Conditions: Cancer Non Small Cell Lung Cancer Metastatic Metastatic Melanoma Neoplasm of Lung Melanoma
Keywords: CD40 Immunotherapy Nivolumab APX005M PD-1
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 140
Healthy volunteers: no

Brief summary:
This study is a Phase 1-2 open-label dose escalation study of the immuno-activating monoclonal antibody APX005M administered in combination with nivolumab to adult subjects with non-small cell lung cancer or metastatic melanoma. The Phase 1 portion is intended to establish the maximum tolerated dose and the recommended phase 2 dose of APX005M when administered in combination with nivolumab. The Phase 2 portion of the study will evaluate safety and efficacy of the combination.

Detailed description:
APX005M-002 is an open-label Phase 1-2 study and comprises a dose-escalation portion (Phase 1) followed by a Phase 2 tumor specific portion.

Eligible subjects with non-small cell lung cancer or metastatic melanoma will receive intravenous APX005M in combination with nivolumab until disease progression, unacceptable toxicity or death, whichever occurs first.

Study objectives include:

* Determine the maximum tolerated dose and the recommended phase 2 dose of APX005M when given in combination with nivolumab
* Evaluate safety of the APX005M and nivolumab combination
* Evaluate the objective response rate, duration of response and median PFS by RECIST 1.1 in subjects with non-small cell lung cancer or metastatic melanoma receiving APX005M in combination with nivolumab
* Determine the PK of APX005M

Arms:
arm 1: Non-small cell lung cancer (NSCLC) or metastatic melanoma

APX005M 0.03 mg/kg and nivolumab 360 mg every 3 weeks arm 2: Non-small cell lung cancer (NSCLC) or metastatic melanoma

APX005M 0.1 mg/kg and nivolumab 360 mg every 3 weeks arm 3: Non-small cell lung cancer (NSCLC) or metastatic melanoma

APX005M 0.3 mg/kg and nivolumab 360 mg every 3 weeks arm 4: Immunotherapy naïve, metastatic or locally advanced NSCLC

APX005M 0.3 mg/kg and nivolumab 360 mg every 3 weeks arm 5: Metastatic melanoma progressing during treatment with anti-PD-1/PD-L1 therapy

APX005M 0.3 mg/kg and nivolumab 360 mg every 3 weeks arm 6: Metastatic or locally advanced NSCLC progressing during treatment with anti-PD-1/PD-L1:

* Group A: best response of progressive disease or with stable disease \< 16 weeks
* Group B: tumor response or with stable disease ≥ 16 weeks

Interventions: intervention 1: APX005M intervention 2: Nivolumab
Intervention descriptions: intervention 1: APX005M is a CD40 agonistic monoclonal antibody intervention 2: Nivolumab is an immune checkpoint (PD-1) blocking antibody

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
Clinical Protocol APX005M-002 Amendment 4.0 
 
Title of Protocol: A Study to Evaluate the Safety and Efficacy of 
the CD40 Agonistic Antibody APX005M Administered in 
Combination with Nivolumab in Subjects with Non-Small Cell 
Lung Cancer and Subjects with Metastatic Melanoma 
 
Protocol Number: APX005M-002 
Date of Amendment 4.0: 10-October-2019 
NCT03123783  
 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 1 of 81 
 
 
 
Page:
1 
Protocol Number:
APX005M-002 
IND Number:
122725 
Date of Original Protocol:
January 16, 2017 
 
CLINICAL PROTOCOL APX005M-002 
A Study to Evaluate the Safety and Efficacy of the CD40 Agonistic Antibody APX005M 
Administered in Combination with Nivolumab in Subjects with Non-small Cell Lung Cancer and 
Subjects with Metastatic Melanoma 
 
 
 
Sponsor: 
Apexigen, Inc. 
75 Shoreway Rd, Suite C 
San Carlos, CA 94070 
 
 
Central Medical Monitor: 
Ovidiu C. Trifan M.D., Ph.D. 
75 Shoreway Rd, Suite C 
San Carlos, CA 94070 
Telephone: + 1 (650) 931-6236 ext.509 
Fax: +1 (650) 259-7655 
 
 
 
Date of Amendment 4.0: October 10, 2019   
 
 
 
 
The information contained in this document is the confidential and proprietary 
information of Apexigen, Inc. 
 
This study will be conducted in accordance with Protocol APX005M-002, the International 
Conference on Harmonisation (ICH), Guideline for Good Clinical Practice (GCP), and the 
applicable country and regional (local) regulatory requirements. 
 
 
 
 
 
 


Apexigen, Inc. 
APX005M 
SPONSOR APPROVAL PAGE 
-
Cl~ 
Ovidiu C. TrifanM. _;
h.D. 
CONFIDENTIAL 
Chief Medical Officer, Senior Vice President 
Clinical Development 
Date: October 10, 2019 
Page 2 of 81 
Date 
APX00SM-002 Clinical Protocol 
Amendment 4.0 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 3 of 81 
 
 
 
DOCUMENT HISTORY 
 
Version 
Date 
Replaces 
Description of Changes 
Original Protocol 
January 16, 2017 
N/A 
 
New 
Amendment 1 
March 29, 2017 
Original 
Protocol 
 
The protocol was amended to: 
o 
Enroll subjects at dose level 0.2 mg/kg (DL 2a) before escalating to 0.3 mg/kg 
(DL 3) if clinically significant infusion reaction/cytokine release syndrome is 
observed at the 0.1 mg/kg dose (DL 2) 
o 
Provide enrollment suspending rules pending safety review for severe toxicity 
o 
Clarify that subject with no or unknown activating mutation (EGFR, ALK or 
ROS) are eligible for this study 
o 
Clarify that a subject with a BRAF activating mutation could have also received 
a BRAF inhibitor and/or MEK inhibitor prior to anti-PD-1/PDL1 therapy 
o 
Amend the definition of DLT related to thrombocytopenia 
o 
Extend the duration of treatment for subjects with a CR  
o 
Add periodic thyroid function testing 
o 
Provide guidance regarding pregnancy testing 
o 
Define success/failure in statistical testing 
Amendment 2 
February 28, 2018 
Amendment 1 
 
The protocol was amended to:  
o 
Modify the patient population, specifically  
 
Remove the requirement that subjects with non-small cell lung cancer 
must have received at least one prior platinum-based chemotherapy 
regimen  
 
Allow prior exposure to anti-CTLA-4 in subjects with metastatic 
melanoma as long as treatment was discontinued at least 3 months 
prior to the start of investigational product 
 
Clarify that for subjects with melanoma previous disease progression 
during treatment with anti-PD-1/PD-L1 therapy must be confirmed 
and provide definition of confirmation  
 
Allow subjects with an absolute neutrophil count of ≥ 1.0 x 109/L 
(previously ≥ 1.5) 
 
Allow subjects with hemoglobin value of ≥ 8 g/dL (previously ≥ 9) 
 
Allow protocol-defined second malignancy within 3 years (previously 
5 years) 
 
Remove the exclusion of more than 30 Gy of thoracic radiation within 
the 26 weeks prior to first dose of investigational product 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 4 of 81 
 
 
 
Clarify exclusion criteria for subjects with brain metastases  
o 
Update the iRECIST guidelines for treatment beyond progression  
o 
Update the Serious Adverse Events reporting contact information 
o 
Adjust the Stage 1 and Stage 2 sample size to reflect new response rate 
assumptions for the Cohort 1 (NSCLC)  
o 
Clarify that all subjects will be monitored by a caregiver or healthcare 
professional for 24 hours after the first 2 infusions and then as clinically 
indicated thereafter; subjects in Phase 2 will be monitored as clinically 
indicated.  
o 
Extend the timeframe (from >24 hours to >48 hours) for the recommendation to 
assess for infections in subjects with symptoms consistent with Cytokine 
Release Syndrome/Infusion Reaction 
Amendment 3 
July 26, 2018 
Amendment 2 
 
The protocol was amended to: 
o 
Introduce Cohort 3 enrolling subjects with metastatic or locally advanced 
NSCLC with tumor progression on an immediately preceding PD-1/PD-L1 
containing regimen. Based on response to previous PD-1/PD-L1 containing 
regimen, subjects will be enrolled in one of the following groups: 
 
Group A: Subjects with best response of progressive disease or 
with stable disease < 16 weeks 
 
Group B: Subjects with tumor response or with stable disease ≥ 16 
weeks. 
o 
Add 6-month progression-free survival rate as a secondary endpoint 
o 
Update to guidance for management of severe cytokine release/infusion 
reaction symptoms 
 
Correct inconsistencies in the protocol/synopsis 
Amendment 3.1 
January 16, 2019  
Amendment 3 
 
The protocol was amended to add methods of contraception (Appendix B, only 
applicable to Europe) and update study period 
Amendment 4  
October 4, 2019 
Amendment 3 
 
Provide clarification regarding optional biopsies 
 
Provide clarification regarding confirm 
 
Regroup the Eligibility Criteria for easier reference  
 
Relax the requirement to discuss minor study treatment delays with the Medical 
Monitor 
 
Provide additional guidance regarding the infusion rate following infusion-related 
reactions and premedication regimen  
 
Modify the supportive care guidelines related to elevated liver function tests and 
cytokine release syndrome 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 5 of 81 
 
 
 
Add supportive care guidelines for myocarditis toxicity  
 
Add definition of correlative laboratory testing  
 
Specify that the dose modification regarding neutropenia related to Grade 3-4  and 
not Grades 2 to 4 
 
Remove summary of changes appendices as red-line tracked changes versions of the 
amendment will be provided.  
 
Remove summary of changes appendices as redline versions will be provided. 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 6 of 81 
 
 
Synopsis 
 
 
Protocol Title 
 
A Study to Evaluate the Safety and Efficacy of the CD40 Agonistic Antibody APX005M 
Administered in Combination with Nivolumab in Subjects with Non-small Cell Lung Cancer 
and Subjects with Metastatic Melanoma 
 
Investigational Products 
 APX005M (humanized IgG1 mAb that binds CD40) 
 Nivolumab (fully human IgG4 mAb that blocks the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2) 
Sponsor 
Apexigen, Inc. 
 
Protocol Number 
APX005M-002 
Phase of Development 
Phase 1b-2 
 
Objectives 
 
Primary: 
Phase 1b: 
 Determine the MTD and the RP2D of APX005M when given in combination with 
nivolumab 
Phase 2: 
 Evaluate the ORR by RECIST 1.1 in each cohort/group 
Secondary: 
 Evaluate safety of the APX005M and nivolumab combination 
 Evaluate the 6-month progression-free survival (PFS) rate (PFSR) in each cohort/group 
 Evaluate the DOR and median PFS in each cohort/group by RECIST 1.1 
Exploratory: 
 Determine the immune PDn of the APX005M and nivolumab combination 
 Determine the PK of APX005M  
 Assess incidence of APX005M ADA 
 Identify blood and/or tumor biomarkers that correlate with efficacy and/or resistance  
 Evaluate the ORR by immune related RECIST (iRECIST) in each cohort/group 
 Evaluate DOR and median PFS in each cohort/group by iRECIST 
 
Study Period 
 
Date first subject enrolled (US): 5/17/2017 
Date first subject enrolled (EU): 3/1/2019 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 7 of 81 
 
 
Estimated date last subject enrolled: 5/15/2020 
 
Study Design 
 
This is a phase 1b-2 study. Adult subjects with non-small cell lung cancer and subjects with 
metastatic melanoma will be enrolled. The study will include 2 parts.  
 Study Phase 
Dose 
Level 
 
APX005M 
 
Nivolumab 
 
 
Phase1b  
Dose-escalation 
 
mg/kg 
 
 
mg 
 
 
N 
 
DL 1 
 
0.03 
q 21 days 
 
360 
q 21 days 
 
3 
 
DL 2 
 
0.1 
q 21 days 
 
360  
q 21 days 
 
3  
 
DL2a 
 
0.2 
q 21 days 
 
360  
q 21 days 
 
3 to 6 
 
DL 3 
 
0.3 
q 21 days 
 
360  
q 21 days 
 
3 to 6 
 
 
 
 
 
 
Subtotal 
~ 
18 
Phase 2 
Dose-expansion 
 
 
 
 
 
 
 
 
Cohort 1 inNSCLC 
Stage 1 
 
RP2D 
q 21 days 
 
360 
q 21 days 
 
24 
 
Stage 2 
 
RP2D 
q 21 days 
 
360 
q 21 days 
 
21 
 
 
 
 
 
 
 
 
 
Cohort 2 PD1-MM 
Stage 1 
 
RP2D 
q 21 days 
 
360 
q 21 days 
 
12 
 
Stage 2 
 
RP2D 
q 21 days 
 
360 
q 21 days 
 
25 
 
 
 
 
 
 
 
 
 
 
Cohort 3 PD1-NSCLC 
Stage 1 
 
RP2D 
q 21 days 
 
360 
q 21 days 
 
12 
Group A 
Stage 2 
 
RP2D 
q 21 days 
 
360 
q 21 days 
 
25 
 
 
 
 
 
 
 
 
 
 
Cohort 3 PD1-NSCLC 
Stage 1 
 
RP2D 
q 21 days 
 
360 
q 21 days 
 
12 
Group B 
Stage 2 
 
RP2D 
q 21 days 
 
360 
q 21 days 
 
25 
 
 
 
 
 
 
Total 
~ 
174 
Phase 1b dose-escalation: 
Subjects with non-small cell lung cancer or subjects with metastatic melanoma who meet all of 
the eligibility criteria will be enrolled in the dose-escalation portion of the study. 
There will be a maximum of 3 escalation DLs and 1 de-escalation DL in this study. It is 
expected that up to 18 DLT-evaluable subjects will be enrolled in the dose escalation portion 
of the study over a 6-month period. All subjects that are not DLT-evaluable will be replaced 
for the purpose of establishing MTD. 
The DLT observation period for dose escalation is the 21 days following the first 
administration of APX005M and nivolumab (first 3-week cycle). Safety and tolerability of the 
APX005M and nivolumab combination will be monitored by representatives from Apexigen 
and the Investigators on a regular basis and prior to each dose escalation. 
Dose escalation will continue if 0 out of 3 evaluable subjects experience a DLT during the 
DLT observation period (i.e., <33% DLT-evaluable subjects in that cohort have a DLT). If 1 
DLT-evaluable subject in any DL cohort experiences a DLT, that cohort will be expanded to 
include additional 3 DLT-evaluable subjects (i.e., a total of 6 evaluable subjects). Dose 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 8 of 81 
 
 
escalation will continue if 1 out of 6 evaluable subjects experience a DLT during the DLT 
observation period (i.e., <33% DLT-evaluable subjects in that cohort have a DLT). Decision to 
open a new DL cohort will be based on the totality of the data available at that time. 
 
The MTD is the maximum dose of APX005M combined with 360 mg of nivolumab for which 
<33% of DLT-evaluable subjects experience a DLT.  
 
If the DLT rate in DL 3 exceeds 33%, or 2 or more subjects in DL 2 experience a Grade 2 
infusion reaction/cytokine release syndrome, or at the discretion of the sponsor, the 
intermediate lower dose level 2a will be evaluated (de-escalation). Up to 6 subjects can be 
enrolled in any of dose levels below the MTD or highest DL tested, should sponsor decide to 
discontinue dose escalation prior to reaching the MTD. 
The RP2D will be based on the overall safety and tolerability of the combination of APX005M 
and nivolumab.  
 
Phase 2 dose-expansion: 
After identification of the RP2D of APX005M in combination with nivolumab 360 mg IV 
every 21 days, study will continue with 3 cohorts.  
 Cohort 1: immunotherapy naïve NSCLC (see below) 
 Cohort 2: metastatic melanoma progressing during treatment with anti-PD-1/PD-L1 
therapy (see below) 
 Cohort 3: metastatic or locally advanced NSCLC progressing during treatment with 
anti-PD-1/PD-L1 (see below)  
o Group A: Subjects with best response of progressive disease or with stable disease 
< 16 weeks 
o Group B: Subjects with tumor response or with stable disease ≥ 16 weeks 
Each cohort of the Phase 2 dose-expansion portion of the study will follow a Simon optimal 
2-stage design. Subjects treated at the RP2D in the dose-escalation portion will be included in 
Stage 1 of the relevant cohort. Additional subjects will be enrolled for a total of 24 subjects in 
Cohort 1 and 12 subjects each in Cohort 2, Cohort 3 Group A and Cohort 3 Group B.  
Subjects will be evaluated for tumor response approximately every 8 weeks following the first 
dose of investigational product. Subjects that are non-evaluable for tumor response will be 
replaced. An ORR (CR+PR) of at least 22% in Cohort 1 and 5% in each of Cohort 2, Cohort 3 
Group A and Cohort 3 Group B is required in Stage 1 for the study to proceed to Stage 2. 
Enrollment may continue into Stage 2 while the planned number of subjects for Stage 1 are 
followed for efficacy. 
In Stage 2, an additional 21 subjects will be enrolled in Cohort 1 and an additional 25 subjects 
will be enrolled in each of Cohort 2, Cohort 3 Group A and Cohort 3 Group B. 
A minimum number of 6 subjects per each cohort/group who have a primary or metastatic 
lesion that can be biopsied without interfering with subsequent tumor assessments and who 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 9 of 81 
 
 
consent to collection of tumor biopsies for tumor biomarkers should be enrolled during Phase 
1b and Phase 2. 
At any time during the study, enrollment will be suspended pending safety review if any of the 
following events occur since last safety data review: 
 ≥1 Grade 5 suspected adverse reaction (SAR) (for definition see Section 6.1.2) 
 ≥2 Grade 4 infusion reaction/ cytokine release syndrome 
 ≥2 Grade ≥ 3 immune related AEs in more than 1 subject 
Enrollment will resume following assessment by the Apexigen Medical Monitor, contract 
research organization Medical Monitor and Lead Investigator. 
 
Study Population 
 
Number of Subjects (planned): 
 Phase 1b: approximately 18 subjects 
 Phase 2: up to 156 subjects 
Number of Sites: 
 Multisite (approx. 15-20) 
Sample Size Determination:  
The sample size for the Phase 1b dose-escalation cannot be precisely estimated but depends 
upon the observed toxicities. Cohorts of 3 to 6 subjects will be treated at each DL during dose 
escalation portion of the study. It is anticipated that approximately 18 subjects will be treated 
in this portion of the study depending on the actual rate of DLTs. 
Sample size for Phase 2 is calculated using the Simon optimal 2-stage design: 
 Cohort 1 (inNSCLC): Assuming a false positive rate () of 0.1 (one-sided), a false 
negative rate () of 0.1, a response probability of poor drug (P0) of 22% and a response 
probability of good drug (P1) of 40%, first stage sample size (n1) is 24 and the 
maximum sample size (n) is 45 response evaluable subjects. 
 Cohort 2 (PD1-MM): Assuming  of 0.1 (one-sided),  of 0.1, P0 5% and P1 of 20%, 
n1 is 12 and n is 37 response evaluable subjects. 
 Cohort 3 (PD1-NSCLC) Group A and Group B: Assuming  of 0.1 (one-sided),  of 
0.1, P0 5% and P1 of 20%, n1 is 12 and n is 37 response evaluable subjects. 
 
  
Cohort Specific Inclusion Criteria 
Phase 1b: Subjects that meet eligibility criteria for Phase 2 Cohorts 1 or 2 and all of the 
general eligibility criteria. 
Phase 2 Cohort 1: Histologically or cytologically confirmed, immunotherapy naïve, 
metastatic or locally advanced non-small cell lung cancer not amenable to curative treatment. 
Subjects may be treatment naïve or could have received one prior platinum-based 
chemotherapy for non-small cell lung cancer for any indication (adjuvant, part of combined 
modality therapy or for metastatic disease) within the past 3 years. Subjects with no or 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 10 of 81 
 
 
unknown activating mutation (e.g., EGFR, ALK, ROS) are eligible for this study. Subjects 
with a documented activating mutation (e.g., EGFR, ALK, ROS) amenable to tyrosine kinase 
inhibitor therapy, must also have received the appropriate therapy and progressed.  
Phase 2 Cohort 2: Subjects with histologically or cytologically confirmed unresectable or 
metastatic melanoma that had confirmed progressive disease during treatment with anti-PD-
1/PD-L1 therapy. Subjects with BRAF wild type or unknown status must have received only 
anti-PD-1/PD-L1 therapy. Subjects with BRAF activating mutation could have also received a 
BRAF inhibitor and/or MEK inhibitor regimen prior to anti-PD-1/PD-L1 therapy.  
Confirmed PD (Section 5.2.1) during treatment with anti-PD-1/PD-L1 therapy should be 
documented by 2 consecutive tumor assessments at least 4 weeks apart (the second scan may 
be used as the baseline scan for this study if it was performed within the 21 days prior Cycle 1 
Day 1). Subjects should start study treatment no later than 8 weeks following the last dose of 
anti-PD-1/PD-L1 therapy (with no intervening therapy).  
Subjects with ocular melanoma are excluded. 
Phase 2 Cohort 3: Subjects with histologically or cytologically confirmed, metastatic or 
locally advanced NSCLC not amenable to curative treatment. Subjects must have disease 
progression on an immediately preceding PD-1/PD-L1 containing regimen. Subjects could 
have received no more than one platinum containing regimen, or if subjects have a 
documented activating mutation (e.g. EGFR, ALK, ROS) amenable to tyrosine kinase 
inhibitor therapy, must also have received the appropriate therapy and progressed before the 
PD-1/PD-L1 containing regimen. Based on response to previous PD-1/PD-L1 containing 
regimen, subjects will be enrolled in one of the following groups: 
 Group A: Subjects with best response of progressive disease or with stable disease 
< 16 weeks 
 Group B: Subjects with tumor response or with stable disease ≥16 weeks. 
If possible, confirmed PD (Section 5.2.1 during treatment with anti-PD-1/PD-L1 therapy 
should be documented by 2 consecutive tumor assessments at least 4 weeks apart (the second 
scan may be used as the baseline scan for this study if it was performed within the 21 days 
prior Cycle 1 Day 1). Subjects should start study treatment no later than 8 weeks following the 
last dose of anti-PD-1/PD-L1 containing regimen. 
 
General Inclusion Criteria: 
 Subjects willing and able to provide written informed consent for this study   
 Male or female ≥18 years old at time of consent  
 Measurable disease by RECIST 1.1 
 ECOG performance status of 0 or 1 
 Resolution of 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 
 Adequate organ function within 14 days of first dose of investigational product: 
 WBC ≥1.5 x 109/L in absence of growth factor support 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 11 of 81 
 
 
 ANC ≥1.0 x 109/L in absence of growth factor support 
 Platelet count ≥100 x 109/L 
 Hemoglobin ≥8 g/dL 
 Serum creatinine ≤1.5 mg/dL AND creatinine clearance ≥60 mL/min (calculated [using 
the formula of local laboratory] or measured) 
 AST and ALT ≤2.5 x ULN 
 Total bilirubin ≤1.5 x ULN, or direct bilirubin ≤ULN for subjects with total bilirubin 
levels >1.5 x ULN 
 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 
 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 
 Women of childbearing potential must have a negative serum pregnancy test within the 
7 days prior to first dose of investigational product and a negative urine pregnancy test 
within the 3 days prior to first dose of investigational product, or a negative serum 
pregnancy test within the 3 days prior to first dose of investigational product 
 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 product. 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 product 
 Available archived or fresh tumor tissue sample for PD-L1 and other biomarker 
analysis  
 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. A minimum of 24 subjects (6 subjects with each cohort/group) must consent 
to fresh core biopsies. 
General Exclusion Criteria: 
1. Previous exposure to any immunomodulatory agents (e.g., anti- CD40, CTLA-4, PD-1/ 
PD-L1, IDO inhibitors) with the following exceptions:  
a. For Cohort 2 (unresectable or metastatic melanoma): 
i.  All subjects must have confirmed disease progression while on 
treatment with anti-PD-1/PD-L1 therapy 
ii. Subjects could have received anti-CTLA-4 therapy provided they did 
not have disease progression while on therapy and they discontinue 
treatment with anti-CTLA-4 therapy at least 3 months prior to first dose 
of investigational product 
b. For Cohort 3 (metastatic or locally advanced NSCLC): 
2. All subjects must have disease progression while on treatment with anti-PD-1/PD-L1 
therapy. Second malignancy (solid or hematologic) within the past 3 years except: 
a. Adequately treated basal cell or squamous cell skin cancer, or 
b. Carcinoma in situ of the cervix, or  
c. Prostate cancer Gleason score < 6 with undetectable prostate specific antigen 
(PSA) over 12 months, or 


Apexigen, Inc. 
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APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 12 of 81 
 
 
d. Ductal breast carcinoma in situ with full surgical resection (i.e., negative 
margins), or 
e. Treated medullary or papillary thyroid cancer 
3. Active, known, clinically serious infections (≥ Grade 2 according to NCI-CTCAE v4.03) 
within the 14 days prior to first dose of investigational product 
4. Use of systemic corticosteroids or other systemic immunosuppressive drugs within the 28 
days prior to first dose of investigational product (except inhaled corticosteroids); 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 of first dose of investigational product 
6. Concurrent treatment with any anti-cancer agent, except for hormonal therapy and 
palliative radiation as clinically indicated unless approved by the Medical Monitor 
7. History of allogeneic bone marrow transplantation  
8. Uncontrolled diabetes or hypertension 
9. Active, known or suspected autoimmune disease. Subjects with type I 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 life-threatening toxicity related to prior anti-PD-1/PD-L1 treatment for subjects 
with metastatic melanoma except those that are unlikely to re-occur with standard 
countermeasures (e.g. hormone replacement after adrenal crisis) 
13. History of sensitivity or allergy to mAbs or IgG  
14. Congestive heart failure (New York Heart Association Class III to IV), symptomatic 
ischemia, conduction abnormalities uncontrolled by conventional intervention, or 
myocardial infarction within 6 months prior to the first dose of investigational product 
15. History of any thromboembolic event within 3 months prior to first dose of investigational 
product or an active coagulopathy  
16. 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, 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 
(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 
17. Known human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection 
18. Has received a live-virus vaccination within 30 days of the first dose of investigational 
product. Seasonal flu vaccines that do not contain live virus are permitted 
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 


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subject’s ability to give informed consent. 
 
Statistical Methods and Analyses 
 
Primary Endpoint 
 Establish MTD (Phase 1b) 
 ORR (rate of CR and PR) by RECIST 1.1 in each cohort/group (Phase 2) 
Secondary Endpoints 
 Incidence and severity of AEs and specific laboratory abnormalities graded 
according to NCI-CTCAE, v4.03 
 6-month PFSR by cohort/group (Phase 2) 
 DOR (by RECIST 1.1) by cohort/group  
 PFS (by RECIST 1.1) by cohort/group  
Exploratory Endpoints 
 PK parameters of APX005M, including Cmax, tmax, AUC0-t, and AUC0- 
 Presence and titer of anti-APX005M antibodies 
 Association between potential PDn markers and PK of APX005M; association 
between potential predictive biomarkers and anti-tumor activity 
 ORR  by iRECIST in each cohort/group (Phase 2) 
 DOR (by iRECIST) by cohort/group  
 PFS (by iRECIST) by cohort/group 
Safety Analyses 
 Safety will be assessed through summaries of DLT, AEs, changes in 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), DOR and PFS (Kaplan-Meier estimate) 
will be estimated for each cohort/group and for each tumor assessment criteria. 
Pharmacokinetic Analyses  
 PK parameters of APX005M will be determined using model-independent 
methods. 
 
 


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Table of Contents 
Synopsis .......................................................................................................................................... 6 
1. 
Introduction and Study Rationale ......................................................................................... 18 
1.1 
Background .................................................................................................................... 18 
1.2 
APX005M ...................................................................................................................... 19 
1.2.1 
Pharmacology ......................................................................................................... 19 
1.2.2 
Pharmacokinetics .................................................................................................... 19 
1.2.3 
Clinical Experience ................................................................................................. 20 
1.2.4 
Summary of the Known and Potential Risks and Benefits ..................................... 20 
1.3 
Nivolumab ...................................................................................................................... 21 
1.3.1 
Summary of the Known and Potential Risks and Benefits ..................................... 22 
1.4 
Rationale for APX005M in Combination with Nivolumab ........................................... 22 
2. 
Investigational Plan ............................................................................................................... 24 
2.1 
Study Objectives ............................................................................................................ 24 
2.1.1 
Primary Objective ................................................................................................... 24 
2.1.2 
Secondary Objectives .............................................................................................. 24 
2.1.3 
Exploratory Objectives ........................................................................................... 24 
2.2 
Study Design and Duration ............................................................................................ 24 
2.2.1 
Study Population ..................................................................................................... 28 
2.2.1.1 
Inclusion Criteria ............................................................................................. 28 
2.2.1.2 
General Exclusion Criteria .............................................................................. 30 
2.2.2 
APX005M Dose ...................................................................................................... 31 
2.2.3 
Nivolumab Dose ..................................................................................................... 32 
3. 
Treatment of Subjects ........................................................................................................... 33 
3.1 
Subject Enrollment and Treatment Administration ....................................................... 33 
3.2 
Study Treatment ............................................................................................................. 34 
3.2.1 
Investigational Products .......................................................................................... 34 
3.2.2 
Non-Investigational Product ................................................................................... 34 
3.3 
Timing of Investigational Products Administration ....................................................... 34 
3.3.1 
Nivolumab............................................................................................................... 34 
3.3.2 
APX005M ............................................................................................................... 35 
3.4 
Concomitant Treatments ................................................................................................ 35 
3.4.1.1 
Premedication Prior to Administration of Investigational Product ................. 35 


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3.4.1.2 
Rescue Medications & Supportive Care Guidelines ....................................... 36 
3.4.1.3 
Permitted Concomitant Medications ............................................................... 40 
3.4.1.4 
Prohibited and/or Restricted Therapies ........................................................... 40 
3.5 
Dose Limiting Toxicity .................................................................................................. 41 
3.6 
Retreatment Criteria ....................................................................................................... 41 
3.7 
Dose Modifications ........................................................................................................ 42 
3.8 
Duration of Treatment .................................................................................................... 44 
4. 
Study Discontinuation ........................................................................................................... 44 
4.1 
Discontinuation of Subjects from Treatment ................................................................. 44 
4.1.1 
Treatment Beyond Progression ............................................................................... 45 
4.2 
Discontinuation of Subjects from Study ........................................................................ 45 
4.3 
Study Termination .......................................................................................................... 46 
5. 
Treatment Study Assessments and Procedures ..................................................................... 47 
5.1 
Time and Events Schedule ............................................................................................. 47 
5.2 
Procedures by Visit ........................................................................................................ 50 
5.2.1 
Screening Phase ...................................................................................................... 50 
5.2.2 
Treatment Phase ...................................................................................................... 51 
5.2.3 
End of Treatment Visit............................................................................................ 52 
5.2.4 
Follow-Up ............................................................................................................... 53 
5.3 
Study Materials .............................................................................................................. 53 
5.4 
Safety Assessments ........................................................................................................ 53 
5.4.1 
Physical Examinations ............................................................................................ 53 
5.4.2 
Vital Signs ............................................................................................................... 54 
5.4.3 
Electrocardiogram ................................................................................................... 54 
5.4.4 
Laboratory Tests ..................................................................................................... 54 
5.4.4.1 
Serum Chemistry ............................................................................................. 54 
5.4.4.2 
Thyroid Function Tests .................................................................................... 55 
5.4.4.3 
Hematology ..................................................................................................... 55 
5.4.4.4 
Coagulation ...................................................................................................... 55 
5.4.4.5 
Urinalysis ......................................................................................................... 55 
5.4.4.6 
Pregnancy Test ................................................................................................ 55 
5.5 
Efficacy Assessments ..................................................................................................... 56 
5.5.1 
Modified RECIST 1.1 for Immune-based Therapeutics ......................................... 56 
5.6 
Correlative Studies ......................................................................................................... 56 


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5.6.1 
APX005M Pharmacokinetic Assessments .............................................................. 56 
5.6.2 
Cytokines ................................................................................................................ 57 
5.6.3 
Immune Pharmacodynamics ................................................................................... 57 
5.6.4 
APX005M Anti-drug Antibody .............................................................................. 58 
5.6.5 
Tumor Biomarkers .................................................................................................. 59 
6. 
Adverse Events ..................................................................................................................... 59 
6.1 
Definitions ...................................................................................................................... 60 
6.1.1 
Adverse Event ......................................................................................................... 60 
6.1.2 
Suspected Adverse Reaction ................................................................................... 60 
6.1.3 
Life-threatening AE or Life-threatening SAR ........................................................ 60 
6.1.4 
Serious AE or Serious SAR .................................................................................... 60 
6.1.5 
Unexpected AE or Unexpected SAR ...................................................................... 60 
6.1.6 
Overdose ................................................................................................................. 61 
6.2 
Adverse Event Classification ......................................................................................... 61 
6.2.1 
Relationship to Investigational Products ................................................................ 61 
6.2.2 
Severity ................................................................................................................... 62 
6.3 
Collection and Reporting ............................................................................................... 62 
6.3.1 
General AE Reporting ............................................................................................. 62 
6.3.2 
Disease Progression ................................................................................................ 63 
6.3.3 
Serious AEs or Serious SARs ................................................................................. 63 
6.3.4 
Handling of Expedited Safety Reports ................................................................... 64 
6.3.5 
Non-serious AEs ..................................................................................................... 64 
6.3.6 
Laboratory Test Abnormalities ............................................................................... 64 
6.4 
Pregnancy ....................................................................................................................... 64 
7. 
Statistics ................................................................................................................................ 65 
7.1 
Sample Size Determination ............................................................................................ 65 
7.2 
Populations for Analyses ................................................................................................ 66 
7.3 
Endpoint Definitions ...................................................................................................... 67 
7.3.1 
Primary Endpoint .................................................................................................... 67 
7.3.2 
Secondary Endpoints .............................................................................................. 67 
7.3.3 
Exploratory Endpoints ............................................................................................ 67 
7.4 
Analyses ......................................................................................................................... 67 
7.4.1 
Demographics and Baseline Characteristics ........................................................... 67 
7.4.2 
Safety Analyses ....................................................................................................... 67 


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7.4.3 
Efficacy Analyses ................................................................................................... 68 
7.4.4 
Pharmacokinetic Analyses ...................................................................................... 68 
7.4.5 
Exploratory Analyses .............................................................................................. 69 
8. 
Administrative Section.......................................................................................................... 69 
8.1 
Ethics .............................................................................................................................. 69 
8.1.1 
Compliance with the Protocol and Protocol Revisions ........................................... 69 
8.1.2 
Institutional Review Board/Independent Ethics Committee ................................... 69 
8.1.3 
Informed Consent.................................................................................................... 70 
8.1.4 
Monitoring .............................................................................................................. 71 
8.1.5 
Confidentiality ........................................................................................................ 71 
8.1.6 
Investigational Site Training ................................................................................... 71 
8.2 
Data Collection and Handling ........................................................................................ 72 
8.2.1 
Case Report Forms .................................................................................................. 72 
8.3 
Publications .................................................................................................................... 72 
9. 
List of Abbreviations ............................................................................................................ 74 
REFERENCES ............................................................................................................................. 76 
APPENDIX A: Eastern Cooperative Oncology Group Performance Scale ................................. 78 
APPENDIX B: Methods of Contraception Europe only .............................................................. 79 
SIGNATURE PAGE OF THE INVESTIGATOR ....................................................................... 81 
 
 
 


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1. Introduction and Study Rationale
1.1 
 Background
Among the promising approaches to activating therapeutic anti-tumor 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 and is believed that combination of such 
immunomodulatory agents could lead to a cure for cancer [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 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. Thus, the desired therapeutic CD40 agonist antibody 
should have these functionalities. 


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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 [15]. 
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- 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 
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 [16]. 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-, TNF- and 
IL6.  
1.2.2 Pharmacokinetics 
Nonclinical pharmacokinetics (PK) of APX005M were determined in a Good Laboratory 
Practice (GLP) repeat-dose toxicology study using cynomolgus monkeys. Weekly intravenous 


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(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) [16]. 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 APX005M at dose 
levels of 0.03 mg/kg or less were for the most part below the limit of quantitation (BLOQ). IV 
administration of APX005M at doses between 0.1 and 1 mg/kg lead to rapid increase in serum 
concentrations, reaching a maximum just after the end of the infusion. Levels 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 
Study APX005M-001 is a first in human phase 1 dose escalation study of APX005M with 8 pre-
planned dose levels. APX005M was administered to study subjects at doses up to 1 mg/kg. At 
the 1 mg/kg dose level, 1 out of 6 dose limiting toxicity (DLT)-evaluable subjects experienced a 
DLT (grade 4 cytokine release syndrome). Two additional subjects at the 1mg/kg dose level 
experienced serious adverse events (SAE) in later cycles (Grade 3 cytokine release syndrome 
and Grade 4 thrombocytopenia). On May 2, 2016 Apexigen decided to discontinue dose 
escalation and enroll up to 6 subjects in dose level 0.6 mg/kg (originally designed as an 
intermediate de-escalation dose level) and an additional 3 subjects at the previously completed 
dose level 0.3 mg/kg to better characterize the safety and pharmacodynamics (PDn) of 
APX005M and to help establish the single agent recommended phase 2 dose (RP2D). The RP2D 
for APX005M as a single agent every 21 days is 0.3 mg/kg body weight.  
APX005M demonstrated a dose-dependent activation of APCs (as demonstrated by increases in 
expression of activation markers such as CD54, CD70, CD80, CD86, HLA-DR), T cell 
activation and increases in circulating levels of IL12, INF-, TNF- and IL6.  
For further details on the APX005M-001 study and the overall safety of APX005M please refer 
to latest version of the APX005M Investigator’s Brochure [16]. 
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.  


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Transient transaminase elevations (≤ Grade 2) have been observed in several subjects with liver 
metastases, which were not associated with a particular dose of APX005M. Six subjects with 
liver metastases enrolled in the study experienced a transient increase in total bilirubin. 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 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 recently completed 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 1mg/kg body weight 
suggest a best in class profile for APX005M and the possibility of a safe and tolerable 
combination with other immunomodulatory antibodies such as nivolumab. 
Please refer to the most recent version of the APX005M Investigator Brochure for the most 
current summary of APX005M to date.  
1.3 
Nivolumab 
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes 
CD28, CTLA-4, ICOS, and BTLA [17]. PD-1 signaling has been shown to inhibit CD-28-
mediated upregulation of IL-2, IL-10, IL-13, interferon-γ (IFN-γ) and Bcl-xL. PD-1 expression 
also been noted to inhibit T cell activation, and expansion of previously activated cells. Evidence 
for a negative regulatory role of PD-1 comes from studies of PD-1 deficient mice, which develop 
a variety of autoimmune phenotypes [18]. These results suggest that PD-1 blockade has the 
potential to activate anti-self T-cell responses, but these responses are variable and dependent 
upon various host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a 
universal loss of tolerance to self-antigens. 
Nivolumab (BMS-936558, MDX1106) is a fully human monoclonal antibody (IgG4 kappa) that 
targets PD-1. In vitro, nivolumab binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and 
inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50  1 nM). Nivolumab binds 
specifically to PD-1 and not to related members of the CD28 family such as CD28, ICOS, 
CTLA-4 and BTLA. Blockade of the PD-1 pathway by nivolumab results in a reproducible 
enhancement of both proliferation and IFN-γ release in the mixed lymphocyte reaction (MLR). 
Using a CMV re stimulation assay with human PBMC, the effect of nivolumab on antigen 
specific recall response indicates that nivolumab augmented IFN-γ secretion from CMV specific 
memory T cells in a dose-dependent manner versus isotype-matched control. In vivo blockade of 


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PD-1 by a murine analog of nivolumab enhances the anti-tumor immune response and result in 
tumor rejection in several immunocompetent mouse tumor models (MC38, SA1/N, and PAN02) 
[19]. 
Nivolumab is investigated both as monotherapy and in combination with chemotherapy, targeted 
therapies and other immunotherapies. For study details please refer to the nivolumab 
Investigator’s Brochure [20]. 
1.3.1 Summary of the Known and Potential Risks and Benefits 
Extensive details on the safety profile of nivolumab are available in the Investigator Brochure, 
and will not be repeated herein. Overall, the safety profile of nivolumab monotherapy is 
manageable and generally consistent across completed and ongoing clinical trials with no 
maximum tolerated dose (MTD) reached at any dose tested up to 10 mg/kg. Most AEs were low-
grade (Grade 1 to 2) with relatively few related high-grade (Grade 3 to 4) AEs. There was no 
pattern in the incidence, severity, or causality of AEs with respect to nivolumab dose level. 
A pattern of immune-related adverse events has been defined, for which management algorithms 
have been developed; these are provided in the Investigator’s Brochure. Most high-grade events 
were manageable with the use of corticosteroids or hormone replacement therapy 
(endocrinopathies) as instructed in these algorithms. Additional details on the safety profile of 
nivolumab, including results from other clinical studies, are also available in the nivolumab 
Investigator’s Brochure. 
Nivolumab (Opdivo) monotherapy is approved in multiple countries, including the US and 
members of the EU, for unresectable or metastatic melanoma, previous treated metastatic non-
small cell lung cancer and previously treated advanced renal cell carcinoma. It is also approved 
for the treatment of classical Hodgkin lymphoma in the US. IN addition, nivolumab has been 
approved for use in combination with ipilimumab for unresectable melanoma in multiple 
countries, including the US. 
1.4 
Rationale for APX005M in Combination with Nivolumab  
Antibody therapies blocking PD-1, PD-L1 and CTLA-4 function enhance anti-tumor immunity, 
leading to durable clinical responses for a subset of patients with melanoma, lung cancer and 
other tumor types [21]. However, the majority of patients with melanoma or lung cancer 
continue to have a short response or no response to checkpoint blockade therapies [22]. 
CD40 is a member of the TNFR superfamily, which is expressed on the surface of APCs, plays a 
critical role in the control and regulation of both innate and adaptive immunity against tumors 
[23]. Although phase I studies with monotherapy agonistic CD40 antibodies have demonstrated 
objective tumor responses in solid tumors [24], the greatest potential for CD40 activation lies in 
the combination with other therapeutic agents. The combination of CD40 agonists with 
chemotherapy (e.g., cell death resulting in the release of tumor antigens) may lead to synergistic 
therapeutic effects, as indicated by recent phase I clinical trials [25, 26]. 


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The agonistic CD40 mAb, APX005M, a humanized IgG1 mAb with a mutation in the Fc portion, 
is engineered to enhance interaction with Fc receptors to mediate antibody crosslinking. 
APX005M has demonstrated biological activity in human subjects and a favorable toxicity 
profile when given IV at doses up to 1 mg/kg body weight. 
Recently, Zippelius and co-authors [27] showed in preclinical models that CD40 engagement 
with an agonistic mAb leads to a T cell and IFN- dependent upregulation of PD-L1 on tumor 
infiltrating monocytes and macrophages, thereby feeding into a negative feedback loop, which 
hampers CD40 induced T-cell responses. This resistance mechanism was successfully 
circumvented by co-administration of PD-1/PD-L1 blocking antibodies. 
Similarly, other groups showed in preclinical models of pancreatic cancer that CD40 activation 
drove T-cell immunity and reversed the complete resistance of pancreatic tumors to checkpoint 
blockade. Combining a CD40 agonistic antibody with PD-1/PD-L1 blockade enhanced anti-
tumor immunity and improved overall survival versus either monotherapy [28-30]. 
This clinical protocol will explore the safety and efficacy of APX005M in combination with 
nivolumab in: 

Subjects with histologically or cytologically confirmed, immunotherapy naïve, metastatic
or locally advanced non-small cell lung cancer (NSCLC) not amenable to curative
treatment. Subjects may be treatment naïve or could have received one prior platinum-
based chemotherapy for non-small cell lung cancer for any indication (adjuvant, part of
combined modality therapy or for metastatic disease) within the past 3 years, or if
subjects have a documented activating mutation (e.g. EGFR, ALK, ROS) amenable to
tyrosine kinase inhibitor therapy, must also have received the appropriate therapy and
progressed (inNSCLC)

Subjects with histologically or cytologically confirmed unresectable or metastatic
melanoma (MM) that had confirmed progressive disease during treatment with anti-PD-
1/PD-L1 therapy. Subjects with BRAF wild type or unknown status must have received
only anti-PD-1/PD-L1 therapy. Subjects with BRAF activating mutation could have also
received a BRAF inhibitor and/or MEK inhibitor regimen prior to anti-PD-1/PD-L1
therapy. Subjects with ocular melanoma are excluded (PD1-MM).

Subjects with histologically or cytologically confirmed, metastatic or locally advanced
NSCLC not amenable to curative treatment. Subjects must have disease progression (PD)
on an immediately preceding PD-1/PD-L1 containing regimen. Subjects could have
received no more than one platinum containing regimen, or if subjects have a
documented activating mutation (e.g. EGFR, ALK, ROS) amenable to tyrosine kinase
inhibitor therapy, must also have received the appropriate therapy and progressed before
the PD-1/PD-L1 containing regimen (PD1-NSCLC).


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2. Investigational Plan 
2.1 
Study Objectives 
2.1.1 Primary Objective 
Phase 1b: 
 Determine the MTD and the RP2D of APX005M when given in combination with 
nivolumab 
Phase 2: 
 Evaluate the overall response rate (ORR) by RECIST 1.1 in each cohort/group 
2.1.2 Secondary Objectives 
 Evaluate safety of the APX005M and nivolumab combination 
 Evaluate the 6-month progression-free survival (PFS) rate (PFSR) in each cohort/group 
 Evaluate duration of response (DOR) and median PFS in each cohort/group by RECIST 
1.1 
2.1.3 Exploratory Objectives 
 Determine the immune PDn of the APX005M and nivolumab combination 
 Determine the PK of APX005M  
 Assess incidence of APX005M ADA 
 Identify blood and/or tumor biomarkers that correlate with efficacy and/or resistance 
 Evaluate the ORR by immune related RECIST (iRECIST) in each cohort/group 
 Evaluate DOR and median PFS in each cohort/group by iRECIST 
 
2.2 
Study Design and Duration 
This is a Phase 1b-2 study. The study will include 2 parts (Table 1). 
 Phase 1b dose-escalation of APX005M: 
o Up to 4 dose levels of APX005M administered IV every 21 days 
o In combination with nivolumab 360 mg IV every 21 days 
o Subjects with inNSCLC or PD1-MM  
 Phase 2 dose-expansion (Simon optimal 2-stage design): 
o The RP2D dose of APX005M administered IV every 21 days in combination with 
nivolumab 360 mg IV 
o 3 cohorts 
 Cohort 1: Subjects with inNSCLC 
 Cohort 2: Subjects with PD1-MM 
 Cohort 3: Subjects with PD1-NSCLC 
 Group A: Subjects with PD1-NSCLC with best response of 
progressive disease or with stable disease < 16 weeks while on 


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previous PD-1/PD-L1 containing regimen 
 Group B: Subjects with PD1-NSCLC with tumor response or with 
stable disease ≥ 16 weeks while on previous PD-1/PD-L1 
containing regimen 
 
 
 
Table 1:  
Planned Number of Subjects in Study APX005M-002 
 Study Phase 
Dose Level 
 
APX005M 
 
Nivolumab 
 
 
Phase1b  
Dose-escalation 
 
mg/kg 
 
 
mg 
 
 
N 
 
DL 1 
 
0.03 
q 21 days 
 
360 
q 21 days 
 
3 
 
DL 2 
 
0.1 
q 21 days 
 
360  
q 21 days 
 
3 
 
DL2a 
 
0.2 
q 21 days 
 
360  
q 21 days 
 
3 to 6 
 
DL 3 
 
0.3 
q 21 days 
 
360  
q 21 days 
 
3 to 6 
 
 
 
 
 
 
Subtotal 
~ 
18 
 
Study Phase 
Stage 
 
APX005M 
 
Nivolumab 
 
 
Phase 2 
Dose-expansion 
 
mg/kg 
 
 
mg 
 
 
N 
Cohort 1 inNSCLC 
Stage 1 
 
RP2D 
q 21 days 
 
360 
q 21 days 
 
24 
 
Stage 2 
 
RP2D 
q 21 days 
 
360 
q 21 days 
 
21 
 
 
 
 
 
 
 
 
 
Cohort 2 PD1-MM 
Stage 1 
 
RP2D 
q 21 days 
 
360 
q 21 days 
 
12 
 
Stage 2 
 
RP2D 
q 21 days 
 
360 
q 21 days 
 
25 
 
 
 
 
 
 
 
 
 
 
Cohort 3 PD1-NSCLC 
Stage 1 
 
RP2D 
q 21 days 
 
360 
q 21 days 
 
12 
Group A 
Stage 2 
 
RP2D 
q 21 days 
 
360 
q 21 days 
 
25 
 
 
 
 
 
 
 
 
 
 
Cohort 3 PD1-NSCLC 
Stage 1 
 
RP2D 
q 21 days 
 
360 
q 21 days 
 
12 
Group B 
Stage 2 
 
RP2D 
q 21 days 
 
360 
q 21 days 
 
25 
 
 
 
 
 
 
Total 
~ 
174 
 
Phase 1b dose-escalation: 
Subjects with inNSCLC or PD1-MM who meet all of the general eligibility criteria will be 
enrolled in the dose-escalation portion of the study. 
There will be a maximum of 3 escalation dose levels (DL) and 1 de-escalation dose level in this 
study. The doses of APX005M and minimum number of subjects to be enrolled in each dose 
level are presented in Table 2. It is expected that up to 18 DLT-evaluable subjects (see definition 
in Section 7.2) will be enrolled in the dose-escalation portion of the study over a 6-month period. 
All subjects that are not DLT-evaluable will be replaced for the purpose of establishing MTD. 


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Table 2: APX005M Dose Levels 
Escalation Dose Level 
DL1 
DL2 
 
DL3 
De-escalation Dose Level 
 
 
DL2a 
 
APX005M mg/kg body weight 
0.03 
0.1 
0.2 
0.3 
Minimum number of DLT evaluable subjects 
3 
3 
3 
3 
Abbreviations: DL = dose level; DLT = dose-limiting toxicity. 
 
The DLT observation period for dose escalation is the 21 days following the first administration 
of APX005M and nivolumab (first 3-week cycle). Safety and tolerability of the APX005M and 
nivolumab combination will be monitored by representatives from Apexigen and the 
Investigators on a regular basis and prior to each dose escalation. 
Dose escalation will continue if 0 out of 3 evaluable subjects experience a DLT during the DLT 
observation period (i.e., <33% DLT-evaluable subjects in that cohort have a DLT). If 1 DLT-
evaluable subject in any DL cohort experiences a DLT, that cohort will be expanded to include 
additional 3 DLT-evaluable subjects (i.e. a total of 6 evaluable subjects). Dose escalation will 
continue if 1 out of 6 evaluable subjects experience a DLT during the DLT observation period 
(i.e., <33% DLT-evaluable subjects in that cohort have a DLT). Decision to open a new DL 
cohort will be based on the totality of the data available at that time. 
The MTD is the maximum dose of APX005M combined with 360 mg of nivolumab for which 
<33% of DLT-evaluable subjects experience a DLT.  
If the DLT rate in DL 3 exceeds 33%, or 2 or more subjects in DL 2 experience a Grade 2 
infusion reaction/cytokine release syndrome, or at the discretion of the sponsor, the intermediate 
lower DL 2a will be evaluated (de-escalation). Up to 6 subjects can be enrolled in any of dose 
levels below the MTD or highest DL tested, should sponsor decide to discontinue dose escalation 
prior to reaching the MTD. 
The RP2D will be based on the overall safety and tolerability of the combination of APX005M 
and nivolumab.  
Phase 2 dose-expansion: 
After identification of the RP2D of APX005M in combination with nivolumab 360 mg IV every 
21 days, study will continue with 3 cohorts.  
 Cohort 1: inNSCLC 
 Cohort 2: PD1-MM 
 Cohort 3: PD1-NSCLC 
o Group A 
o Group B 
Each cohort and group of the Phase 2 dose-expansion portion of the study will follow a Simon 
optimal 2-stage design. Subjects treated at the RP2D in the dose-escalation portion will be 
included in Stage 1 of the relevant cohort. Additional subjects will be enrolled for a total of 24 


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subjects in Cohort 1 and 12 subjects in each of Cohort 2, Cohort 3 Group A and Cohort 3 Group 
B.  
Subjects will be evaluated for tumor response approximately every 8 weeks following the first 
dose of investigational product. Subjects that are non-evaluable for tumor response (see 
definition in Section 7.2) will be replaced. An ORR [complete response (CR) + partial response 
(PR)] of at least 22% (6 confirmed out if 24 response evaluable subjects) in the inNSCLC cohort 
and 5% (1 confirmed out if 12 response evaluable subjects) in the PD1-MM cohort or PD1-
NSCLC (Group A or B) is required in Stage 1 for that cohort to proceed to Stage 2. Enrollment 
may continue into Stage 2 while the planned number of subjects for Stage 1 are followed for 
efficacy. 
In Stage 2, an additional 21 subjects will be enrolled in Cohort 1 (inNSCLC) and an additional 
25 subjects will be enrolled in each of Cohort 2 (PD1-MM) and Cohort 3 (PD1-NSCLC) Group 
A and B. The study schema is presented in Figure 1. 
Figure 1: 
APX005M-002 Study Design 
 
A minimum of 6 subjects per cohort/group who have a primary or metastatic lesion that can be 
biopsied without interfering with subsequent tumor assessments and who consent to collection of 
paired tumor biopsies for tumor biomarkers should be enrolled during Phase 1b and Phase 2. 
At any time during the study, enrollment will be suspended pending safety review if any of the 
following events occur since last safety review: 
 ≥1 Grade 5 suspected adverse reaction (SAR) (for definition see Section 6.1.2) 
 ≥2 Grade 4 infusion reaction/ cytokine release syndrome 
Subjects with 
PDl-MM or 
inNSCLC 
Dose Escalation 
N"' 174 
( 
Cohort 1 inNSCLC 
[,,....-s-~=-g2-e4_1 ______ H Stage 2 
N=21 
Cohort 2 PDl-MM 
Stage 1 
~ 
Stage 2 
N=12 
N=25 
Cohort 3 PDl-NSCLC 
Grau A 
-----
Stage 1 
N=12 
Stage 2 
N=25 
Grau B 
-----
Stage 1 
N=12 
Stage 2 
N=25 
Tumor Specific Expansion 
l 
) 


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 ≥2 Grade ≥ 3 immune related AEs in more than 1 subject 
Enrollment will resume following assessment by the Apexigen Medical Monitor, contract 
research organization Medical Monitor and lead Investigator. 
For subjects that require confirmation of PD while on treatment with anti-PD-1/PD-L1 therapy, 
any of the following criteria must be met: 
 ≥ 5mm further increase in sum of measures of target lesion 
 ≥ 5mm further increase in sum of measures of new lesion 
 further increase in the size of non-target lesion(s) 
 new non-target lesions  
 appearance of new lesion(s) when none have previously been recorded  
 increase in the number of new lesions 
 all of the following  
o maintain > 20% increase in target lesion burden at confirmed PD scan relative 
to nadir (as per RECIST1.1)  
o target lesion burden at confirmatory PD scan greater than 90% of target lesion 
burden at uncomfirmed PD (initial PD) scan (to account for intra-subject 
reader variability)  
o no disappearance of all new lesions. 
2.2.1 Study Population 
2.2.1.1 Inclusion Criteria 
Cohort Specific Inclusion Criteria 
Phase 1b: Subjects that meet eligibility criteria for Phase 2 Cohorts 1 or 2 and all of the general 
eligibility criteria. 
Phase 2 Cohort 1: Histologically or cytologically confirmed, immunotherapy naïve, metastatic 
or locally advanced non-small cell lung cancer not amenable to curative treatment. Subjects may 
be treatment naïve or could have received one prior platinum-based chemotherapy for non-small 
cell lung cancer for any indication (adjuvant, part of combined modality therapy or for metastatic 
disease) within the past 3 years. Subjects with no or unknown activating mutation (e.g., EGFR, 
ALK, ROS) are eligible for this study. Subjects with a documented activating mutation (e.g., 
EGFR, ALK, ROS) amenable to tyrosine kinase inhibitor therapy, must also have received the 
appropriate therapy and progressed.  
Phase 2 Cohort 2: Subjects with histologically or cytologically confirmed unresectable or 
metastatic melanoma that had confirmed progressive disease during treatment with anti-PD-
1/PD-L1 therapy. Subjects with BRAF wild type or unknown status must have received only 
anti-PD-1/PD-L1 therapy. Subjects with BRAF activating mutation could have also received a 
BRAF inhibitor and/or MEK inhibitor regimen prior to anti-PD-1/PD-L1 therapy.  
Confirmed PD (Section 5.2.1) during treatment with anti-PD-1/PD-L1 therapy should be 
documented by 2 consecutive tumor assessments at least 4 weeks apart (the second scan may be 
used as the baseline scan for this study if it was performed within the 21 days prior Cycle 1 Day 


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1). Subjects should start study treatment no later than 8 weeks following the last dose of anti-PD-
1/PD-L1 therapy (with no intervening therapy).  
Subjects with ocular melanoma are excluded. 
Phase 2 Cohort 3: Subjects with histologically or cytologically confirmed, metastatic or locally 
advanced NSCLC not amenable to curative treatment. Subjects must have disease progression on 
an immediately preceding PD-1/PD-L1 containing regimen. Subjects could have received no 
more than one platinum containing regimen, or if subjects have a documented activating 
mutation (e.g. EGFR, ALK, ROS) amenable to tyrosine kinase inhibitor therapy, must also have 
received the appropriate therapy and progressed before the PD-1/PD-L1 containing regimen. 
Based on response to previous PD-1/PD-L1 containing regimen, subjects will be enrolled in one 
of the following groups: 
 Group A: Subjects with best response of progressive disease or with stable disease 
< 16 weeks 
 Group B: Subjects with tumor response or with stable disease ≥16 weeks. 
If possible, confirmed PD (Section 5.2.1 during treatment with anti-PD-1/PD-L1 therapy should 
be documented by 2 consecutive tumor assessments at least 4 weeks apart (the second scan may 
be used as the baseline scan for this study if it was performed within the 21 days prior Cycle 1 
Day 1). Subjects should start study treatment no later than 8 weeks following the last dose of 
anti-PD-1/PD-L1 containing regimen. 
 
General Inclusion Criteria 
1. Subjects willing and able to provide written informed consent for this study   
2. Male or female ≥18 years old at time of consent  
3. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
5. Resolution of 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 
6. Adequate organ function within 14 days of first dose of investigational product: 
a. White blood cell count (WBC) ≥1.5 x 109/L in absence of growth factor support 
b. Absolute neutrophil count (ANC) ≥1.0 x 109/L in absence of growth factor 
support 
c. Platelet count ≥100 x 109/L 
d. Hemoglobin ≥8 g/dL 
e. Serum creatinine ≤1.5 mg/dL AND creatinine clearance ≥60 mL/min (calculated 
[using the formula of local laboratory] or measured) 
f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x 
upper limit of normal (ULN) 
g. Total bilirubin ≤1.5 x ULN, or direct bilirubin ≤ULN for subjects with total 
bilirubin levels >1.5 x ULN 
h. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 x ULN 
unless subject is receiving anticoagulant therapy as long as PT or Partial 
Thromboplastin Time (PTT) is within therapeutic range of intended use of 


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anticoagulants 
i. Activated Partial Thromboplastin Time (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 
7. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test 
within the 7 days prior to first dose of investigational product and a negative urine 
pregnancy test within the 3 days prior to first dose of investigational product, or a 
negative serum pregnancy test within the 3 days prior to first dose of investigational 
product 
8. WOCBP 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 product. 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 product 
9. Available archived or fresh tumor tissue sample for PD-L1 and other biomarker analysis   
10. 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. A 
minimum of 24 subjects (6 subjects with each cohort/group) must consent to fresh core 
biopsies. 
2.2.1.2 General Exclusion Criteria 
1. Previous exposure to any immunomodulatory agents (e.g., anti- CD40, CTLA-4, 
PD-1/PD-L1, IDO inhibitors) with the following exceptions: 
a.  For Cohort 2 (unresectable or metastatic melanoma): 
i. All subjects must have confirmed disease progression while on treatment 
with anti-PD-1/PD-L1 therapy 
ii. Subjects could have received anti-CTLA-4 therapy provided they did not 
have disease progression while on therapy and they discontinue treatment 
with anti-CTLA-4 therapy at least 3 months prior to first dose of 
investigational product 
b. For Cohort 3 (metastatic or locally advanced NSCLC): 
i. All subjects must have disease progression while on treatment with anti-
PD-1/PD-L1 therapy 
2. Second malignancy (solid or hematologic) within the past 3 years except: 
a. Adequately treated basal cell or squamous cell skin cancer, or 
b. Carcinoma in situ of the cervix, or  
c. Prostate cancer Gleason score < 6 with undetectable prostate specific antigen 
(PSA) over 12 months, or 
d. Ductal breast carcinoma in situ with full surgical resection (i.e., negative 
margins), or 
e. Treated medullary or papillary thyroid cancer 
3. Active, known, clinically serious infections (≥ Grade 2 according to NCI-CTCAE v4.03) 
within the 14 days prior to first dose of investigational product 
4. Use of systemic corticosteroids or other systemic immunosuppressive drugs within the 28 
days prior to first dose of investigational product (except inhaled corticosteroids); the use 
of physiologic doses of corticosteroids may be approved after consultation with the 


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Apexigen Medical Monitor (or designee) 
5. Major surgery within 4 weeks of first dose of investigational product 
6. Concurrent treatment with any anti-cancer agent, except for hormonal therapy and 
palliative radiation as clinically indicated unless approved by the Medical Monitor 
7. History of allogeneic bone marrow transplantation  
8. Uncontrolled diabetes or hypertension 
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 I 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 life-threatening toxicity related to prior anti-PD-1/PD-L1 treatment for 
subjects with metastatic melanoma except those that are unlikely to re-occur with 
standard countermeasures (e.g. hormone replacement after adrenal crisis) 
13. History of sensitivity or allergy to mAbs or IgG  
14. Congestive heart failure (New York Heart Association Class III to IV), symptomatic 
ischemia, conduction abnormalities uncontrolled by conventional intervention, or 
myocardial infarction within 6 months prior to the first dose of investigational product 
15. History of any thromboembolic event within 3 months prior to first dose of 
investigational product or an active coagulopathy  
16. 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, 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 
17. Known human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection 
18. Has received a live-virus vaccination within 30 days of the first dose of investigational 
product. Seasonal flu vaccines that do not contain live virus are permitted 
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. 
2.2.2 APX005M Dose 
APX005M has been administered in the APX005M-001 study to subjects with solid tumors as a 
single-agent at 7 dose levels starting at 0.1 g/kg up to 1.0 mg/kg body weight every 21 days. At 


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0.6 and 1 mg/kg dose level 1 out of 6 subjects experienced a DLT. The RP2D for APX005M as a 
single agent every 21 days is 0.3 mg/kg body weight. 
The proposed starting dose level for APX005M in this study is 0.03 mg/kg which is 
approximately 33 times lower than the highest dose of APX005M administered to human 
subjects. Three subjects were enrolled at this dose level in the APX005M-001 study and received 
a total of 8 infusions of APX005M. One additional subject enrolled at a lower dose level was 
allowed per protocol to have the dose of APX005M escalated and received 3 infusions of 0.03 
mg/kg of APX005M. The only AE considered as possibly related to APX005M for all subjects 
receiving 0.03 mg/kg of APX005M was one event of vomiting (Grade 1) shortly after the 
administration of APX005M. This dose level was also the lowest to show a PDn effect across 
multiple markers of APC activation measured 24 hours after the start of infusion, although 
APX005M was detectable in the peripheral blood only during and at the end of infusion.  
The highest dose level of APX005M to be tested in combination with nivolumab will be 0.3 
mg/kg body weight (Table 1). At all dose levels proposed, APX005M has been well tolerated; all 
adverse reactions have been moderate (≤ Grade 2), transient and easily managed in outpatient 
setting. All available data suggests that 0.03 mg/kg every 21 days is a safe and 
pharmacodynamically active dose of APX005M. 
2.2.3 Nivolumab Dose 
The approved dose of nivolumab is 240 mg infused over 60 minutes every 2 weeks for NSCLC, 
unresectable or metastatic melanoma and advanced renal cell carcinoma (RCC). In this study, a 
flat dose of 360 mg nivolumab administered as an IV infusion over 30 minutes and a dosing 
schedule of every 3 weeks has been selected. Nivolumab has been shown to be safe and well 
tolerated up to a dose level of 10 mg/kg (Bristol-Myers Squibb, internal data). Population 
pharmacokinetic analyses have shown that the pharmacokinetics of nivolumab is linear with 
proportional exposure over a dose range of 0.1 to 10 mg/kg; no differences in pharmacokinetics 
across ethnicities and tumor types were observed. Using the population pharmacokinetic model 
developed, the exposures following administration of several dosing regimens of nivolumab 
administered as a flat dose were simulated, including 360 mg administered every 3 weeks. The 
simulated steady state average concentration following administration of nivolumab 360 mg 
every 3 weeks are expected to be similar to those following administration of nivolumab 240 mg 
every 2 weeks and 3 mg/kg every 2 weeks to subjects weighing 80 kg, the approximate median 
weight of subjects with NSCLC, unresectable or metastatic melanoma and RCC used in the 
population pharmacokinetic analyses. The steady state peak concentrations following nivolumab 
360 mg every 3 weeks are predicted to be less than those following the administration of 
nivolumab 10 mg/kg every 2 weeks providing sufficient safety margins. Finally, nivolumab is 
being studied as nivolumab 360 mg combined with platinum-doublet chemotherapy administered 
every 3 weeks for the treatment of NSCLC in a Phase 3 study.  
Previous clinical studies of nivolumab monotherapy have used a 60 minute infusion duration 
wherein, nivolumab has been safely administered up to 10 mg/kg over long treatment periods. 
Infusion reactions including high-grade hypersensitivity reactions have been uncommon across 
nivolumab clinical program. In CA209010, a dose association was observed for infusion site 
reactions and hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 


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mg/kg). All the events were Grade 1-2 and were manageable. An infusion duration of 30 minutes 
for nivolumab 360 mg is not expected to present any safety concerns compared to the prior 
experience at 10 mg/kg nivolumab dose infused over a 60 minute duration. The safety of 
nivolumab 3 mg/kg administered as a 30 minutes infusion was assessed in subjects (n=322) with 
previously treated advanced NSCLC. Overall, there were no clinically meaningful differences in 
the frequency of hypersensitivity/infusion-related reactions (of any cause or treatment-related) in 
subjects administered nivolumab over a 30 minutes infusion compared with that reported for 
subjects with the 60 minutes infusion. Thus, it was shown that nivolumab can be safely infused 
over 30 minutes. 
 
 
3. Treatment of Subjects 
3.1 
Subject Enrollment and Treatment Administration 
All subjects who sign a consent form will 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 considered enrolled after receiving any investigational 
product; consented subjects who do not receive investigational product will be considered screen 
failures.  
The Apexigen Medical Monitor (or designee) will review the subject’s information before 
enrollment. Only subjects who are approved by the Apexigen Medical Monitor (or designee) will 
be allowed to enroll in the study. During normal business days, a minimum of 24 hours will be 
required for the Apexigen Medical Monitor (or designee) to approve a subject for enrollment. 
Additional time may be required when approval is sought during a weekend or holiday.  
Subject enrollment into a DL cohort of the Phase 1b dose-escalation or in the Phase 2 dose-
expansion will follow the rules outlined in Section 2.2. 
 
On treatment days, nivolumab will be administered first, followed by APX005M. 
During Phase 1b dose-escalation, in any of the multi-subject cohorts, the first two subjects must 
receive the first dose of investigational product at least 72 hours apart. 
During the Phase 1b dose-escalation portion of the study all subjects will be monitored in the 
research clinic for 4 hours after the first 2 infusions of APX005M and as clinically indicated 
thereafter and during the Phase 2 dose-expansion portion of the study. 
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, heart 
rate <110 beats/min.  


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After discharge, all subjects in Phase 1b 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. Subjects in the Phase 2 dose-expansion portion of the study should be monitored as 
clinically indicated. 
 
3.2 
 Study Treatment 
3.2.1 Investigational Products 
An investigational product, also known as investigational medicinal product, is defined as 
follows: 
 
A pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization 
but used or assembled (formulated or packaged) in a different way than the authorized 
form, or used for an unauthorized indication, or when used to gain further information 
about the authorized form. 
In this protocol, the investigational products are APX005M and nivolumab. 
The Pharmacy Manual contains detailed information about packaging, labeling, storage, 
dispensing, preparation and administration of the infusion solutions of APX005M and 
nivolumab. 
3.2.2 Non-Investigational Product 
Any other medications used in the study as support or rescue medication for preventative, 
diagnostic, or therapeutic reasons, components of the standard of care for a given diagnosis, are 
considered non-investigational products. 
 
3.3 
Timing of Investigational Products Administration 
Investigational products may be administered up to 3 days before or after the scheduled Day 1 in 
the 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); if retreatment 
criteria are met subjects should restart treatment within 12 weeks of last dose of investigational 
product unless otherwise discussed with Apexigen (or designee). Every effort should be made to 
maintain a 21-day dosing schedule. The reason for delay will be documented in the patient's 
study record. 
3.3.1 Nivolumab 
Nivolumab is administered on Day 1 of each 3-week treatment cycle as a dose of 360 mg using a 
30-minute IV infusion. It is not to be administered as an IV push or bolus injection. Nivolumab 
injection can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, 


Apexigen, Inc. 
CONFIDENTIAL 
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APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 35 of 81 
 
 
USP or 5% Dextrose Injection, USP to protein concentrations as low as 1 mg/mL. Nivolumab 
injections should be administered through a 0.2-micron to 1.2-micron pore size, low-protein 
binding in-line filter and are compatible with polyvinyl chloride (PVC) or polyolefin containers 
and infusion sets, and glass bottles.  
Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps from site to site, a window between -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 25 minutes to 40 minutes). The nivolumab 
infusion can be interrupted in the case of infusion reaction (see Section 3.4.1.2). Once symptoms 
resolve, infusion should be restarted at 50% of the initial infusion rate (e.g., from 100 mL/hr to 
50 mL/hr). 
The Pharmacy Manual contains specific instructions for the preparation of the nivolumab 
infusion and administration of infusion solution. 
3.3.2 APX005M 
APX005M is administered on Day 1 of each 3-week treatment cycle approximately 30 minutes 
following nivolumab using a 60 minute IV infusion. 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 APX005M infusion can be interrupted in the case of infusion reaction (see Section 3.4.1.2). 
Once symptoms resolve, infusion should be restarted at 50% of the initial infusion rate (e.g., 
from 50 mL/hr to 25 mL/hr). A lower infusion rate may be considered for patients who 
experience repeated infusion reactions, after discussion with Apexigen Medical Monitor (or 
designee). 
The Pharmacy Manual contains specific instructions for the preparation of the APX005M 
infusion and administration of infusion solution. 
 
3.4 
Concomitant Treatments 
3.4.1.1 Premedication Prior to Administration of Investigational Product 
 
All subjects should be premedicated approximately 30 minutes before the administration of first 
investigational product with a regimen containing: 
 Oral H1 antagonist (e.g., loratadine 10 mg) 
 Optional oral or IV H2 antagonist (e.g., ranitidine 150−300 mg, cimetidine 300−800 mg, 
nizatidine 150−300 mg, and famotidine 20−40 mg) 
 Oral or IV nonsteroidal anti-inflammatory drug (may comprise ibuprofen 400 mg or 
equivalent) 
 Oral or IV acetaminophen 500-650 mg. 
 
When the time between premedication and scheduled APX005M administration exceeds 4 hours, 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 36 of 81 
 
 
or if a subject experiences a Grade 2 infusion reaction to nivolumab, subjects may receive an 
additional course of premedication prior to APX005M administration.  
 
3.4.1.2 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 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 
nivolumab combination and should not substitute for investigational product dose delays and/or 
modifications (Section 3.7). Additional guidance for management of AEs with potential 
immunologic etiology is provided in the APX005M and nivolumab Investigator’s Brochures. 
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. 
Steroid tapering may be necessary for prolonged exposures to corticosteroids, or if symptoms 
worsen when the corticosteroid dose is decreased. 
 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. Add prophylactic antibiotics for 
opportunistic infections. Consider renal biopsy and consult nephrologist. 
 Pneumonitis  


Apexigen, Inc. 
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APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
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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-
inflammatory measures, as needed. Add prophylactic antibiotics for opportunistic 
infections. Consider bronchoscopy and lung biopsy.  
 Liver Function Tests 
o Grade 2: monitor liver function tests more frequently until returned to Grade 1 or 
less. If no improvement in 5-7 days, treat with IV or oral corticosteroids until 
symptoms improve to Grade 1 or less. 
o Grade 3 and 4: treat with IV corticosteroids for 24-48 hours followed by oral 
corticosteroids until symptoms improve to Grade 1 or less. If no improvement in 
3-5 days administer additional immunosuppressive measures (e.g. mycophenolate 
mofetil), as needed. Add prophylactic antibiotics for opportunistic infections. 
Consult gastroenterologist.  
 Endocrinopathy 
o Asymptomatic TSH abnormality: monitor fT4 if TSH is <0.5 x LLN, > 2 x 
ULN or consistently out of range in two subsequent measurements. Consider 
endocrinology consult. 
o Symptomatic endocrinopathy: evaluate endocrine function and consider a 
pituitary scan. For abnormal laboratory results/pituitary scan initiate IV 
corticosteroids followed by oral or IV corticosteroids until symptoms improve to 
Grade 1 or less. Initiate appropriate hormone therapy. For normal laboratory 
results/pituitary scan repeat labs in 1-3 weeks and pituitary scan in 1 month. 
o Suspicion of adrenal crisis: rule out sepsis, administer IV fluids. Consult 
endocrinologist and if adrenal crisis is ruled out, treat as for symptomatic 
endocrinopathy. Otherwise, administer stress dose of IV steroids with 
mineralocorticoid activity.  
 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 and nivolumab. 
Emergency agents including oxygen, oral and endotracheal airways, intubation 
equipment epinephrine, antihistamines, and corticosteroids should be available and used 
if required at the Investigator’s discretion. 
 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 38 of 81 
 
 
Subjects should be instructed that symptoms associated with cytokine release 
syndrome/infusion reaction can occur within 48 hours following the administration of the 
APX005M or nivolumab, and if such symptoms develop while they are at home, they 
should contact the Investigator and/or seek emergency medical care if appropriate. 
o Grade 2: stop infusion and treat symptoms following guidance in Table 3. 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 3. 
 
 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 39 of 81 
 
 
Table 3: 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 > 48 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 (per 
ACTEMRA prescribing 
information)  
 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 
 Neurological Toxicity 
o Grade 2: symptomatic treatment per local guidelines.  
o Grade 3-4: obtain neurological consult and treat symptoms per local guidelines. 
Administer IV corticosteroids followed by oral corticosteroids until symptoms 
improve to Grade 2 or less. If symptoms worsen or for atypical presentation 
consider and additional immunosuppressive measures per local guidelines.  
 Myocarditis Toxicity 
o Grade 2: Hospitalize with cardiac monitoring. Obtain cardiology consult for 
evaluation and monitoring. Administer IV corticosteroids followed by oral 
corticosteroids until symptoms improve. 


Apexigen, Inc. 
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APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 40 of 81 
 
 
o Grade 3-4: Hospitalize to intensive cardiac monitoring. Obtain cardiology 
consult for evaluation and monitoring. Immediately, administer IV corticosteroid 
bolus. For Grade 4, transfer to institution with cardiac expertise and consider 
Antithymocyte Globulin (ATG) as second agent.  
 
3.4.1.3 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 will be recorded on the electronic case report form 
(eCRF) including all prescription, over-the-counter, herbal supplements and IV medications and 
fluids. If changes occur during the Treatment Phase, documentation of drug dosage, frequency, 
route, and date may also be included on the eCRF. 
All concomitant medications received from the time of first dose of investigational product and 
up to 30 days after the last dose of trial treatment should be recorded.  
3.4.1.4 Prohibited and/or Restricted Therapies 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
 Antineoplastic systemic chemotherapy or biological therapy  
 Investigational agents other than APX005M and nivolumab 
 Radiation therapy (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, and typhoid 
(oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed. However, intranasal influenza vaccines (e.g. Flu - Mist®) are 
live attenuated vaccines and are not allowed. 
 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 may be discontinued from study.  
Herbal medicine for anticancer treatment (such as botanical formulation ‘Xiao Chai Hu Tang’) 
should be stopped 1 week prior to 1st dose of investigational product. 
Subjects taking narrow therapeutic index medications (such as warfarin, phenytoin, quinidine, 
carbamazepine, phenobarbital, cyclosporine, and digoxin) should be monitored proactively.  


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 41 of 81 
 
 
There are no prohibited therapies during the Follow-up Phase. 
 
3.5 
Dose Limiting Toxicity 
All toxicity will be graded according to the NCI-CTCAE version 4.03. DLT will be defined as 
any of the following events attributed to APX005M and nivolumab combination (e.g., AEs that 
are not clearly attributable to extraneous causes), and occurring during the first 21-day following 
the administration of APX005M and nivolumab (the first 3-week cycle): 
 Grade 4 hematologic toxicity lasting ≥ 7 days (except asymptomatic lymphopenia)  
 Grade 3 or 4 neutropenia with a single temperature of >38.3◦ C (101◦ F) or a sustained 
temperature of ≥38◦ C (100.4◦ F) for more than one hour 
 Grade 4 thrombocytopenia (platelet count <25,000 cells/mm3) or Grade ≥3 
thrombocytopenia with signs or symptoms of bleeding or requiring platelet 
transfusion 
 Grade 4 non-hematologic toxicity (not laboratory) 
 Grade 3 non-hematologic toxicity (not laboratory) lasting >3 days despite optimal 
supportive care 
 Any Grade ≥ 3 non-hematologic laboratory value if: 
 Medical intervention is required to treat the subject, or 
 The abnormality leads to hospitalization, or 
 The abnormality persists for >1 week 
 Failure to recover from a treatment-related AE to baseline or ≤ Grade 1 within 12 
weeks of last dose of investigational product (except Grade 2 alopecia and Grade 2 
fatigue) 
 Grade 5 toxicity. 
 
3.6 
Retreatment Criteria 
Subjects that do not meet any of the criteria for treatment discontinuation (Section 4.1) may start 
a new cycle of APX005M and nivolumab as scheduled if WBC >1,500/mm3, ANC >1,000/mm3, 
platelets >100,000/mm3, hemoglobin ≥8 g/dL, and disease or treatment-related AE has 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. 
Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before 
treatment is resumed. Subjects with persistent Grade 1 pneumonitis after completion of a steroid 
taper over at least 1 month may be eligible for retreatment if discussed with and approved by 
Apexigen Medical Monitor (or designee). 
For subjects requiring corticosteroid treatment, allow for a minimum of 7 days from last dose 
before beginning a new cycle.   


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 42 of 81 
 
 
If a subject fails to meet criteria for retreatment then the treatment cycle should be delayed and 
the subject should be re-evaluated weekly. 
 
3.7 
Dose Modifications 
Suspected adverse reactions (SAR) (for definition see Section 6.1.2) associated with APX005M 
and nivolumab exposure may represent an immunologic etiology. These AEs may occur shortly 
after the administration of investigational products or several months after the last dose of 
investigational product. Management of suspected adverse drug reactions may require treatment 
hold, dose reduction of APX005M, or discontinuation of one of both investigational products as 
per Table 4. If a subject experiences several toxicities, the recommended dose modification 
should be based on the highest grade toxicity. 
See Section 3.4.1.2 for supportive care guidelines, including use of corticosteroids. 
Table 4: 
Dose Modification Guidelines for Suspected Adverse Reactions 
Toxicity 
Grade 
APX005M 
Nivolumab 
Neutropenia (± febrile) 
3-4 
Hold 
Hold 
Thrombocytopenia 
3 
Hold. Dose reduction if > 7 days 
Hold 
4 
Hold. Dose reduction 
Hold. Discontinue if > 7 days 
3-4 with 
bleeding 
Discontinue 
Discontinue 
Diarrhea/colitis 
2 
 
1st occurrence: hold 
2nd occurrence: dose reduction 
Hold 
3 
1st occurrence: dose reduction 
2nd occurrence: discontinue 
Discontinue 
4 
Discontinue 
Discontinue 
Uveitis, eye pain or 
blurred vision that does 
not improve to Grade 1 
before next cycle 
2-4 
Hold 
Discontinue 
Increased bilirubin 
2 
Hold 
Hold 
3-4 
Discontinue 
Discontinue 
Increased AST, ALT  
2 
Hold 
Hold 
3 
Hold. Dose reduction 
For subjects with liver metastasis reduce 
dose only if Grade 3 > 72 hours 
Discontinue  
4 
Discontinue 
Discontinue 
Endocrinopathies 
2 
Hold 
Hold 
3-4 
1st occurrence: Hold. Institute endocrine 
replacement therapy 
2nd occurrence: discontinue after 
consultation with Medical Monitor 
1st occurrence: Hold. Institute endocrine 
replacement therapy* 
2nd occurrence: discontinue after 
consultation with Medical Monitor 
Nivolumab 
infusion reaction 
2 
Administer additional premedication. 
Increase infusion time to 90 min 
1st occurrence: continue 
2nd occurrence: discontinue 
3 
Hold for 1 cycle. Continue single agent at 
following cycle 
Discontinue 
4 
Discontinue 
Discontinue 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 43 of 81 
 
 
Toxicity 
Grade 
APX005M 
Nivolumab 
APX005M infusion 
reaction/cytokine release 
syndrome 
3 
Hold. Dose reduction 
Hold 
4 
Discontinue 
Discontinue 
Pneumonitis 
2 
1st occurrence: hold 
2nd occurrence: discontinue 
1st occurrence: hold 
2nd occurrence or if > 14 days: discontinue 
3-4 
Discontinue 
Discontinue 
Creatinine elevation 
2 
Hold 
Hold. Discontinue if > 7 days 
3 
Hold 
Hold. Discontinue if > 7 days 
4 
Discontinue 
Discontinue 
Rash or other skin toxicity 
2 
Hold 
Continue. Hold if > 7- 14 days 
 
3 
Hold 
Hold 
 
4 
Discontinue 
Discontinue 
Neurological toxicity 
2 
Continue 
Hold 
3-4 
Hold 
Discontinue 
Hypotension, severe 
dehydration, shock out of 
proportion to current 
illness or suspected 
adrenal crisis 
3 
Hold. Dose reduction 
Hold 
4 
Discontinue 
Discontinue 
Fatigue 
2 >6 
weeks 
3 
Dose reduction 
Grade 2: continue 
Grade 3: hold 
Myocarditis  
2 
Hold 
Hold 
3-4 
Discontinue 
Discontinue 
All other drug-related non-
hematologic toxicity 
3 or 
Severe 
1st occurrence: hold 
2nd occurrence: dose reduction 
Hold 
4 
Discontinue# 
Discontinue# 
Hold = hold until retreatment criteria are met (Section 3.6) 
Dose reduction = reduce dose by one dose level in following cycle (Section 3.7) 
Discontinue = permanently discontinue that investigational product 
* Adrenal insufficiency requires discontinuation of nivolumab regardless of control with hormone replacement 
# Subjects may continue treatment for transient Grade 4 toxicity (such as electrolyte imbalances ≤ 72h, amylase or lipase increase) 
not associated with clinical sequelae after discussion with the Apexigen Medical Monitor (or designee). 
 
Dose reductions for APX005M are defined in Table 5. Subjects requiring more than 2 dose 
reductions or a dose reduction below DL1, must discontinue APX005M.  
Table 5: 
Modified DLs for APX005M Following Qualifying Suspected Adverse 
Reactions 
Dose Level 
(mg/kg) 
DL1 
(0.03) 
 
 
DL2 
(0.1) 
 
 
DL2a 
(0.2) 
DL3 
(0.3) 
 
 
First Dose Reduction 
Discontinue 
0.06 
0.1 
0.2 
Second Dose Reduction 
Not applicable 
0.03 
0.06 
0.1 
 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
Amendment 4.0 
Date:  October 10, 2019 
Page 44 of 81 
3.8 
Duration of Treatment 
Subjects may continue to receive APX005M and nivolumab until any of the criteria in Section 
4.1 are met.  
Subjects with confirmed CR may continue combination therapy up to 8 cycles (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. 
4. Study Discontinuation
4.1 
Discontinuation of Subjects from Treatment
Subjects MUST discontinue receiving investigational product for any of the following reasons: 

Disease progression by RECIST 1.1, or disease progression following treatment beyond
progression (Section 4.1.1)

Death

Toxicity requiring discontinuation of both investigational products as outlined in the dose
modification guidelines (Section 3.7)

Failure to recover from a disease or treatment-related AE to baseline or ≤ Grade 1 within
12 weeks of last dose of investigational product (except Grade 2 alopecia and Grade 2
fatigue), unless the subject is benefiting from therapy and after discussion with and
approval by Apexigen Medical Monitor (or designee)

Failure to recover within 4 weeks of last dose of investigational product if AE is related
to infusion reaction/cytokine release

Inability to reduce corticosteroid to 10 mg or less of prednisone or equivalent per day
within 12 weeks of last dose of investigational product and after discussion with and
approval by Apexigen Medical Monitor (or designee)

Subject’s decision to withdraw for any reason from study treatment (subject withdraws
consent)

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.  


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 45 of 81 
 
 
Apexigen (or designee) must be notified within 24 hours if a subject is withdrawn from 
treatment. 
4.1.1 Treatment Beyond Progression 
Accumulating evidence indicates that patients with solid tumors treated with immunotherapy 
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 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 drug 
 Subject has stable ECOG performance status  
 Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., central nervous system 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 must 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 (Section 5) should be performed continuously, including tumor assessments as 
described in Section 5.5. 
Subjects will be discontinued from the treatment upon further evidence of disease progression, 
defined as a further increase in tumor burden as evidenced (as applicable) by a ≥5 mm increase 
in sum of measures of target or new target lesions, further increase in non-target or new non-
target lesions, or an increase in the number of new lesions, as described in the iRECIST 
guidelines by Seymour et al [31]. 
 
4.2 
Discontinuation of Subjects from Study 
Subjects who are withdrawn from both investigational products will enter the follow-up period 
unless treatment discontinuation is due to any of the following: 
 Subject death 
 Withdrawal of consent for all study procedures 
 Initiation of any anticancer therapy 
 Subject is lost to follow-up 
 Study termination by Apexigen 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 46 of 81 
 
 
For all subjects receiving investigational products, the subsequent anticancer therapy will be 
documented and response to that therapy, if possible. Once this information is collected, a 
subject is considered off-study. 
 
4.3 
Study Termination 
Apexigen has the right to terminate this study or a study site from participating in a 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 withdrawn from treatment, completed 
participation in the study, or are lost to follow-up. 
 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 47 of 81 
 
 
5. Treatment Study Assessments and Procedures 
5.1 
Time and Events Schedule 
Phase 1b 
Dose-escalation 
Screening 
Phase 
(within 
21 days 
prior to 
C1D1) 
Treatment Phase 
EOT 
(approx. 
21 days 
after last 
treatment) 
Follow-
up 
Cycles 1 & 2 
Cycles 3+ 
  
Day 
Procedure 
1 
2 
3 
8 
15
 
1 
 
8 
2nd 
Biopsy 
Written Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
 
X 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
X 
 
Vital Signsa 
X 
X 
X
X
X
X 
X 
X 
 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
ECOG Performance 
Status 
X 
X 
 
 
 
 
X 
 
 
X 
 
Serum Chemistryb 
X 
X 
X
X
X
X 
X 
X 
 
X 
 
Thyroid Function 
Testsb 
X 
 
 
 
 
 
X 
 
 
 
 
Hematology Testsb 
X 
X 
X
X
X
X 
X 
X 
 
X 
 
Coagulationb 
X 
X 
 
 
X
X 
X 
X 
 
X 
 
PK Blood Testsc 
 
X 
X
X
X
 
X 
 
 
 
 
Immune PDnd 
 
X 
X
X
X
 
X 
X 
X 
X 
 
Cytokinese 
 
X 
X
X
X
 
X 
X 
X 
X 
 
AEs and ConMeds 
 
X 
X
X
X
X 
X 
X 
 
X 
X 
Dosing Nivolumab 
 
X 
 
 
 
 
X 
 
 
 
 
Dosing APX005M 
 
X 
 
 
 
 
X 
 
 
 
 
Tumor Assessmentf 
X 
 
 
 
 
 
X 
 
 
 
X 
Archived or Fresh 
Tumor Submissiong 
X 
 
 
 
 
 
 
 
 
 
 
Fresh Tumor Biopsyh 
X 
 
 
 
 
 
 
 
X 
 
 
ADAi 
 
X 
 
 
 
 
X 
 
 
X 
 
Pregnancy Test (if 
applicable)j 
X 
 
 
 
 
 
Xj
 
 
 
 
Date of PD and 
Subsequent Therapy 
 
 
 
 
 
 
 
 
 
 
X 
~ 


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APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 48 of 81 
 
 
Abbreviations: ADA = anti-drug antibodies; AE = adverse event; APTT = activated partial thromboplastin time; 
C1D1 = Cycle 1 Day 1; ConMeds = concomitant medications; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EOT = end of treatment; ICF = informed consent form; INR = international 
normalized ratio; PD = progressive disease/disease progression; PDn = pharmacodynamics; PK = 
pharmacokinetics; PT = prothrombin time; WOCBP = women of childbearing potential. 
 
a Vital signs: Vital signs measured within 30 min prior to nivolumab dose and at the end of the infusion, within 30 
min prior to APX005M dose, end of the infusion, and 2 & 4 hours after infusion. All time points are ± 30 min 
b Serum chemistry, hematology and coagulation tests performed at the local laboratory. Thyroid function tests 
performed every other cycle starting with Cycle 3  
c Blood samples for PK analyses collected in Cycles 1 and 2 before APX005M administration and at end of 
infusion, 4, 24 (Day 2), 48 (Day 3), and 168 hours (Day 8) from start of the infusion in that cycle. In addition, 
predose and end of infusion blood samples on Cycles 3 and 4 will be collected 
d Blood samples for immune PDn collected in Cycles 1 and 2 before APX005M administration, and 24 (Day 2), 48 
(Day 3), and 168 hours (Day 8) from the start of the infusion in that cycle, in Cycles 3 and 4 before APX005M 
administration and 168 hours (Day 8), time of second biopsy (if applicable) and at the EOT visit  
e Blood samples for cytokines collected in Cycles 1 and 2 before APX005M administration, end of infusion, 4, 24 
(Day 2), 48 (Day 3), and 168 hours (Day 8) from the start of the infusion in that cycle, in Cycles 3 and 4 before 
APX005M administration and 168 hours (Day 8), time of second biopsy (if applicable) and at the EOT visit 
f Tumor assessment: will be performed within 21 days prior to start of investigational products and during 
Treatment Phase every 8 weeks ± 1 week. For subjects who discontinue treatment without documented PD, every 
effort should be made to continue monitoring their disease status by tumor imaging using the same schedule used 
while on treatment 
g Archived or fresh tumor block or minimum 12 unstained slides with tumor tissue should be obtained. Provision of 
archived or fresh tumor tissue for analysis is dependent upon the subject's eligibility and signing the designated 
ICFs 
h Fresh tumor core biopsies will be collected from consenting subjects prior to start of investigational products and 
prior to 1st scheduled tumor assessment. Selection of tumor lesions should not affect tumor assessment when 
feasible 
i Blood samples for anti-APX005M antibodies will be collected before dosing on Cycles 1, 2, 3, 4, and at the EOT 
visit 
j In WOCBP only, serum pregnancy test to be done within 7 days followed by a urine pregnancy test within 3 days 
of first dose of investigational product, or serum pregnancy test to be done within 3 days prior to first dose of 
investigational product. Pregnancy testing should be conducted every other cycle 
 
 


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Amendment 4.0 
 
Date:  October 10, 2019 
Page 49 of 81 
 
 
 
Phase 2 
Dose-expansion 
Screening 
Phase 
(within 21 
days prior to 
C1D1) 
Treatment Phase 
EOT 
 
(approx. 
21 days 
after last 
treatment) 
Follow- 
Up 
                                                 
Day 
Procedure 
 
1 
 
8 
2nd 
Biopsy 
Written Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
X 
 
Height 
X 
 
 
 
 
 
Weight 
X 
 
 
 
X 
 
Vital Signsa 
X 
X 
X 
 
X 
 
12-lead ECG 
X 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
ECOG Performance Status 
X 
X 
 
 
X 
 
Serum Chemistryb 
X 
X 
X 
 
X 
 
Thyroid Function Testsb 
X 
Xb 
 
 
 
 
Hematology Testsb 
X 
X 
X 
 
X 
 
Coagulationb 
X 
X 
X 
 
X 
 
Immune PDnc 
 
X 
X 
X 
X 
 
Cytokinesc 
 
X 
X 
X 
X 
 
AEs and ConMeds 
 
X 
X 
 
X 
X 
Dosing Nivolumab 
 
X 
 
 
 
 
Dosing APX005M 
 
X 
 
 
 
 
Tumor Assessmentd 
X 
 
 
 
 
X 
Archived or Fresh Tumor 
Submission (baseline)e 
X 
 
 
 
 
 
Optional Paired Fresh 
Tumor Biopsyf 
X 
 
 
X 
 
 
PK Blood Testsg 
 
X 
 
 
 
 
ADAh 
 
X 
 
 
X 
 
Pregnancy Test (if 
applicable)i 
X 
Xi 
 
 
 
 
Date of PD and Subsequent 
Therapy 
 
 
 
 
 
X 
 
Abbreviations: ADA = anti-drug antibodies; AE = adverse event; APTT = activated partial thromboplastin time; 
C1D1 = Cycle 1 Day 1; ConMeds = concomitant medications; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EOT = end of treatment; ICF = informed consent form; INR = international 
normalized ratio; PD = progressive disease/disease progression; PDn = pharmacodynamics; PK = 
pharmacokinetics; PT = prothrombin time; WOCBP = women of childbearing potential. 
 
a Vital signs: Vital signs measured within 30 min prior to nivolumab dose and at the end of the infusion, within 30 
min prior to APX005M dose and at the end of the infusion. All time points are ± 30min 
b Serum chemistry, hematology and coagulation tests performed at the local laboratory, within 24-48 hours of day 1 
for each cycle. Thyroid function tests performed every other cycle starting with cycle 3. INR only required at 
~ 


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APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 50 of 81 
 
 
screening and as clinically indicated thereafter. 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.  
c Blood samples for immune PDn and cytokines collected in Cycles 1 and 2 before APX005M administration, 168 
hours (Day 8) from the start of the infusion in that cycle, Cycle 3 Day 1, time of second biopsy (if applicable) and 
at the EOT visit. Additional blood samples for cytokines collected in cycles 1 and 2 at the end of infusion and 4 
hours after the start of infusion and for TCR/BCR on Cycle 3 preinfusion 
d Tumor assessment: will be performed within 21 days prior to start of investigational products and during 
Treatment Phase every 8 weeks ± 1 week. For subjects who discontinue treatment without documented PD, every 
effort should be made to continue monitoring their disease status by tumor imaging using the same schedule used 
while on treatment 
e Archived or fresh tumor block or minimum 12 unstained slides with tumor tissue should be obtained for baseline 
analysis. Provision of archived or fresh tumor tissue for analysis is dependent upon the subject's eligibility and 
signing the ICF. 
f Optional fresh paired tumor core biopsies will be collected from consenting subjects prior to start of 
investigational products and prior to 1st scheduled tumor assessment. The biopsy should not interfere with the 
RECIST 1.1 tumor assessment.  . 
g Blood samples for PK analyses collected every 3rd cycle (i.e., Cycles 1, 3, 6, 9, 12, etc) at predose and at end of 
infusion  
h Blood samples for anti-APX005M antibodies will be collected before dosing every 3rd cycle (i.e., Cycles 1, 3, 6, 9, 
12, etc) and at the EOT visit 
i In WOCBP only, serum pregnancy test to be done within 7 days followed by a urine pregnancy test within 3 days 
of first dose of investigational product, or serum pregnancy test to be done within 3 days prior to first dose of 
investigational product. Pregnancy testing should be conducted every other cycle 
 
5.2 
 Procedures by Visit 
5.2.1 Screening Phase 
The following procedures and investigations should be performed during the screening Phase 
(within 21 days prior to start of investigational product):  
 Obtain signed informed consent form (ICF) prior to any study specific procedures; 
enrollment in the study is defined as the signing the ICF 
 Verify study eligibility (inclusion/exclusion criteria)  
 Allocate a unique Subject Identification Number 
 Document type of tumor histology 
 Collect demographic and medical history information, including smoking history  
 Collect prior immunotherapy administration and response history (if applicable) 
including: 
o Date of first and last dose  
o The reason for discontinuation  
o Date of initial PD 
o Date of confirmed radiological PD 
o Confirmation of PD criteria that was met, i.e.: 
 ≥ 5mm further increase in sum of measures of target lesion 
 ≥ 5mm further increase in sum of measures of new lesion 
 further increase in the size of non-target lesion(s) 
 new non-target lesions  
 appearance of new lesion(s) when none have previously been recorded  
 increase in the number of new lesions 


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Amendment 4.0 
 
Date:  October 10, 2019 
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 all of the following  
 maintain > 20% increase in target lesion burden at confirmed PD 
scan relative to nadir (as per RECIST1.1)  
 target lesion burden at confirmatory PD scan greater than 90% of 
target lesion burden at uncomfirmed PD (uPD) scan (to account for 
intra-subject reader variability)  
 no disappearance of all new lesions 
o Date of clinical progression (if applicable) 
o Best overall response to prior PD-1/PD-L1 therapy 
 Perform a physical examination (including weight, height, and vital signs) and a 12-lead 
electrocardiogram 
 Determine ECOG performance status (Appendix A) 
 Laboratory evaluations: 
o serum chemistry 
o thyroid function tests 
o hematology 
o coagulation 
o urinalysis 
 Tumor assessment following RECIST 1.1 Guidelines 
 Submit archived or fresh tumor tissue for baseline 
 Collect and submit a tumor core biopsy from subjects who consent to optional paired 
biopsies. Selection of tumor lesions should not interfere with subsequent tumor 
assessments (RECIST), when feasible 
 Perform pregnancy test(s), if applicable 
5.2.2 Treatment Phase 
The following procedures and investigations should be performed during the Treatment Phase.  
Day 1: 
 Physical examination (including weight and vital signs)  
 Determine ECOG performance status (Appendix A) 
 Record AEs and concomitant medication 
 Laboratory evaluations (for Cycle 1, laboratory values from Screening Phase may be 
used if within 72 hours): 
o serum chemistry 
o thyroid function tests (every other cycle starting with cycle 3) 
o hematology 
o coagulation 
 Collect blood samples for PK, ADA, cytokines and iPDn at designated timepoints 
(Section 5.6) 
 Administer premedication 
 Administer nivolumab 
 Administer additional premedication (if applicable) 
 Administer APX005M 
 Phase 1b dose-escalation collect blood samples for PK, PDn, and cytokines according to 


Apexigen, Inc. 
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APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 52 of 81 
 
 
schedule in Section 5.6 
 Phase 2 dose-expansion collect blood samples for PDn, and cytokines according to 
schedule in Section 5.6 
 Check criteria for discharge from clinic (see Section 3.1) 
Days 2 and 3 of Cycles 1 & 2 Phase 1b: 
 Vital signs  
 Record AEs and concomitant medication 
 Laboratory evaluations: 
o serum chemistry 
o hematology 
 In Phase 1b dose-escalation collect blood samples for PK, PDn, and cytokines according 
to schedule in Section 5.6 
Day 8: 
 Vital signs  
 Record AEs and concomitant medication 
 Laboratory evaluations (all test may be performed up to 24 hour in advance): 
o serum chemistry 
o hematology 
o coagulation 
 Collect blood samples for PK, PDn, and cytokines according to schedule in Section 5.6 
Day 15 of Cycles 1 and 2 Phase 1b: 
 Vital signs  
 Record AEs and concomitant medication 
 Laboratory evaluations (all test might be performed up to 24 hour in advance): 
o serum chemistry 
o hematology 
o coagulation 
Tumor assessments: 
Tumor assessment will be performed within 21 days prior to start of investigational product and 
during Treatment Phase every 8 weeks ± 1 week. Tumor response (CR or PR) or PD should be 
confirmed ≥ 4 weeks later. 
Optional Second tumor core biopsy: 
From patients who have consented to the optional paired biopsy, fresh tumor core biopsies from 
the lesion selected at baseline will be collected prior to first scheduled tumor assessment (during 
Cycle 3, at approximately 7–8 weeks from first dose of investigational product).  
5.2.3 End of Treatment Visit 
End of treatment visit (EOT) should occur on Day 22 of the last cycle started or as soon as 
possible thereafter. The following procedures and investigations should be performed: 
 Physical exam (including weight and vital signs)  
 Determine ECOG performance status (Appendix A) 


Apexigen, Inc. 
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Date:  October 10, 2019 
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 Record AEs and concomitant medication 
 Laboratory evaluations (all tests can be performed up to 24 hour in advance): 
o serum chemistry 
o hematology 
o coagulation 
 collect blood samples for PDn, ADA, and cytokines 
5.2.4 Follow-Up 
Follow-up period begins after the EOT visit. For subjects who discontinue treatment without 
documented PD, every effort should be made to continue monitoring their disease status by 
tumor imaging using the same schedule used while on treatment. 
Subjects should be contacted approximately every 1 month for the first 3 months and every 3 
months thereafter to: 
 Collect information on subsequent therapy and response, if possible 
 Record the time of documented PD for subjects who discontinue treatment without 
documented PD and cannot have regular tumor assessments. 
 Collect information on SAEs, AEs with potential immunologic etiology and pregnancies. 
 
5.3 
Study Materials 
The following study materials will be provided at study start: 
 NCI-CTCAE version 4.03 
 APX005M and Nivolumab Investigator’s Brochures 
 Laboratory Manual for collection and handling of archived or fresh tumor tissue, fresh 
tumor core biopsies, PK, PDn, and cytokines samples 
 Pharmacy Manual 
 
5.4 
Safety Assessments  
5.4.1 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.  
ECOG performance status should be assessed at the time of the physical examination. 
At screening, a medical history will be obtained to capture relevant underlying conditions. 


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APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 54 of 81 
 
 
5.4.2 Vital Signs 
Vital sign measurements include blood pressure, pulse rate, respiration rate, and temperature. 
Subjects should be monitored during and after nivolumab and APX005M infusions for potential 
infusion reactions. Vital signs will be measured: 
 within 30 minutes prior to nivolumab dose 
 at the end of the nivolumab infusion 
 within 30 minutes prior to APX005M dose (if APX005M infusion is delayed more than 
30 min after the completion of nivolumab infusion)  
 end of the APX005M infusion 
 4 hours after the end of APX005M infusion (Cycles 1 and 2 in Phase 1b and as clinically 
indicated in Phase 2). 
All time points are ± 30 minutes. At the Investigator’s discretion, vital sign monitoring may be 
extended beyond the time points specified. Additional measures should be performed as 
clinically indicated. 
5.4.3 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. 
5.4.4 Laboratory Tests 
All laboratory tests (e.g., serum chemistry, hematology, coagulation) will be performed at local 
laboratories. 
 
5.4.4.1 Serum Chemistry 
The laboratory tests included in the full chemistry panel are: 
 ALT 
 Albumin 
 Alkaline phosphatase 
 AST 
 Bicarbonate 
 Blood urea nitrogen 
 Calcium 
 Chloride 
 Creatinine 
 Creatinine clearance (calculated or measured) 
 Glucose 
 Lactate dehydrogenase 
 Magnesium 
 Phosphorous 
 Potassium 


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Amendment 4.0 
 
Date:  October 10, 2019 
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 Sodium 
 Total bilirubin 
 Total protein 
 Uric acid 
5.4.4.2 Thyroid Function Tests 
Thyroid function tests, to be collected every other cycle starting at Cycle 3, should include: 
 Thyroid stimulating hormone (TSH) 
 Triiodothyronine (T3) 
 Free Triiodothyronine (fT3) 
 Free thyroxine (FT4) 
5.4.4.3 Hematology 
The laboratory tests included in the hematology panel are: 
 Hemoglobin 
 Hematocrit 
 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 
5.4.4.4 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. 
5.4.4.5 Urinalysis 
Routine urinalysis will be performed at screening and whenever clinically indicated. 
5.4.4.6 Pregnancy Test 
For WOCBP, a pregnancy test is required for eligibility determination and should be performed 
at the local laboratory.  
This protocol defines a WOCBP as a sexually mature woman who: 
a) has not undergone a hysterectomy or bilateral oophorectomy, or 
b) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had 


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APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 56 of 81 
 
 
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 of first dose of investigational product, or a serum pregnancy test should be 
done within 3 days prior to first dose of investigational product. Pregnancy testing should be 
conducted every other cycle. More frequent pregnancy tests may be conducted if required per 
local regulations. 
 
5.5 
Efficacy Assessments 
Tumor assessment will be performed within 21 days prior to start of investigational products and 
during Treatment Phase every 8 ± 1 weeks. Complete or partial responses should be confirmed at 
a subsequent time point 4-5 weeks later. 
 
Tumor assessments for the purpose of establishing the Phase 2 primary endpoint will follow 
RECIST 1.1 guidelines. 
5.5.1 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 
[31]) will be used to assess tumor response for all treated subjects. 
Subjects with RECIST 1.1-defined PD 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 4.1.1 and they don’t have confirmed PD as defined by iRECIST. Subjects that 
are deemed clinically unstable are not required to have repeat imaging for confirmation of PD.  
 
5.6 
Correlative Studies 
Correlative laboratory samples include whole blood, serum, and plasma samples collected for 
Pharmacokinetic, anti-drug antibodies, cytokine and immune pharmacodynamic analyses will be 
obtained in relation to the APX005M infusion. Predose blood samples can be collected up to 72 
hours in advance of the scheduled APX005M infusion time. End of infusion samples should be 
collected within the 5 minutes after the completion of the infusion (before flushing the IV line). 
The 4 hour post start of infusion should be collected within ± 30minutes. The 24 hour post-start 
of APX005M infusion should be collected within ± 10 minutes (Phase 1b only); time points on 
Days 3 and 8 are ± 60 minutes based on start of APX005M infusion. If samples cannot be 
collected within the protocol-specified window they should be collected as soon as practicable.  
5.6.1 APX005M Pharmacokinetic Assessments  
Phase 1b: Blood samples will be collected from all subjects at (relative to APX005M infusion): 


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Date:  October 10, 2019 
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 Cycles 1 & 2: 
o Day 1: predose, end of infusion and 4 hours after the start of the infusion 
o Day 2: 24 hours after the start of the infusion 
o Day 3: 48 hours after the start of the infusion 
o Day 8: 168 hours after the start of the infusion 
 Cycles 3 & 4: 
o Day 1: predose and at end of infusion 
Phase 2: Predose and at end of APX005M infusion blood samples will be collected every 3rd 
cycle (i.e., Cycles 1, 3, 6, 9, 12, etc.). 
Details about collection procedure, volumes, and processing and shipping of PK samples are 
provided in the Laboratory Manual. 
5.6.2 Cytokines 
When time points are overlapping, blood samples for cytokine analysis should be collected at the 
same time with PK samples. Blood samples for cytokine analysis will be collected from all 
subjects at (relative to APX005M infusion): 
 Cycles 1 & 2: 
o Day 1: predose, end of infusion and 4 hours after the start of APX005M infusion 
o Day 2: 24 hours after the start of APX005M infusion (Phase 1b dose-escalation 
only) 
o Day 3: 48 hours after the start of the APX005M infusion (Phase 1b dose-
escalation only) 
o Day 8: 168 hours after the start of the APX005M infusion 
 Cycles 3 & 4 (Phase 1b dose-escalation only): 
o Day 1: predose 
o Day 8: 168 hours after the start of the APX005M infusion 
 Time of 2nd tumor biopsy when applicable  
 EOT visit 
Details about collection procedure, volumes, and processing and shipping of blood samples are 
provided in the Laboratory Manual. When time points are overlapping, blood samples for 
cytokines should be collected at the same time with blood samples for PK and immune PDn. 
Predose blood samples can be collected up to 72 hours in advance.  
Concentrations of cytokines including but not limited to interleukin (IL)-1, TNF-α, IL-12p70, IL-
6 will be determined in serum. 
5.6.3 Immune Pharmacodynamics 
When time points are overlapping, blood samples for immune PDn profile should be collected at 
the same time with PK samples. Blood samples for the immune PDn profile will be collected 
from all subjects at: 
 Cycles 1 & 2: 
o Day 1: predose 
o Day 2: 24 hours after the start of the APX005M infusion (Phase 1b dose-


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escalation only) 
o Day 3: 48 hours after the start of the APX005M infusion (Phase 1b dose-
escalation only) 
o Day 8: 168 hours after the start of the APX005M infusion 
 Cycles 3  
o Day 1: predose 
o Day 8: 168 hours after the start of the APX005M infusion (Phase 1b dose-
escalation only): 
 Cycle 4 (Phase 1b dose-escalation only): 
o Day 1: predose 
o Day 8: 168 hours after the start of the APX005M infusion 
 Time of 2nd tumor biopsy when applicable  
 EOT visit 
Details about collection procedure, volumes, and processing and shipping of PDn samples are 
provided in the Laboratory Manual. When time points are overlapping, blood samples for 
immune PDn should be collected at the same time with blood samples for PK and cytokines. 
Predose blood samples can be collected up to 72 hours in advance. 
Immune PDn testing might include but would not be limited to: 
Analysis of APC activation: non-manipulated peripheral blood lymphocytes will be analyzed 
using flow cytometry to measure cell surface immune markers of peripheral blood B cells and 
DCs, such as, but not limited to, CD19, CD123, CD11c, CD86, major histocompatibility 
complex class I and II, CD70, and CD54. Dead cells are excluded using 7-AAD and non-B cells 
or non-DC are excluded using a panel of mAb, all analyzed on a “dump” channel.  
Analysis of T-cell activation: together with complete blood count differentials, flow cytometry 
of peripheral blood will be used to measure both the percentages and absolute count (cells/mm3) 
of important T cell subsets defined by immunophenotyping, such as total CD3+ cells, CD3+ 
CD8+ T cells, CD3+ CD4+ T cells, and CD3+ CD4+ Foxp3+ regulatory T cells. For each subset, 
differentiation status (e.g. naïve, central memory, and effector memory) or activation status will 
be assessed using additional markers including CD45RA, CD45RO, CCR7, CD28, CD27, CD57, 
CD25, CD69, HLA-DR, CTLA4, Eomes, granzyme B, Ki-67, CD154, and PD-1. When possible, 
trends can be tracked in T cell subsets based on analysis of multiple post-treatment samples. NK 
cell subsets can also be assessed using CD16 and CD56, with CD69 as an activation marker. 
Analysis of T and/or B clonotype changes: the clonotypic composition of the T and/or B cell 
repertoire will be assessed by T and/or B cell receptor sequencing performed on PBMCs. T 
and/or B cell clonotype evolution will be assessed at baseline, one certain treatment cycles, and 
at EOT. 
5.6.4 APX005M Anti-drug Antibody 
In Phase 1b blood samples for anti-APX005M antibodies will be collected before dosing on 
Cycles 1, 2, 3, 4, and at the EOT visit. 


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In phase 2 blood samples for anti-APX005M antibodies will be collected before dosing every 3rd 
cycle (e.g., Cycles 1, 3, 6, 9, 12, etc.) and at the EOT visit. 
5.6.5 Tumor Biomarkers 
Archived or fresh tumor tissue will be obtained from all subjects in this study. Submission of 
formalin-fixed paraffin embedded tumor tissue sample blocks are preferred; if submitting 
unstained slides, the slides should be freshly cut and submitted to the testing laboratory within 14 
days from site slide sectioning date otherwise a new specimen will be requested.  
When possible, paired fresh tumor core biopsies will be collected from consenting subjects prior 
to first dose of investigational product and an optional second biopsy prior to first scheduled 
tumor assessment (during Cycle 3, at approximately 7–8 weeks from first dose of investigational 
product of investigational product). A minimum of 24 subjects (6 subjects with each 
cohort/group) must consent to fresh core biopsies.  
Samples might be analyzed by hematoxylin and eosin staining, Masson’s trichrome, and by 
immunohistochemistry for markers such as, but not limited to: 
 Immune markers (e.g., PD-L1, CD40, CD45, CD68, CD3, CD8, CD4, Foxp3, CD20, and 
myeloperoxidase) 
 Tumor markers (e.g., EpCAM, Ki-67, and cleaved caspase 3) 
 Vascular markers (e.g., CD31) 
 Stromal markers (e.g., collagen type I) 
If sufficient material is available, cell suspensions of tumor will be studied by flow cytometry to 
evaluate immune phenotyping. Tumor samples and peripheral blood may also be examined for 
gene expression (e.g. Quantigene), T and B cell receptor repertoire assessment by deep 
sequencing, and somatic tumor mutations. Data will be analyzed to examine specific hypotheses 
about whether drug response is related to alterations in gene regulation. These data will also be 
used to derive new hypotheses about mechanisms of drug response, resistance, and safety. 
 
 
6. Adverse Events 
The AE definitions and reporting procedures provided in this protocol comply with current 21 
Code of Federal Regulations Part 312.32. The Medical Monitor assigned by Apexigen (or 
designee) must promptly review all information relevant to the safety of the investigational 
product received from any source. The Investigator or appropriately qualified designee (e.g., a 
certified nurse practitioner or physician’s assistant properly listed on the Form FDA 1572) will 
carefully monitor each subject throughout the study for possible AEs.  
 


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6.1 
Definitions 
6.1.1 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. 
6.1.2 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 
lesser degree of certainty about causality than adverse reaction, which means any AE caused by a 
drug. 
6.1.3 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. 
6.1.4 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. 
6.1.5 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 


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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. 
6.1.6 Overdose 
For this trial, an overdose will be defined as APX005M >1 mg/kg body weight or nivolumab 
≥1000 mg total dose.  
It is expected that an overdose of APX005M will be associated with severe cytokine release 
syndrome. No specific information is available on the treatment of overdose of nivolumab. 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). 
 
6.2 
Adverse Event Classification 
6.2.1 Relationship to Investigational Products 
The Investigator will assign attribution of the possible association of the event with use of the 
investigational products, and this information will be entered into electronic data capture (EDC) 
system using the classification system listed below:  
Related to Investigational Product 
The event is suspected to be related if: 
 There is a clinically plausible time sequence between the AE onset and administration of 
investigational product 
 There is a biologically plausible mechanism for the investigational product to cause or 
contribute to the AE 
 The event improves or diminishes upon temporary interruption of the investigational 
product 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 Product 
The event is not suspected to be related if: 


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 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 product 
 The event is not related to the investigational product 
6.2.2 Severity 
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 6 should be used. 
Table 6: 
Toxicity Grading for AEs Not Covered in NCI-CTCAE (Version 4.03) 
Severity 
Description 
GRADE 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
GRADE 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of ADL* 
GRADE 3 
Severe; medically significant but not immediately life threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL** 
GRADE 4 
Life-threatening consequences; urgent intervention indicated 
GRADE 5 
Death related to AE 
Abbreviations: ADL = activities of daily living. Semi-colon indicates “or” within the description 
* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden 
 
Abnormal laboratory findings should be reported as AEs only if they are clinically relevant (see 
Section 6.3.6). 
AE will be reported at the highest grade experienced. AEs which completely resolve and then 
recur will be recorded as a new AE. 
6.3 
Collection and Reporting 
6.3.1 General AE Reporting 
All AEs will be collected from the time the subject receives any investigational product through 
30 days after receiving the last dose of investigational product, death, or initiation of new 
anticancer therapy, whichever occurs first. SAEs and AEs with potential immunologic etiology 
will be recorded up to 100 days and pregnancies up to 120 days after the last dose of 
investigational product, death, or initiation of new anticancer therapy, whichever occurs first. 
Events that occur after the subject signs the informed consent but prior to the first dose of 
investigational product will be recorded as past medical history; events that start after the first 
dose of investigational product will be recorded as AEs. In addition, the Investigator should 
report any AEs that may occur after this time period which are assessed to have a reasonable 
possibility of being associated with investigational products. 


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All AEs must be promptly documented on the AE eCRF. The minimum information required for 
each AE includes event, duration (start and end dates), start time (for events occurring within 48 
hours after the start of APX005M infusion) severity, seriousness, causality to investigational 
product, action taken, and outcome. Whenever possible, reporting specific diagnosis is preferred 
when reporting AEs in the AE eCRF rather than reporting individual signs and symptoms except 
for infusion related reactions and cytokine release syndrome.  
All AEs that are considered related to investigational products must be followed to resolution, 
stabilization, until improvement is not expected, 30 days after receiving the last dose of 
investigational product, death, or initiation of new anticancer therapy, whichever occurs first. 
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 product should have a comment in the source file by the Investigator that the 
event has stabilized or is not expected to improve. 
The Investigator is responsible for evaluating all AEs, obtaining supporting source documents, 
and determining that documentation of the event is adequate. The Investigator may delegate 
these duties to subinvestigators and must ensure that these subinvestigators are qualified to 
perform these duties under the supervision of the Investigator and that they are listed on the FDA 
Form 1572. 
6.3.2 Disease Progression 
Disease progression will be documented in an eCRF intended to capture such information. Signs 
and symptoms related to disease progression should be reported in the appropriate eCRF as an 
AE or as a SAE if applicable. Verbatim terms such as “disease progression,” “progressive 
disease,” etc. should not be reported as AEs or SAEs unless the Investigator considers the 
progression to be atypical, accelerated, or caused by the investigational products. Similarly, 
death occurring as a result of disease progression should be reported on the eCRF intended to 
capture death information and should not be reported as an SAE. 
 
6.3.3 Serious AEs or Serious SARs 
Apexigen (or designee) must be notified of the occurrence of any SAE/SSAR within 24 hours of 
Investigator’s knowledge of the event. The SAE/SSAR will be reported by completing and 
submitting the SAE/SSAR report form by: 
Email:  DrugSafety002@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 


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(IRB)/Independent Ethics Committee (IEC). The sponsor may request additional source 
documentation pertaining to the SAE/SSAR from the investigational site. If a subject is 
permanently withdrawn from the study due to an SAE/SSAR, this information must be included 
in the initial or follow up SAE/SSAR report in the eCRF. 
The sponsor is responsible for notifying the appropriate health authorities of serious and 
unexpected SAR (SUSAR) through expedited IND safety reports (ISR) in accordance with 
applicable laws and regulations. 
6.3.4 Handling of Expedited Safety Reports 
Apexigen (or designee) will notify Investigators of all ISRs. Upon receiving an ISR from 
Apexigen (or designee), the Investigator must review and retain the ISR with the Investigator’s 
Brochure. Where required by local regulations or when there is a central IRB/IEC for the study, 
Apexigen (or designee) will submit the ISR to the appropriate IRB/IEC. The Investigator and 
IRB/IEC will determine if the informed consent requires revision. The Investigator should also 
comply with the IRB/IEC procedures for reporting any other safety information. 
6.3.5 Non-serious AEs 
The collection of AE information begins after subject’s written consent to participate in the 
study: AEs that occur after consent, but prior to the first dose should be recorded as Medical 
History. If an ongoing AE changes in its intensity or in its perceived relationship to 
investigational product, a new AE entry for the event should be completed. AEs should be 
followed to resolution, stabilization, a minimum of 30 days after the discontinuation of the 
investigational product, or reported as SAEs if they become serious. 
6.3.6 Laboratory Test Abnormalities 
Laboratory test values captured as part of the study should be recorded on the appropriate pages 
of the eCRF. Laboratory abnormalities that meet any of the following criteria will also be 
captured on the AE or SAE reporting eCRF page as appropriate: 
 Require the subject to have any of the investigational products discontinued, delayed, or 
interrupted 
 Require the subject to receive specific corrective therapy 
 Are clinically significant 
 Meet the definition of an SAE/SSAR. 
 
6.4 
Pregnancy 
Subjects will be instructed to notify the Investigator as soon as possible after becoming pregnant 
or learning of the pregnancy of a partner. If a subject or partner of a subject becomes pregnant 
during treatment or up to 120 days following the last study drug administration, the Investigator 
will notify Apexigen (or designee) within 24 hours of learning of the pregnancy.  


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If the subject becomes pregnant while receiving investigational product, the investigational 
product will be permanently discontinued. Exceptions to the investigational product 
discontinuation may be considered for life-threatening conditions only after consultation with the 
sponsor. 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. 
 
 
7. Statistics 
7.1 
 Sample Size Determination  
This is a Phase 1b-2, study. The sample size for the Phase 1b dose-escalation cannot be precisely 
estimated but depends upon the observed toxicities. Cohorts of 3 to 6 subjects will be treated at 
each DL during dose escalation portion of the study. It is anticipated that approximately 18 
subjects will be treated in this portion of the study depending on the actual rate of DLTs. 
Sample size for Phase 2 is calculated using the Simon optimal 2-stage design [32]: 
 Cohort 1 (inNSCLC): Assuming a false positive rate () of 0.1 (one-sided), a false 
negative rate () of 0.1, a response probability of poor drug (P0) of 22% and a response 
probability of good drug (P1) of 40%, first stage sample size (n1) is 24 and the maximum 
sample size (n) is 45 response evaluable subjects. In the first stage, if there are 5 or less 
responses in 24 subjects, the enrollment in this cohort will be stopped. Otherwise, if 6 or 
more responses are observed, 21 additional subjects will be accrued in Stage 2 for total of 
45. Enrollment may continue into Stage 2 while the planned number of subjects for Stage 
1 are followed for efficacy. By the end of Stage 2, if 13 or less responses are observed in 
45 subjects, then no further investigation is warranted. If 14 or more responses are 
observed, the null hypothesis will be rejected and true RR is 40%. 
The sample size of 45 subjects, provides 97% power to statistically test the null 
hypothesis of historical 6-month PFS rate (PFSR) of 60% (estimated for pembrolizumab 
in Keynote-024 [33]) versus the alternative hypothesis of 6-month PFSR rate of 80%. 
This calculation assumes exponential PFS, 1-sided 5% type I error rate, enrollment of 
subjects for 8 months with 6 months of follow-up prior to conducting the final analysis. 
 


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 Cohort 2 (PD1-MM): Assuming  of 0.1 (one-sided),  of 0.1, P0 5% and P1 of 20%, n1 
is 12 and n is 37 response evaluable subjects. In the first stage, if there are no responses 
in 12 subjects, the enrollment in this cohort will be stopped. Otherwise, if 1 or more 
responses are observed, 25 additional subjects will be accrued in Stage 2 for total of 37. 
Enrollment may continue into Stage 2 while the planned number of subjects for Stage 1 
are followed for efficacy. By the end of Stage 2, if 3 or less responses are observed in 37 
subjects, then no further investigation is warranted. If 4 or more responses are observed, 
the null hypothesis will be rejected and true RR is 20%. 
The sample size of 37 subjects, provides 92% power to statistically test the null 
hypothesis of historical 6-month PFSR of 19% (estimated for ipilimumab following 
nivolumab or pembrolizumab [34]) versus the alternative hypothesis of 6-month PFSR 
rate of 38%. This calculation assumes exponential PFS, 1-sided 5% type I error rate, 
enrollment of subjects for 8 months with 6 months of follow-up prior to conducting the 
final analysis. 
 Cohort 3 (PD1-NSCLC) Group A and Group B: Assuming  of 0.1 (one-sided),  of 0.1, 
P0 5% and P1 of 20%, n1 is 12 and n is 37 response evaluable subjects in each group. In 
the first stage, if there are no responses in 12 subjects, the enrollment in that group will 
be stopped. Otherwise, if 1 or more responses are observed, 25 additional subjects will be 
accrued in Stage 2 for total of 37 per group. Enrollment may continue into Stage 2 while 
the planned number of subjects for Stage 1 are followed for efficacy. By the end of Stage 
2, if 3 or less responses are observed in 37 subjects, then no further investigation is 
warranted. If 4 or more responses are observed, the null hypothesis will be rejected and 
true RR is 20%. 
The sample size of 37 subjects/group, provides 94% power to statistically test the null 
hypothesis of historical 6-month PFSR of 22% (estimated for chemotherapy regimens 
[35, 36]) versus the alternative hypothesis of 6-month PFSR rate of 43%. This calculation 
assumes exponential PFS, 1-sided 5% type I error rate, enrollment of subjects for 8 
months with 6 months of follow-up prior to conducting the final analysis. 
 
Accrual is expected to be completed within 24 months from study start. 
 
7.2 
Populations for Analyses 
All subjects receiving both investigational products will be included in the safety population. 
Subjects evaluable for DLT are defined as those who meet study eligibility criteria, receive the 
entire planned dose of APX005M and nivolumab and have follow-up for at least 21 days (i.e., 
subject does not come off study for reasons other than toxicity). 
Subjects evaluable for efficacy (tumor response) are defined as those who meet study eligibility 
criteria and have at least one on treatment (post baseline) tumor assessment. 
Subjects evaluable for PK are defined as those who have adequate APX005M serum 
concentration-versus-time data to allow proper estimation of PK parameters. 


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7.3 
Endpoint Definitions  
7.3.1 Primary Endpoint 
 Establish MTD (Phase 1b) 
 ORR (rate of CR and PR) by RECIST 1.1 in each cohort/group (Phase 2).  
7.3.2 Secondary Endpoints 
 Incidence and severity of AEs and specific laboratory abnormalities graded according to 
NCI-CTCAE, v4.03 
 6-month PFSR by cohort/group (Phase 2), defined as the proportion of subjects that did 
not have disease progression (by RECIST 1.1) or died due to any cause at 6 months from 
the first dose of investigational product 
 DOR (by RECIST 1.1) by cohort/group, defined as the time from the first evidence of 
confirmed PR or better to disease progression or death due to any cause  
 PFS (by RECIST 1.1) by cohort/group, defined as time from first dose of investigational 
product to the earlier of PD or death due to any cause. 
7.3.3 Exploratory Endpoints 
 PK parameters of APX005M, including Cmax, time to maximum serum concentration 
(tmax), area under the curve at the last measurable time point (AUC0-t), and AUC0- 
 Presence and titer of anti-APX005M antibodies 
 Association between potential PDn markers and PK of APX005M; association between 
potential predictive biomarkers and anti-tumor activity 
 ORR  by iRECIST in each cohort/group (Phase 2) 
 DOR (by iRECIST) by cohort/group, defined as the time from the first evidence of 
confirmed PR or better to disease progression or death due to any cause  
 PFS (by iRECIST) by cohort/group, defined as time from first dose of investigational 
product to the earlier of PD or death due to any cause 
 
7.4 
Analyses 
7.4.1 Demographics and Baseline Characteristics  
Demographics and baseline characteristics by cohort/group will be summarized using descriptive 
statistics. 
7.4.2 Safety Analyses 
Safety will be assessed through summaries of DLT, AEs, changes in 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. 


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The MTD is maximum dose for which <33% of DLT-evaluable subjects experience a DLT. 
The RP2D will be taking into account the MTD of APX005M (if applicable), as well as the 
nature, severity and causal relationship for all AEs. Prior to establishing the RP2D all subjects 
enrolled in the phase 1 portion of the study must be followed until PD, study discontinuation due 
to toxicity or at least 2 cycles. 
7.4.3 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/group and for each tumor assessment method. Additional details will 
be provided in the Statistical Analysis Plan. 
7.4.4 Pharmacokinetic Analyses  
Blood samples will be collected from all subjects for determination of serum concentrations of 
APX005M at time points specified in Section 5.6.1.  
PK parameters of APX005M will be determined using model-independent methods. The 
following parameters will be calculated whenever practical: 
 
Parameter 
Description 
tmax 
Time from the start of dosing at which the maximum concentration was observed.
Cmax 
Maximum observed concentration.
Cmax/D 
Dose-normalized Cmax.
AUC0–t 
Area under the concentration versus time curve from the start of dose administration to 
the last quantifiable point within the dosing interval.
AUC0– 
Area under the concentration versus time curve for the dosing interval, using the 
trapezoidal rule. 
AUC0–/D 
Dose-normalized AUC0–.
 
When the concentration-time data permit, the slope of the terminal phase of each individual 
concentration versus time curve (λz) will be determined by log-linear regression for the first and 
third doses, and the following additional parameters will be estimated.  
 
Parameter 
Description 
t1/2 
Terminal half-life. 
AUC0– 
Area under the concentration versus time curve from the start of dose administration to 
infinity, using the trapezoidal rule (first dose only).
CL 
Total body clearance, calculated as D/AUC0– (first dose only). 
Vz 
Terminal volume of distribution, calculated as CL/λz (first dose only). 
 
Steady-state achievement will be assessed by comparing predose and end-of-infusion 
concentrations on Cycles 2, 3, and 4. Accumulation on Cycle 3 will be assessed by comparing 
AUC0– and Cmax of the third and first doses and comparing predose concentrations of Cycles 3 
to the predose sample of Cycle 2. Pharmacokinetic linearity will be examined by examining the 


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relationship between exposure (Cmax, Cmax/D, AUC0–, and AUC0–/D) with dose on the first and 
third doses. 
Individual and mean serum concentration-time profiles will be tabulated separately for each dose 
by subject and nominal sampling time and summarized using descriptive statistics (mean and 
standard deviation). Pharmacokinetic parameters will also be summarized using descriptive 
statistics (mean and standard deviation) by dose and dosing day.  
7.4.5 Exploratory Analyses 
Potential tumor and blood biomarkers identified in the exploratory biomarker research may be 
correlated with PK, safety, and efficacy outcomes. 
 
 
8. Administrative Section 
8.1 
Ethics 
8.1.1 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:  
1. The consent form must be revised and submitted to the IRB/IEC for review and 
approval/favorable opinion 
2. The revised consent form must be used to obtain consent from subjects currently enrolled 
in the study if they are affected by the amendment 
3. The new consent form must be used to obtain consent from new subjects prior to 
enrollment 
If the revision is an administrative letter, Investigators must inform their IRB/IEC. 
8.1.2 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.  


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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. 
8.1.3 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 
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.  


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


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 72 of 81 
 
 
If necessary, Apexigen (or designee) will provide investigational staff training prior to study 
initiation. Training topics will include, but are not limited to, GCP, AE reporting, study details 
and procedure, study documentation, informed consent, and enrollment of WOCBP. 
 
8.2 
Data Collection and Handling 
8.2.1 Case Report Forms 
As part of the responsibilities assumed by participating in the study, the Investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol. The Investigator agrees to maintain accurate eCRFs and source documentation as part 
of the case histories. These source documents may include subject diaries, laboratory reports, and 
other documents. Apexigen (or designee) will supply the eCRF, which will be completed in 
English. 
Data collection will involve the use of the EDC system, to which only authorized personnel will 
have access. 
The Investigator or designee must enter all results collected during the clinical study into eCRFs. 
Guidelines for completion of eCRFs will be reviewed with study site personnel at the site 
initiation visits. Investigators are responsible for approval of the entered/corrected data. Detailed 
instructions may be found in the other study-specific documents. 
All entries made on the eCRF must be verifiable against source documents. In addition to 
periodic monitoring occurring within the system by study monitors, programmatic edit checks 
and data listings will be used to review the data for completeness, logic, and adherence to study 
protocol. As a result of this monitoring and these checks and queries may be electronically issued 
to the clinical study sites and electronically resolved by those sites. 
All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records. Also, data will be stored and 
evaluated in such a way as to assure subject confidentiality in accordance with the legal and 
regulatory requirements applying to protected health information. Study records (e.g., copies of 
eCRFs and regulatory documents) will be retained at the study site, along with adequate source 
documentation. The study file and all source data should be retained for the time period required 
by applicable regulatory requirements and will not be destroyed until written notification is given 
by Apexigen (or designee) for destruction. 
 
8.3 
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 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 73 of 81 
 
 
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. 
 
 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 74 of 81 
 
 
 
9. 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  
AR 
Adverse reaction 
AST 
Aspartate aminotransferase 
AUC0‒ 
Area under the curve extrapolated to infinity 
AUC0‒t 
Area under the curve at the last measurable time point 
BCR 
B-cell receptor 
BRAF 
Human proto-oncogene encoding B-Raf protein 
CD40 
Cluster of differentiation 40 
CD40L 
CD40 ligand 
Cmax 
Maximum serum concentration 
CNS 
Central nervous system 
CR 
Complete response 
CTLA-4 
Cytotoxic T-lymphocyte associated protein 4 
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 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IL 
Interleukin 
IND 
Investigational New Drug application 
INR 
International normalized ratio  


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 75 of 81 
 
 
Abbreviation 
Definition 
inNSCLC 
Immunotherapy naïve NSCLC 
IRB 
Institutional Review Board 
iRECIST 
Immune-related RECIST Modified RECIST 1.1 for Immune-based Therapeutics 
ISR 
IND safety report 
IV 
Intravenous 
Kd 
Dissociation constant 
mAb 
Monoclonal antibody 
mL 
Milliliter 
MTD 
Maximum tolerated dose 
MM 
Unresectable or metastatic melanoma 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NOAEL 
No observed adverse effect level 
NSCLC 
Non-small cell lung cancer 
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 
PD1-MM 
MM with progressive disease during treatment with anti-PD-1/PD-L1 
PDn 
Pharmacodynamics 
PK 
Pharmacokinetics 
PFS 
Progression-free survival 
PFSR 
Progression-free survival rate 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RCC 
Advanced renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SAR 
Suspected adverse reaction 
SSAR 
Serious suspected adverse reaction 
TCR 
T-cell receptor 
TKI 
Tyrosine kinase inhibitor 
tmax 
Time to maximum serum concentration 
TNFR 
Tumor necrosis factor receptor 
ULN 
Upper limit of normal 
WOCBP 
Women of childbearing potential 
 
 
 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 76 of 81 
 
 
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. 
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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. 
Barr TA, Heath AW. Functional activity of CD40 antibodies correlates to the position of binding 
relative to CD154. Immunology 2001;102:39–43. 
16. 
APX005M Investigator's Brochure. 
17. 
Freeman FJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunohibitory receptor by a novel 
B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 
192(7): 1027-34. 
18. 
Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its ligands 
in regulating autoimmunity and infection. Nature Immunol. 2007;8:237-45. 
19. 
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in 
solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412-20. 
20. 
Nivolumab Investigator’s Brochure. 
21. 
Sharma P, Allison JP. The future of immune checkpoint therapy. Science 2015; 348:56-61 
22. 
Bu X, Mahoney KM, Freeman GJ. Learning from PD-1 Resistance: New Combination Strategies. 
Trends Mol Med. 2016; 22:448-51. 
23. 
van Kooten C, Banchereau J. CD40-CD40 ligand. J Leukoc Biol 2000;67:2–17. 


Apexigen, Inc. 
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APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 77 of 81 
 
 
24. 
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. 
25. 
Vonderheide RH, Burg JM, Mick R, Trosko JA, Li D, Shaik MN, Tolcher AW, Hamid O. Phase I 
study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in 
patients with advanced solid tumors. Oncoimmunology 2013;2:e23033. 
26. 
Beatty GL, Torigian DA, Chiorean EG, Saboury B, Brothers A, Alavi A, Troxel AB, Sun W, 
Teitelbaum UR, Vonderheide RH, O'Dwyer PJ. A phase I study of an agonist CD40 monoclonal 
antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic 
ductal adenocarcinoma. Clin Cancer Res 2013;19:6286–95. 
27. 
Zippelius A, Schreiner J, Herzig P, Müller P. Induced PD-L1 expression mediates acquired 
resistance to agonistic anti-CD40 treatment. Cancer Immunol Res 2015;3:236-44. 
28. 
Winograd R, Byrne KT, Evans RA, Odorizzi PM, Meyer AR, Bajor DL, Clendenin C, Stanger 
BZ, Furth EE, Wherry EJ, Vonderheide RH. Induction of T-cell Immunity Overcomes Complete 
Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma. 
Cancer Immunol Res 2015;3:399-411. 
29. 
Luheshi NM, Coates-Ulrichsen J, Harper J, Mullins S, Sulikowski MG, Martin P, Brown L, 
Lewis A, Davies G, Morrow M, Wilkinson RW. Transformation of the tumour microenvironment 
by a CD40 agonist antibody correlates with improved responses to PD-L1 blockade in a mouse 
orthotopic pancreatic tumour model. Oncotarget 2016;7:18508-20. 
30. 
Ngiow SF, Young A, Blake SJ, Hill GR, Yagita H, Teng MW, Korman AJ, Smyth MJ. Agonistic 
CD40 mAb-driven IL-12 reverses resistance to anti-PD1 in a T cell-rich tumor. Cancer Res 
2016;76:6266-77. 
31. 
 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. 
doi:10.1016/S1470-2045(17)30074-8. 
32. 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1-10. 
33. 
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, et al. Pembrolizumab versus 
Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 
2016;375(19):1823-1833. 
34. 
Bowyer S, Prithviraj P, Lorigan P, Larkin J, McArthur G, et al. Efficacy and toxicity of treatment 
with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-
PD-1 therapy. Br J Cancer. 2016;114(10):1084-9. 
35. 
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, et al. Comparison of four 
chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346(2):92-
8. 
36. 
Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, et al. Randomized phase III trial 
of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated 
with chemotherapy. J Clin Oncol. 2004;22(9):1589-97. 
 
 
 
 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 78 of 81 
 
 
APPENDIX A: Eastern Cooperative Oncology Group Performance Scale 
 
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 
 
 
 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 79 of 81 
 
 
APPENDIX B: Methods of Contraception Europe only  
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 
 
 
 


Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
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Apexigen, Inc. 
CONFIDENTIAL 
APX005M-002 Clinical Protocol 
APX005M 
 
Amendment 4.0 
 
Date:  October 10, 2019 
Page 81 of 81 
 
 
SIGNATURE PAGE OF THE INVESTIGATOR 
 
 
 
 
 
 
 
Title: 
 
A Study to Evaluate the Safety and Efficacy of the CD40 
Agonistic Antibody APX005M Administered in Combination with 
Nivolumab in Subjects with Non-small Cell Lung Cancer and 
Subjects with Metastatic Melanoma 
Protocol Number: APX005M-002 
Version: Amendment 4.0 
Date: October 10, 2019 
EudraCT Number: 2018-003866-14 
Sponsor: Apexigen, Inc. 
 
 
 
I have read and agree to the protocol of the above-mentioned clinical study.  I am aware of my 
responsibilities as an Investigator under the 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 
 

SAP_001.pdf: 
 
 
 
 
 
Statistical Analysis Plan Version 2.0 
 
Title of Protocol: A Study to Evaluate the Safety and Efficacy of 
the CD40 Agonistic Antibody APX005M Administered in 
Combination with Nivolumab in Subjects with Non-Small Cell 
Lung Cancer and Subjects with Metastatic Melanoma 
 
Date of SAP: 04-February-2021 
NCT03123783  


Page 1of30 
-;Pivotal 
STATISTICAL ANALYSIS PLAN 
Study Code: 
APXOOSM-002 
Protocol Version: 
Amendment 4 
Protocol Date: 
1 O-Oct-2019 
A Study to Evaluate the Safety and Efficacy of the CD40 Agonistic Antibody APX005M 
Administered in Combination with Nivolumab in Subjects with Non-Small Cell Lung Cancer and 
Subjects with Metastatic Melanoma 
ln~~;ati~nal ~;~;~~;-i-;P~00-5M and Nivolumab 
_i_n~~c_:iti~~- ~~~ie_~ ----
[ ~o~~~rri_~1 _ce11 __ ~~~g-~:ncer an~_ Metastat~c- ~~~~o~a 
EudraCT No 
I 2018-003866-14 
P~~~ of ~tud~ = 
-1 P~~~~ ~":2 -=-- _ 
.. ·--------------=--~---_:_~~~~--~--
rponsor 
d dd 
) 
I Apexigen Inc., 75 Shoreway Road, Suite C, San Carlos, CA 94070, USA. 
~;.;;~;~~;~~enyj~v;:: ~,;ta~D, P~~-=-···· -----· .. ·_ --=-~-----
Approved by 
Signature: 
Name: Tho as Jahn, MD/PhD 
Role: VP Clinical Development 
Pages N° 
30 
· SAP Version 
2.0 
1-SAP D~t~ -- ----1---o··-4·--F·--e-b---2--0·2--1-------
-- ----- ------ ---·"------·--···-·-------··-
APXOOSM-002 
SAP version 2.0 
04-Feb-2021 
Confidential and Property of Pivotal S.L.U 


Page 2 of 30 
APX005M-002 
SAP version 2.0 
04-Feb-2021 
 
 
Confidential and Property of Pivotal S.L.U 
 
 
 
 
Statement: 
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, and all regulatory 
guidelines. 
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. 
 


Page 3 of 30 
APX005M-002 
SAP version 2.0 
04-Feb-2021 
 
 
Confidential and Property of Pivotal S.L.U 
 
 
 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE 
CHANGES COMPARED TO PREVIOUS STATISTICAL ANALYSIS PLAN (SAP) VERSIONS 
 
 
Previous SAP 
section 
Change 
V1.0 --30MAY2016 
N.A. 
V2.0 –01FEB2021 
Exploratory, sensitivity and subgroups analyses requested by the Sponsor are included 
Phase 2 TFLs 
 
 


Page 4 of 30 
APX005M-002 
SAP version 2.0 
04-Feb-2021 
 
 
Confidential and Property of Pivotal S.L.U 
 
 
Table of contents 
Changes compared to previous statistical analysis plan (SAP) versions 
3 
1. List of Abbreviations ........................................................................................................ 6 
1.1 Abbreviations 
6 
2. Introduction ....................................................................................................................... 8 
2.1 Background & Rationale 
8 
2.2 Study Objectives and Analyses 
9 
2.2.1 Primary Objective 
9 
2.2.2 Secondary Objectives 
9 
2.2.3 Exploratory Objectives 
9 
2.2.4 Additional exploratory efficacy analyses (Phase 2 only) 
9 
2.2.5 Subgroup efficacy analyses (Phase 2 only) 
9 
2.2.6 Sensitivity efficacy analyses (Phase 2 only) 
10 
2.3 Study Design 
10 
2.3.1 Eligibility and Randomization 
11 
2.3.2 Eligibility Criteria 
11 
2.3.3 Withdrawals 
14 
2.3.4 Study treatment 
15 
2.3.5 Replacement of Patients 
15 
3. Study Populations .......................................................................................................... 15 
3.1 Screened Population 
15 
3.2 Safety Population 
15 
3.3 DLT-Evaluable Population 
15 
3.4 Efficacy Population 
15 
4. DEFINITION of Study Endpoints and Derived Variables ............................................. 16 
4.1 Baseline and Demographics Characteristics 
16 
4.2 Efficacy Endpoint 
16 
4.3 Safety Endpoints 
17 
4.3.1 Extent of exposure and compliance 
17 
4.4 Other Derived Variables 
18 
5. General Statistical Methods ........................................................................................... 19 
5.1 Sample Size 
19 
5.2 Disposition of Study Participants 
20 
5.3 Protocol Deviations 
20 
5.4 Summary of Statistical Methods 
20 
5.4.1 Demographics, Other Baseline Characteristics and Medication 
21 
5.4.2 Efficacy Analyses 
23 
5.4.3 Safety Analyses 
23 
5.4.4 Exploratory Analyses 
25 


Page 5 of 30 
APX005M-002 
SAP version 2.0 
04-Feb-2021 
 
 
Confidential and Property of Pivotal S.L.U 
 
 
5.4.5 Interim Analyses 
26 
5.4.6 Missing Data 
26 
5.4.7 Reporting Conventions 
26 
5.4.8 Study Timelines 
27 
5.4.9 Technical Details 
27 
5.4.10 Software 
27 
6. References ...................................................................................................................... 28 
7. Tables, Listings and Figures.......................................................................................... 29 
List of Figures 
Figure 1 APX005M-002 Study Design 
11 
 
 


Page 6 of 30 
APX005M-002 
SAP version 2.0 
04-Feb-2021 
 
 
Confidential and Property of Pivotal S.L.U 
 
 
1. 
LIST OF ABBREVIATIONS 
1.1 
Abbreviations 
Abbreviation 
Description 
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 
AR 
Adverse reaction 
AST 
Aspartate aminotransferase 
AUC0‒∞ 
Area under the curve extrapolated to infinity 
AUC0‒t 
Area under the curve at the last measurable time point 
BCR 
B-cell receptor 
BOR 
Best overall response 
BRAF 
Human proto-oncogene encoding B-Raf protein 
CD40 
Cluster of differentiation 40 
CD40L 
CD40 ligand 
Cmax 
Maximum serum concentration 
CNS 
Central nervous system 
CR 
Complete response 
CTLA-4 
Cytotoxic T-lymphocyte associated protein 4 
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 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IL 
Interleukin 
IND 
Investigational New Drug application 


Page 7 of 30 
APX005M-002 
SAP version 2.0 
04-Feb-2021 
 
 
Confidential and Property of Pivotal S.L.U 
 
 
Abbreviation 
Description 
INR 
International normalized ratio 
inNSCLC 
Immunotherapy naïve NSCLC 
IRB 
Institutional Review Board 
iRECIST 
Immune-related RECIST Modified RECIST 1.1 for Immune-based Therapeutics 
ISR 
IND safety report 
IV 
Intravenous 
Kd 
Dissociation constant 
mAb 
Monoclonal antibody 
mL 
Milliliter 
MTD 
Maximum tolerated dose 
MM 
Unresectable or metastatic melanoma 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NOAEL 
No observed adverse effect level 
NSCLC 
Non-small cell lung cancer 
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 
PD1-MM 
MM with progressive disease during treatment with anti-PD-1/PD-L1 
PDn 
Pharmacodynamics 
PK 
Pharmacokinetics 
PFS 
Progression-free survival 
PFSR 
Progression-free survival rate 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RCC 
Advanced renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SAR 
Suspected adverse reaction 
SSAR 
Serious suspected adverse reaction 
TCR 
T-cell receptor 
TKI 
Tyrosine kinase inhibitor 
Tmax 
Time to maximum serum concentration 
TNFR 
Tumor necrosis factor receptor 
ULN 
Upper limit of normal 
WOCBP 
Women of childbearing potential 
 
 


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APX005M-002 
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Confidential and Property of Pivotal S.L.U 
 
 
2. 
INTRODUCTION 
2.1 
Background & Rationale 
Among the promising approaches to activating therapeutic anti-tumor 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, 2, 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 and is believed that combination 
of such immunomodulatory agents could lead to a cure for cancer [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 and through the release of cytokines from activated 
APCs [7, 8][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 
patients [11, 12, 13, 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. Thus, the desired therapeutic CD40 agonist antibody should have these functionalities. 
 
 


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2.2 
Study Objectives and Analyses 
This statistical analysis plan describes the methods and statistical models to be applied for the generation 
of the statistical report. As a reference, the Amendment 4 of the protocol (dated on 10 October 2019) has 
been used in order to prepare this document. 
2.2.1 Primary Objective 
• 
Determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) of 
APX005M when given in combination with nivolumab (Phase 1b only) 
• 
Evaluate the overall response rate (ORR) by RECIST v1.1 in each cohort/group (Phase 2 only) 
2.2.2 Secondary Objectives 
• 
Evaluate safety of the APX005M and nivolumab combination by analysing the incidence and severity 
of AEs and specific laboratory abnormalities graded according to NCI-CTCAE, v4.03 
• 
Evaluate the 6-month progression-free survival (PFS) rate (PFSR) in each cohort/group (Phase 2 
only) 
• 
Evaluate duration of response (DoR) in each cohort/group by RECIST v1.1 (Phase 2 only) 
• 
Evaluate the median PFS by cohort/group by RECIST v1.1 (Phase 2 only) 
2.2.3 Exploratory Objectives 
• 
Determine the immune PDn of the APX005M and nivolumab combination 
• 
Determine the PK of APX005M 
• 
Assess incidence of APX005M ADA 
• 
Identify blood and/or tumor biomarkers that correlate with efficacy and/or resistance 
• 
Evaluate the ORR in each cohort/group by immune related RECIST (iRECIST) 
• 
Evaluate DoR and median PFS in each cohort/group by iRECIST 
 
Note: 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, association between 
PDn markers and PK, and association between biomarkers and anti-tumor activity. These analyses will 
be carried out by Apexigen, Inc. or a different provider. 
2.2.4 Additional exploratory efficacy analyses (Phase 2 only) 
Exploratory analyses of efficacy will be carried out including occurrences of unconfirmed responses: 
• 
ORR - including unconfirmed response (efficacy and safety population)  
• 
DoR - including unconfirmed response (efficacy and safety population) 
Exploratory analysis: Characterization of progressive disease. (efficacy population) 
2.2.5 Subgroup efficacy analyses (Phase 2 only) 
Subgroup analyses by prior therapy: 
• 
Subgroup analysis Cohort 1: Prior therapy - platinum-based vs other  
• 
Subgroup analysis Cohort 1: Prior therapy - anti-EGFRi+TKI vs other 


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• 
Subgroup analysis Cohort 2: Prior therapy - pembrolizumab vs. nivolumab 
• 
Subgroup analysis Cohort 2: Prior therapy - BRAF/MEK inhibition vs other 
• 
Subgroup analysis Cohorts 3A+3B: Prior therapy - pembrolizumab vs. nivolumab 
Subgroup analysis by LDH 
• 
Subgroup analysis Cohort 2: LDH baseline values above the upper normal range vs normal/lower 
Subgroup analysis by country 
• 
Subgroup Analysis by country: US vs. non-US 
2.2.6 Sensitivity efficacy analyses (Phase 2 only) 
Parameters of Response by RECIST v1.1 in the safety population: 
• 
ORR (RECIST v 1.1, safety population 
• 
DoR (RECIST v1.1, safety population 
2.3 
Study Design 
This is a Phase 1b-2 study. The study will include 2 parts. 
Phase 1b dose-escalation of APX005M: 
• 
Up to 4 dose levels of APX005M administered IV every 21 days 
• 
In combination with nivolumab 360 mg IV every 21 days 
• 
Participants with inNSCLC or PD1-MM 
 
Phase 2 dose-expansion (Simon optimal 2-stage design): 
• 
The RP2D dose of APX005M administered IV every 21 days in combination with nivolumab 360 mg 
IV 
• 
3 cohorts 
▪ Cohort 1: Participants with inNSCLC 
▪ Cohort 2: Participants with PD1-MM 
▪ Cohort 3: Participants with PD1-NSCLC 
 
• Group A: Participants with PD1-NSCLC with best response of progressive disease or with 
stable disease < 16 weeks while on previous PD-1/PD-L1 containing regimen 
• Group B: Participants with PD1-NSCLC with tumor response or with stable disease ≥ 16 
weeks while on previous PD-1/PD-L1 containing regimen 
Participants will be evaluated for tumor response approximately every 8 weeks following the first 
dose of investigational product. An ORR of at least 22% (6 out if 24 response evaluable participants) 
in the inNSCLC cohort and 5% (1 out if 12 response evaluable participants) in the PD1-MM cohort 
or PD1-NSCLC (Group A or B) is required in Stage 1 for that cohort to proceed to Stage 2. Enrollment 
may continue into Stage 2 while the planned number of participants for Stage 1 are followed for 
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Figure 1 APX005M-002 Study Design 
 
2.3.1 Eligibility and Randomization 
This is an open-label study, and there is no randomization or blinding needed. 
2.3.2 Eligibility Criteria 
2.3.2.1 
Phase-Specific Criteria 
Phase 1b: Participants that meet eligibility criteria for Phase 2 Cohorts 1 or 2 and all the general eligibility 
criteria. 
Phase 2 Cohort 1: Histologically or cytologically confirmed, immunotherapy naïve, metastatic or locally 
advanced non-small cell lung cancer not amenable to curative treatment. Participants may be treatment 
naïve or could have received one prior platinum-based chemotherapy for non-small cell lung cancer for 
any indication (adjuvant, part of combined modality therapy or for metastatic disease) within the past 3 
years. Participants with no or unknown activating mutation (e.g., EGFR, ALK, ROS) are eligible for this 
study. Participants with a documented activating mutation (e.g., EGFR, ALK, ROS) amenable to tyrosine 
kinase inhibitor therapy, must also have received the appropriate therapy and progressed. 
Phase 2 Cohort 2: Participants with histologically or cytologically confirmed unresectable or metastatic 
melanoma that had confirmed progressive disease during treatment with anti-PD-1/PD-L1 therapy. 
Participants with BRAF wild type or unknown status must have received only anti-PD-1/PD-L1 therapy. 
Participants with BRAF activating mutation could have also received a BRAF inhibitor and/or MEK 
inhibitor regimen prior to anti-PD-1/PD-L1 therapy. 
Confirmed PD during treatment with anti-PD-1/PD-L1 therapy should be documented by 2 consecutive 
tumor assessments at least 4 weeks apart (the second scan may be used as the baseline scan for this 
study if it was performed within the 21 days prior Cycle 1 Day 1). Participants should start study treatment 
no later than 8 weeks following the last dose of anti-PD-1/PD-L1 therapy. 


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Participants with ocular melanoma are excluded. 
Phase 2 Cohort 3: Participants with histologically or cytologically confirmed, metastatic or locally 
advanced NSCLC not amenable to curative treatment. Participants must have disease progression on 
an immediately preceding PD-1/PD-L1 containing regimen. Participants could have received no more 
than one platinum containing regimen, or if participants have a documented activating mutation (e.g. 
EGFR, ALK, ROS) amenable to tyrosine kinase inhibitor therapy, must also have received the appropriate 
therapy and progressed before the PD-1/PD-L1 containing regimen. 
Based on response to previous PD-1/PD-L1 containing regimen, participants will be enrolled in one of 
the following groups: 
• 
Group A: Participants with best response of progressive disease or with stable disease < 16 weeks 
• 
Group B: Participants with tumor response or with stable disease ≥16 weeks. 
If possible, confirmed PD during treatment with anti-PD-1/PD-L1 therapy should be documented by 
2 consecutive tumor assessments at least 4 weeks apart (the second scan may be used as the baseline 
scan for this study if it was performed within the 21 days prior Cycle 1 Day 1). Participants should start 
study treatment no later than 8 weeks following the last dose of anti-PD-1/PD-L1 containing regimen. 
2.3.2.2 
General Inclusion Criteria 
1. Subjects willing and able to provide written informed consent for this study 
2. Male or female ≥18 years old at time of consent 
3. Measurable disease by RECIST criteria v1.1 
4. ECOG performance status of 0 or 1 
5. Resolution of prior treatment-related toxicities to Grade 1 (check the protocol for some exceptions) 
6. Adequate organ function within 14 days of first dose of investigational product (check protocol for 
appropriate parameters guidelines)  
7. Women of childbearing potential (WOCBP) must have negative pregnancy test (check protocol for 
more details) 
8. WOCBP and males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception (check protocol for more details) 
9. Available archived or fresh tumor tissue sample for PD-L1 and other biomarker analysis 
10. 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. A minimum 
of 24 subjects (6 subjects with each cohort/group) must consent to fresh core biopsies. 
2.3.2.3 
General Exclusion Criteria 
1. Previous exposure to any immunomodulatory agents (check exceptions in the protocol) 
2. Second malignancy (solid or hematologic) within the past 3 years (check exceptions in the 
protocol) 
3. Active, known, clinically serious infections (≥ Grade 2 according to NCI-CTCAE v4.03) within the 
14 days prior to first dose of investigational product 
4. Use of systemic corticosteroids or other systemic immunosuppressive drugs within the 28 days 
prior to first dose of investigational product (except inhaled corticosteroids); the use of physiologic 
doses of corticosteroids may be approved after consultation with the Apexigen Medical Monitor 
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5. Major surgery within 4 weeks of first dose of investigational product 
6. Concurrent treatment with any anti-cancer agent, except for hormonal therapy and palliative 
radiation as clinically indicated unless approved by the Medical Monitor 
7. History of allogeneic bone marrow transplantation 
8. Uncontrolled diabetes or hypertension 
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 I 
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 life-threatening toxicity related to prior anti-PD-1/PD-L1 treatment for subjects with 
metastatic melanoma except those that are unlikely to re-occur with standard countermeasures 
(e.g. hormone replacement after adrenal crisis) 
13. History of sensitivity or allergy to mAbs or IgG 
14. Congestive heart failure (New York Heart Association Class III to IV), symptomatic ischemia, 
conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 
6 months prior to the first dose of investigational product 
15. History of any thromboembolic event within 3 months prior to first dose of investigational product 
or an active coagulopathy 
16. 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, 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 
17. Known human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection 
18. Has received a live-virus vaccination within 30 days of the first dose of investigational product. 
Seasonal flu vaccines that do not contain live virus are permitted 
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. 
 
 


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2.3.3 Withdrawals  
Participants MUST discontinue receiving investigational product for any of the following reasons: 
• 
Disease progression by RECIST 1.1, or disease progression following treatment beyond progression 
• 
Death 
• 
Toxicity requiring discontinuation of both investigational products 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 investigational product (except Grade 2 alopecia and Grade 2 fatigue), unless the 
participant is benefiting from therapy and after discussion with and approval by Apexigen Medical 
Monitor (or designee) 
• 
Failure to recover within 4 weeks of last dose of investigational product if AE is related to infusion 
reaction/cytokine release 
• 
Inability to reduce corticosteroid to 10 mg or less of prednisone or equivalent per day within 12 weeks 
of last dose of investigational product and after discussion with and approval by Apexigen Medical 
Monitor (or designee) 
• 
Participant’s decision to withdraw for any reason from study treatment (participant withdraws consent) 
• 
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 participant 
• 
Requirement for alternative therapy 
• 
Noncompliance with study procedures, including use of prohibited medications 
• 
Participant 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. 
Apexigen (or designee) must be notified within 24 hours if a participant is withdrawn from treatment. 
Participants who are withdrawn from both investigational products will enter the follow-up period unless 
treatment discontinuation is due to any of the following: 
• 
Participant death 
• 
Withdrawal of consent for all study procedures 
• 
Initiation of any anticancer therapy 
• 
Participant is lost to follow-up 
• 
Study termination by Apexigen 
For all participants receiving investigational products, the subsequent anticancer therapy will be 
documented. Once this information is collected, a participant is considered off-study. 
 
 


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2.3.4 Study treatment 
In this study, the investigational products are APX005M and nivolumab. 
Nivolumab is administered on Day 1 of each 3-week treatment cycle as a dose of 360 mg using a 30-
minute IV infusion. 
APX005M is administered on Day 1 of each 3-week treatment cycle approximately 30 minutes following 
nivolumab using a 60-minute IV infusion. Up to 4 dose levels of APX005M could be used in Phase 1b 
and the RP2D will be used for Phase 2, which will be determined during the Phase 1b of this study 
(between 0.03 and 0.3 mg/kg). 
2.3.5 Replacement of Patients 
• 
For Phase 1b of the study, all participants that are not DLT-evaluable will be replaced for the purpose 
of establishing MTD. 
• 
For Phase 2 of the study, participants will be evaluated for tumor response approximately every 
8 weeks following the first dose of investigational product. Participants that are non-evaluable for 
tumor response will be replaced. 
3. 
STUDY POPULATIONS 
3.1 
Screened Population 
The screened population is defined as all screened participants, including screen failures. Screen failures 
will be captured and listed, including the reason for screen failure. 
3.2 
Safety Population 
All participants receiving both investigational products will be included in the safety population. 
3.3 
DLT-Evaluable Population 
The DLT-evaluable population is defined as all participants of Phase 1b who met all eligibility criteria, 
received the entire planned dose of APX005M and nivolumab during the DLT observation period and 
have completed a follow-up period after administration of study drug for at least 21 days (one full 
treatment cycle; i.e., participant does not come off study for reasons other than toxicity). 
3.4 
Efficacy Population 
Participants evaluable for efficacy (tumor response) are defined as those who meet study eligibility criteria 
and have at least one on treatment (post baseline) tumor assessment. 
 
 


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4. 
DEFINITION OF STUDY ENDPOINTS AND DERIVED VARIABLES 
4.1 
Baseline and Demographics Characteristics  
Demographics and baseline characteristics by cohort/group will be summarized using descriptive 
statistics. 
• 
Time from diagnosis is defined as the time elapsed (in months) since the date of first positive biopsy 
for this disease until the informed consent date. 
4.2 
Efficacy Endpoint 
• 
The Progression-Free Survival (PFS) is defined as the time from first dose of investigational product 
to the earlier of PD (by RECIST 1.1 and iRECIST) or death due to any cause. 
PFS will be calculated as time in months between (first date of PD or death due to any cause – date 
of first dose).  
− 
For participants with no baseline assessment, PFS will be censored on the date of first dose.  
− 
For alive participants with no post baseline tumor assessment will be censored on the date of 
first dose however they will be considered an event in case of record end of treatment by 
clinical progression within eight weeks of first treatment dose (before the first tumor 
assessment schedule)  
− 
For participants who have at least 1 post baseline tumor assessment, if they do not have PD 
or do not die, PFS will be censored on the date of last tumor assessment documenting the 
absence of PD. 
 
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 (Brookmeyer and Crowley method). PFS by 
RECIST 1.1 and by iRECIST will be summarized by dose level and overall in each tumor type for 
Phase 1b and by cohort for Phase 2 (including participants treated at RP2D in Phase 1b) in 2 separate 
tables. A graph of the Kaplan Meier curve will be presented for Phase 2 (including participants treated 
at RP2D in Phase 1b). 
▪ 
The Best Overall Response (BOR) is defined as the best response presented according to RECIST 
v1.1 from the inclusion in the study to progressive disease (PD). 
▪ 
The Objective Response Rate (ORR) is defined as the incidence of patients who show as best overall 
response a complete response (CR) or partial response (PR). The ORR can be calculated based on 
two tumor assessment methods, RECIST 1.1 and iRECIST.  
The point estimate of the ORR will be presented along with exact two-sided 90% confidence interval 
(CI) using the exact method (Clopper-Pearson). 
▪ 
The Duration of Response (DoR) is defined as the time in months from the first evidence of confirmed 
PR or better to disease progression or death due to any cause, whichever occurs earlier (by RECIST 
1.1 and iRECIST). DoR will be calculated for the participants with a response of PR or better. If 
participants do not have PD or do not die, DoR will be censored on the date of last tumor assessment 
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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 (Brookmeyer and Crowley method). The DoR 
by RECIST 1.1 and iRECIST will be summarized by dose level and overall for Phase 1b and by cohort 
for Phase 2 (including participants treated at RP2D in Phase 1b) in 2 separate tables. A graph of the 
Kaplan Meier curve will be presented for Phase 2 (including participants treated at RP2D in Phase 
1b). 
• 
The 6-month Progression-Free Survival Rate (PFSR) is defined as the proportion of participants that 
did not have disease progression (by RECIST 1.1) or died due to any cause at 6 months from the 
first dose of investigational product. It will be depicted in a Kaplan Meier survival curve. 
4.3 
Safety Endpoints 
Safety will be assessed through summaries of DLTs, incidence and severity of AEs, specific laboratory 
abnormalities graded according to NCI-CTCAE, ECG, vital signs, and APX005M exposure.  
All AE data collected will be listed by study site, cohort, participant number, and cycle day. 
4.3.1 Extent of exposure and compliance 
▪ 
The MTD is maximum dose for which <33% of DLT-evaluable participants experience a DLT (only 
Phase 1b) 
▪ 
The RP2D will be stablished taking into account the MTD of APX005M (if applicable), as well as the 
nature, severity and causal relationship for all AEs. Prior to establishing the RP2D all participants 
enrolled in the Phase 1b portion of the study must be followed until PD, study discontinuation due to 
toxicity or at least 2 cycles 
▪ 
The duration of treatment of each patient will be computed as the time in weeks from the date of the 
first dose of any investigational product until the last dose administration (APX005M or nivolumab)+ 
(21 days, one cycle)/7. 
• 
The relative dose intensity (RDI) and its components will be described for each of the drugs 
administered in the study 
▪ 
Dose intensity (DI) is defined as the drug dose delivered per time unit and is expressed as mg/kg (for 
APX005M) or mg (for nivolumab) per week. In the case of APX005M, the weight registered for each 
cycle will be used to calculate the administered dose in mg/kg (in case a cycle’s weight is missing it 
will be imputed via the LOCF –last observation carried forward– method) 
▪ 
Target dose intensity (TDI) 
▪ 
Relative dose intensity (RDI) is the ratio of DI and TDI, and can be expressed as a percentage: 
RDI (%) = (DI/TDI) * 100 
▪ 
Number of cycles administered per patient will be described 
▪ 
Dose delays and dose reductions per patient and the reasons for these dose modifications will be 
described by patient. 


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4.4 
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. Once the variables are created, it will 
be checked that their values are correct and that they represent exactly what it is expected. 
 
 


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5. 
GENERAL STATISTICAL METHODS 
5.1 
Sample Size  
The sample size for the Phase 1b dose-escalation cannot be precisely estimated but depends upon the 
observed toxicities. Cohorts of 3 to 6 participants will be treated at each DL during dose escalation portion 
of the study. It is anticipated that approximately 18 participants will be treated in this portion of the study 
depending on the actual rate of DLTs. 
Sample size for Phase 2 is calculated using the Simon optimal 2-stage design: 
• 
Cohort 1 (inNSCLC): Assuming a false positive rate (α) of 0.1 (one-sided), a false negative rate (β) 
of 0.1, a response probability of poor drug (P0) of 22% and a response probability of good drug (P1) 
of 40%, first stage sample size (n1) is 24 and the maximum sample size (n) is 45 response evaluable 
participants. 
− 
In the first stage, if there are 5 or less responses in 24 participants, the enrollment in this cohort 
will be stopped. Otherwise, if 6 or more responses are observed, 21 additional participants will 
be accrued in Stage 2 for total of 45. Enrollment may continue into Stage 2 while the planned 
number of participants for Stage 1 are followed for efficacy.  
− 
By the end of Stage 2, if 13 or less responses are observed in 45 participants, then no further 
investigation is warranted. If 14 or more responses are observed, the null hypothesis will be 
rejected, and true RR is 40%. 
− 
The sample size of 45 participants, provides 97% power to statistically test the null hypothesis 
of historical 6-month PFS rate (PFSR) of 60% versus the alternative hypothesis of 6-month PFSR 
rate of 80%. This calculation assumes exponential PFS, 1-sided 5% type I error rate, enrollment 
of participants for 8 months with 6 months of follow-up prior to conducting the final analysis. 
• 
Cohort 2 (PD1-MM): Assuming α of 0.1 (one-sided), β of 0.1, P0 5% and P1 of 20%, n1 is 12 and n 
is 37 response evaluable participants. 
− 
In the first stage, if there are no responses in 12 participants, the enrollment in this cohort will be 
stopped. Otherwise, if 1 or more responses are observed, 25 additional participants will be 
accrued in Stage 2 for total of 37. Enrollment may continue into Stage 2 while the planned 
number of participants for Stage 1 are followed for efficacy.  
− 
By the end of Stage 2, if 3 or less responses are observed in 37 participants, then no further 
investigation is warranted. If 4 or more responses are observed, the null hypothesis will be 
rejected and true RR is 20%. 
− 
The sample size of 37 participants, provides 92% power to statistically test the null hypothesis 
of historical 6-month PFSR of 19% (estimated for ipilimumab following nivolumab or 
pembrolizumab) versus the alternative hypothesis of 6-month PFSR rate of 38%. This calculation 
assumes exponential PFS, 1-sided 5% type I error rate, enrollment of participants for 8 months 
with 6 months of follow-up prior to conducting the final analysis. 
• 
Cohort 3 (PD1-NSCLC) Group A and Group B: Assuming α of 0.1 (one-sided), β of 0.1, P0 5% and 
P1 of 20%, n1 is 12 and n is 37 response evaluable participants. 
− 
In the first stage, if there are no responses in 12 participants, the enrollment in that group will be 
stopped. Otherwise, if 1 or more responses are observed, 25 additional participants will be 


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accrued in Stage 2 for total of 37 per group. Enrollment may continue into Stage 2 while the 
planned number of participants for Stage 1 are followed for efficacy.  
− 
By the end of Stage 2, if 3 or less responses are observed in 37 participants, then no further 
investigation is warranted. If 4 or more responses are observed, the null hypothesis will be 
rejected, and true RR is 20%. 
− 
The sample size of 37 participants/group, provides 94% power to statistically test the null 
hypothesis of historical 6-month PFSR of 22% (estimated for chemotherapy regimens) versus 
the alternative hypothesis of 6-month PFSR rate of 43%. This calculation assumes exponential 
PFS, 1-sided 5% type I error rate, enrollment of participants for 8 months with 6 months of follow-
up prior to conducting the final analysis. 
5.2 
Disposition of Study Participants 
For participant study status, the number and percentage of participants for each one of the following 
categories will be presented by dose level and overall for Phase 1b and by cohort and overall for Phase 
2 (including participants treated at RP2D in Phase 1b) in separate tables. 
• 
Participants in Screened Population (the number only) 
• 
Screen-failure participants (the number only) 
• 
Enrolled participants (the number only) 
• 
Participants in Safety Population 
• 
Participants in Efficacy Population 
• 
Participants in DLT Evaluable Population 
• 
Participants who discontinued study treatment by primary reason 
• 
Participants who discontinued study participation by primary reason 
The data for participant disposition, protocol deviation, eligibility, and whether a participant is included in 
the analysis populations will be listed. Patients who discontinue treatment prematurely will be displayed 
in a listing, indicating the reason for such discontinuation. 
5.3 
Protocol Deviations 
Deviations from the protocol, including violations of inclusion/exclusion criteria, will be assessed as 
“minor” or “major” by the clinical team. All protocol deviations will be collected separately from the 
database and listed. 
All protocol deviations will be listed and major deviations from the protocol will lead to the exclusion of a 
patient from the EP. 
5.4 
Summary of Statistical Methods 
Participants treated at the RP2D in Phase 1b will be included in Stage 1 of the relevant disease-specific 
cohort for Phase 2. All the data (e.g., safety and efficacy) from these participants will be used in the 
relevant summary tables and listings for both Phase 1b and Phase 2 (including participants treated at 
RP2D in Phase 1b). 
All relevant participant data will be included in listings. All participants entered into the database will be 
included in participant data listings. The listings will be generally sorted by first dose level (Phase 1b) or 


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cohort (Phase 2, including participants treated at RP2D in Phase 1b) and then Participant ID, unless 
specified otherwise.  
All applicable data will be summarized by dose level and overall for Phase 1b, and by cohort and overall 
for Phase 2 (including participants treated at RP2D in Phase 1b), 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), mean, standard deviation 
(SD), median, Q1, Q3, minimum, and maximum along with the total number of patients contributing 
values.  
Descriptive statistics for categorical/qualitative data will include frequency counts and percentages. The 
total number of participants in the dose level or cohort (N) will be used as the denominator for percent 
calculations, unless stated otherwise in the table footnote.  
Kaplan-Meier model will be used to analyze duration of response, PFS and OS. In all these analyses, in 
addition to the Kaplan-Meier curve, median, Q1, Q3 and their corresponding CI 95%, number of events 
and censored cases distribution will be shown. 
5.4.1 Demographics, Other Baseline Characteristics and Medication 
5.4.1.1 
Demographic Characteristics 
Descriptive statistics will be summarized for the demographic characteristics and disease history based 
on the safety population and efficacy population. Listings will also be presented for the demographic 
characteristics and disease history, respectively. 
The following variables will be described by dose level and overall for Phase 1b and by cohort and overall 
for Phase 2 (including participants treated at RP2D in Phase 1b) in separate tables: age (years), sex, 
race, ethnicity, height (cm), weight (kg), and baseline ECOG performance status. 
5.4.1.2 
Disease History 
The following variables for disease history will be summarized by dose level and overall for Phase 1b 
and by cohort and overall for Phase 2 (including participants treated at RP2D in Phase 1b) in separate 
tables:  
• 
Primary diagnosis 
• 
Time (months) from the first positive biopsy for this disease to the date of first dose. This will be 
defined as the number of months between the date of first dose and date of first positive biopsy.  
• 
Histology 
• 
Histological grade 
• 
Metastatic sites at study entry 
 
 


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5.4.1.3 
Medical & Smoking History 
Medical history will only be listed but not summarized. 
The smoking history of each patient will also be described. 
5.4.1.4 
Prior Systemic Therapy 
A listing will be provided for the prior systemic therapy by verbatim term, WhoDrug codification won’t be 
performed. 
5.4.1.5 
Prior Radiation 
A listing will be provided for the prior radiation. 
5.4.1.6 
Prior Surgery 
A listing will be provided for the prior surgery. 
5.4.1.7 
Subsequent Systemic Therapy 
A listing will be provided for the subsequent systemic therapy by verbatim term, WhoDrug codification 
won’t be performed. 
5.4.1.8 
Subsequent Radiation 
A listing will be provided for the subsequent radiation. 
5.4.1.9 
Subsequent Surgery 
A listing will be provided for the subsequent surgery. 
5.4.1.10 Prior and Concomitant Medications 
All medications, including all prescription, over the counter, herbal supplements and IV medications and 
fluids, will be recorded on the electronic case report form (eCRF). No coding will be performed for 
medications.  
• 
Prior medications are defined as medications that started and stopped before the first dose of any 
investigational product.  
• 
Concomitant medications are defined as medications 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. 
Prior and concomitant medications will be listed by verbatim term, WhoDrug codification won’t be 
performed, therefore they will not be summarized; a column will be included in the listing to indicate if the 
medication is prior or concomitant. 
5.4.1.11 Concomitant Procedures 
A listing will be provided for the concomitant procedures performed. 
 
 


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5.4.2 Efficacy Analyses  
The efficacy analysis is based on tumor assessments, which will be performed with two methods 
(RECIST 1.1 and iRECIST) at Screening, about every 8 weeks during Treatment Phase and Follow-up. 
The efficacy analysis will be performed for Efficacy Population. 
ORR (and 90% confidence interval by exact distribution), DoR and PFS (Kaplan-Meier estimate) will be 
estimated for each cohort/group and for each tumor assessment method (by RECIST 1.1 and iRECIST).  
The listings by-individual participants will be generated for the detailed tumor assessment, the response 
assessment by RECIST1.1 and iRECIST, and the derived DoR and PFS. 
5.4.3 Safety Analyses 
The population used for safety analyses will be the Safety Population.  Safety of APX005M in combination 
with nivolumab will be assessed on the basis of the exposures of investigational products, DLT, AE, 
laboratory data, vital signs, electrocardiogram (ECG), physical examinations, and Eastern Cooperative 
Oncology Group (ECOG) performance status. 
A TEAE is an AE that occurs after administration of the first dose of the investigational product or a 
worsening (by CTCAE Grade) of a pre-existent condition, and through 30 days after the last dose of the 
investigational product, death or initiation of new anticancer therapy, whichever occurs first. SAEs and 
AEs with potential immunologic etiology will be recorded up to 100 days and pregnancies up to 120 days 
after the last dose of investigational product, death, or initiation of new anticancer therapy, whichever 
occurs first. 
For AEs, events that occur prior to the first dose of investigational product will be recorded as medical 
history; events that start after the first dose of investigational product will be recorded on the AE eCRF 
pages. Thus, all AEs collected from AE eCRF pages are considered as TEAEs. 
5.4.3.1 
Treatment Exposure  
Exposure of the investigational products (APX005M and nivolumab) will be summarized for Phase 1b (by 
dose level and total) and for Phase 2 (by cohort and total, including participants treated at RP2D in 
Phase 1b). The following variables will be summarized: 
• 
Maximum number of cycles started 
• 
Number of participants who started the maximum cycle of 1, 2, 3, 4, and so on  
• 
Duration of treatment (weeks) 
The following variables will be summarized separately for each investigational product (APX005M or 
nivolumab) by dose level and overall for Phase 1b and by cohort and overall for Phase 2 (including 
participants treated at RP2D in Phase 1b). 
• 
Number of infusions administered per participant 
• 
Number of participants with dose reductions 
• 
Number of participants with dose interruptions 
• 
Number of participants with dose delivered off schedule  
In addition, the following variables will be summarized in the APX005M exposure table mentioned above. 
• 
Dose intensity (mg/kg/week) 


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• 
Relative dose intensity (%)  
Treatment assignment will be listed by participant. A listing of investigational product infusion data will be 
provided; a separate listing will be presented for cumulative actual dose, cumulative target dose, and 
relative dose intensity (%). In addition, separate listings will be provided for the pre-medications prior to 
administration of investigational products. 
5.4.3.2 
Dose Limiting Toxicities 
Dose-limiting toxicities (DLTs) are defined in the study protocol. In brief, DLTs are defined events 
attributed to APX005M and nivolumab combination treatment (e.g., AEs that are not clearly attributable 
to extraneous causes occurring during the first 21-day following the administration of APX005M and 
nivolumab (the first 3 weeks-cycle). DLTs will be identified using a checkbox on the AE eCRF pages. The 
medical monitor will review all AEs and ensure that DLTs are appropriately checked as such in the EDC.  
DLTs will be summarized for participants in DLT Evaluable Population, by dose level and overall for 
Phase 1b. In addition, DLT will be listed for Phase 1b. 
5.4.3.3 
Adverse Events  
All AEs will be collected in the eCRF from the time the participant signs informed consent through 30 
days after the last dose of investigational product, death, or initiation of new anticancer therapy, 
whichever occurs first. AEs will be coded to system organ (SOC) and preferred term (PT) using the 
MedDRA dictionary v18.0. 
The NCI-CTCAE will be used to assess the severity of AEs. 
The relationship of each AE to the investigational product will be classified as related or unrelated. If 
relationship is missing, the event will be listed as missing relationship but summarized as related.  
Summaries will focus on the TEAEs. They will be summarized by dose level and overall for Phase 1b 
and by cohort and overall for Phase 2 (including participants treated at RP2D in Phase 1b). The following 
summary tables will be provided: 
• 
An overall summary of the frequency of participants reporting all TEAEs, serious TEAEs, TEAEs with 
CTCAE grade 3 or higher, treatment-related TEAEs (separately for APX005M and nivolumab), and 
TEAEs leading to treatment discontinuation (separately for APX005M and nivolumab), TEAEs with 
fatal outcome.   
• 
TEAEs by SOC and PT 
• 
Serious TEAEs by SOC and PT 
• 
TEAEs with CTCAE grade 3 or higher by SOC and PT 
• 
Treatment-related TEAEs by SOC and PT (separately for APX005M and nivolumab) 
• 
TEAEs leading to treatment discontinuation by SOC and PT (separately for APX005M and nivolumab) 
• 
TEAEs with fatal outcome by SOC and PT 
• 
TEAEs by SOC and PT, and by maximum CTCAE grade  
All AEs will be listed by dose level (Phase 1b)/cohort (Phase 2, including participants treated at RP2D in 
Phase 1b), and then study site, participant number, and cycle day. Separate listings will be produced for 
TEAEs, serious TEAEs, TEAEs leading to APX005M discontinuation, delay, and interruption, and TEAEs 
with fatal outcome. Separate listings will be generated for immune-mediated events. 


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5.4.3.4 
Clinical Laboratory Evaluation 
The following laboratory tests will be performed locally to evaluate the safety profile: serum chemistry 
(including thyroid tests), hematology (including coagulation), urinalysis, and pregnancy. Except for 
urinalysis and pregnancy tests which are scheduled at Screening only, the other tests will be performed 
at Screening, Treatment Phase and End of Treatment (EOT). 
For each laboratory parameter, the actual will be summarized and the frequency of participants with 
clinically significant abnormal laboratory values will be tabulated for baseline and each scheduled post 
baseline visit, by dose level and overall for Phase 1b and by cohort and overall for Phase 2. 
All serum chemistry, hematology and urinalysis data will be listed by participant; the clinically significant 
abnormal values will be flagged. The pregnancy results will also be listed. 
5.4.3.5 
Vital Signs 
Vital sign measurements, including blood pressure (systolic/diastolic), pulse rate, respiration rate, 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 participant. 
5.4.3.6 
12-Lead Electrocardiogram (ECG) 
12-lead ECG measurements will be conducted locally, including the heart rate, RR Interval, PR interval, 
QRS interval, QT interval. ECG overall interpretation will also be collected on eCRF. 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 participant. 
5.4.3.7 
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 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 participant. 
5.4.3.8 
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 participant. 
5.4.4 Exploratory Analyses 
Blood samples will be collected from all participants for determination of serum concentrations of 
APX005M at time points specified in the protocol. PK parameters of APX005M will be determined using 
model-independent methods. 
Potential tumor and blood biomarkers identified in the exploratory biomarker research may be correlated 
with PK, safety, and efficacy outcomes. 


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The analyses about pharmacokinetics (PK), immune pharmacodynamics (PDn), cytokines, APX005M 
anti-drug antibody (ADA), and tumor biomarkers will be carried out by Apexigen or a different provider. 
Only listings will be produced for archival tumor tissue samples and fresh tumor biopsy.   
5.4.5 Interim Analyses 
No formal interim analyses are considered in the protocol.  
However, a brief report with the main results of efficacy and safety will be prepared when each cohort 
completes the Stage 1 expected recruitment to check if the study continues.  
The monthly generated outputs (mainly for safety) will provide enough information for the decision-
making processes during the study. 
5.4.6 Missing Data 
5.4.6.1 
General imputation method 
Missing data will not be imputed, and it will be considered as missing values for the analysis.  
5.4.6.2 
Specific imputations 
5.4.6.2.1 
Partial dates 
Only in case of any incomplete dates (missing day) necessary for the analysis, the 15th  day of the month 
and year indicated in each case will be imputed.  
Only in case of any incomplete dates (missing day and month) necessary for the analysis, the 15th  day 
of the January year indicated in each case will be imputed.  
For instance, Partial AE onset dates will be imputed so that if the partial AE onset date information does 
not indicate that the AE started prior to treatment or after the TEAE period, the AE will be classified as 
treatment-emergent.  
These data imputations are for categorization purpose only and will not be used in listings.  
5.4.6.2.2 
Weight 
In case a cycle’s weight is missing it will be imputed via the LOCF–last observation carried forward– 
method. 
5.4.7 Reporting Conventions 
The 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 a single decimal 
place. P-values ≥0.0001 will be reported to 4 decimal places; p-values less than 0.0001 will be reported 
as “<0.0001”. 
 
 


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5.4.8 Study Timelines 
• 
Date first participant enrolled: 17-May-2017 
• 
Estimated date last participant enrolled: Q2-2020. The primary analysis of safety and efficacy is 
planned after all participants complete the final study visit or terminate early from the study. 
5.4.9 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 be archived in the 
PIVOTAL’s File System. 
5.4.10 
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 
 
[1]  D. M. Pardoll, “The blockade of immune checkpoints in cancer immunotherapy,” Nat Rev Cancer, 
no. 12, pp. 252-64, 2012.  
[2]  J. D. Wolchok, H. Kluger and M. K. Callahan, “Nivolumab plus ipilimumab in advanced melanoma,” 
N Engl J Med, no. 369, pp. 122-33, 2013.  
[3]  R. J. Motzer, B. Escudier and D. F. McDermott, “Nivolumab versus Everolimus in Advanced Renal-
Cell Carcinoma,” N Engl J Med, no. 373, pp. 1803-13, 2015.  
[4]  K. M. Mahoney, P. D. Rennert and G. J. Freeman, “Combination cancer immunotherapy and new 
immunomodulatory targets,” Nat Rev Drug Discov, no. 14, pp. 561-84, 2015.  
[5]  B. B. Aggarwal, “Signalling pathways of the TNF superfamily: a double-edged sword,” Nat Rev 
Immunol, no. 3, pp. 745-56, 2003.  
[6]  J. Banchereau, F. Bazan and D. Blanchard, “The CD40 antigen and its ligand,” Annu Rev Immunol, 
no. 12, pp. 881-922, 1994.  
[7]  E. A. Clark and J. A. Ledbetter, “How B and T cells talk to each other,” Nature, no. 367, pp. 425-8, 
1994.  
[8]  I. S. Grewal and R. A. Flavell, “CD40 and CD154 in cell-mediated immunity,” Annu Rev Immunol, 
no. 16, pp. 111-35, 1998.  
[9]  A. G. Eliopuolos and L. S. Young, “The role of the CD40 pathway in the pathogenesis and treatment 
of cancer,” Curr Opin Pharmacol, no. 4, pp. 360-7, 2004.  
[10] S. Hess and H. Engelmann, “A novel function of CD40: induction of cell death in transformed cells,” 
J Exp Med, no. 183, pp. 159-67, 1996.  
[11] A. Khong, D. J. Nelson and A. K. Nowak, “The use of agonistic anti-CD40 therapy in treatments for 
cancer,” Int Rev Immunol, no. 31, pp. 246-66, 2012.  
[12] C. L. Law and I. S. Grewal, “Therapeutic interventions targeting CD40L (CD154) and CD40: the 
opportunities and challenges,” Adv Exp Med Biol, no. 647, pp. 8-36, 2009.  
[13] A. L. Rakhmilevich, K. L. Alderson and P. M. Sondel, “T-cell-independent anti-tumor effects of CD40 
ligation,” Int Rev Immunol, no. 31, pp. 267-78, 2012.  
[14] A. W. Tong and M. J. Stone, “Prospects for CD40-directed experimental therapy of human cancer,” 
Cancer Gene Ther, no. 10, pp. 1-13, 2003.  
 
 


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7. 
TABLES, LISTINGS AND FIGURES 
This information has been detailed and collected in an external document with the following file name: 
APX002 - Statistical Analysis Plan TFLs v2.0 -04FEB2021.docx 
Note:  The final report of phase 1b was performed based on the SAP and TFLs version 1.0 (30MAY2016) 
 


 
 
 
 
 
 
 
 
 
 
 
 
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