Response Rate (iORR) is defined as the proportion of subjects who show as Best 
Overall Response by iRECIST an immune confirmed Complete Response (iCR) or immune confirmed 
Partial Response (iPR).  
4.4.3 
Disease Control Rate  
4.4.3.1 
RECIST Disease Control Rate (DCR) 
The confirmed Disease Control Rate (DCR) is defined as the proportion of subjects having reached a 
confirmed Complete Response (CR), Partial Response (PR), or Stable Disease (SD) by RECIST 1.1, 
relative to the number of subjects belonging to the analysis population set. 
4.4.3.2 
iRECIST Disease Control Rate (iDCR) 
The immune Disease Control Rate (iDCR) is defined as the proportion of subjects who show as Best 
Overall Response by iRECIST an immune confirmed Complete Response (iCR), immune confirmed 
Partial Response (iPR), or immune SD (iSD). 
 
 


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4.4.4 
Duration of Response  
4.4.4.1 
RECIST Duration of Response (DoR) - Secondary Objective 
The Duration of Response (DoR) is defined as the time (in months) from the first evidence of confirmed 
objective response (CR or PR) to the event or censoring date. 
An event is defined as the first documentation of progression disease (disease progression assessed 
based on tumor assessment or clinical progression) or death due to any cause, whichever occurs earlier.  
 
The rules for censoring cases are defined as follows: 
If a subject is discontinued or lost to follow up before reporting an event will be censored at the date of 
the last tumor assessment documenting the absence of PD. 
Subjects who start other systemic anti-cancer therapy before an event will be censored at the date of the 
start of this therapy. 
Subjects who die 
 from the last tumor 
assessment visits will be censored at the date of the last tumor assessment before the tumor assessment 
of progressive disease or death.  
The censoring and event date rules for Duration of Response are presented below. 
Table 5 Event and censoring dates for DoR analyses 
Events scheme: 
Scenario 
Date of event 
Objective progression. 
First date at which progression criteria are met. 
Death due to any cause. 
Date of death. 
Non-objective progression but discontinuation  of 
treatment due to clinical progression. 
Date the last tumor assessment before the 
clinical progression (if any). 
In case of not having any tumor assessment, the 
date of clinical progression should be considered.
 
 
Censoring scheme: 
Scenario 
Date of censoring 
PD after 2 or more missed tumor assessments 
during the follow up period from the last tumor 
assessment 
Date of the last tumor assessment before the 
event. 
No PD and no Death. 
Date of last tumor assessment documenting the 
absence of PD.  
 


 
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Receive any systemic therapy after treatment 
discontinuation.  
Date of last tumor assessment documenting the 
absence of PD before starting systemic therapy 
DoR analysis will be calculated for subjects with confirmed CR or PR as Best Overall Response. 


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4.4.5 
Progression-Free survival  
4.4.5.1 
RECIST progression-free survival (PFS)-Exploratory Objective 
The Progression-Free Survival (PFS) is defined as the time (in months) from the first administration of 
APX005M to the event or censoring date. 
An event is defined as the first documentation of progression disease (disease progression assessed 
based on tumor assessment or clinical progression) or death due to any cause, whichever occurs earlier. 
 
The rules for censoring cases are defined as follows: 
If a subject is discontinued or lost to follow up before reporting an event will be censored at the date of 
the last tumor assessment documenting the absence of PD. 
Subjects who start other systemic anti-cancer therapy before reporting an event will be censored at the 
date of the start of this therapy. 
Subjects who die or progress during the follow up period 
 from the last tumor 
assessment visits will be censored at the date of the last tumor assessment before the tumor assessment 
of progressive disease or death. 
The censoring and event date options to be considered for PFS are listed below. 
Table 6 Event and censoring dates for PFS analyses 
Events scheme: 
Scenario 
Date of event 
Objective progression. 
First date at which progression criteria are met. 
Death.  
Date of death. 
Non-objective progression but discontinuation of 
treatment by clinical progression. 
Date the last tumor assessment before the 
clinical progression (if any). 
In case of not having any tumor assessment, the 
date of clinical progression should be considered.
 
Censoring scheme: 
Scenario 
Date of censoring 
No tumor assessment after the baseline. 
Date of the first dose. 
PD after 2 or more missed tumor assessments
during follow up period. 
Date of the last tumor assessment before the 
event. 
No PD and no Death. 
Date of last tumor assessment documenting the 
absence of PD.  
Receive any systemic therapy after treatment 
discontinuation.  
Date of last tumor assessment documenting the 
absence of PD before starting systemic therapy 
 


 
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4.4.5.2 
iRECIST progression-free survival (iPFS)-Exploratory Objective 
The immune Progression-Free Survival (iPFS) is defined as the time (months) from the first 
administration of APX005M to the event or censoring date. 
An event is defined as the first documentation of iCPD, clinical progression, or death due to any cause, 
whichever occurs earlier. 
If subjects have iUPD which is confirmed at the next assessment as iCPD, then iPFS is the time from the 
first administration of APX005M to the first date of iUPD that is subsequently confirmed. 
 
The rules for censoring cases are defined as follows: 
If a subject is discontinued or lost to follow up before reporting an event will be censored at the last tumor 
assessment documenting the absence of PD. 
Subjects who start other systemic anti-cancer therapy before reporting an event will be censored at the 
date of the start of this therapy. 
Subjects who death or progress during t
 from the last 
tumor assessment visits will be censored at the date of the last evaluable tumor assessment before the 
tumor assessment of progressive disease or death.  
The censoring and event date rules for Duration of Response are presented below. 
Table 7 Event and censoring dates for iPFS analyses 
Events scheme: 
Scenario 
Date of event 
iUPD confirmed at the next assessment. 
The first date of iUPD is subsequently confirmed. 
If iUPD progression is not confirmed and there is 
no subsequent iSD, iPR, or iCR. The following 
scenarios may occur: 
 
 
 
The first date of iUPD is not subsequently 
confirmed. 
1.No further response assessments are done (Subject 
refusal, protocol noncompliance...). 
2.The next timepoint response is iUPD, and iCPD never 
occurs. 
Subject with non-objective progression but 
discontinuation 
of 
treatment 
by 
clinical 
progression.  
Date of last tumor assessment 
Date of withdrawal discontinuation of treatment. 
Death. 
Date of death. 
 
 
 


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Censoring scheme: 
Scenario 
Date of censoring 
No tumor assessment after the baseline. 
Date of the first dose. 
iPD after 2 or more missed tumor assessments
during follow up period. 
Date of the last tumor assessment before the 
event. 
No iPD and no Death. 
Date of last tumor assessment documenting the 
absence of iPD.  If last response is iSD with no 
previous iPD, date of end of treatment. 
Receive any systemic therapy after treatment 
discontinuation. 
Date of last tumor assessment documenting the 
absence of PD before starting systemic therapy 
 
 


 
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4.5 
Safety Endpoints 
Safety will be assessed by cohort through summaries of AEs, incidence and severity of AEs, laboratory 
test results, specific laboratory abnormalities grades according to NCI-CTCAE, ECG, vital signs, 
APX005M exposure, and premedication prior to APX005M. 
4.5.1 
Treatment   
4.5.1.1 
Duration of treatment 
The duration of treatment (in weeks) of each subject will be computed as:  
 
4.5.1.2 
Duration of treatment at starting dose  
The duration of treatment (in weeks) at starting dose will be computed as: 
*Starting dose=0.3 mg/kg 
4.5.1.3 
Dose intensity (DI) 
Dose intensity (DI) is defined as the APX005M dose delivered per time unit and is expressed as mg/kg 
per week.  
The weight registered for each cycle will be used to calculate the administered dose in mg/kg (in case a 
last observation carried forward  method). 
4.5.1.4 
Relative dose intensity (RDI) 
Relative dose intensity (RDI) is defined as the ratio of administered dose intensity to planned (reference) 
dose intensity, expressed as a percentage: 
4.5.1.5 
Number of cycles 
The absolute and relative frequencies of the cycles administered per subject will be described. (Only 
cycles with doses greater than 0 are taken into account). 
4.5.1.6 
Dose delay, interruptions, and reduction 
Dose delays, interruptions, and reductions per subject and the reasons for these dose modifications will 
be described by subject. Information on delays and dose reductions reported in the study database will 
be considered. 
 
 
 


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4.5.2 
Safety  
4.5.2.1 
Medical history, TEAEs and SAEs 
TEAE is an AE occurs after administration of the first dose of the investigational product and through 30 
days after the last dose of the investigational product, death, or initiation of new anticancer therapy, 
whichever occurs first. 
 
SAEs, pregnancies, and TEAEs with potential immunologic etiology will be recorded up to 90 days after 
the last dose of investigational product, death, or initiation of new anticancer therapy, whichever occurs 
first. These SAEs / AEs will be considered TEAEs in the safety analysis. 
 
In addition, the investigator should report any AEs that may occur after this period which are assessed 
to have a reasonable possibility of being associated with investigational therapy(ies). These AEs will be 
considered TEAEs in the safety analysis. 
 
Notes: 
 
All AEs occurring after administration of first dose of investigational product will be considered as 
TEAEs in the analysis. 
 
If an AE date of onset is incomplete, an imputation rule will be used to classify the AE as treatment-
emergent or not. The algorithm for imputing date of onset is provided in the section Handling of 
Missing Data. 
 
Medical history: Events that occur after the subject signs the informed consent but prior to the first dose 
of APX005M will be recorded as past medical history. 
 
4.5.2.2 
Cytokine release syndrome / infusion reaction 
Cytokine release syndrome/infusion reactions have been recorded as an adverse event.  
In addition, all associated symptoms have been described as adverse events independently. 
 
For AE terms coded 
reaction  it should be selected 
that it is not a symptom of a 
. 
 
All the symptoms associated with each 
ytokine release syndrome
nfusion reaction  should 
be reported. For these symptoms, it has been indicated that it is a symptom of a 
.  
4.6 
Other Derived Variables 
In the case that more derived variables than the ones described in this document are required for the 
analysis, they will be defined and described in the statistical report. 
 


 
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5. 
GENERAL STATISTICAL METHODS 
5.1 
Sample Size  
This is an exploratory Phase 2 study. Cohorts 1 and 2 will enroll 11 subjects each. Assuming a true 
response rate of about 18.2% (2 subjects with tumor response out of 11 subjects) in each of these 
cohorts, the estimated standard error of the response rate in each of these cohorts will be 11.6%. Cohort 
3 will enroll 18 subjects. Assuming a true response rate in this cohort of about 16.7% (3 responders out 
of 18 subjects) the estimated standard error will be 8.8%. 
5.2 
Subject´s Disposition  
For subject study status, the number and percentage of subjects for each one of the following categories 
will be presented. 
 
Screened subjects, including screened failures (the number only) 
 
Screened-failure subjects (the number only)  
 
Enrolled subjects (the number only) 
 
Enrolled and treated subjects  
 
Subjects in Efficacy Population 
 
Subjects in Safety Population 
 
Subjects in Per protocol Population. 
 
Subjects who discontinued study treatment by primary reason 
 
Subjects who discontinued study by primary reason 
For all categories of subjects, percentages will be calculated using the number of enrolled subjects. 
The data for subject disposition, protocol deviation, eligibility, and whether a subject is included in the 
analysis populations will be listed. 
End of treatment and end of study reasons will be displayed in a listing. 
5.2.1 
Protocol Deviations 
All protocol deviations will be collected separately from the clinical database. They will be recorded and 
categorized by the Pivotal study monitors in Danah, a specific clinical trial management system provided 
by Pivotal.  
A listing of all patients with protocol deviations will be maintained by Pivotal and periodically reviewed by 
the Sponsor. The Sponsor may upgrade or downgrade the category of the protocol deviation, always 
based on the approved Deviation Plan.  
All protocol deviations will be listed by category and deviation type. 
The final list of protocol deviations will be reviewed before the database lock and provided to the 
biostatistician. 
Some major deviations from the protocol that will potentially impact the primary efficacy objective and 
may lead to the exclusion of a subject from the per protocol population.  


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5.3 
Summary of Statistical Methods 
All subjects entered in the database will be included in subject data listings. The listings will be generally 
sorted by cohort and then Subject ID unless specified otherwise. All relevant subject data will be included 
in listings. 
All applicable data will be summarized by cohort unless specified otherwise. In addition, data will be 
summarized by visit and/or time-point when appropriate. Unscheduled or repeat assessments will not be 
included in summary tables but will be included in listings. 
Continuous variables will be summarized using the number of observations (n), the number of subjects 
with non-missing values, mean, standard deviation (SD), median, Q1, Q3, minimum, and maximum along 
with the total number of subjects contributing values.  
Descriptive statistics for categorical/qualitative data will include frequency counts and percentages. The 
total number of subjects in the cohort (N) will be used as the denominator for percent calculations unless 
stated otherwise in the table footnote.  
Time to event distributions (eg, PFS and DoR) will be estimated using the Kaplan-Meier methodology. In 
these analyses, in addition to the Kaplan-Meier curve, the median, Q1, Q3, and their corresponding CI 
90% (if estimable), the number of events and censored cases distribution will be shown. 


 
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5.3.1 
Demographics, Other Baseline Characteristics and Medication 
Listings will also be presented for the demographic characteristics and disease history, respectively. 
5.3.1.1 
Demographic Characteristics 
The following variables for demographics characteristics will be summarized by cohort and overall:  
 
Gender (Male/ Female) 
 
Age (years) 
 
Race (American Indian or Alaska Native Asian/ Black or African American/ Native Hawaiian or 
other Pacific Islander/ White or Caucasian/Other) and Ethnicity (Hispanic or Latino/Not Hispanic 
or Latino/Unknown). Only categories with any occurrence will be listed. 
 
Height (cm) and weight (kg) 
 
ECOG performance status (0/ 1/ 2/ 3/ 4/ 5). Only categories with any occurrence will be listed. 
5.3.1.2 
Disease characteristics 
The following variables for disease history will be summarized by cohort and overall:  
Subjects with disease prior to advance or metastatic disease. 
For these subjects: 
 
Time (months) from the first biopsy of disease and diagnosis date of advanced or metastatic 
disease. 
 
For all subjects 
 
Time (months) from diagnosis of advanced or metastatic disease and date of informed consent  
 
Histology (Superficial spreading malignant melanoma/Nodular malignant melanoma/Lentigo 
malignant melanoma/Acral lentiginous melanoma/Amelanotic melanoma/Oral/Mucosal/Skin- 
Limbs (upper)/Skin- Limbs (lower)/Skin- Trunk/Missing). Only categories with any occurrence will 
be listed. 
 
Histological grade (G1 
 well differentiated/ G2 -moderately differentiated / G3 
 poorly 
differentiated/ G4 -undifferentiated/ GX -grade cannot be assessed or Not Applicable /Missing). 
Only categories with any occurrence will be listed. 
 
Metastatic sites at study entry 
Any metastatic sites at study entry? (Yes/No), in case of No a note will be included in the table 
footnote. 
Subjects with a metastatic lesion at the time of study entry will be shown. 
Specific metastatic sites 
(Bone/ CNS/ Distant Lymph Nodes/ Liver/ Local or Regional Lymph Nodes/ Lung/ Skin or 
Subcutaneous/ Other) 
 
Unresectable/metastatic  
 
PD-L1 Status (Positive/Negative/Unknown) 
 


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5.3.1.3 
Medical History 
Medical history abnormalities will be coded to Medical Dictionary for Regulatory Activities (MedDRA) 
terms. The version used will be specified in the data display footnote. 
The medical history will only be listed but not summarized. 
5.3.1.4 
Prior Systemic Therapy 
A table with the maximum number of prior therapies by cohort will be summarized. 
A table with the prior treatment regimen by cohort and by the number of lines will be summarized. 
A table with the prior immunotherapy treatment by cohort will be summarized.  
A listing will be provided for the Prior Systemic Therapy. 
5.3.1.5 
Prior Radiation 
A listing will be provided for the Prior Radiation. 
5.3.1.6 
Prior Surgery 
A listing will be provided for the Prior Surgery. 
5.3.1.7 
Prior and Concomitant Medications 
Prior and concomitant medications will be listed in the same table but not summarized; a column will be 
included in the listing to indicate if the medication is prior or concomitant. 
The premedication information will be included in the safety analysis.  
5.3.1.8 
Concomitant Procedures 
A listing will be provided for the concomitant procedures performed. 
 
 


 
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5.3.2 
Efficacy Analyses  
5.3.2.1 
Primary efficacy endpoint (ORR by RECIST 1.1) 
The primary efficacy endpoint is ORR by RECIST 1.1, as defined in Section 4.4.2, is based on tumor 
assessments which will be performed by RECIST1.1 at Screening, about every 8 weeks during Treatment 
Phase.  
The point estimate of the ORR will be presented along with an exact two-sided 90% confidence interval 
(CI) using the exact (Clopper-Pearson) method. 
The ORR by RECIST 1.1 will be estimated for each cohort and overall. 
In addition, swimmer, spider, and waterfall plots will be provided. 
5.3.2.2 
Secondary efficacy endpoints: 
ORR by iRECIST (and 90% confidence interval by exact distribution) will be estimated for each cohort 
and overall, as a secondary efficacy objective. 
DoR will be estimated for each cohort and each tumor assessment method (by RECIST 1.1 and 
iRECIST). The DOR will be summarized using the Kaplan Meier method; the median event time (if 
appropriate) and two-sided 90%CI for the median will be provided.  
 
The by-subject listings will be generated for the detailed tumor assessment, the response assessment 
by RECIST1.1 and iRECIST, and the derived DoR and PFS. 
 
5.3.2.3 
Exploratory efficacy endpoints: 
PFS will be summarized using the Kaplan-Meier method; the median event time (if appropriate) and two-
sided 90%- CI for the median will be provided. The corresponding Kaplan Meier curve will also be 
presented. 
PFS will be estimated for each cohort and overall either RECIST 1.1 and iRECIST criteria. 
Note: 
Pivotal will not perform the TFLs associated with the below exploratory objectives: 
 
Evaluate the association between potential tumor and blood biomarkers and antitumor activity 
and/or resistance 
 
Determine the presence and titre of anti-APX005M antibodies (ADA). 
 
 


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5.3.3 
Safety Analyses 
The population used for safety analyses will be the Safety Population.  
Safety of APX005M will be assessed by cohort through summaries of TEAEs, the incidence, and 
severity of TEAEs, laboratory test results, specific laboratory abnormalities grades according to NCI-
CTCAE, ECG, vital signs, APX005M exposure, and premedication administered prior to APX005M. 
5.3.3.1 
Treatment Exposure and pre-medication 
5.3.3.1.1 
APX005M  
Exposure of the APX005M will be summarized by cohort and overall. The following variables will be 
summarized: 
 
Maximum number of cycles started (Mean, SD, Median, Q1, Q3, Min and Max) 
 
Number of subjects who started the maximum cycle of 1, 2, 3, 4, and so on (number and 
percentage) 
 
Duration of treatment (weeks) (Mean, SD, Median, Q1, Q3, Min and Max) 
The following variables will be summarized by cohort and overall.  
 
Number of infusions administered per subject (Mean, SD, Median, Q1, Q3, Min and Max) 
 
Number of subjects with dose reductions (number and percentage) 
 
Number of subjects with dose interruptions (number and percentage) 
 
Number of subjects with dose delivered off schedule (number and percentage) 
In addition, the following variables will be summarized in the APX005M exposure table mentioned above. 
 
Dose intensity (mg/kg/week) (Mean, SD, Median, Q1, Q3, Min and Max) 
 
Relative dose intensity (%) (Mean, SD, Median, Q1, Q3, Min and Max) 
Treatment assignment will be listed by subject, a listing of APX005M infusion information will be provided 
per subject and cycle. 
The maximum number of cycles started, duration of treatment(weeks), and total dose will be listed per 
subject. 
In addition, a separate listing will be provided for the pre-medications prior to the administration of 
investigational products. 
5.3.3.1.2
Radiotherapy
Subjects included in cohort 3 receive treatment with radiotherapy. 
 
Maximum number of cycles started (Mean, SD, Median, Q1, Q3, Min and Max) 
 
Number of subjects who started the maximum cycle of 1, 2, 3, 4, and so on (number and 
percentage) 
 
Duration of treatment (weeks) (Mean, SD, Median, Q1, Q3, Min and Max) 
 
Total dose administered. (Mean, SD, Median, Q1, Q3, Min and Max) 
In addition, a separate listing will be provided for the date of the session time of session and dose per 
cycle and subject. 
 


 
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5.3.3.2 
Treatment Emergent Adverse Events  
All TEAEs will be coded to System Organ Class (SOC) and Preferred Term (PT) using the MedDRA 
dictionary v24.0. or later. 
Related Adverse Events to APX005M: adverse events with relationship to study treatment (as recorded  
on the AE eCRF page, Relationship with APX005M = Related) reported by the investigator and those of 
missing or unknown relationship. 
Related Adverse Events to Radiotherapy: adverse events with relationship to radiotherapy (as recorded 
on the AE eCRF page, Relationship with Radiotherapy = Related) reported by the investigator and those 
of missing or unknown relationship. 
Serious Adverse Events (SAE): serious adverse events (as recorded on the AE eCRF page,  
Serious Adverse Event = Yes). 
Adverse Events Leading to Treatment Discontinuation: adverse events leading to permanent 
discontinuation of study treatment (as recorded on the AE eCRF page, Action taken with study treatment 
= Drug withdrawn). 
Adverse Events Leading to Death: adverse event leading to death (as recorded on the AE  
eCRF page, Outcome = Fatal, as well as AEs of Grade 5). 
Immune mediated Adverse Events: immune mediated adverse events (as recorded on the AE eCRF 
page, Immune mediated adverse event= Yes). 
Infusion Reactions and or Cytokine Release Syndrome: are identified based on an AE term coded as 
syndrome
 
The constellation of symptoms that comprise an APX005M infusion related reaction or cytokine release 
syndrome will be described. 
 
The NCI-CTCAE version 4.03 will be used to assess the severity grade of TEAEs. 
 
 


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5.3.3.2.1 
TEAEs  Overview 
 
An overall summary table will be provided showing the number of TEAEs, the number, and proportion of 
subjects who presented:  
 
Any TEAE. 
 
Any TEAE grade 3 or higher.  
 
Any TEAE grade 3.  
 
Any TEAE grade 4.  
 
Any TEAE grade 5.  
 
 
Any TEAE related to APX005M.  
 
Any TEAE related to APX005M grade 3 or higher. 
 
Any TEAE related to APX005M grade 3.  
 
Any TEAE related to APX005M grade 4.  
 
Any TEAE related to APX005M grade 5.  
 
Any TEAE related to APX005M only 
 
 
Any TEAE leading to dose reduction (APX005M). 
 
 
Any TEAE leading to dose delay (APX005M) 
 
Any TEAE leading to treatment interruption (APX005M) 
 
Any TEAE leading to treatment discontinuation (APX005M). 
 
 
Any TEAE related to Radiotherapy (applicable to Cohort 3) 
 
Any TEAE related to Radiotherapy only (applicable to Cohort 3) 
 
 
Any TEAE leading to radiation discontinuation (only applicable in Cohort 3) 
 
 
Any TEAE Immune Mediated.  
 
 
Any TEAE Infusion reaction/ cytokine release syndrome.  
 
 
Any Serious TEAE. 
 
Any Serious TEAE with a fatal outcome.  
 
Any Serious TEAE related to APX005M.  
 
Any Serious TEAE related to APX005M with fatal outcome.  
 
Any Serious TEAE related to APX005M only 
 
Any Serious TEAE related to Radiotherapy (applicable to Cohort 3) 
 
Any Serious TEAE related to Radiotherapy only (applicable to Cohort 3) 
 


 
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This information will be presented by cohort and overall. 
 


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Separate listings will be produced for: 
 
TEAEs 
 
TEAEs excluding events marked as a symptom of CRS/IRR 
 
Serious TEAEs 
 
TEAEs leading to APX005M discontinuation 
 
TEAEs leading to APX0005M delay 
 
TEAEs leading to APX005M reductions 
 
TEAEs leading to infusion interruption 
 
TEAEs with fatal outcome  
 
TEAEs immune-mediated events 
 
TEAEs marked as a symptom of CRS / IRR 
 
The listings will be sorted by Subject ID. 
 
 


 
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5.3.3.2.2 
TEAEs. 
Treatment Emergent Adverse Events will be summarized in different approaches: 
- 
By worst grade according to National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTAE version 4.03) per subject, using the latest version of MedDRA as event 
category. 
When calculating the incidence of TEAEs by grade each subject will only be counted once 
(corresponding to the maximum toxicity grade), and any repetitions of adverse events will be 
ignored; the denominator will be the corresponding total Safety population Overall.  
- 
By cohort 
When calculating the incidence of TEAEs by cohort each subject will only be counted once, and 
any repetitions of adverse events will be ignored; the denominator will be the corresponding total 
Safety population Overall.  
 
 
The following tables will be created: 
TEAEs: by cohort: 
 
Incidence of TEAEs will be tabulated by Primary System Organ Class (SOC) and Preferred Term 
(PT), showing the total incidence of SOC and PT within SOC.  
 
Incidence of TEAEs will be tabulated by Preferred Term (PT), in order of highest number of 
subjects.  
TEAEs: Worst grade by subject (by cohort): 
 
Incidence of TEAEs will be tabulated by Primary System Organ Class (SOC), Preferred Term 
(PT) and maximum CTCAE grade, showing the total incidence of SOC and PT within SOC. A 
table will be included for each cohort. 
 
Incidence of TEAEs will be tabulated by Preferred Term (PT) and maximum CTCAE grade, in 
order of highest number of subjects. A table will be included for each cohort. 
TEAEs: Worst grade by subject grade 3 or higher (by cohort): 
 
Incidence of TEAEs grade 3 or higher will be tabulated by SOC, PT and maximum CTCAE grade, 
showing the total incidence of SOC and PT within SOC. A table will be included for each cohort. 
 
Incidence of TEAEs grade 3 or higher will be tabulated by PT and maximum CTCAE grade, in 
order of highest number of subjects. A table will be included for each cohort. 
TEAEs: Worst grade by subject related to APX005M (by cohort):  
 
Incidence of TEAEs related to APX005M will be tabulated by SOC, PT and maximum CTCAE 
grade, showing the total incidence of SOC and PT within SOC. A table will be included for each 
cohort. 
 
Incidence of TEAEs related to APX005M will be tabulated by PT and maximum CTCAE grade, in 
order of highest number of subjects. A table will be included for each cohort. 


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TEAEs: Worst grade by subject related to Radiotherapy (only cohort 3)  
 
Incidence of TEAEs related to radiotherapy will be tabulated by SOC, PT and maximum CTCAE 
grade, showing the total incidence of SOC and PT within SOC.  
 
Incidence of TEAEs related to radiotherapy will be tabulated by PT, and maximum CTCAE grade, 
in order of highest number of subjects.  
TEAEs: Leading to treatment discontinuation (by cohort)  
 
Incidence of TEAEs leading to treatment discontinuation will be tabulated by SOC and PT and 
cohort, showing the total incidence of SOC and PT within SOC.  
 
Incidence of TEAEs leading to treatment discontinuation will be tabulated by PT and cohort in 
order of highest number of subjects. 
TEAEs: Worst grade by subject Immune mediated: 
 
Incidence of TEAEs immune mediated will be tabulated by SOC, PT and maximum CTCAE grade, 
showing the total incidence of SOC and PT within SOC.  
 
Incidence of TEAEs immune mediated will be tabulated by PT and maximum CTCAE grade, in 
order of highest number of subjects.  
TEAEs: Worst grade by subject of symptoms that compromise an APX005M Infusion reaction 
and/or cytokine release syndrome: 
 
Incidence of TEAEs considered symptoms that compromise an APX005M infusion reaction and/or 
cytokine release syndrome will be tabulated by SOC, PT and maximum CTCAE grade, showing 
the total incidence of SOC and PT within SOC.  
 
Incidence of TEAEs considered symptoms that compromise an APX005M infusion reaction and/or 
cytokine release syndrome will be tabulated by PT and maximum CTCAE grade, in order of 
highest number of subjects. 
Serious Adverse events (by cohort): 
 
Incidence of SAEs will be tabulated by SOC, PT and cohort, showing the total incidence of SOC 
and PT within SOC. 
 
Incidence of SAEs will be tabulated by PT and cohort, in order of highest number of subjects. 
Serious Adverse events related to APX005M (by cohort): 
 
Incidence of SAEs related to APX005M will be tabulated by SOC, PT and cohort, showing the 
total incidence of SOC and PT within SOC. 
 
Incidence of SAEs related to APX005M will be tabulated by Preferred Term (PT) in order of 
highest number of subjects. 
Adverse events with fatal outcome (by cohort): 
 
Incidence of TEAEs with fatal outcome will be tabulated by SOC, PT and cohort, showing the total 
incidence of SOC and PT within SOC. 
 
Incidence of TEAEs with fatal outcome will be tabulated by Preferred Term (PT) in order of highest 
number of subjects.  


 
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5.3.3.3 
Deaths  
The primary cause of death will be described for safety population (Death due to disease / Death due to 
AE / Death, cause unknown / Other). 
A listing of deaths will be provided. 
5.3.3.4 
Clinical Laboratory Evaluation 
To evaluate the safety profile the following laboratory tests will be performed locally:  
 
Serum chemistry 
 
Hematology 
 
Coagulation 
 
Urinalysis 
 
Pregnancy.  
For each quantitative laboratory parameter, the values, and changes from baseline will be summarized 
(including number, mean, SD, median, Q1, Q3, minimum, and maximum) will be calculated for each visit 
or study assessment by cohort.  
The frequency of subjects with clinically significant abnormal laboratory values will be tabulated for 
baseline and each scheduled post baseline visit, by cohort and overall. 
The shift tables for baseline versus all visits will be presented for all chemistry and hematology laboratory 
parameters based on categories of below, within and above normal range.  
Lab Original results with ND/ NA/ NE/ UNK/ NQ/ UN etc: will not be evaluated or used for the analysis 
purpose.  
 
All serum chemistry, hematology, coagulation, and urinalysis data will be listed by subject; the clinically 
significant abnormal values will be flagged.  
Notes: 
 
Clinical laboratory data will be analysed using standardized values. 
 
Repeated or unscheduled tests will not be summarized for each scheduled visit but will be 
included in the listing. 
 
The tables will include the visits until the number of patients will be representative. 
 
Only evaluable data will be used, and missing data will not be imputed. 
 
The pregnancy results will also be listed only. 
5.3.3.4.1 
Selected laboratory parameters 
Selected laboratory parameters will be graded according to CTCAE Version 4.03, the worst CTCAE 
grade will be summarized. All values will be considered, regardless of whether it is considered clinically 
significant or not. 


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For each test, subjects will be characterized based on their worst severity grade observed during on 
treatment period.  
 
 


 
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5.3.3.4.1.1 
Hematology 
In hematology, a table with the following abnormalities of laboratory parameters will be described: 
 
White Blood Cells decreased 
 
Neutrophil count decreased 
 
Platelet count decreased 
 
Lymphocyte count decreased 
 
Hemoglobin decreased. 
 
White Blood Cells increased 
 
Lymphocyte count increased 
Note:  
Repeated or unscheduled tests will be considered in calculating this information. 
Table 8 Grading of selected laboratory parameters - Hematology 
Laboratory 
abnormality 
CTCA V4.03 Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Leukocytes 
(Low) 
White Blood Cells decreased
<LLN-3000/mm3;  
<LLN-3.0x10e9/L 
<3000-2000/mm3; 
<3.0-2.0x10e9/ 
<2000-1000/mm3; 
<2.0-1.0x10e9/L 
<1000/mm3; 
<1.0x10e9/L 
Neutrophil 
(Low) 
Neutrophil count decreased 
<LLN-1500/mm3; 
<LLN-1.5 x 10e9/L 
<1500-1000/mm3; 
<1.5-1.0 x10e9/L 
<1000-500/mm3;  
<1.0-0.5x10e9/L 
<500/mm3;  
<0.5x10e9/L 
Platelet 
(Low) 
Platelet count decreased 
<LLN-75000/mm3; 
<LLN-75.0x10e9/L 
<75000-
50000/mm3; 
<75.0-50.0x10e9/L
<50000-
25000/mm3; <50.0-
25.0x10e9/L 
<25000/mm3; 
<25.0x10e9/L 
Lymphocyte 
(Low) 
Lymphocyte 
count 
decreased 
<LLN-800/mm3; 
<LLN-0.8 x10e9/L 
<800-500/mm3;  
<0.8-0.5 x10e9/L 
<500-200/mm3; 
<0.5-0.2x10e9/L 
<200/mm3;  
<0.2x10e9/L 
Hemoglobin 
(Low) 
Anemia 
<LLN - 10.0 g/dL; 
<LLN- 6.2 mmol/L; 
<LLN - 100 g/L 
<10.0 - 8.0 g/dL;  
<6.2 - 4.9 mmol/L; 
<100 - 80g/L 
<8.0 g/dL; 
<4.9 mmol/L;  
<80 g/L;  
__ 
White Blood Cells  
(High) 
Leukocytosis 
__ 
__ 
 > 100000/mm3; 
__ 
Lymphocyte  
(High) 
Lymphocyte count increased
__ 
>4000-
20000/mm3 
>20000/mm3; 
__ 
 
 


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5.3.3.4.1.2 
Serum chemistry 
In serum chemistry, a table with the following abnormalities of laboratory parameters will be described: 
 
AST increased 
 
ALT increased 
 
Total bilirubin increased 
 
Alkaline phosphatase increased 
 
Concurrent (AST or ALT) and Total Bilirubin 
 
Note:  
 
Repeated or unscheduled tests will be considered in calculating this information. 
Table 9 Grading of selected laboratory parameters  Serum chemistry 
Laboratory 
abnormality 
CTCA V4.03 Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4
Aspartate 
Aminotransferase 
(High) 
Aspartate Aminotransferase 
increased 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN
Alanine 
Aminotransferase 
(High) 
Alanine 
Aminotransferase 
increased 
 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN
Total bilirrubin 
(High) 
Blood bilirubin Increased 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 10.0 x ULN 
>10.0 x ULN
Alkaline 
Phospatase 
(High) 
Alkaline 
Phospatase 
increased 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20 x ULN 
 
 
Concurrent (AST or ALT) and Total Bilirubin. 
 
The number of subjects and events reported per cohort will be included 
 
eDISH plots will be provided. (Scatter plots of peak ALT/AST versus peak Total bilirubin in the 
same date) 
 
 


 
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5.3.3.5 
Vital Signs 
Vital sign measurements, including blood pressure (Systolic/Diastolic) (mmHg), Pulse Rate 
(beats/minute), Respiration Rate (breaths/min), and Temperature, will be performed at Screening, during 
and after the investigational product infusion within Treatment Phase, and at EOT. 
All vital signs measurements will be listed by subject. 
5.3.3.6 
12-Lead Electrocardiogram (ECG) 
12-lead ECG measurements will be conducted locally, including RR Interval (msec), PR interval (msec), 
QRS interval (msec), QT interval (msec).  
ECG overall interpretation will also be collected on eCRF (Normal / Abnormal NCS / Abnormal CS).  
The ECG measurements are required at Screening only; additional ECGs can be performed as clinically 
indicated. 
All ECG measurements and overall interpretation results will be listed by subject. 
5.3.3.7 
Physical Examination 
A physical examination (including examination of the skin, head and neck, chest (heart and lungs), 
abdomen, limbs, and a brief neurological examination) will be assessed at the Screening, Treatment 
Phase, and EOT. 
Any clinically significant abnormality at Screening will be recorded on eCRF pages for medical history; 
any clinically significant abnormality at all other visits will be recorded on AE forms. 
Data from examinations will be listed by subject. 
5.3.3.8 
ECOG Performance Status 
The six-grade ECOG Performance Status will be recorded at Screening, Treatment Phase, and EOT.  
All ECOG performance status data will be listed by subject. 
 
5.3.4 
Subgroup analysis  
5.3.4.1 
Steroids during treatment- Subgroup  
For subjects receiving steroids for each dose of APX005M, the BOR will be provided. It will be 
summarized in different approaches: 
 
Subjects receiving steroids during treatment: For the first dose, the window should be from 
screening to 5 days after the first dose - all other cycles should be +/-5 days from the APX005M 
 
Subjects receiving steroids for the first dose: the window should be from screening to 5 days after 
the first dose of APX005M. 
5.3.4.2 
LDH pre-treatment values- Subgroup 
Subjects will be classified according to their presenting Lactate Dehydrogenase (LDH) pre-treatment 
(screening or C1D1) values above the upper normal range vs. below the upper normal range. 
 
Best Overall Response, ORR and DCR will be presented in a table. (Overall and by cohort) 
 
PFS will be provided in a table. (Overall and by cohort) 


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5.3.4.3 
LDH pre-treatment values and prior anti-CTLA4 - Subgroup 
 
Summary of Subjects prior anti-CTLA4 and elevated pre-treatment LDH and BOR.  
A table of BOR will be included. For each level of response, the number of subjects who received 
prior-anti CTLA4, and the number of subjects with elevated pre-treatment LDH. 
 
The following variables will be provided for each subject in a listing. 
Subject ID, Time on Prior PD1(months), Prior anti-CTLA4 (yes/no), Elevated pre-treatment LDH 
(>ULN) (yes/no)), Pre-study anti-PD1 to study start (months) and Best Overall Response on 
Study. 
 
 


 
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5.3.5 
Interim Analyses 
No formal interim analyses are considered in the protocol.  
Support material has been provided for the regular meetings during the life of the study. 
Safety Assessment Committee meetings are organized every three months (approximately). 
Medical Monitoring Meetings are organized regularly (approximately every month). 
 
 


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5.3.6 
Handling of Missing Data 
General imputation method: missing data will not be imputed, and it will be considered as missing values 
for the analysis. 
Specific imputations:  
Weight  
last observation carried forward  
method. 
Partial dates 
Only in case of any incomplete date necessary for the analysis: 
 
Missing day: day 15 th of the month and year indicated in each case will be imputed. 
 
Missing day and month: day15th of January of the year indicated. 
 
If the date is completely missing, no imputation will be performed. 
Just in case the previous imputation generated an incoherence considering the rest of dates reported for 
any subject, the day imputed would be the corresponding day according to the rest of dates for the same 
subject. 
These data imputations are for analysis purpose only and will not be used in listings. 
TEAEs severity. 
If severity is missing, the event will be listed as missing severity but summarized as a CTCAE grade 3.  
TEAEs relationship 
If relationship is missing or unknown, the event will be listed as missing or unknown relationship but 
summarized as related.  
5.3.7 
Reporting Conventions 
Descriptive statistics will be reported to 2 decimal places. 
Estimated parameters, such as regression coefficients will be reported to 3 decimal places.  
Percentages should be rounded to 2 decimal places. 
P-
-values less than 0.0001 will be reported as 
 
Listings will be presented and sorted by subject ID, and cohort, when available, listings will also sort by 
visit. 
5.3.8 
Study Timelines 
Date first subject enrolled: 16-Dec-2019 
Date last subject enrolled:  21-Oct-2021 
 
 


 
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5.3.9 
Technical Details 
The most updated study protocol has been used as a reference for this document.  
SAS programs, SAS Logs and SAS outputs generated during the creation of the Statistical Report will 
 
5.3.10 
Software 
The statistical analysis will be performed using the scientific software SAS® V9.4 or later releases and 
SAS® Enterprise Guide V7.15 or later releases. 
 


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6. 
REFERENCES 
Study protocol, Amendment A2 of the protocol (dated on 28 Dec 2020) has been used to prepare this 
document. 
7. 
TABLES, LISTINGS AND FIGURES 
This information has been detailed and collected in an external document with the following file name: 
APX010 - Statistical Analysis Plan - TFLs v1_0